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Etiology, diagnosis and treatment of non-allergic rhinitis

Segboer, C.L.

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Download date: 27 feb 2020

ETIOLOGY, DIAGNOSIS AND TREATMENT OF NON-ALLERGIC RHINITIS Christine L. Segboer
Voor mijn ouders
Etiology, diagnosis and treatment
of non-allergic rhinitis

Christine Louise Segboer

Colofon

Thesis, University of Amsterdam, The Netherlands

Etiology, diagnosis and treatment of non-allergic rhinitis

ISBN/EAN: 978-94-028-1898-7
Author: Christine Segboer
Cover design and layout: Birgit Vredenburg, persoonlijkproefschrift.nl
Printing: Ipskamp Printing, proefschriften.net

Copyright © 2019 Christine Segboer

All rights reserved. No part of this thesis may be reproduced, stored or transmitted in
any way or by any means without the prior permission of the author, or when applicable,
of the publishers of the scientific papers.
Etiology, diagnosis and treatment
of non-allergic rhinitis

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam

op gezag van de Rector Magnificus

prof. dr. ir. K.I.J. Maex

ten overstaan van een door het College voor Promoties ingestelde commissie,
in het openbaar te verdedigen in de Aula der Universiteit

op vrijdag 7 februari 2020, te 11.00 uur

door

Christine Louise Segboer

geboren te ’s-Gravenhage
PROMOTIECOMMISSIE

Promotor: Prof. dr. W.J. Fokkens AMC-UvA

Copromotores: Dr. C.M. van Drunen AMC-UvA

Dr. I. Terreehorst AMC-UvA

Overige leden: Prof. dr. E.H.D. Bel AMC-UvA

Prof. dr. P.P.G. van Benthem Universiteit Leiden

Prof. dr. F.G. Dikkers AMC-UvA

Prof. dr. P.W. Hellings AMC-UvA

Prof. dr. L. Klimek Ruprecht-Karls University,

Heidelberg

Prof. dr. B. Kremer Universiteit Maastricht

Faculteit der Geneeskunde

CONTENTS

Chapter 1 General introduction 12

Chapter 2 Nasal hyper-reactivity is a common feature in both 32

allergic and non-allergic rhinitis
Allergy 2013; 68(11):1427-34

Chapter 3 Endotyping of non-allergic, allergic and mixed rhinitis 48

patients using a broad panel of biomarkers in nasal
secretions
PLoS One 2018; 13(7): e0200366

Chapter 4 Quality of life is significantly impaired in non-allergic 72

rhinitis patients
Allergy 2018; 73(5):1094-1100

Chapter 5 Intranasal corticosteroids for non‐allergic rhinitis 88

Cochrane Database Syst Rev. 2019; 2(11)

Chapter 6 Capsaicin for non-allergic rhinitis 280

Cochrane Database Syst Rev. 2015; 14(7)

Chapter 7 Inhibition of capsaicin-driven nasal hyper-reactivity 348

by SB-705498, a TRPV-1 antagonist
Br J Clin Pharmacol. 2014; 77(5):777-88

Chapter 8 General discussion and future perspectives 374

Appendices Summary 386

Samenvatting 388

Authors and affiliations 392

Portfolio 394

List of publications 398

About the author 400

Dankwoord 402
CHAPTER 1
General introduction
CHAPTER 1

GENERAL INTRODUCTION

Non-allergic rhinitis

Definitions in rhinitis
Rhinitis is an umbrella term used to describe nasal symptoms such as nasal
congestion/obstruction, rhinorrhea, sneezing, and pruritus resulting from inflammation
(‘itis’) and/or dysfunction. One can differentiate infectious rhinitis, allergic rhinitis (AR)
and non-allergic rhinitis (NAR) (1-3).
Most of the cases of infectious rhinitis are acute, self-limiting viral infections (‘common
cold’), lasting not much longer than one week. Sometimes these infections are
prolonged because of a secondary bacterial superinfection like in patients with a septal
perforation, nose picking, and/or corpus alienum, but even then they are usually self-
limiting. More rare is chronic infectious rhinitis, an example of which is atrophic rhinitis.
AR is defined as an inflammatory condition caused by an IgE-mediated response to
environmental allergens such as pollens, dust mites, cockroaches, animal dander,
molds, and occupational allergens. The presence of systemic allergen-specific IgE can
be tested by skin prick test (SPT) or in serum. Symptoms can be either intermittent or
persistent and with varying severity (mild to moderate-severe) as defined in the ARIA
classification (3) (4) (5). AR can be further differentiated into phenotypes that have
either mono- or polysensitization and that come with or without concurrent asthma (1).
NAR is a dysfunction and non-infectious inflammation of the nasal mucosa that is
caused by factors/provoking agents other than allergens or microbes, although often
the exact cause is not known (2, 6).

NAR was known by several names and definitions in the past, like non-infectious non-
allergic rhinitis (NINAR) and non-allergic non-infectious perennial rhinitis (NANIPER)
(2). NAR and idiopathic rhinitis are often -but wrongly- used interchangeably (for
explanation of the difference see section below on phenotypes). The assessment of
prevalence rate and other epidemiologic data of NAR can therefore be hampered by
variation in definition and diagnostic criteria. Besides the need of uniform definitions
and diagnostic criteria, to reliably assess prevalence rates there is a need for population-
based cohort studies. These however, unfortunately are rather limited when it comes
to NAR. Population-based cohort studies (a representative sample of the population
or an entire population) have the benefit of no to little risk of selection-bias but bring
high costs and resources. A Finnish population study assessing prevalence rates
of asthma, eczema and allergic rhinitis in military recruits (98% of the Finnish men
between age 18-19 years old are examined on their fitness for military service) between
1966 and 2003, reported a prevalence rate of AR of 8.9% but did not report on NAR
(7). A population cohort-study in a representative sample of the Belgium population
of 4959 patients of 15 years or older using questionnaires, showed a high prevalence
rate of self-declared chronic rhinitis patients, with a three times higher prevalence

12
 GENERAL INTRODUCTION

rate of presumed AR (prevalence rate 29.8%) than presumed NAR (prevalence rate
9.6%) (8). A cross-sectional population-based study in Italy using questionnaires that
were sent to a random sample of the Italian population reported prevalence rates of
15.6-26.6% in AR and 7.5-12.0% in NAR, depending on the age-class of the sampled
individuals (9). Studies assessing prevalence rates in either the first-, second- or third-
line of health care are more common but have the risk of patient selection bias and
could therefore be unreliable.

Within NAR one can differentiate several disease subgroups (or phenotypes) based 1
on clinically relevant characteristics (3). The different phenotypes have more or
less well-defined underlying triggers or mechanisms that cause rhinitis symptoms.
Change in temperature is an important trigger in NAR with an almost linear relationship
between decrease in temperature and increase in NAR symptoms (10). Also atmos-
pheric pollution or meteorological conditions are able to trigger NAR symptoms like
humidity, NO, O3, Ox, atmospheric pressure, wind velocity and cloudiness (10). One
can distinct the following phenotypes, i.e. non-allergic occupational rhinitis, smoking
rhinitis, hormonal rhinitis, drug-induced rhinitis, gustatory rhinitis, rhinitis of the elderly
(senile rhinitis), non-allergic rhinitis with eosinophilia syndrome (NARES), local allergic
rhinitis (LAR) and idiopathic rhinitis. NAR endotypes describe disease subtypes based
on cellular and molecular mechanisms. In NAR we can distinct a neurogenic, inflam-
matory or idiopathic endotype (table 1) (3).

Table 1. Pheno- and endotypes in NAR*

Neurogenic Inflammatory Idiopathic

Idiopathic rhinitis with nasal
Idiopathic rhinitis
hyper-reactivity
Gustatory rhinitis NARES1
Occupational Occupational
Senile rhinitis LAR 2

Smoking Smoking
Hormonal
Drug-induced Drug-induced

* Columns represent endotypes and rows represent phenotypes.

(1) NARES: non-allergic rhinitis with eosinophilia syndrome

(2) LAR: local allergic rhinitis

The prevalence rates of the distinct phenotypes within NAR are unclear because of
differences in classification across studies. In case no underlying causal trigger or
mechanism can be identified, a patient is diagnosed as having idiopathic rhinitis (IR)
(3). Often one considers the idiopathic subtype in NAR as the most common one,

13
CHAPTER 1

however this is not confirmed by objective data. Although we think that nasal hyper-re-
activity is an important feature of IR, it is unclear from the literature whether it is a
necessity.

Nasal hyper-reactivity is an increased sensitivity of the nasal mucosa to various

nonspecific stimuli like changes in temperature, air humidification or barometric
pressure, strong odors, fumes or tobacco smoke, exercise, emotions and stress.
The golden standard to diagnose nasal hyper-reactivity is cold dry air provocation
(11). However, simply asking for symptoms of nasal hyper-reactivity and recognizing
hyper-reactivity symptoms during ENT-examination -i.e. rhinitis symptoms when
performing nasal endoscopy- can easily lead the way to the diagnosis of this symptom
in clinical practice.

In case AR and NAR are combined in one patient, this is called mixed rhinitis (3). An
example is a patient with a clinically relevant seasonal allergen sensitization (AR)
in combination with continuing rhinitis symptoms outside pollen season (NAR).
Diagnosis of mixed rhinitis can be complicated in case of a persistent (perennial)
allergen sensitization like house dust mite.

Phenotypes in NAR
As mentioned above, within NAR one can differentiate several phenotypes, i.e. environ-
mental (occupational, smoking), hormonal (pregnancy, anti-conceptive medication),
drug-induced, gustatory, age (rhinitis of the elderly), inflammatory (NARES/LAR) and
idiopathic.

Occupational rhinitis
Non-allergic occupational rhinitis is defined as a non-allergen driven, Th2-inflammation
of the nasal mucosa due to exposure to a particular factor in work environment (1) (12).

It can be the result of exposure to airborne irritants like chemicals, metal salts, wood
dust or animal dander. Low molecular weight agents are thought to be responsible
for non-allergic occupational rhinitis.

Besides from an inflammatory reaction, also nasal hyper-reactivity to these agents

can be responsible for symptoms. A proportion of non-allergic occupational rhinitis
can develop into non-allergic asthma (3) (13) (14).

Smoking rhinitis
Cigarette smoke (in both active as passive smoking and in both adults as children) is
known for its irritating effect on the mucosa of the respiratory tract. It can induce a
mucosal cellular infiltration with a Th2-like profile, including eosinophils, IgE positive

14
 GENERAL INTRODUCTION

cells and increased interleukin 4 (IL-4) levels, resulting in rhinitis symptoms (15) (16)
(17).

Hormonal rhinitis
Hormonal imbalances are often associated with NAR (3). Elevation of estrogens/
progesterone during pregnancy can induce rhinitis symptoms by means of elevation of
histamine H-1 receptors resulting in vasodilatation in the nasal mucosa and influencing
function of eosinophils. In general, elevation of estrogen levels is thought to induce
vascular engorgement and with that nasal congestion (3) (18) (19) (20). Smoking is 1
thought to be a risk factor for pregnancy rhinitis (21). But also fluctuation of the level of
estrogen or progesterone hormones during menstruation, puberty and menopause or
during the use of oral anti-conceptive (OAC) medication can induce rhinitis symptoms.
In postmenopausal women the hormonal imbalance can additionally result in atrophic
nasal mucosa. Thyroid or growth hormones (mucosal hypertrophy) are also thought
to be able to induce rhinitis symptoms, although it is rarely reported (1) (20) (22).

Drug-induced rhinitis
Several types of medication are able –by means of different and sometimes unknown
mechanisms- to induce non-allergic rhinitis symptoms; examples are NSAIDS and
aspirin, anti-depressants, ACE-inhibitors, calcium-antagonists and anti-psychotics (1)
(3) (23) (24). Drug-induced rhinitis can be differentiated into three endotypes depending
on the mechanism of disease, i.e. local inflammatory, neurogenic and idiopathic (1).
The most well known type of drug-induced rhinitis is rhinitis medicamentosa, a result
of use of xylometazoline or oxymetazoline for more than 10 days (25). Xylometazoline
has an α-adrenergic agonistic (sympathomimetic) activity inducing improvement of
nasal airflow by means of nasal vessel constriction. Unfortunately, this also results
in a compensatory upregulation of the parasympathetic innervation of the nasal
mucosa leading to rhinorrhea and nasal blockage. This stimulates the repetitive use
of xylometazoline and ends in a vicious cycle of temporary improvement in nasal
airflow after use of xylometazoline, evolving to renewed nasal blockage and re-use
of xylometazoline.

Aspirin and non-steroidal anti-inflammatory drugs (NSAID) are able to induce rhinitis
symptoms and aggravate lower airway disease, also summarized by the term
NSAID-exacerbated respiratory disease (NERD). Rhinitis symptoms are the result of
inhibition of cyclooxygenase-1 (COX-1) with overproduction of cysteinyl leukotrienes.
This disease entity is also associated with chronic rhinosinusitis with nasal polyps
and asthma. Besides from the drug hypersensitivity reaction, NERD-patients tend to
have a more severe course of both upper (chronic rhinosinusitis with nasal polyposis)
and lower airway disease (asthma) with eosinophilic hyperplastic inflammation of the
upper and lower airways (24) (26).

15
CHAPTER 1

Gustatory rhinitis
Gustatory rhinitis is characterized by the acute onset of watery rhinorrhea after inges-
tion of food, often hot or spicy food (1) (3) (27) (28).

Rhinitis of the elderly

Rhinitis of the elderly is defined as late-onset, bilateral watery nasal secretions without
endonasal mucosal and/or anatomic pathology and it is not associated with a specific
trigger. It often occurs in the male, elderly (>65 years old) patient (3) (29, 30).

NARES
Non-allergic rhinitis with eosinophilia syndrome (NARES) is defined as rhinitis in
NAR patients that have the defining feature of eosinophilia in nasal mucosal smears.
Patients often have symptoms of hyposmia/anosmia and of bronchial hyper-respon-
sivess. It can develop into (micro-) nasal polyposis and aspirin hypersensitivity (1)
(31, 32).

LAR
Local allergic rhinitis (LAR) is characterized by the presence of a nasal Th2-inflamma-
tory response with local production of allergen-specific IgE antibodies and a positive
response to a nasal allergen provocation test (NAPT) without evidence of systemic
atopy (33). It can be diagnosed by means of nasal allergen provocation tests (NAPT),
to which LAR patients will respond with both clinical symptoms of rhinitis as with
elevation of local allergen-specific IgE in nasal mucosa (33, 34).

Idiopathic rhinitis
Patients with chronic rhinitis with no underlying causal trigger or mechanism are
identified as idiopathic rhinitis (IR). Most often these patients have symptoms of nasal
hyper-reactivity (1, 3).

Rhinitis diagnosis and examination

Diagnosis of the different types of NAR starts by taking an ENT-history and includes
the onset of symptoms, duration and time relationships, severity, possible triggers
(allergens and nonspecific stimuli), aggravating and mitigating factors, smoking, and
use (and success of) previous medication. The next step is performing an ENT-exam-
ination including anterior rhinoscopy and nasal endoscopy to assess both anatomical
abnormalities as pathology of the nasal mucosa and/or secretions.

To assess allergen sensitization a skin prick test (SPT) and/or blood test for aller-
gen-specific IgE in serum (like ImmunoCAP or RAST) is performed (4).

To objectify a reduction in nasal airflow, a peak nasal inspiratory flow (PNIF), acoustic
rhinometry or rhinomanometry can be performed.

16
 GENERAL INTRODUCTION

To diagnose LAR a nasal allergen provocation test (NAPT) with one or more allergens
can be performed, assessing both symptoms of rhinitis (rhinitis questionnaire, PNIF,
amount of nasal secretions etc.) and allergen-specific IgE in nasal mucosa and/or
nasal secretions (33, 34).

To assess impairment of quality of life (QoL) validated and disease specific quality of
life (QoL) questionnaires are available for AR but to our knowledge not for NAR (35).

Endotypes in NAR 1
Within NAR roughly three main endotypes are recognized: the inflammatory endotype,
the neurogenic endotype and the idiopathic endotype (1, 3). More than one endotype
can be present within one phenotype. Besides these three major endotypes, most likely
there is a (primary or secondary) role for dysfunction of epithelial cells or ciliae (36).

The inflammatory endotype is a mainly Th2-inflammatory endotype. Primarily, NARES

and LAR belong to the inflammatory endotype. To a certain extent also drug-induced
rhinitis (NSAIDs, aspirin), hormonal rhinitis and environmental -occupational and
smoking- rhinitis belong to the inflammatory endotype (1, 3).

Within the neurogenic endotype there are several neurogenic mechanisms that
involve different nerve fibers of both the central nervous system and locally in the
nasal mucosa. A number of mediators might play a role and have their effect on nasal
mucosal blood vessels, glands and epithelial cells (figure 1). The below described
mechanisms intertwine and interact. They are responsible for normal nasal mucosal
defense mechanisms in healthy people. Only when they are unbalanced, upregulated
or otherwise disturbed, they can cause rhinitis symptoms. This is not only limited to
NAR, but also in other types of chronic rhinitis these mechanisms might play a role
(37) (38). Finally, it is important to emphasize there is still a lot unknown about the
neurogenic endotype.

To start, there might be an autonomic imbalance with an overactivity of the parasym-

pathetic autonomic nervous system and/or an underactivity of the sympathetic
autonomic nervous system (38, 39, 40). The vidian nerve innervates the nasal mucosa
and contains both sympathetic and parasympathetic nerve fibers that have opposite
activity. In healthy conditions this opposite activity is balanced. Parasympathetic nerve
fibers activate both subepithelial mucosal blood vessels and exocrine nasal glands.
They secrete acetylcholine (Ach) that mainly acts on vessel dilatation and the neuro-
peptide vasoactive intestinal peptide (VIP) that mainly acts on glandular hypersecre-
tion. Overactivity of the parasympathetic activity therefor results in respectively both
nasal congestion and rhinorrhea. Sympathetic nerve fibers secrete norepinephrine and
neuropeptide Y (NPY) and innervate mainly subepithelial mucosal vessels. In healthy
conditions the sympathetic nervous system is dominant and thereby maintains a

17
CHAPTER 1

(normal) vascular tonus. Underactivity of sympathetic nerve fibers results in vessel

dilatation and symptoms of nasal congestion (37) (41, 42). An example of a NAR pheno-
type with a neurogenic dysbalance endotype is rhinitis of the elderly, with symptoms
as result of hyperactivity of the parasympathetic nervous system. Also, rhinitis medic-
amentosa (xylometazoline abuse with fluctuating sympathetic overactivity and under-
activity and a relative overdrive of the parasympathetic nervous system), some other
types of drug-induced rhinitis phenotypes (like sildenafil with parasympathetic action)
and gustatory rhinitis (for a part the result of overactivity of parasympathetic nervous
system) belong to this endotype.

Secondly, there seems to be an important role for intraepithelial and perivascular

nonadrenergic noncholinergic (NANC) sensory nerve fibers in the nasal mucosa,
mainly unmyelinated trigeminal sensory C-fibers. These fibers contain neuropeptides,
i.e. vasoactive intestinal peptide (VIP), substance P, calcitonin gene-related peptide
(CGRP) and neurokinin A and B (NKA and NKB) (41) (43, 44, 45, 46, 47). These neuro-
peptides are released after activation of the sensory nerve fibers by nonspecific stimuli
(temperature changes, changes in osmolality etc.) or inflammatory mediators like
histamine and bradykinin, but also nicotine, cigarette smoke or capsaicin (42, 48).
Capsaicin, together with other physical or chemical stimuli, is capable of activating
(depolarizing) sensory C-fibers by means of activation of the TRPV-1 receptor -a noci­
ceptive transducer and member of the transient receptor potential (TRP) receptor
family-, which is present on the sensory trigeminal nerve endings. Both TRPV-1 and
TRPA-1 receptors can respond to nonspecific stimuli, inducing symptoms of nasal
hyper-­reactivity (41) (48).

The released neuropeptides from the sensory fibers are thought to induce rhinitis
symptoms by acting on epithelial submucosal blood vessel dilatation/transudation
and permeability and/or glandular function.

Either an upregulation of the NANC system and/or an upregulation or hyperactivity of

TRPV-1 or TRPA-1 receptors is thought to induce symptoms of nasal hyper-reactivity,
as in idiopathic rhinitis with nasal hyper-reactivity (3).

It is assumed that activation of the NANC system and release of neuro-inflamma-

tory mediators might also upregulate the parasympathetic activity of the autonomic
nervous system, thereby interacting with each other. The combination of these two
mechanisms within the neurogenic endotype is clearly represented in gustatory
rhinitis in which there is both an upregulation of the parasympathetic nervous system
and upregulation of the NANC system. In addition to idiopathic rhinitis with nasal
hyper- reactivity and gustatory rhinitis that both have a clear neurogenic inflamma-
tory endotype, there also seems to be a role for neurogenic inflammation in smoking
rhinitis and occupational rhinitis (12) (3).

18
 GENERAL INTRODUCTION

Figure 1. Neurogenic endotype

In idiopathic rhinitis the underlying mechanisms -besides from the mechanism of

nasal hyper-reactivity that is described above- are still largely unknown, and for that
reason IR belongs to both the neurogenic and the idiopathic endotype (3). Also the
other phenotypes have an important share in the idiopathic endotype.

Treatment
In the past, NAR patients were often unsuccessfully treated in a so-called ‘trial and
error’ approach.

The increasing knowledge on pheno- and endotyping in the previous years, shifts
treatment from a ‘trial and error’ approach to an endotype-specific treatment in the
upper airways (3, 49).

Intranasal corticosteroids
Intranasal corticosteroids (INCS) have immunosuppressant and anti-inflammatory
effects, modifying and reducing inflammation. They suppress the synthesis of pro-in-
flammatory cytokines, pro-inflammatory enzymes, inhibit lymphocyte proliferation
and chemotaxis (50).

They are (one of) the first-line therapy options in AR and chronic rhinosinusitis (CRS)
(51) (52) (53). INCS have been extensively studied in NAR however with inconclusive
results and a study with large patient numbers cannot show a positive treatment
effect (54). It is likely that INCS work better in the inflammatory endotypes like LAR
and NARES although evidence in this direction is moderate and hampered by definition
of NAR patient groups (55) (56).

19
CHAPTER 1

INCS can also be considered as an alternative treatment in case of rhinitis medica-

mentosa when patients have to stop the use of xylometazoline, although evidence is
limited (57) (58).

Anti-histamines
In general, as histamine does not seem to play a role in NAR, an anti-histamine therapy
would not be expected to be an effective therapy for this patient group.

Oral anti-histamines
No strong recommendations can be made for the use of oral anti-histamines in NAR
(1).

Intranasal anti-histamines
Azelastine, a second-generation anti-histamine was shown to be effective for treat-
ment of idiopathic rhinitis with nasal hyper-reactivity in two multicenter double-blind
placebo controlled trials (59) (60). One of the possible explanations is that it works on
neurogenic inflammatory processes. The latter could be the result of TRPV-1 receptor
desensitization by influencing intracellular calcium homeostasis (61).

Combinations of INCS and anti-histamine

There are very few study data available for this combination treatment in NAR patients
only, showing a beneficial effect (62).

Intranasal anticholinergics
An intranasal anticholinergic, like ipratroprium bromide nasal spray (Atronase) with
antimuscarinic activity seems to be a very effective treatment in NAR patients with
overactivity of the parasympathetic system and in whom rhinorrhea is the most impor-
tant symptom (1) (3). The effectiveness of ipratroprium bromide is studied in perennial
non-allergic rhinitis (in combination with other therapy), common cold and healthy
volunteers during skiing (63, 64, 65, 66). NAR phenotypes for whom this treatment
can be considered are rhinitis of the elderly, idiopathic rhinitis and gustatory rhinitis
(1). However, it has to be mentioned that randomized placebo-controlled trials on the
effectiveness of ipratroprium bromide for these specific phenotypes are not available.

Iptratroprium bromide acts as an antagonist of the acetylcholine-receptor in the same

way as ipratroprium (for example Atrovent) acts on this receptor in the lower airways
in asthmatic patients with bronchial hyper-reactivity (41). It has very few local and
systemic side effects (65) (67).

Oral corticosteroids
There is no evidence-based recommendation of oral steroids in NAR (1).

20
 GENERAL INTRODUCTION

Nasal irrigations
There is no evidence-based recommendation of saline nasal irrigations in NAR (1, 3).

Capsaicin
Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the therapeutic component of the
red-hot chili pepper. After a shown degeneration of sensory C-fibers in nasal mucosa
of animals after treatment with capsaicin and a therapeutic effect in rhinosinusitis
patients, several studies in NAR patients followed (68, 69).
1
The study of Blom et al was the first placebo-controlled randomized trial in a clear
defined group of IR to confirm the therapeutic effect of capsaicin in IR (70, 71). Recently
was shown that capsaicin works on the TRPV-1 receptors that are present on sensory
C-fibers in the nasal mucosa. Being a TRPV-1 agonist, capsaicin induces massive
release of neurogenic inflammatory mediators like substance-P and calcitonin gene-­
related peptide (CGRP) from sensory C-fibers, resulting in symptoms of rhinitis like
rhinorrhea, sneezing, itching and a burning sensation of the nose and eyes. After that,
the sensory C-fibers enter a refractory state resulting in a decreased hyper-reactivity to
nonspecific irritants. The sensory C-fibers seem to desensitize and degenerate (revers-
ible over time) and the concentration of TRPV-1 receptors decreases together with
the concentration of neuro-inflammatory mediators (42, 48) (72). Cap­sai­cin therefor
seems to be effective in endotypes with neurogenic inflammation and elevated
TRPV-1. The effectiveness of capsaicin in different pheno- and endotypes of NAR are
unknown, and there are no clear recommendations for treatment regimen or dosage.

Vidian neurectomy
Vidian neurectomy can be considered in case of persisting watery rhinorrhea in the
neurogenic dysbalance endotype (hyperactivity of the parasympathetic nervous
system) like in senile rhinitis, when all other treatment options failed (73) (74). However,
evidence for this treatment modality is weak as it mainly consists out of (non-­rand-
omized) case series and is hampered by heterogeneity in (definition of) patient groups.

Inferior turbinate reduction

Several studies have looked at the effect of inferior turbinate reduction in rhinitis but
not many specifically in non-allergic rhinitis only, let alone in individual phenotypes
and endotypes. Studies on this topic are hampered by variation in patient selection
and definition. No clear recommendation for inferior turbinate reduction in NAR can
therefore be made.

Aim and outline of this thesis

The aim of this thesis is to better understand the diagnosis of NAR, its impact on quality
of life (QoL) and to evaluate treatment options in the light of different phenotypes.

21
CHAPTER 1

In explaining NAR to patients, doctors often referred to the concept of nasal hyper-
reactivity. For that reason, NAR -or idiopathic rhinitis- was also called vasomotor
rhinitis in the past. However, in literature it is not clear whether nasal hyper-reactivity
strictly belongs to NAR or can also occur in AR or other chronic rhinitis patients. In
the lower airways, bronchial hyper-responsiveness is a nonspecific symptom of lower
airway inflammation.

Years ago, the Food and Drug Association (FDA) proposed a strict division in two
types of nasal hyper-reactivity, i.e. chemical hyper-reactivity (rhinitis symptoms in
response to chemical nonspecific stimuli like strong odors/perfumes/tobacco smoke)
and physical hyper-reactivity (symptoms in response to physical nonspecific stimuli
like temperature changes, osmolality or changes in air humidification) (54). Whether
one should distinct two separate groups of hyper-reactivity patients, i.e. patients
with strictly chemical or strictly physical hyper-reactivity, is another point of debate.
Although the golden standard to assess nasal hyper-reactivity is cold dry air provo-
cation (CDA), in clinical practice -for practical reasons- we often simply ask about
symptoms of hyper-reactivity.

Therefore, in chapter 2 we assessed the prevalence rate of nasal hyper-reactivity in

AR and NAR patients by means of both subjective (questionnaires) and objective (cold
dry air provocation, CDA) measurements. We also evaluated whether it is possible to
differentiate a strictly physical and chemical type of nasal hyper-reactivity.

Endotyping of NAR is of interest as it guides the way to endotype-specific treatment.

The most clinically relevant phenotype to unravel is the one of idiopathic rhinitis
because of lack of effective treatment options. Besides from neurogenic inflamma-
tion being responsible for symptoms of nasal hyper-reactivity in idiopathic rhinitis,
one could question whether there is a role for Th2-inflammation or Th1-inflammation
in idiopathic rhinitis. This question is important when one thinks about treatment
effectiveness of intranasal corticosteroids in these patients. In the past, no clear
inflammatory profile in idiopathic rhinitis could be found (75). However, these studies
focused on a limited panel of inflammatory mediators related to IgE-inflammation,
i.e. IgE, IL-5 and eosinophils. Another relevant question relates to the role of (ongoing)
Th2-inflammation in the group of mixed rhinitis patients, a patient group that shows
features of both AR and NAR.

Therefore, in chapter 3 we assessed a wide panel of inflammatory mediators in NAR

(mainly idiopathic rhinitis), AR and mixed rhinitis patients and healthy controls. To have
a better profile of the non-allergic part of mixed rhinitis patients, this assessment was
done unrelated to allergen exposure.

22
 GENERAL INTRODUCTION

Awareness of the socioeconomic burden and (non-) healthcare related costs in NAR
are important for future investments in research. As pointed out above, although
NAR is very much comparable to AR in both its rhinitis symptoms and (estimated)
prevalence rate, data on quality of life (QoL) in NAR are lacking. In contrast to AR,
no validated QoL questionnaires are available for NAR. Besides from epidemiologic
purposes, QoL questionnaires have an important role in the diagnostic process as it
can give an estimation of a patients’ individual severity and burden of disease in the
outpatient clinic.
1
Therefore, in chapter 4, we performed both a validation of the mini-RQLQ question-
naire for NAR patients and assessed QoL in NAR patients, compared to AR and
healthy controls. Secondly, the use of the different available treatment options and the
resulting treatment satisfaction in NAR patients is unknown. Therefore, we assessed
by means of questionnaires both the type and number of used treatment modalities
and the general treatment satisfaction of NAR patients.

Intranasal corticosteroids (INCS) are one of the most often prescribed effective drugs
in (inflammatory) diseases of the upper airways, like allergic rhinitis, chronic rhinosi-
nusitis (CRS) with or without nasal polyposis and inflammation of adenoid tissue.
Studies on the effectiveness of INCS in NAR show contradicting results although in
number they seem to lean towards the conclusion that INCS are not effective in NAR.
Heterogeneity of selected NAR patient groups, small patient numbers and the use of
different types or dosages of INCS and so on make it difficult to make a firm recom-
mendation when it comes to the use of INCS in NAR.

Therefore, in chapter 5 we performed a meta-analysis of the performed randomized

controlled trials (RCT’s) to assess the effectiveness of INCS in NAR.

The shown effectiveness of capsaicin in NAR has been very promising (71). Only a
few randomized controlled trials were performed on the effectiveness in NAR. These
studies often had only small numbers of participants and variation in dosage and
schedule of capsaicin administration. The now known working-mechanism of capsa-
icin as TRPV-1 agonist resulting in treatment of neurogenic inflammation, does not
answer the question in which phenotypes of NAR capsaicin can be effective and what
is the optimal dosage or treatment schedule.

In chapter 6 we performed a meta-analysis of RCT’s to give better recommendations

on the effectiveness of capsaicin, together with when and how (dosing and schedule
of administration) to use capsaicin.

As upregulation of TRPV-1 receptors in nasal mucosa plays an important role in

neurogenic inflammation, and capsaicin as TRPV-1 agonist has proven therapeutic

23
CHAPTER 1

effectiveness in idiopathic rhinitis (IR), a relevant question is whether a TRPV-1

­antagonist (SB-705498) can also be effective in IR.

Therefore, in chapter 7, we assess the safety, tolerability, pharmacokinetics (PK) and

pharmacodynamics (PD) of intranasal SB-705498, a selective TRPV-1 antagonist.

24
 GENERAL INTRODUCTION

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28
 GENERAL INTRODUCTION

70. Blom HM et al. The effect of nasal steroid aqueous spray on nasal complaint scores and
cellular infiltrates in the nasal mucosa of patients with nonallergic, noninfectious perennial
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72. Fokkens W et al. Capsaicin for Rhinitis. Curr Allergy Asthma Rep, 2016. 16 (8): p. 60.
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Rhinology, 2003. 41 (1): p. 25-30.

29
CHAPTER 2
Nasal hyper-reactivity is
a common feature in both
allergic and non-allergic
rhinitis
 C.L. Segboer
C.T. Holland
S.M. Reinartz
I. Terreehorst
A. Gevorgyan
P.W. Hellings
C.M. van Drunen
W.J. Fokkens

Allergy 2013 Nov; 68(11):1427-34

CHAPTER 2

ABSTRACT

Background
Nasal hyper-reactivity is an increased sensitivity of the nasal mucosa to various
nonspecific stimuli. Both allergic rhinitis (AR) and non-allergic rhinitis (NAR) patients
can elicit nasal hyper-reactivity symptoms. Differences in the prevalence or type of
nasal hyper-reactivity in AR and NAR patients are largely unknown. In this study, we
quantitatively and qualitatively assessed nasal hyper-reactivity in AR and NAR.

Methods
In the first part, an analysis of a prospectively collected database was performed to
reveal patient-reported symptoms of hyper-reactivity. In the second part, cold dry
air provocation (CDA) was performed as a hyper-reactivity measure in AR and NAR
patients and healthy controls, and symptoms scores, nasal secretions and peak nasal
inspiratory flow were measured. Comparisons were made between AR and NAR
patients in both studies.

Results
The database analysis revealed high hyper-reactivity prevalence in AR (63.4%) and NAR
(66.9%). There were no differences between AR and NAR in terms of the number or
type of hyper-reactivity stimuli. Hyper-reactivity to physical stimuli did not exclude a
response to chemical stimuli, or vice versa. CDA provocation resulted in a significant
increase in rhinitis symptoms and the amount of nasal secretions in AR and NAR
patients, but not in controls.

Conclusions
We found no quantitative or qualitative differences in nasal hyper-­reactivity between
AR and NAR patients. It is not possible to differentiate NAR sub­populations based on
physical or chemical stimuli.

32
 NASAL HYPER-REACITIVITY IS A COMMON FEATURE

INTRODUCTION

Nasal hyper-reactivity is an increased sensitivity of the nasal mucosa to everyday

nonspecific stimuli, both physical and chemical, such as sudden temperature changes,
cigarette smoke or chemical pollutants (1, 2). Nasal hyper-reactivity can be found in
different types of rhinitis, varying from common cold to both allergic and non-­allergic
chronic rhinitis (3, 4). However, specific data on prevalence and type of nasal hyper-­
reactivity in different types of rhinitis are very limited. There is only one small epide-
miological study by Shusterman et al. (5), which evaluated self-reported nasal hyper-­
reactivity in allergic rhinitis (AR) (31 patients) and non-allergic rhinitis (NAR) (29
patients). The only study with patient groups of sufficient size that compared nasal 2
hyper-reactivity of AR with that of NAR is the study of Lindberg et al. (6). In this study,
however, they reported only symptoms after the chemical exposure to cigarette smoke
and perfumes to be similar in both groups, and hyper-reactivity to other physical stimuli
was not investigated. Another limitation of this study was the lack of a control group.

The lack of assessment of physical stimuli is relevant because in recent years, the
Food and Drug Association (FDA) imposed to differentiate NAR patients based on
hyper-reactivity to chemical and physical sensitivity only (7). Bronchial hyper-­reactivity
is a common and aspecific symptom of diseased lower airway mucosa without exclu-
sive sensitivity to chemical or physical stimuli only. It seems likely that the same
applies to nasal hyper-reactivity in the upper airways. This would assume no differ-
ences in nasal hyper-reactivity between types of rhinitis or in sensitivity to types of
aspecific stimuli between patients.

In this study, we investigated quantitative and qualitative aspects of nasal hyper­

reactivity in AR and NAR by means of patient-reported responses to different forms
of nasal hyper-reactivity. We also addressed whether it is possible to identify subtypes
of hyper-reactivity based on responses to physical or chemical stimuli only. To further
validate the patient-reported outcomes, we performed cold dry air (CDA) provocation
in a random selection of AR and NAR patients and healthy controls.

METHODS

Study design
We performed a prospectively collected database analysis of chronic rhinitis patients
(Database study) to elucidate the rate of hyper-reactivity based on patient-reported
symptoms. To validate these results, we performed a CDA provocation study to
measure hyper-reactivity in AR and NAR patients and healthy controls (Figures 1 and
2).

33
CHAPTER 2

Database study
Patient characteristics
The patients were prospectively recruited from the outpatient clinic of the Department
of Otorhinolaryngology of the Academic Medical Centre, Amsterdam, the Netherlands.
All patients had a positive history of rhinitis symptoms and were referred to our tertiary
care outpatient clinic by their general practitioner or another otorhinolaryngology clinic.
AR patients had at least one positive skin prick test result and clinical symptoms
relevant to their sensitization. NAR was defined as clinically relevant symptoms of
rhinitis without positive skin prick test results. Severity of symptoms was assessed
according to Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines (8). We
excluded patients with chronic rhinosinusitis (CRS) with or without nasal polyposis,
nasal surgery within the previous 3 months, a serious and/or unstable disease and
history of immunotherapy and patients with other causes of rhinitis (infectious or
anatomic). Patients were not allowed to use antihistamines 14 days before inclusion,
and patients using medication affecting nasal function were excluded. All patients in
whom symptoms could not be explained by sensitization only were excluded, leaving
only those with classic AR and NAR.

Skin prick test

To assess allergic sensitization, we used the Global Allergy and Asthma European
Network’s (GA 2LEN) standardized method of skin prick test (SPT) (9). Patients were
asked to stop their antihistamine medication 14 days before SPT. A positive reaction to
SPT was defined as a skin reaction > 3 mm for one or more of the 18 tested allergens
and no reaction to the negative control.

Patient-reported outcomes
All rhinitis patients were routinely asked to fill in a questionnaire regarding symptoms
of rhinitis, allergy and nasal hyper-reactivity. In regard to nasal hyper-reactivity, patients
were asked to report sensitivity to temperature change, tobacco smoke or scents,
exercise, emotional stress and humidity. Patients were allowed to choose more than
one option. Patients were asked to report number and type of rhinitis symptoms,
duration and periods of symptoms and severity according to ARIA classification (8).

34
 NASAL HYPER-REACITIVITY IS A COMMON FEATURE

Figure 1 A and B. Subjective report of rhinorrhea (A) and objective amount of nasal secretion (B) in
Healthy controls, AR and NAR patients before and after CDA provocation
Individual patient results are shown in small circles; median results for each group are shown in
large squares

Figure 2 A and B. Subjective report of nasal congestion (A) and objective PNIF values (B) in
Healthy controls, AR and NAR patients before and after CDA provocation
Individual patient results are shown in small circles; median results for each group are shown in
large squares

35
CHAPTER 2

CDA provocation study

Patient characteristics
Cold dry air provocation was performed in a random selection of the database patients
(AR and NAR) as well as in healthy volunteers. Patients were classified according to
ARIA guidelines (8). Patients were asked to stop antihistamine medication 4 weeks
before CDA provocation and any medication possibly influencing nasal function,
including all nasal medication, 2 weeks before provocation. A healthy control group
consisted of individuals, recruited via advertisement, who had no medical history of
rhinitis and a negative skin prick test to allergens. All subjects signed an informed
consent form. This study was approved by the institutional Medical Ethics Committee.

Dose escalation CDA provocation

Patients were first provoked with a vehicle, that is, air at room temperature and
humidity for 1 min. Following this, patients were provoked with CDA at a temperature
of at least 10°C and humidity of around 20% in 5 dose-escalating steps as described
in the validated protocol of CDA provocation by Braat et al. (10).

Questionnaires during the CDA provocation

At 1, 5 and 10 min after each provocation (including with the vehicle), patients were
asked to assess their symptoms of rhinorrhea, nasal congestion, burning, itching and
sneezing on visual analogue scale (VAS, 0–100 mm).

Nasal secretion during the CDA provocation

To assess the amount of nasal secretions, 2 min after each provocation, a 3.5-cm
Ivalon” Post-Op Sinus Packing (Endovision BVBA, Holsbeek, Belgium) was placed
anteriorly in the same nostril for 3 min. The nasal dressing, placed in a 3-ml BD
FalconTM tube (BD Biosciences, San Jose, CA, USA), was weighed before and after
provocation to measure the amount (in mg) of nasal secretions.

Peak nasal inspiratory flow (PNIF) during the CDA provocation

To measure nasal inspiratory flow, we used PNIF 5 min after each provocation. Patients
were instructed to exhale through their mouth, place the mask over their nose and
mouth in a way that the nose would not be compressed and inspire air through their
nose with their mouth closed. Patients were allowed to perform the PNIF exercise
three times. The highest recorded value (ml) was used for analysis.

Statistical Analyses
In both studies, all statistical analyses were performed using SPSS, version 19.0 for
Windows (IBM Corporation, New York, NY, USA). Despite multiple testing, the cut-off
value of statistically significance was kept at P values of < 0.05. Bonferroni correction
was not performed because we did not want to underestimate potential differences
between the groups.

36
 NASAL HYPER-REACITIVITY IS A COMMON FEATURE

Database study
The Fisher’s exact test was used to compare hyper-reactivity between NAR and AR
based on total prevalence and type of different provoking stimuli.

CDA provocation study

Due to data being not normally distributed, nonparametric statistics was used. The
Wilcoxon signed rank test was used to compare rhinitis symptoms before and after
CDA provocation measured by means of VAS (0–100 mm), PNIF (ml) and amount of
nasal secretions (mg). Median values were used.

2
RESULTS

Database study

Patient characteristics
Table 1 demonstrates patient characteristics, the use of medication and ARIA classi-
fication in the database study. There were no significant differences between both
patient groups for age, gender, smoking and ARIA classification, with an exception of
asthma, which was more prevalent in the AR group (P < 0.0001, Fisher’s exact test).
Table 1 also demonstrates the type and frequency of medication use in the previous
4 weeks.

Skin prick test

The five most frequent sensitizations (not exclusive of each other) were grass mix
(61.9%), house dust mites (56.6%), birch (46.8%), dog (46.5%) and hazel (41.5%).

Patient-reported outcomes
Nasal hyper-reactivity is a common feature in AR and NAR.
Table 2 demonstrates the number and type of hyper-reactivity provoking stimuli in AR
and NAR patients. There were no differences between AR and NAR patients.

No specificity in the reaction to individual stimuli or to classes of stimuli.

No significant differences were seen in the type of provoking stimuli reported by AR
and NAR patients, with the highest prevalence in both groups being for ‘temperature
changes’ and ‘smoke/scents’ (Table 2). We selected individuals who reported ‘tempera-
ture change’ and determined whether this would exclude a response to ‘smoke/scents’
(7). In both AR and NAR, a majority of those reporting sensitivity to ‘temperature
change’ also reported sensitivity to ‘smoke/scents’ (58.9% in AR and 53.8% in NAR).
As expected in the reciprocal analysis of individuals responding to smoke/scents, we
saw no indication of this precluding a response to temperature changes (63.6% in AR
and 65.6% in NAR responded to both smoke/scents and temperature stimuli).

37
CHAPTER 2

Hyper-reactivity is not different between individuals suffering from intermittent or

persistent rhinitis.
We investigated whether individuals diagnosed with either intermittent or persistent
rhinitis (AR or NAR) would demonstrate a different pattern of responsiveness in terms
of the number and type of stimuli causing hyper-reactivity (Table 3). There were no
significant differences in the number or type of provoking stimuli between intermittent
or persistent rhinitis patients. The exclusion was the significantly higher frequency of
a single hyper-reactivity stimulus per patient in intermittent vs persistent NAR.

Table 1. Patient characteristics, the use of medication and ARIA classification in the database
study

Total, n = 993 AR, n = 585 NAR, n = 408

Male (%) 45.6 34.3
Mean age (years) 39.0 43.3
Smoking N (%) 122 (20.9) 93 (22.8)
Asthma N (%) 100 (17.1) 34 (8.3)
Sensitizations (skin prick testing) N (%) 585 (100.0) 0 (0)
Medication use (per patient) N (%)
Medication 292 (49.9) 225 (55.1)
No medication 122 (20.9) 88 (21.6)
Unknown 171 (29.2) 95 (23.3)
Type of medication last 4 weeks N (%)
Nasal corticosteroids 243 (41.5) 217 (53.1)
Oral antihistamines * 54 (9.2) 8 (2.0)
Xylometazoline (intermittent use) 5 (0.9) 2 (0.5)
Nasal sodium cromoglicate 2 (0.3) 0 (0.0)
Other medication 3 (0.5) 0 (0.0)
ARIA grading N (%)
Mild intermittent 10 (1.7) 15 (3.7)
Moderate-severe intermittent 112 (19.1) 64 (15.7 )
Mild persistent 13 (2.2 ) 12 (2.9)
Moderate-severe persistent 403 (68.9) 281 (68.9)
Undefined 47 (8.0 ) 36 (8.8)
AR – allergic rhinitis; ARIA – Allergic Rhinitis and its Impact on Asthma; NAR – non-allergic rhinitis
* Antihistamines were stopped 14 days before inclusion

38
 NASAL HYPER-REACITIVITY IS A COMMON FEATURE

Table 2. Prevalence of the number and type of hyper-reactivity provoking stimuli per AR or NAR
patient, based on questionnaire reports in the database study

AR, N (%) NAR, N (%) AR vs. NAR

(p, Fisher’s Exact Test)
Number of hyper-reactivity stimuli per patient
None 214 (36.6) 135 (33.1) NS
At least one 371 (63.4) 273 (66.9) NS
One 129 (22.1) 87 (21.3) NS
Two 138 (23.6) 91 (22.3) NS
Three 68 (11.6) 58 (14.2) NS
2
Four 24 (4.1) 26 (6.4) NS
Five 12 (2.1) 11 (2.7) NS
Total 585 408
Types of hyper-reactivity provoking stimuli
Temperature changes 246 (42.1) 195 (47.8) NS
Smoke, smells 228 (39.0) 160 (39.2) NS
Exercise 127 (21.7) 110 (27.0) NS
Emotional stress 101 (1.7) 85 (20.8) NS
Humidity 63 (10.8) 52 (12.7) NS
Total 765 602
AR – allergic rhinitis; NAR – non-allergic rhinitis
NS: not significant, p> 0.05
Italic values denote P = 0.2798 (comparing AR and NAR for responding to at least 1 stimulus).

CDA provocation study

Patient characteristics
We performed CDA provocation as a reliable measure of nasal hyper-reactivity in a
subpopulation of rhinitis patients [18 patients with AR (mean age 40.3) and 21 with
NAR (mean age 47.0), as well as 17 healthy controls (mean age 31.8). There were
no significant differences for gender ratio (AR: NAR, NAR: healthy: P = 0.2753, AR:
healthy: P = 1.000, Fisher’s exact test). There were no significant differences in age in
AR and NAR between the database and the CDA provocation studies (AR: P = 0.682,
Mann–Whitney U-test; NAR: P = 0.213, Mann–Whitney U-test).

In AR and NAR, respectively, 83.3% and 72.6% of patients were classified as moderate­-
-to-severe persistent according to ARIA classification, and 5.6% of AR and 14.3% of
NAR classified as moderate-to-severe intermittent and 5.6% of AR mild intermittent (8).

39
CHAPTER 2

Skin prick testing

The five most frequent sensitizations were grass mix (94.1%), hazel (47.1%), alder
(47.1%), birch (47.1%) and house dust mites (35.3%).

Results of CDA provocation

In contrast to controls, patients with AR and NAR react to CDA provocation. Patient with
both AR and NAR demonstrated a significant response to CDA provocation, while the
control population did not (Table 4). Specifically, both patient groups demonstrated a
significant increase in rhinitis symptoms after CDA provocation (rhinorrhea, congestion
and burning, with a trend of congestion in NAR and sneezing in AR) and a significant
increase in the amount of secretion. This was in contrast with the control group that
did not demonstrate any significant reaction to CDA.

The median PNIF after CDA provocation decreased in AR and NAR, with a trend in NAR
and not reaching significance in AR. There was no change in PNIF in control patients.

Table 3. Prevalence of the number and type of hyper-reactivity provoking stimuli per patient as
a function of rhinitis duration (intermittent or persistent) in the database study*

Number of Intermittent Persistent Intermittent vs. Intermittent Persistent Intermittent

stimuli per persistent vs. persistent
patient AR AR AR NAR, NAR, NAR
N (%) N (%) p (Fisher’s N (%) N (%) p (Fisher’s
Exact test) Exact test)
Number of hyper-reactivity stimuli per patient
None 43 (35.2) 150 (36.1) NS 21 (26.6) 102 (34.8) NS
At least one 79 (64.8) 266 (63.9) NS 58 (73.4) 191 (65.2) NS
One 27 (20.0) 91 (22.9) NS 26 (32.9) 49 (16.7) NS
Two 37 (30.0) 90 (21.6) NS 21 (26.6) 64 (218) NS
Three 13 (10.0) 52 (12.5) NS 6 (7.6) 49 (16.7) P = 0.049
Four 2 (0) 21 (5.0) NS 4 (5.1) 20 (6.8) NS
Five 0 (0) 12 (2.9) NS 1 (1.3) 9 (3.1) NS
Total 122 (100) 416 (100) 79 (100) 293 (100)
Types of hyper-reactivity provoking stimuli
Temperature 50 (33.8) 180 (31.5) NS 40 (37.4) 140 (31.2) NS
changes
Smoke, 52 (35.1) 165 (28.9) NS 26 (24.3) 121 (26.9) NS
smells
Exercise 22 (14.9) 96 (16.8) NS 18 (16.8) 84 (18.7) NS
Emotional 13 (8.8) 80 (14.0) NS 13 (12.1) 64 (14.3) NS
stress
Humidity 11 (7.4) 50 (8.8) NS 10 (9.3) 40 (8.9) NS
Total 148 (100) 571 (100) 107 (100) 449 (100)

40
 NASAL HYPER-REACITIVITY IS A COMMON FEATURE

Table continued

*ARIA classification (intermittent or persistent) is missing on 47 patients with AR and 36 patients

with NAR.
AR – allergic rhinitis; ARIA – Allergic Rhinitis and its Impact on Asthma; NAR – non-allergic
rhinitis
NS: not significant, P > 0.05
Italic values denote P = 0.9147 (comparing intermittent AR and persistent AR for responding to at
least 1 stimulus); P = 0.1802 (comparing intermittent NAR and persistent NAR for responding to
at least 1 stimulus).
Bold values denote P = 0.0025 (comparing intermittent NAR and persistent NAR for responding
to 1 stimulus only).

2
Table 4. Response to CDA provocation in AR patients

Outcome parameter Median Median Pre- vs.

post -CDA
pre-CDA post-CDA Median (p, Wilcoxon
(25-75th inter- (25-75th interquar- Delta Signed Rank
quartiles) tiles) Test)
Allergic rhinitis
Rhinorrhea (VAS, mm) 0 (0.00-1.75) 4 (0.00-0.20) 2.5 P = 0.008
Congestion (VAS, mm) 0 (0.00-6.75) 7.5 (0.00-36.50) 6.5 P = 0.04
Burning (VAS, mm) 0 (0.00-3.00) 6 (0.00-25.00) 6 P = 0.013
Sneezing (VAS, mm) 0 (0.00-1.50) 0 (0.00-0.50) 0 NS
Itching (VAS, mm) 0 (0.00-4.50) 0 (0.00-8.00) 0 NS
Nasal secretion (mg) 30 (30.00-50.00) 65 (30.00-170.00) 40 P = 0.003
PNIF (ml) 150 (117.50-172.50) 135 (100.0-170.00) -15 NS
Non-allergic rhinitis
Rhinorrhea (VAS, mm) 0 (0.00-4.50) 3 (0.00-15.00) 1 P = 0.020
Congestion (VAS, mm) 0 (0.00-10.00) 4 (1.00-32.50) 2 NS
Burning (VAS, mm) 0 (0.00-0.00) 0 (0.00-1.00) 0 P = 0.039
Sneezing (VAS, mm) 0 (0.00-0.00) 0 (0.00-0.00) 0 NS
Itching (VAS, mm) 0 (0.00-4.00) 0 (0.00-1.00) 46 NS
Nasal secretion (mg) 30 (10.00-50.00) 40 (30.00-80.00) 20 P = 0.021
PNIF (mL) 140 (95.00-180.00) 120 (100.00-155.00) -10 NS
Healthy
Rhinorrhea (VAS, mm) 1 (0.00-3.50) 2 (0.00-8.50) 0 NS
Congestion (VAS, mm) 0 (0.00-0.00) 0 (0.00-3.00) 0 NS
Burning (VAS, mm) 0 (0.00-0.00) 0 (0.00-2.00) 0 NS
Sneezing (VAS, mm) 0 (0.00-0.00) 0 (0.00-0.00) 0 NS
Itching (VAS, mm) 0 (0.00-0.00) 0 (0.00-0.00) 0 NS
Nasal secretion (mg) 40 (30.00-100.00) 55 (20.00-90.00) 0 NS
PNIF (ml) 150 (110.00-185.0) 140 (125.00-140.00) 0 NS
CDA – cold dry air; PNIF – peak nasal inspiratory flow; VAS – visual analogue scale
NS: not significant; bold denotes significant value (P < 0.05).

41
CHAPTER 2

DISCUSSION

In accordance with the concept of nasal hyper-reactivity being a general outcome of

disturbed nasal mucosa of the upper airways, our patient-reported outcomes demon-
strated no differences in quantitative or qualitative aspects of nasal hyper-reactivity
between AR and NAR (11). Within NAR, the higher frequency of a single hyper-reactivity
stimulus per patient in patients with intermittent vs persistent symptoms could be
explained by less severe rhinitis symptoms in the former. Hyper-reactivity has been
shown to be a phenomenon of uncontrolled disease in rhinitis, conjunctivitis and
asthma (12–14).

As we did not perform nasal provocation tests, it is possible that some of the NAR
patients had local allergic rhinitis (LAR) causing confounding of patient groups (15).
However, in the past, several studies were performed in our clinic assessing inflam-
matory cells and cytokines in nasal secretions of NAR patients, and no sign of inflam-
mation was demonstrated in these patients (16–18).

The FDA recently imposed a distinction between nasal hyper-reactivity symptoms

exclusively elicited to either physical or chemical stimuli (7). This distinction, however,
was not confirmed in our database analysis. Most AR and NAR patients responded to
both physical and chemical stimuli.

To validate the patient-reported outcomes, a CDA provocation was performed.

Hyper-reactivity can be objectively determined with either direct (histamine, metha-
choline, capsaicin) or indirect (CDA provocation) stimuli. CDA provocation, contrary
to histamine, is able to distinguish patients with hyper-reactivity from healthy controls
(8, 10, 19–21). In bronchial hyper-reactivity, indirect stimuli, such as CDA, exercise and
adenosine monophosphate, also appear to be more clinically relevant and better corre-
late with eosinophilic inflammation than direct stimuli (22–26). For this purpose, we
randomly selected 25 patients per group from the database study. Unfortunately, not all
patients who originally indicated that they were willing to participate did so, because of
time and other practical constraints. As we aimed to perform the provocation outside
pollen season, we decided to stop further inclusion. This resulted in smaller and
unequal sized patient groups for CDA provocation than originally planned. As a result of
relatively small group sizes in the latter, there were some differences between patient
groups. ARIA classification in the CDA provocation study showed a higher proportion
of moderate-to-severe persistent rhinitis compared with the database patient group.
Therefore comparisons based on severity of symptoms cannot be performed.

Reactions to CDA were significant for symptoms of rhinorrhea, congestion and

burning. This was accompanied by a significant increase in nasal secretions in both
AR and NAR, but not in healthy patients. PNIF decreased in both groups; however, it

42
 NASAL HYPER-REACITIVITY IS A COMMON FEATURE

did not reach a statistically significant level. Most likely, this was caused by the large
variation in PNIF values and relatively small groups sizes. These results are in agree-
ment with a recent study by Hellings et al. demonstrating a significant response to
CDA in both AR and NAR patients compared with controls (27).

As our results demonstrate that nasal hyper-reactivity is as common in NAR, as in

AR, while no inflammatory cells or markers are present in NAR (according to previous
studies), the question of the underlying mechanism causing nasal hyper-reactivity
remains unknown (16–18, 28). Possible explanations of nasal hyper-responsiveness
can be an upregulation of the nervous system with a (para-)sympathetic dysbalance or
neurogenic inflammation with release of neuropeptides as part of an antidromic reflex 2
in the nose. Another hypothesis refers to the release of substance P from the trigem-
inal nerve (28–30). Substance P is suggested to induce hyper-reactivity in allergic
and non-allergic airway disease by directly and indirectly (via histamine and mast
cell degranulation) affecting smooth muscle tissue and vasculature (31, 32). While
hyper-reactivity is the result of smooth muscle contraction in lower airway disease, the
absence of muscle tissue in the upper airways suggests another pathogenic mecha-
nism, that is, vasodilation and increased vascular permeability. Another interesting
aspect of airway hyper-reactivity is a (dysfunctional) role of the mucosal membrane
barrier and its phospholipid composition (11, 33).

In conclusion, nasal hyper-reactivity seems to be an indistinctive feature of upper

airway disease, irrespective of inflammation.

Conflicts of interest
C.M. van Drunen and W.J. Fokkens receive private sector support for research and/or
clinical trials related to the treatment of allergic and non-allergic rhinitis from Allergop-
harma, ALK-Abello, GlaxoSmithKline, HAL Allergy, MSD, Optinose UK, as well as public
sector research support from InterUniveristy Attraction Poles (Belgium), ZonMW (the
Netherlands), and Global Allergy and Asthma European Network (EU). C.M. van Drunen
has received royalties for legal consultation/expert witness testimony from Staller-
gens; W.J. Fokkens has received royalties for legal consultation/expert witness testi-
mony for Stallergens, GSK, MSD. Other authors have no potential conflict of interest.
Peter W. Hellings is the recipient of unrestricted research grants of GlaxoSmithKline,
MSD, and Stallergens and participated in clinical trials on allergic rhinitis of HAL and
GlaxoSmithKline.

43
CHAPTER 2

REFERENCES
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3. Cassano M et al. May nasal hyper-reactivity be a sequela of recurrent common cold? J
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4. Vaidyanathan S et al. Nasal AMP and histamine challenge within and outside the pollen
season in patients with seasonal allergic rhinitis. J Allergy Clin Immunol 2011;127(1):173-
178, 178 e171-173.
5. Shusterman D et al. Nasal hyper-reactivity in allergic and non-allergic rhinitis: a potential
risk factor for non-specific building-related illness. Indoor Air 2007;17(4):328-333.
6. Lindberg S et al. Comparison of allergic rhinitis and vasomotor rhinitis patients on the
basis of a computer questionnaire. Allergy 1993;48(8):602-607.
7. Jacobs R et al. Weather/temperature-sensitive vasomotor rhinitis may be refractory to
intranasal corticosteroid treatment. Allergy Asthma Proc 2009;30(2):120-127.
8. Bousquet J et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in
collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy 2008;63
Suppl 86:8-160.
9. Bousquet J et al. Practical guide to skin prick tests in allergy to aeroallergens. Allergy
2012;67(1):18-24.
10. Braat JP et al. Intranasal cold dry air is superior to histamine challenge in determining
the presence and degree of nasal hyper-reactivity in nonallergic noninfectious perennial
rhinitis. Am J Respir Crit Care Med 1998;157(6 Pt 1):1748-1755.
11. Golebski K et al. The multi-faceted role of allergen exposure to the local airway mucosa.
Allergy 2013;68(2):152-160.
12. Leonardi A et al. Ocular allergy: recognizing and diagnosing hypersensitivity disorders
of the ocular surface. Allergy 2012;67(11):1327-1337.
13. Brannan JD. Bronchial hyperresponsiveness in the assessment of asthma control:
Airway hyperresponsiveness in asthma: its measurement and clinical significance. Chest
2010;138(2 Suppl):11S-17S.
14. Hellings PW et al. Uncontrolled allergic rhinitis and chronic rhinosinusitis: where do we
stand today? Allergy 2013;68(1):1-7.
15. Rondon C et al. Local allergic rhinitis: concept, pathophysiology, and management. J
Allergy Clin Immunol 2012;129(6):1460-1467.
16. Blom HM et al. Mast cells, eosinophils and IgE-positive cells in the nasal mucosa of
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17. Blom HM et al. The effect of nasal steroid aqueous spray on nasal complaint scores and
cellular infiltrates in the nasal mucosa of patients with nonallergic, noninfectious perennial
rhinitis. J Allergy Clin Immunol 1997;100(6 Pt 1):739-747.
18. Blom HM et al. The long-term effects of capsaicin aqueous spray on the nasal mucosa.
Clin Exp Allergy 1998;28(11):1351-1358.
19. Kim YH et al. Use of cold dry air provocation with acoustic rhinometry in detecting
nonspecific nasal hyper-reactivity. Am J Rhinol Allergy 2010;24(4):260-262.
20. Hellings PW et al. Executive summary of European Task Force document on diagnostic
tools in rhinology. Rhinology 2012;50(4):339-352. 2
21. Scadding G et al. Diagnostic tools in Rhinology EAACI position paper. Clin Transl Allergy
2011;1(1):2.
22. Cockcroft DW et al. Diagnostic and therapeutic value of airway challenges in asthma.
Curr Allergy Asthma Rep 2009;9(3):247-253.
23. Hassan NM et al. Airway responsiveness to indirect challenges in COPD. COPD
2010;7(2):133-140.
24. Rundell KW et al. Exercise and other indirect challenges to demonstrate asthma or
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246; quiz 247-238.
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exhaled nitric oxide: a random-sample population study. J Allergy Clin Immunol
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27. Van Gerven L et al. Up-date on neuro-immune mechanisms involved in allergic and
non-allergic rhinitis. Rhinology 2012;50(3):227-235.
28. van Rijswijk JB et al. Idiopathic rhinitis, the ongoing quest. Allergy 2005;60(12):1471-1481.
29. Bousquet J et al. Important research questions in allergy and related diseases: nonal-
lergic rhinitis: a GA2LEN paper. Allergy 2008;63(7):842-853.
30. Taylor-Clark TE et al. Nasal sensory nerve populations responding to histamine and
capsaicin. J Allergy Clin Immunol 2005;116(6):1282-1288.
31. Baumgarten CR et al. Substance P is generated in vivo following nasal challenge of
allergic individuals with bradykinin. Clin Exp Allergy 1997;27(11):1322-1327.
32. Hanf G et al. Substance P induced histamine release from nasal mucosa of subjects
with and without allergic rhinitis. Inflamm Res 2000;49(10):520-523.
33. Bohm M et al. Liposomes: a new non-pharmacological therapy concept for season-
al-allergic-rhinoconjunctivitis. Eur Arch Otorhinolaryngol 2012;269(2):495-502

45
CHAPTER 3
Endotyping of non-
allergic, allergic and
mixed rhinitis patients
using a broad panel of
biomarkers in nasal
secretions
 C.L. Segboer
W.J. Fokkens
I. Terreehorst
C.M. van Drunen

PLoS One 2018 Jul; 13(7): e0200366

CHAPTER 3

ABSTRACT

Background
Endotyping chronic rhinitis has proven hardest for the subgroup of non-allergic rhinitis
(NAR) patients. While IgE-related inflammation is typical for allergic rhinitis (AR), no
markers have been found that can be seen to positively identify NAR. A further compli-
cation is that AR and NAR might co-exist in patients with mixed rhinitis. As previous
studies have considered only a limited number of inflammatory mediators, we wanted
to explore whether a wider panel of mediators could help us refine the endotyping in
chronic rhinitis patients.

Objective
To endotype chronic rhinitis, and non-allergic rhinitis in particular, with help of
­molecular or cellular markers.

Method
In this study we included 23 NAR patients without allergen sensitizations and with
persistent rhinitis symptoms, 22 pollen sensitized rhinitis patients with seasonal
symptoms, 21 mixed rhinitis patients with pollen-related symptoms and persis-
tent symptoms outside of the pollen season, and 23 healthy controls without any
symptoms. Nasal secretions were collected outside of pollen season and differences
between the endotypes were assessed for a broad range of inflammatory mediators
and growths factors using a multiplex ELISA.

Results
Although we were able to identify two new nasal secretion markers (IL-12 and HGF)
that were low in mixed and AR patients versus NAR and healthy controls, the most
intriguing outcome is that despite investigating 29 general inflammatory mediators
and growth factors no clear profile of non-allergic or mixed rhinitis could be found.

Conclusion
Classical inflammatory markers are not able to differentiate between non-allergic or
mixed rhinitis patients and healthy controls.

48
 ENDOTYPING OF NON- ALLERGIC, ALLERGIC AND MIXED RHINITIS PATIENTS

INTRODUCTION

Rhinitis can be subdivided into a number of discrete pheno- and endotypes (1). The
characterization of phenotypes is hampered by limited clinical tools (2). Identifying
the molecular processes underlying rhinitis in a particular patient may help us to
identify different endotypes more readily and may help to optimize treatment for these
patients (3).

If we disregard infectious rhinitis, the most common rhinitis phenotype is allergic

rhinitis (AR), in which a clinical response to an otherwise innocent environmental
factor or allergen results in symptoms. This clinical response, in combination with
specific IgE targeting aeroallergens constitutes allergic rhinitis. The second most
common rhinitis phenotype is non-allergic rhinitis (NAR), which is defined as a form
of non-infectious rhinitis in which it is not possible to identify an allergic component
3
(1) (4). NAR can be subdivided into the following phenotypes: environmental (occupa-
tional, smoking), hormones (pregnancy), medication-induced (rhinitis medicamentosa,
NSAIDS (non-steroidal anti-inflammatory drugs), aspirin etc.), gustatory, age (rhinitis
of the elderly) and/or inflammation (non-allergic rhinitis with eosinophilia syndrome
(NARES) or local allergic rhinitis (LAR)). However, in a significant proportion of patients,
none of these triggers are present and the disease is considered to be idiopathic (1)
(3) (5). However, the phenotypes are dynamic and overlapping, and they may evolve
into one another (1).

For a long time, nasal hyper-reactivity was seen as a symptom that made it possible
to differentiate between patients affected by idiopathic rhinitis (former known
as vasomotor rhinitis) and other chronic rhinitis patients. However, we recently showed
that nasal hyper-reactivity is a widespread symptom that is common to both AR and
NAR patients (6, 7). Furthermore, quality of life (QoL) is equally impaired in both NAR
and AR patients (8).

In addition to phenotypes, NAR can be subdivided into inflammatory, neurologic and

idiopathic endotypes (4, 9) (Table 1). The prevalence of the different endotypes of
NAR is unknown and this area will require research in the future. The inflammatory
endotype includes two clear subendotypes: local allergic rhinitis (LAR) and NARES
(non-allergic rhinitis with eosinophilia syndrome) (1) (10). These two usually have a
Th2 endotype involving an increase in eosinophils, IL-5, IL-4, IL-13 and, in the case of
LAR, specific IgE (1) (9). This endotype may also include the environmental pheno-
type (occupational, smoking)–with low-molecular-weight substances initiating a Th2
response by means of TSLP, IL-33 etc.–, the drug-induced inflammatory endotype
(NAIDS, aspirin) and hormonal rhinitis involving histamine H1-receptor overexpression
(1) (4). Although there is no hard evidence one can expect that the NAR inflammatory

49
CHAPTER 3

endotype will be successfully treated with a combination of intranasal corticosteroids

and/or antihistamines.

Table 1. NAR phenotypes and endotypes

Phenotypes (4) Endotypes (1, 4, 9)

NARES/LAR Th2-inflammation
Occupational Neurogenic inflammation, Th2-inflammation
Medication-induced Neurogenic dysbalance, Th2-inflammation, idiopathic
Hormonal Neurogenic dysbalance, Th2-inflammation
Idiopathic rhinitis Neurogenic inflammation, idiopathic
Rhinitis of the Elderly Neurogenic dysbalance
Gustatory Neurogenic dysbalance and neurogenic inflammation

In the case of the neurological endotype, one can differentiate between neurological
inflammation in idiopathic rhinitis with nasal hyper-reactivity and disease attributed to
hyperactivity in the parasympathetic nervous system (primarily senile and gustatory
rhinitis, but also, to a certain extent, hormonal and drug-induced rhinitis). In idiopathic
rhinitis, studies have indicated that neurogenic signs of disease (transient potential
receptor channels (TRP receptors)) affect trigeminal nerves, substance P, and calci-
tonin gene-related peptide (11). Capsaicin treatment in these patients induces the
reduction of TRPV-1 receptors in nasal mucosa, reducing the symptoms of nasal
hyper-reactivity (11) (12) (13). Recent literature shows that azelastine (nasal anti-­
histamine) can achieve the same effect in TRP desensitization (14). In patients with
senile and gustatory rhinitis, ipratroprium nasal spray (atronase) reduces parasym-
pathetic activity in the nose (15). When all other treatments fail, vidian neurectomy
may be a way of disrupting the parasympathetic innervation of the nose and stopping
rhinorrhea (16).

We are not aware of a type 1 or type 3 inflammatory endotype (INF-y, IL-17, TNF) in
NAR; type 1 inflammation would seem to be related mainly to infectious rhinitis and
not to NAR phenotypes (4).

It is also important to realize that the underlying mechanism of NAR can also be
present in AR. When there is a seasonal allergen sensitization accompanied by peren-
nial symptoms, symptoms outside the pollen season may be the result of ongoing,
minimal persistent, allergic inflammation or the same underlying mechanism as in
NAR may be responsible for symptoms (9, 17).

Studies to assess single cellular or molecular markers (or combinations of these

markers) with the aim of defining the endotype of AR and NAR are scarce (3) (18).
Unfortunately, it is difficult to combine the data from these studies due to differences

50
 ENDOTYPING OF NON- ALLERGIC, ALLERGIC AND MIXED RHINITIS PATIENTS

in the inclusion criteria that resulted in unclear phenotypes. In general terms, these
studies have mainly identified differences between AR and NAR that are linked to cells
and markers related to IgE inflammation in AR: total and specific IgE, eosinophils,
mast cells, and IL-5 (19). However, some of these studies showed comparable levels
of allergic inflammation in AR and NAR patients, possibly indicating some form of
local allergic inflammation in these NAR patients (20) (21). In cases where idiopathic
rhinitis patient were studied, levels of inflammatory mediators or cells were found to
be the same as in healthy controls (22).

We wondered whether the endotyping of chronic rhinitis patients–and non-allergic

rhinitis patients in particular–with molecular or cellular markers could be helpful. In
this cross-sectional study we studied nasal secretions for the presence of potentially
relevant mediators related to different rhinitis endotypes. We looked at non-allergic
rhinitis patients (selected to represent idiopathic rhinitis), grass-pollen-allergic rhinitis
3
patients (outside allergen exposure) as an example of minimal persistent, allergic
inflammation, mixed rhinitis patients and healthy controls (17).

MATERIAL AND METHODS

Inclusion and exclusion criteria

Patients were recruited from the outpatient clinic of the Department of Otorhinola-
ryngology of the Academic Medical Center, Amsterdam, the Netherlands. Medical
ethical approval was obtained (MEC 08/356) by the Institutional Medical Ethics Review
Committee (MRTC) of the Academic Medical Centre of Amsterdam (AMC) and all
participants gave their written informed consent. A patient information document
(approved by the Institutional Medical Ethics Review Committee) was signed per
included patient. All rhinitis patients had a positive history of rhinitis symptoms at
least one year and were referred to our tertiary care outpatient clinic by their general
practitioner or another otorhinolaryngology clinic.

Only pollen-sensitized AR patients were included, excluding AR patients with a

perennial allergen sensitization like for example house dust mite. Pollen-sensitized
AR patients had at least one positive SPT result for a pollen allergen (defined as: a
wheal equal in size or larger than 3 mm and no response to the negative control) and
clinical symptoms relevant to their sensitization and no symptoms outside the pollen
season when they were included in the study. NAR was defined as clinically relevant
symptoms of rhinitis without a positive SPT. In this study, we selected non-allergic
rhinitis patients and excluded smoking, senile, gustatory, occupational, medication-­
induced and pregnancy rhinitis. Mixed rhinitis patients had perennial rhinitis symptoms
with peak symptoms during the pollen season and a positive SPT for one or more

51
CHAPTER 3

pollen allergens, mixed rhinitis patients with perennial allergen sensitizations were
excluded as well. The healthy control group had no symptoms of rhinitis and a negative
SPT.

The exclusion criteria for all patient groups were anatomic abnormalities, or any
systemic disease or medication influencing nasal function. Patients had to be free of
symptoms of upper airway infection for at least 1 week. Patients with symptoms of
chronic rhinosinusitis (CRS) (diagnosed according to EPOS criteria, i.e. two or more
symptoms of the following: nasal congestion/blockage, (anterior/posterior) rhinor-
rhea, hyposmia/anosmia, facial pain/pressure; with at least either nasal congestion
or rhinorrhea, combined with signs of CRS with nasal endoscopy and/or CT sinus)
with or without nasal polyposis were excluded, as were patients who had undergone
nasal surgery in the previous 3 months, patients with a history of immunotherapy or
asthma, and patients who smoked (23).

STUDY DESIGN

Data collection
Nasal secretions were collected to compare molecular biological parameters in nasal
secretions of 23 pollen-sensitized AR patients outside the season, 23 symptomatic
NAR patients, 23 symptomatic pollen-sensitized mixed rhinitis patients and 23 healthy
controls. Nasal secretions were obtained outside the pollen season from September
to March-May, with the latter limit depending on the patient’s seasonal sensitizations.

Screening visit
Patients were seen for a screening visit and a sampling visit, both outside the pollen
season. Patients were asked to stop with their antihistamines for 48 hours before both
visits and with nasal corticosteroid medication or any other medication influencing
nasal function for at least 4 weeks. The screening visit included a skin prick test (SPT),
and an Ear-Nose-Throat (ENT) history and examination. Patients were categorized
using the ARIA classification system (24).

Sampling visit
The sampling visit included an assessment of nasal symptoms (rhinorrhea, nasal
congestion, itch and sneezing) with a Visual Analogue Scale (VAS) (maximum 100
mm per nasal symptom) and a nasal airflow assessment based on Peak Nasal Inspir-
atory Flow (PNIF). To collect the secretion, a small merocel (Ivalon, ThinPack™) was
inserted into the inferior meatus of one nostril for three minutes. Which nostril was
used depended on the anatomical situation of the individual patient. The merocel
was weighed before and after application to calculate total secretion weights and the
secretion was eluted by soaking in 3 mL (0.9% w/v) NaCl at 4°C for two hours and

52
 ENDOTYPING OF NON- ALLERGIC, ALLERGIC AND MIXED RHINITIS PATIENTS

collected after centrifugation for 15 min at 1,500g. Aliquots were stored at -80°C until
use in a multiplex ELISA.

Protein multiplex ELISA

The samples collected from the three patient groups and healthy control group were
used to determine protein levels for a broad range of inflammatory mediators and
growth factors (the lower detection limit for each mediator is stated in pg/mL between
brackets): IL-1RA (13.4 pg/mL), IL-1β (3.7 pg/mL), IL-2R (10.5 pg/mL), IL-2 (4.7 pg/mL),
IL-4 (16.6 pg/mL), IL-5 (4.2 pg/mL), IL-6 (2.7 pg/ml), IL-8 (2.4 pg/mL), IL-10 (9.5), IL-12
(4.6), IL-13 (5.0), IL-15 (11.0), IL-17 (8.6 pg/mL), eotaxin (1.6 pg/mL), TNF-α (3.9 pg/mL),
INF-α (6.7 pg/mL), IFN-γ (11.0 pg/mL), MCP-1 (4.9) pg/mL), GM-CSF (10.3 pg/mL),
G-SCF (26.8 pg/mL), VEGF (3.5 pg/mL), FGF-β (1.6 pg/mL), EGF (3.3 pg/mL), HGF
(6.8 pg/mL), IP-10 (1.9 pg/mL), MIG (1.7 pg/mL), RANTES (5.4 pg/mL), MIP1-α (6.9
pg/mL), MIP1-β (3.3 pg/mL).
3

The function of the measured cytokines and their relation to an underlying endotype
can be found in Figure 1.

53
CHAPTER 3

Figure 1. Function of measured cytokines

Cytokine levels were measured with a Human Cytokine Thirty-Plex Antibody Bead Kit
(Biosource, USA) in combination with a Bio-Plex workstation (Bio-Rad, NL). All stand-
ards were diluted in HBSS medium as required by the manufacturer. All standards were
diluted in HBSS medium (3 mL) as required by the manufacturer. Luminex software
was employed for the protein concentration calculations and all these concentra-
tions–after correcting for the different amounts of nasal secretions collected–were
expressed in pg/mL.

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 ENDOTYPING OF NON- ALLERGIC, ALLERGIC AND MIXED RHINITIS PATIENTS

Statistics and principal component analysis

SPSS 20.0 (Chicago, IL, USA) was used for statistical analysis. Cytokine, chemokine,
and growth factor values that were below the detection limits were recoded to the
lowest measurable value. The distribution of the data was not normal and Kruskal-
Wallis non-parametric tests were therefore performed to check for significant
between-group variability. Where significant between-group variability was found,
Mann-Whitney-U non-parametric tests were performed for between-group compari-
sons. The level of statistical significance was set to <0.003 after Bonferroni correction
for multiple testing (0.05/15). Principal component analysis involving the extraction of
11 components in a rotated component matrix (Varimax with Kaiser normalization)
took place to determine whether a combination of cytokines could distinguish between
groups of patients.

3
RESULTS

Characterization of participants
The patient groups were comparable in terms of age, gender and percentage of
patients with moderate-severe persistent disease (Table 2).

55
CHAPTER 3

Table 2. Patient characteristics

The NAR and the mixed rhinitis group had significantly (p< 0.001) higher total VAS
scores and VAS scores for congestion and itch (p< 0.001 and p< 0.011 respectively)
than healthy controls and allergic rhinitis patients (outside the season). Although the
PNIF was higher in the healthy controls than in the patient groups, the differences
were not statistically significant. Two patients in the mixed rhinitis group and one in
the allergic rhinitis group were excluded: one patient in the mixed rhinitis group started
smoking again and the other was found to have a perennial allergen sensitization for
cat combined with daily exposure to this allergen, and the bothersome symptoms of
rhinitis disappeared in the patient in the AR group.

56
 ENDOTYPING OF NON- ALLERGIC, ALLERGIC AND MIXED RHINITIS PATIENTS

Nasal secretion analysis

Nasal secretions of non-allergic rhinitis patients cannot be differentiated

from healthy controls
Above the detection levels were:
IL-8, IL-12, IL1RA, MCP1, MIP1α, MIP1β, EGF, VEGF, HGF, INFα, RANTES, IP10, IL7,
FGFβ and MIG. No significant differences were found between non-allergic rhinitis
and healthy controls for any of the mediators above detection level. The functions of
these mediators can be found in Figure 1.

Levels of IL-12 and HGF are low in nasal secretions of mixed and allergic
rhinitis patients
There was a significant difference between patient groups (Kruskal-Wallis, p < 0.003)
for two mediators above detection level, IL-12 and HGF (Table 3). Median IL-12 levels
3
were significantly higher in the NAR group than in the AR and mixed groups. Median
IL-12 levels in AR and mixed rhinitis were lower than in healthy controls but they
reached significance in the mixed patient group only. A similar pattern was seen for
HGF but it was not found to be significant when we set the level of significance at p <
0.003 for the correction of multiple testing (Figure 2A and 2B).

57
CHAPTER 3

Figure 2 (A and B). Cytokines that were (significantly) different between groups: IL12 (A) and HGF (B)
(A and B): Expression of cytokines (pg/mL) in nasal lavage fluid in a healthy control group and in
mixed, non-allergic (NAR) and allergic (AR) rhinitis patient groups. Individual concentrations are rep-
resented with a symbol; median concentration levels per group are represented with a horizontal line.
* IL12 is significantly lower in mixed versus healthy controls.
** IL12 is significantly lower in AR and mixed versus NAR.

58
 ENDOTYPING OF NON- ALLERGIC, ALLERGIC AND MIXED RHINITIS PATIENTS

Table 3. Cytokine levels in nasal secretions

Principal component analysis reveals high inter- and intra-group variance

as a consequence of the large dynamic range of expression for multiple
mediators
As has been shown above, some of the individual cytokines showed significant differ-
ences between the groups, but neither the three patient groups nor the healthy controls
expressed a feature cytokine. We used principal component analysis to explore
whether the use of combinations of mediators rather than single mediators could
improve molecular characterization for our study population.

Mapping individual patients in multi-dimensional space showed that we could reduce

the dataset to the first five principal components with eigenvalues over 1 that together
account for more than 75% of total variance (Figure 3) in all samples.

59
CHAPTER 3

Figure 3. Proportion of contribution to total variance of principal components

Table 4 shows the relative contribution of each of the mediators to these five principal
components. The first three principal components showed significant loading of more
than 0.5 for multiple mediators: MCP1, IP10, and IL-15 on PCA1, EGF and MCP1 on
PCA2, and the related mediators MIP1α and MIP1β on PCA3. The last two principal
components seemed to depend on single mediators: PCA4 on IL-12 and PCA5 on IL-17.
Pairwise plotting of the five principal components did not result in a full separation
of an individual patient group; the plot of PCA1/PCA2 is shown in Figure 4A as an
example. The best separation of groups was obtained when PCA4 was involved. For
instance, plotting PCA2 against PCA4 (Figure 4B) revealed the unique low vales for
the mixed rhinitis group.

60
 ENDOTYPING OF NON- ALLERGIC, ALLERGIC AND MIXED RHINITIS PATIENTS

Table 4. Contribution of individual cytokines to the principal components

61
CHAPTER 3

A.

B.

Figure 4 (A and B). Principal component analysis

(A): PC1 versus PC2: no distinction between groups
(B): PC2 versus PC4: distinction between mixed and AR patients (with low values for PC4) and
healthy and NAR (with low values for PC2).

62
 ENDOTYPING OF NON- ALLERGIC, ALLERGIC AND MIXED RHINITIS PATIENTS

We evaluated potential correlations between mediators on the basis of the significant

loadings of multiple mediators for each principal component. Indeed, Pearson’s corre-
lation coefficient was highly significant for mediators that weighted PCA1 (MCP1,
IP10, and IL-15): MCP1 versus IP10 (r  =  0.642,  P  =  < 0.0001), MCP1 versus IL-15
(r = 0.669, P = < 0.0001), and IP10 versus IL-15 (r = 0.907, P = < 0.0001). The same
picture emerges for the mediators weighting PCA2 (EGF versus MCP1, r = 0.776, P = <
0.0001) and for MIP1α versus MIP1β (r = 0.764, P = < 0.0001) on PCA3.

DISCUSSION

The most important outcome of this study is that, looking at a wide panel of media-
tors related to endotypes of (general/Th2/Th1) inflammation, no clear profile could
be found in non-allergic rhinitis patients. In the past, only a limited panel of mainly
3
Th2 mediators–examples being IL-5, IgE, and eosinophils–were taken into account
when comparing non-allergic rhinitis patients with allergic rhinitis patients (18). The
aim of this study was to broaden that panel in order to establish a wider picture, and
to assess a large number of mediators and chemokines related to growth, inflam-
mation (general/Th1/Th2/Th3), eosinophils, and neutrophils. In NAR patients, none
of the levels of these mediators differed significantly from those in healthy controls,
emphasizing that no distinction can be made between the inflammatory patterns
in non-allergic rhinitis (mainly idiopathic rhinitis) and healthy controls (Table 3). We
have to acknowledge that in this study we have not looked at the typical neurogenic
inflammatory markers in NAR patients. This might have shown a distinctive pattern
in NAR compared to healthy controls.

On a phenotype level, it is important to realize that -although we excluded NAR patients

with senile, gustatory, occupational, medication-induced and pregnancy rhinitis- we
cannot objectively claim to have excluded NARES or LAR. The history of NAR patients
was however not suggestive for an allergen sensitization. Differentiating at a pheno-
type level between AR–particularly when there is concomitant perennial sensitization–
and mixed rhinitis can be extremely complicated. AR and mixed patients in this study
were therefore pollen-sensitized only and the study was performed outside the pollen
season. At the phenotype level, this meant that AR patients did not have symptoms
during the study but that mixed and NAR patients did and that molecular differences
between AR, NAR and mixed patients were independent of allergic inflammation. We
aimed to identify, where present, the specific endotype of the NAR profile in NAR and
mixed patients.

In a broad panel of inflammatory mediators, the mediator profile of non-allergic

rhinitis patients resembles that of healthy controls whereas the profile of mixed
rhinitis patients resembles that of allergic rhinitis patients. The analysis of multiple

63
CHAPTER 3

inflammatory mediators did reveal differences in the levels of the mediators IL-12 and
HGF (which were significantly lower in AR and mixed rhinitis than in NAR and healthy
controls) that have not been extensively explored previously in the context of different
forms of rhinitis.

Traditionally, IL-12 has been seen as a hallmark Th1 cytokine produced by dendritic cells
that skews native T lymphocytes to produce INF-gamma. As we know, there is cross-­
regulation of anti-viral Th1 and allergic Th2 responses by the mutual inhibitory effects
of IL-12 on Th2, and IL-4 on Th1, responses. It might therefore be assumed that, in our
study, the AR patients with a predominant Th2-skewed inflammation would have lower
levels of IL-12 than healthy controls or non-allergic rhinitis patients. Nevertheless, IL-12
levels in these pollen-allergic patients were very low, even when taking into consideration
the fact that these patients were seen outside of the pollen season. We also failed to
detect IL-4, IL-5, and IL-13 in nasal secretions, which suggest that it is unlikely that low
IL-12 levels are a result of active Th2-dominated inflammation. This suggests that the
low IL-12 levels could be an intrinsic characteristic of pollen-allergic patients.

A similar pattern in the nasal secretion levels was seen for HGF. This mediator is known to
regulate dendritic cell migration, inhibit epithelial apoptosis, and reduce airway eosinophilia
in OVA-allergic mice (25) (26). HGF can also suppress IL-13-induced eotaxin expression
in airway epithelial cells (27) (28). The low level of HGF may therefore facilitate Th2
responses in AR and mixed rhinitis patients.

The overall low expression of IL-12 and HGF in mixed rhinitis patients may be a small
step towards this goal and it does show that a more unbiased approach may help to
reveal new aspects of a disease that have not been previously considered.

Although IL-12 is best known in relationship to dendritic cells, it has been shown that
other cells such as epithelium produce IL-12 in substantial quantities; we have shown
that IL-12 expression in an epithelial cell line can be up-regulated through the activation
of the cells by pollen allergen (29) (30). Epithelial cells can also secrete HGF, which
is in line with the concept that proteins from the nasal epithelium could dominate
the protein content of nasal secretion. The potential contribution of nasal epithelium
and the potential intrinsically low level of IL-12 and HGF in pollen-allergic individuals
outside the pollen season could concur with our observations of the nasal epithe-
lium of HDM-allergic individuals, which seems to stay activated when these cells are
cultured ex vivo in the absence of allergen exposure (31). How the differences we
have observed may contribute to the pathological mechanisms of allergic rhinitis or
idiopathic rhinitis remains to be explored. However, low levels of IL-12 and HGF could
facilitate a stronger Th2 response upon allergen exposure. In addition to the obvious
targets of the nasal mediators we may also need to consider potential contributions
from the family of innate lymphoid cells. Type 2 innate lymphoid cells (ILC2) play an

64
 ENDOTYPING OF NON- ALLERGIC, ALLERGIC AND MIXED RHINITIS PATIENTS

important role in chronic inflammatory airway diseases (such as chronic rhinosinusitis

and diseases of the lower airways). IL-12 and IL-4 can switch the function of ILC2 into
either type 1 or type 2 inflammation (32), (33).

Also looking at groups of mediators instead of only individual mediators–as was done
in the principal component analysis–did not help us in differentiation between patient
groups. Principal component analysis showed us that the cytokines present on the first
principal component contribute most to variation between patient groups. The clinical
implications, however, remain unknown as the numbers and types of cytokines and/
or the defined sets of phenotypes cannot differentiate between groups of patients.

In conclusion, looking at a broad panel of mediators did not allow us to identify a

mediator profile that links non-allergic rhinitis to a general or Th2/Th1 inflammatory
or neurogenic endotype. Nor could we identify a specific combination of mediators
3
that differentiate between non-allergic rhinitis and healthy controls. This confirms
previous data that looked at a limited number of mediators in idiopathic rhinitis patients
(mainly at IgE, eosinophils, IgE, mast cells) and found no differences from healthy
controls (19, 22).

The panel of inflammatory mediators was still limited in number and function: we did
not look at, for example, neuropeptides such as SP or CGRP as markers of neurogenic
inflammation. Further research to assess differences in a completely unbiased way
–in other words at the mRNA level (micro-array) and including mediators related to
neurogenic inflammation–may help us to identify the distinct features of this patient
group, for which treatment is unsatisfactory owing to our lack of understanding of the
underlying etiology.

ACKNOWLEDGEMENTS

Esther de Groot and Danielle van Egmond contributed to this study by performing
multiplex protein ELISA analyses.

65
CHAPTER 3

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3. Muraro A et al. Precision medicine in patients with allergic diseases: Airway diseases and
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lergic rhinitis. Allergy. 2013;68(11):1427-34.
7. Van Gerven L et al. Up-date on neuro-immune mechanisms involved in allergic and
non-allergic rhinitis. Rhinology. 2012;50(3):227-35.
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Allergy. 2017.
9. Hellings PW et al. Non-allergic rhinitis: Position paper of the European Academy of Allergy
and Clinical Immunology. Allergy. 2017;72(11):1657-65.
10. Campo P et al. Local Allergic Rhinitis. Immunology and allergy clinics of North America.
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11. Van Gerven L et al. Capsaicin treatment reduces nasal hyper-reactivity and transient
receptor potential cation channel subfamily V, receptor 1 (TRPV-1) overexpression
in patients with idiopathic rhinitis. The Journal of allergy and clinical immunology.
2014;133(5):1332-9,
12. Van Rijswijk JB et al. Intranasal capsaicin reduces nasal hyper-reactivity in idiopathic
rhinitis: a double-blind randomized application regimen study. Allergy. 2003;58(8):754-61.
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14. Gehanno P et al. Vasomotor rhinitis: clinical efficacy of azelastine nasal spray in compar-
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15. Bronsky EA et al. A clinical trial of ipratropium bromide nasal spray in patients with
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Pt 2):1117-22.
16. Robinson SR et al. Endoscopic vidian neurectomy. Am J Rhinol. 2006;20(2):197-202.
17. Ricca V et al. Minimal persistent inflammation is also present in patients with seasonal
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18. Bachert C et al. Advances in rhinitis and rhinosinusitis in 2015. The Journal of allergy
and clinical immunology. 2016;138(5):1277-83.
19. Blom HM et al. Mast cells, eosinophils and IgE-positive cells in the nasal mucosa
of patients with vasomotor rhinitis. An immunohistochemical study. Eur Arch Otorhi-
nolaryngol. 1995;252
20. Comoglu S et al. Inflammatory cell patterns in the nasal mucosa of patients with
idiopathic rhinitis. American journal of rhinology & allergy. 2012;26(2):e55-62.
21. Klimek L et al. Local (exclusive) IgE production in the nasal mucosa. Evidence for local
allergic rhinitis). Hno. 2013;61(3):217-23.
22. van Rijswijk J et al. Inflammatory cells seem not to be involved in idiopathic rhinitis.
Rhinology. 2003;41(1):25-30. 3
23. Fokkens WJ et al. EPOS 2012: European position paper on rhinosinusitis and nasal
polyps 2012. A summary for otorhinolaryngologists. Rhinology. 2012;50(1):1-12.
24. Bousquet J et al. Allergic Rhinitis and its Impact on Asthma (ARIA): achieve-
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25. Baek JH et al. The HGF receptor/Met tyrosine kinase is a key regulator of dendritic
cell migration in skin immunity. Journal of immunology (Baltimore, Md : 1950).
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allergic airway inflammation in mice. International archives of allergy and immunology.
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28. Reh DD et al. The role of hepatocyte growth factor/c-Met in chronic rhinosinusitis with
nasal polyps. American journal of rhinology & allergy. 2010;24(4):266-70.
29. Junghans V et al. Epidermal cytokines IL-1beta, TNF-alpha, and IL-12 in patients with
atopic dermatitis: response to application of house dust mite antigens. The Journal of
investigative dermatology. 1998;111(6):1184-8.
30. Roschmann K et al. Timothy grass pollen extract-induced gene expression and signal-
ling pathways in airway epithelial cells. Clinical and experimental allergy: journal of the
British Society for Allergy and Clinical Immunology. 2011;41(6):830-41.
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32. Kortekaas Krohn I et al. Emerging roles of innate lymphoid cells in inflammatory
diseases: clinical implications. Allergy. 2017. doi: 10.1111/all.13340.

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69
CHAPTER 4
Quality of life is
significantly impaired
in non-allergic rhinitis
patients
 C.L. Segboer
I. Terreehorst
A. Gevorgyan
P.W. Hellings
C.M. van Drunen
W.J. Fokkens

Allergy 2018 Nov; 73(5):1094-1100

CHAPTER 4

ABSTRACT

Background
In contrast to the well-known significant impairment of quality of life (QoL) in allergic
rhinitis (AR), the degree of impairment in QoL in non-allergic ­rhinitis(NAR) remained
unknown for a long time, due to a lack of a validated questionnaire to assess QoL in the
NAR patient group. In this study, a validation of the mini-RQLQ questionnaire in NAR
patients was performed, followed by an assessment of QoL in NAR patients compared
to AR and healthy controls. Secondly, use of medication and treatment satisfaction in
AR and NAR was assessed.

Methods
The study was an observational cohort study in 287 AR and 160 NAR patients. Patients
with symptoms of rhinitis were recruited from a tertiary care ­out­­patient clinic of the
Otorhinolaryngology Department. Allergic rhinitis (AR) was defined as one or more
positive results on skin prick testing and clinically relevant symptoms of rhinitis related
to their sensitization. Non-allergic rhinitis (NAR) was defined as clinically relevant
symptoms of rhinitis but without positive results on skin prick testing. The mini-RQLQ
was successfully validated in this study for NAR patients.

Results
Quality of life (QoL) in NAR patients was equally—and for some aspects even more—
impaired compared to AR. More than half of both AR and NAR patients were unsat-
isfied with treatment.

Conclusion
These results demonstrate a significant impairment in both AR and NAR patients
in their QoL combined with a low treatment satisfaction, emphasizing the need for
adequate treatment, especially in the NAR patient group.

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QUALITY OF LIFE IS SIGNIFICANTLY IMPAIRED IN NON-ALLERGIC RHINITIS PATIENTS

INTRODUCTION

Both allergic rhinitis (AR) and non-allergic rhinitis (NAR) are amongst the most
common chronic diseases with a significant impact on quality of life (QoL). Allergic
rhinitis (AR) is an inflammatory condition caused by an IgE-mediated response to
allergen exposure (1). Patients with NAR have similar symptoms without clinical
evidence for an infectious, anatomic, or allergic aetiology (1).

The worldwide estimated prevalence of NAR exceeds 200-400 million people (2).
Around half of the adult rhinitis patients (20% to 70%) are considered to have NAR
(2, 3, 4).

Clinically, NAR shows largely the same symptoms of rhinitis as AR (5). Also, NAR and
AR patients have the same prevalence and type of nasal hyper-reactivity, although in
the past nasal hyper-reactivity was considered a hallmark of NAR patients only (6).
However, some characteristic features of AR and NAR do exist. AR patients will have 4
allergen induced rhinitis symptoms that usually is accompanied with symptoms of
conjunctivitis, more often seasonality and other signs of the atopic syndrome. Data
on lower airway involvement are contradictory indicating lower or the same level of
lower airway involvement in NAR compared to AR (4, 7-10).

A number of subphenotypes can be discerned within the context of NAR: drug-induced

rhinitis, gustatory rhinitis, hormonal-induced rhinitis, rhinitis of the elderly, atrophic
rhinitis, NARES, LAR and idiopathic rhinitis (1) (11).

When considering pathophysiology, a subdivision in a neurogenic and an inflammatory

endotype is often made. Although not proven, one may consider anti-inflammatory
treatment to be more effective in the inflammatory endotype like NARES and LAR and
capsaicin to be more effective in the neurogenic endotype (12).

A consequence of the lack of evidence-based treatment for NAR patients compared

to AR, is that many NAR patients are unsuccessfully treated. This could cause a high
impairment of quality of life in NAR. In contrast to the significant literature on the
impairment of the QoL seen in patients with AR (13-17), the degree of impairment of
health-related QoL in NAR patients is under-evaluated (3) (18, 19). For this reason, we
wanted to assess the QoL of NAR patients in comparison to AR and healthy controls.

In contrast to AR however, for NAR no disease specific and validated questionnaires

to measure quality of life were available until now (20).

Van Oene et al. showed that for measurement of health related quality of life in AR
patients, the RQLQ(S) and the mini-RQLQ were the best tests with optimal discriminant

73
CHAPTER 4

validity and responsiveness (13). For that reason, we first validated the RQLQ for evalu-
ation of QoL in patients with NAR. Then we assessed QoL in NAR compared to healthy
controls and AR patients as a positive control group.

Finally, we assessed the use of nasal medication in NAR, and compared NAR with AR
for number and type of nasal medication and treatment satisfaction.

METHODS

Study design

An observational cohort study was performed using

questionnaires
Quality of life was assessed by comparing NAR with both healthy controls as with AR
as a positive control group. The use of nasal medication was assessed by comparing
NAR with AR.

Allergic rhinitis (AR) and non-allergic rhinitis (NAR) patients were recruited between
June 2006 and February 2015 from a database composed of rhinitis patients visiting
the outpatient clinic of the Ear-Nose-Throat Department of the Academic Medical
Centre (Amsterdam, The Netherlands) that went for skin prick testing. If patients met
inclusion and exclusion criteria based on history, Ear-Nose-Throat routine examination
and allergy skin prick testing, two sets of questionnaires (assessing quality of life and
use of nasal medication) were sent to patient’s home address. Questionnaires were
sent between October 2011 and February 2015.

Inclusion criteria

AR patients
Allergic rhinitis (AR) patients had at least one positive skin prick test result and chronic
rhinitis symptoms relevant to their sensitization. Rhinitis was defined as one or more
of the following symptoms: watery, anterior rhinorrhea, paroxysmal sneezing, nasal
obstruction and/or nasal pruritus. Patients were classified as having intermittent or
persistent symptoms of rhinitis according to ARIA classification. This classification
was done with help of a questionnaire that accompanied the skin prick test, assessing
duration of symptoms (< or >4 days per week and/or < or >4 weeks per year) and
severity of symptoms (influence on daily life). To assess allergic sensitization, we used
the GA2LEN standardized method of skin prick testing (SPT) (21). A positive reaction
to SPT was defined as a skin reaction larger than 3 mm for one or more of the 18
tested allergens, and no reaction to the negative control. Patients were asked to stop
their antihistamine medication 48 hours before allergy testing.

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QUALITY OF LIFE IS SIGNIFICANTLY IMPAIRED IN NON-ALLERGIC RHINITIS PATIENTS

NAR patients
Non-allergic rhinitis (NAR) was defined as clinically relevant symptoms of chronic
rhinitis without positive skin prick test results and no other reason for rhinitis symptoms
(see Exclusion Criteria). Intermittent or persistent rhinitis was defined in the same way
as in AR (according to ARIA classification).

Controls
To validate the mini-RQLQ for use in NAR patients, 49 healthy controls were included.
Healthy controls were employees from the AMC and were randomly recruited
between December 2012 and January 2013. Healthy controls had to be free of rhinitis
symptoms.

Exclusion criteria
Patients with anatomical deformities or other forms of nasal obstruction, such as
septal deviation, septal perforation, choanal atresia and/or nasal valve collapse or
dysfunction being responsible for nasal obstruction, were excluded. Also, patients 4
with signs of infectious rhinitis (purulent/discoloured discharge, fever) and/or chronic
rhinosinusitis (CRS) with or without nasal polyposis based on nasal endoscopy
(purulent/discoloured discharge, nasal polyps) and/or CT scan were excluded, as were
pregnant patients, patients with nasal/sinus surgery within the previous 3 months, a
serious and/or unstable disease affecting nasal function, unilateral nasal symptoms
and/or patients with a history of immunotherapy.

Questionnaires
Both the mini Rhinoconjunctivitis Quality-of-Life Questionnaire (mini-RQLQ) and
a questionnaire assessing use and success rate of nasal medication were sent to
patients’ home address.

Mini-RQLQ questionnaire
The mini-RQLQ was used to assess quality of life in AR and NAR patients and healthy
controls. This questionnaire was primarily developed to assess QoL in AR and includes
14 questions divided into 5 subdomains assessing daily activities, practical issues,
complaints of nose and eyes.

Validation of the RQLQ for NAR

The psychometric properties of the questionnaire, reliability, validity, responsiveness
and clinically significant change have been described for AR (22). Because sympto-
matology of NAR and AR is quite similar, we expected the content of the mini-RQLQ
to be valid for NAR patients. Internal reliability was measured estimated by calculating
Cronbach’s α. Test-retest reliability was not measured because we did not expect it
to be different from AR patients. We determined convergent construct validity by
comparing the outcomes of the mini-RQLQ in NAR patients to the ARIA classification.

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The discriminant construct validity was determined by comparing the NAR patients
group to healthy controls. The clinically significant change was expected to be compa-
rable to AR and not evaluated separately for the NAR group (13).

Nasal medication questionnaire

To assess the use of nasal medication in NAR and AR, patients completed a question-
naire concerning present and past medication in the last 2 years, assessing number
and type of medication use, rate of improvement of different treatment modalities
and overall treatment satisfaction with current treatment. Patients were asked if they
were on medication at the moment of filling in the questionnaire and/or in the previous
years. Subsequently, they filled in the name of (a) currently used medicament(s) and
-if applicable- the name(s) of medicaments they used in the past. As a supplement,
we attached a list of allergy and nasal drugs in case patients forgot the name of their
medicament. We included space for “description in own words.” Per medicament
patients had to tick a box for “duration of use” and “rate of improvement.” Duration of
use was classified as: incidentally, less than 4 weeks, 1-6 months and more than 6
months. Rate of improvement was classified as: no improvement, small improvement,
large improvement and no more symptoms.

Finally, patients had to tick a box whether they were satisfied or unsatisfied with their
treatment.

Statistics
The Kolmogorov-Smirnov test showed that data of the mini-RQLQ results were
not normally distributed. Therefore, a Mann-Whitney U test was used to compare
mini-RQLQ results between AR and NAR patients and between NAR and healthy
controls. A general linear model (GLM) analysis was performed to assess the influ-
ence of patient characteristics age and sex on outcome results of QoL. Chi-square
test was used to compare AR and NAR nonresponders and responders according to
ARIA classification. Fisher’s exact test was performed to compare type and rate of
improvement of treatment modalities between AR and NAR.

RESULTS

Validation of mini-RQLQ in NAR

Because symptomatology of NAR and AR is quite similar, we expected the content
of the mini-RQLQ to be valid for NAR patients. Non-allergic rhinitis (NAR) patients
indeed had comparable outcomes to AR in the different domains of the questionnaire.
The Cronbach’s α of 0.883 indicated high internal consistency between mini-RQLQ
outcomes within the NAR patient group. A test-retest analysis in 36 patients demon-
strated a Pearson’s correlation coefficient of 0.717 with a significance level of P <

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QUALITY OF LIFE IS SIGNIFICANTLY IMPAIRED IN NON-ALLERGIC RHINITIS PATIENTS

.0001. Previously performed language validation of the (mini-)RQLQ showed that its
Dutch translation is adequately adapted to be used in the Dutch population (23). The
convergent construct validity showed higher values in the mini-RQLQ in patients with
moderate to severe symptoms as defined by the ARIA classification than patients with
mild symptoms. On all subdomains of the mini-RQLQ, NAR patients had significantly
higher outcomes compared to healthy controls (Table 1).

Table 1. Mini-rhinoconjunctivitis quality of life questionnaire (Mini-RQLQ) in non-allergic rhinitis

(NAR) versus healthy controls

NAR, n=160 Healthy, n=49 NAR vs Healthy

Mini – RQLQ Median Mean Median Mean Mann – Whitney
domains (range) (SD) (range) (SD) U test (p)
Activitities 2.67 2.63 0.00 0.46 < 0.0001
(0.00 – 6.00) (1.58) (0.00 – 3.33) (0.84)
Practical problems 3.00
(0.50 – 6.00)
3.04
(1.50)
0.00
(0.00 – 4.50)
0.67
(1.01)
< 0.0001
4
Nose symptoms 2.67 2.84 0.33 0.49 < 0.0001
(0.33 – 6.00) (1.28) (0.00 – 3.00) (0.76)
Eye symptoms 1.00 1.52 0.00 0.35 < 0.0001
(0.00 – 6.00) (1.70) (0.00 – 4.33) (0.76)
Other symptoms 2.17 2.47 0.67 0.71 < 0.0001
(0.00 – 6.00) (1.72) (0.00 – 2.67) (0.79)
Overall 2.36 2.46 0.43 0.53 < 0.0001
(0.29 – 5.64) (1.20) (0.00 – 2.57) (0.62)

Response rate
We selected AR and NAR patients who fulfilled the inclusion and exclusion criteria
based on ENT history and examination from our database of patients who visited
our outpatient clinic with symptoms of rhinitis and/or allergy and who received a skin
prick test. This resulted in 556 allergic rhinitis patients and 329 non-allergic rhinitis
patients. The questionnaires were sent to these patients home address followed by
a reminder a month later. Patients who did not return the questionnaire after the first
postal reminder were repeatedly tried to be reached by postal mail, telephone and/
or email. 31 AR and 19 NAR patients were untraceable (“sample loss”) because of
changed address, telephone number and/or email. In AR 216 and in NAR 108 patients
did not respond (not to the postal questionnaire nor to postal, email, or telephone
reminders). 22 AR and 42 NAR patients refused to participate. Finally, completed
questionnaires of 287 AR (response rate 54.7%) and 160 NAR (response rate 51.6%)
patients were analysed.

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CHAPTER 4

Patient characteristics
Table 2 shows the patient characteristics of both patient groups. Patients with AR
and NAR had a comparable mean age. Distribution by ARIA (Allergic Rhinitis and
its Impact on Asthma) classification concerning duration and severity of symptoms
was also comparable between the two groups. In the NAR group, a significant higher
proportion of patients smoked (21.3% vs 13.9%, P = .046, chi-square test, without Yates
correction). In the AR group, there was a higher proportion of patients with asthma than
in the NAR group (16.4% vs 7.5%, P = .008, chi-square test, without Yates correction).

Table 2. Patient characteristics

NAR, n=160 AR, n=287

Male: female 1: 2.1 1: 1.2
Mean age 47.4 42.4
Smoking (%) 34 (21.3%) 40 (13.9%)
Asthma (%) 12 (7.5%) 47 (16.4%)
ARIA grading Moderate-severe persistent Moderate-severe persistent
115/151 (76.2%) 204/279 (73.1%)
Perennial sensitization Not applicable 218
House dust mite Not applicable 156
Strictly seasonal sensitzation Not applicable 69

Questionnaire outcomes

Mini-RQLQ outcome
Table 3 shows the results of impairment of QoL as assessed by means of the
mini-RQLQ-questionnaire. A higher score means a higher level of impairment indicating
a lower QoL. Non-allergic rhinitis (NAR) patients had an overall trend of having higher
mini-RQLQ scores than AR (P=.053). Non-allergic rhinitis (NAR) patients were signif-
icantly more bothered by nasal complaints. Other complaints such as tiredness and
lack of sleep were also more prominent in NAR patients. A general linear model (GLM)
analysis did not show a significant influence of age and gender on QoL results in both
patient groups. A separate analysis per mini-RQLQ domain comparing NAR and AR
patients is shown in Table 4. Non-allergic rhinitis (NAR) patients have significantly
higher scores for blocked and running nose compared to AR patients.

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QUALITY OF LIFE IS SIGNIFICANTLY IMPAIRED IN NON-ALLERGIC RHINITIS PATIENTS

Table 3. Mini-rhinoconjunctivitis quality of life questionnaire (Mini-RQLQ) in non-allergic rhinitis

(NAR) versus allergic rhinitis (AR)

NAR, n=160 AR, n=287 NAR vs AR

Mini – RQLQ domains Median Mean Median Mean Mann – Whitney
(range) (SD) (range) (SD) U test (p)
Activities 2.67 2.63 2.33 2.39 0.116
(0.00 – 6.00) (1.58) (0.00 – 6.00) (1.68)
Practical problems 3.00 3.04 2.50 2.71 0.056
(0.50 – 6.00) (1.50) (0.00 – 6.00) (1.67)
Nose symptoms 2.67 2.84 2.33 2.49 0.005
(0.33 – 6.00) (1.28) (0.00 – 6.00) (1.52)
Eye symptoms 1.00 1.52 1.33 1.70 0.095
(0.00 – 6.00) (1.70) (0.00 – 6.00) (1.62)
Other symptoms 2.17 2.47 1.67 1.91 0.001
(0.00 – 6.00) (1.72) (0.00 – 6.00) (1.55)
Overall 2.36 2.46 2.07 2.21 0.053 4
(0.29 – 5.64) (1.20) (0.00 – 5.50) (1.24)

Table 4. Mini-rhinoconjunctivitis quality of life questionnaire (mini-RQLQ) domain scores in

non-allergic rhinitis (NAR) versus allergic rhinitis (AR)

NAR (n=160) AR (n=287)

Median Mean Median Mean NAR vs AR
(range) (SD) (range) (SD) Mann-Whit-
ney U test (P)
1. Activities 2.67 2.63 2.33 2.39 0.116
(0.00 – 6.00) (1.58) (0.00 – 6.00) (1.68)
Regular activities at 3.00 2.71 3.00 2.64 0.631
home and at work (0.00 – 6.00) (1.74) (0.00 – 6.00) (1.91)
Recreational 3.00 2.68 2.00 2.47 0.232
activities (0.00 – 6.00) (1.81) (0.00 – 6.00) (1.93)
Sleep 3.00 2.50 2.00 2.06 0.023
(0.00 – 6.00) (2.01) (0.00 – 6.00) (2.08)
2. Practical 3.00 3.04 2.50 2.71 0.056
problems (0.50 – 6.00) (1.50) (0.00 – 6.00) (1.66)
Need to rub nose/ 3.00 2.66 3.00 2.76 0.622
eyes (0.00 – 6.00) (1.88) (0.00 – 6.00) (1.99)
Need to blow nose 3.50 3.42 3.00 2.67 < 0.001
repeatedly (0.00 – 6.00) (1.65) (0.00 – 6.00) (1.87)
3. Nose symptoms 2.67 .84 (1.28) 2.33 2.49 0.005
(0.33 6.00)2 (0.00 6.00) (1.52)
Sneezing 2.00 2.43 2.00 2.50 0.802
(0.00 – 6.00) (1.75) (0.00– 6.00) (1.84)

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CHAPTER 4

Table continued

Stuffy blocked mose 3.00 3.50 3.00 2.80 < 0.001

(0.00 – 6.00) (1.78) (0.00 – 6.00) (2.04)
Runny nose 3.00 2.58 2.00 2.14 0.022
(0.00 – 6.00) (1.94) (0.00 – 6.00) (1.93)
4. Eye symptoms 1.00 1.52 1.33 1.70 0.095
(0.00 6.00) (1.70) (0.00 – 6.00) (1.61)
Itchy eyes 1.00 1.59 2.00 2.09 0.008
(0.00 – 6.00) (1.81) (0.00 – 6.00) (2.00)
Sore eyes 0.00 1.36 0.00 1.42 0.561
(0.00 – 6.00) (1.85) (0.00 – 6.00) (1.89)
Watery eyes 1.00 1.58 1.00 1.57 0.577
(0.00 – 6.00) (2.04) (0.00 – 6.00) (1.85)
5. Other symptoms 2.17 2.47 1.67 1.91 0.001
(0.00 6.00) (1.72) (0.00 – 6.00) (1.55)
Tiredness and/or 3.00 2.99 2.00 2.55 0.022
fatigue (0.00 6.00) (2.00) (0.00 – 6.00) (1.97)
Thirst 2.00 2.19 1.00 1.50 0.001
(0.00 6.00) (2.06) (0.00 – 6.00) (1.81)
Feeling irritable 2.00 2.23 1.00 1.70 0.009
(0.00 6.00) (2.07) (0.00 – 6.00) (1.89)

Medication questionnaire outcome

Table 5 shows the proportion of AR and NAR patients using medication now or in the
past. Non-allergic rhinitis (NAR) patients used significantly less medication than AR
patients. In NAR, 71.6% used only one medicament, 20.9% used two medicaments, and
7.5% used three medicaments. In AR, 60.3% used only one medicament, 27.8% used
two medicaments, and 11.9% used three medicaments. Table 6 shows the four most
frequent used nasal drugs at the moment of filling in the questionnaire for both AR
and NAR. Corticosteroid nasal spray and antihistamine tablets were the most frequent
used drugs in AR, compared to corticosteroid nasal spray and xylometazoline in NAR.
A significant higher proportion of AR patients used anti-histamine tablets compared
to NAR (P = .0001). Treatment satisfaction was not significantly different (Fisher’s
exact test, P = .6588) between AR and NAR. Both AR and NAR patients were not very
satisfied with their current treatment with a treatment satisfaction rate of 43.3% in
NAR and 47.0% in AR.

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QUALITY OF LIFE IS SIGNIFICANTLY IMPAIRED IN NON-ALLERGIC RHINITIS PATIENTS

Table 5. Use of medication

NAR, n = 160 AR, n = 287 Fisher’s Exact

Use of medication Number of patients (%) Number of patients (%) Test (p)

Current use 67 (41.9%) 151 (52.6%) 0.0305

No current use but use of 43 (26.9%) 82 (28.6%) 0.7423
medication last two years
Only use of medication 23 (14.4%) 25 (8.7%) 0.0791
> 2 years ago
Never used medication 27 (16.9%) 29 (10.1%) 0.0518

Table 6. Type of medication

NAR AR Fisher’s
n (% of patients n (% of patients Exact Test
Type of medication currently on medication) * currently on medication) * (p)
4
Corticosteroid nasal spray 57 (85.1%) 107 (70.9%) 0.0273
Xylometazoline 16 (23.9%) 22 (14.6%) 0.1210
Antihistamine tablet 6 (9.0%) 67 (44.4%) 0.0001
Antihistamine nasal spray 2 (3.0%) 4 (2.6%) 1.0000
Other 10 (14.9%) 29 (19.2%) 0.5663

* A proportion of patients used more than one medicament

DISCUSSION
There have been a substantial number of studies assessing several social-economic
aspects, including QoL in AR, in contrast to NAR (24). This is the first study assessing
QoL in NAR patients with a validated questionnaire. Until now, there was no validated
questionnaire to assess QoL in NAR patients. In this study, we performed a valida-
tion of the mini-RQLQ in NAR patients, showing a high discriminant construct validity
(strongly significant higher outcomes in the NAR group compared to healthy controls),
a Cronbach’s alpha indicating strong internal consistency and a high convergent
construct validity by comparing the mini-RQLQ in NAR to the ARIA classification.
Use of the (now validated for NAR) mini-RQLQ questionnaire showed that the QoL in
NAR patients is equally -and for some aspects even more- impaired compared to AR,
emphasizing the need for adequate treatment in NAR.

For the mini-RQLQ subdomains “nasal complaints” and “other complaints” (ie, tired-
ness), NAR scored significantly higher compared to AR. The subdomain “practical
problems” nearly reached significance with a higher burden in NAR. Only, for the subdo-
main “eye complaints,” AR scored slightly higher compared to NAR, as expected.

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CHAPTER 4

One might explain the higher impairment of nasal symptoms, practical problems,
etc. in NAR by the lack of effective treatment options in this patient group, because
of lack of knowledge of underlying pathophysiology. The higher impairment of eye
symptoms in AR can be explained by the fact that allergic conjunctivitis is an intrinsic
feature of AR (19).

Interpretation of these QoL results seems complicated by the fact that not all AR
patients were allergen exposed during the time of completion of the questionnaire.
Unfortunately, this was inevitable because some patients did not respond directly but
after several reminders. However, assessment of mini-RQLQ scores in AR patients
with and without allergen exposure surprisingly did not show significant differences
between the two, not even in strictly seasonal AR patients. This might be influenced
by the fact that around half of patients were using medication at time of filling in the
questionnaire, independent of allergen exposure. Whether patients were not using
medication because of mild symptoms or because of severe symptoms unrespon-
sive to treatment remains an almost impossible question to answer. This study was
combined with an assessment of the use of numbers and types of (nasal) medication
and the (subjective) efficacy of these medications in the different patient groups.

The “use of medication” questionnaire showed that a smaller proportion of NAR

patients use medication for their symptoms compared to AR.

This is likely to be the result of a lack of effective treatment options in this difficult
to treat patient group, also shown in a treatment satisfaction rate of 43.3%. Also,
AR patients have a less than 50% treatment satisfaction. Looking at these results, it
is necessary to keep in mind that we are assessing an academic (thirdline) patient
group, with a risk of selecting more treatment-resistant AR patients. For NAR patients,
it is possible that referral to an ENT clinic will happen sooner when atopy cannot be
demonstrated by the GP and nasal (corticosteroid) spray is unsuccessful. One can
speculate that comparing AR and NAR in a general population, the difference in QoL
and treatment satisfaction will be even larger.

Assessing the numbers of patients using different types of medication, one notices
that most NAR patients end up with the longterm use of a corticosteroid nasal spray. A
proportion of 23.9% of NAR patients admits to use xylometazoline (Table 6). Unknown
is the duration and frequency of use of this medicament in these individuals and
thereby whether one can define these patients as actual “rhinitis medicamentosa.”
Moreover, for some patients, there was a (small) time gap between this ENT assess-
ment at the outpatient clinic and the completion of the questionnaire, allowing a
change in use of medication to take place.

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QUALITY OF LIFE IS SIGNIFICANTLY IMPAIRED IN NON-ALLERGIC RHINITIS PATIENTS

Concluding, these results demonstrate a clinically relevant impairment in both AR and

NAR patients in their QoL combined with a low treatment satisfaction, emphasizing
the need for adequate treatment. This is especially of importance in the NAR patient
group where lack of understanding of its underlying mechanism hampers finding
adequate treatment solutions.

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CHAPTER 4

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19. Kalpaklioglu AF et al. Allergic and nonallergic rhinitis: can we find the differences/
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CHAPTER 5
Intranasal corticosteroids
for non‐allergic rhinitis
 C. Segboer
A. Gevorgyan
K. Avdeeva
S. Chusakul
J. Kanjanaumporn
S. Aeumjaturapat
L. Reeskamp
K. Snidvongs
W. Fokkens

Cochrane Database Syst Rev. 2019 Nov; 2;(11)

CHAPTER 5

ABSTRACT

Background
Non-allergic rhinitis is defined as a dysfunction and non-infectious inflammation of the
nasal mucosa that is caused by provoking agents other than allergens or microbes.
It is common, with an estimated prevalence of around 10% to 20%. Patients experi-
ence symptoms of nasal obstruction, anterior rhinorrhoea/post-nasal drip and
sneezing. Several subgroups of non-allergic rhinitis can be distinguished, depending
on the trigger responsible for symptoms; these include occupation, cigarette smoke,
hormones, medication, food and age. On a cellular molecular level different disease
mechanisms can also be identified. People with non-allergic rhinitis often lack an effec-
tive treatment as a result of poor understanding and lack of recognition of the under-
lying disease mechanism. Intranasal corticosteroids are one of the most common
types of medication prescribed in patients with rhinitis or rhinosinusitis symptoms,
including those with non-allergic rhinitis. However, it is unclear whether intranasal
corticosteroids are truly effective in these patients.

Objectives
To assess the effects of intranasal corticosteroids in the management of non-allergic
rhinitis.

Search methods
The Cochrane ENT Information Specialist searched the Cochrane ENT Register;
Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 7); PubMed; Ovid
Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for
published and unpublished trials. The date of the search was 1 July 2019.

Selection criteria
Randomised controlled trials (RCTs) comparing intranasal corticosteroids, delivered
by any means and in any volume, with (a) placebo/no intervention or (b) other active
treatments in adults and children (aged ≥ 12 years).

Data collection and analysis

We used the standard methodological procedures expected by Cochrane. The primary
outcomes were patient-reported disease severity and a significant adverse effect
epistaxis. Secondary outcomes were (disease-specific) health-related quality of life,
objective measurements of airflow and other adverse events. We used GRADE to
assess the certainty of the evidence for each outcome.

Main results
We included 34 studies (4452 participants); however, only 13 studies provided data
for our main comparison, intranasal corticosteroids versus placebo. The participants

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

were mainly defined as patients with perennial rhinitis symptoms and negative allergy
tests. No distinction between different pheno- and endotypes could be made, although
a few studies only included a specific phenotype such as pregnancy rhinitis, vasomotor
rhinitis, rhinitis medicamentosa or senile rhinitis. Most studies were conducted in a
secondary or tertiary healthcare setting. No studies reported outcomes beyond three
months follow-up. Intranasal corticosteroid dosage in the review ranged from 50 µg
to 2000 µg daily.

Intranasal corticosteroids versus placebo
Thirteen studies (2045 participants) provided data for this comparison. These studies
used different scoring systems for patient-reported disease severity, so we pooled
the data in each analysis using the standardised mean difference (SMD). Intranasal
corticosteroid treatment may improve patient-reported disease severity as measured
by total nasal symptom score compared with placebo at up to four weeks ­(SMD
-0.74, 95% confidence interval (CI) -1.15 to -0.33; 131 participants; 4 studies; I2 = 22%)
(low-certainty evidence). Between four weeks and three months the evidence is
very uncertain (SMD -0.24, 95% CI -0.67 to 0.20; 85 participants; 3 studies; I2  = 0%)
(very low-certainty evidence). Intranasal corticosteroid treatment may not mprove 5
patient-reported disease severity as measured by total nasal symptom score change
from baseline when compared with placebo at up to four weeks (SMD -0.54, 95% CI
-1.18 to 0.10); 1465 participants; 4 studies; I2 = 96%) (low-certainty evidence).

All four studies evaluating the risk of epistaxis showed there is probably a higher risk
in the intranasal corticosteroids group (65 per 1000) compared to placebo (31 per
1000) (risk ratio (RR) 2.10, 95% CI 1.24 to 3.57; 1174 participants; 4 studies; I2  = 0%)
(­moderate-certainty evidence). The absolute risk difference (RD) was 0.04 with
a number needed to treat to harm (NNTH) of 25 (95% CI 16.7 to 100).

Only one study reported numerical data for quality of life. It did report a higher quality
of life score in the intranasal corticosteroids group (152.3 versus 145.6; SF-12v2 range
0 to 800); however, this disappeared at longer-term follow-up (148.4 versus 145.6)
(low-certainty evidence).

Only two studies provided data for the outcome objective measurements of airflow.
These data could not be pooled because they used different methods of outcome
measurement. Neither found a significant difference between the intranasal corti-
costeroids and placebo group (rhinomanometry SMD -0.46, 95% CI -1.06 to 0.14; 44
participants; peak expiratory flow rate SMD 0.78, 95% CI -0.47 to 2.03; 11 participants)
(very low-certainty evidence).

89
CHAPTER 5

Intranasal corticosteroids probably resulted in little or no difference in the risk of other

adverse events compared to placebo (RR 0.99, 95% CI 0.87 to 1.12; 1130 participants;
3 studies; I2 = 0%) (moderate-certainty evidence).

Intranasal corticosteroids versus other treatments

Only one or a few studies assessed each of the other comparisons (intranasal corti-
costeroids versus saline irrigation, intranasal antihistamine, capsaicin, cromoglycate
sodium, ipratropium bromide, intranasal corticosteroids combined with intranasal
antihistamine, intranasal corticosteroids combined with intranasal antihistamine and
intranasal corticosteroids with saline compared to saline alone). It is therefore uncer-
tain whether there are differences between intranasal corticosteroids and other active
treatments for any of the outcomes reported.

Authors’ conclusions
Overall, the certainty of the evidence for most outcomes in this review was low or very
low. It is unclear whether intranasal corticosteroids reduce patient-reported disease
severity in non-allergic rhinitis patients compared with placebo when measured at up
to three months.

However, intranasal corticosteroids probably have a higher risk of adverse effects such
as epistaxis. There are very few studies comparing intranasal corticosteroids to other
treatment modalities making it difficult to draw conclusions.

PLAIN LANGUAGE SUMMARY

Intranasal corticosteroids for non-allergic rhinitis

Review question
We wanted to find out whether intranasal corticosteroids (steroids applied into the
nose) are effective for the treatment of rhinitis that is not caused by allergy.

Background
Non-allergic rhinitis is a chronic disease of the nose, which is not caused by infection
or allergies. People with non-allergic rhinitis experience symptoms that affect their
quality of life, such as nasal obstruction, runny nose and sneezing. Non-allergic rhinitis
patients can be divided into different subgroups who have different underlying causes
for their disease. The underlying causes of non-allergic rhinitis are not fully understood,
therefore treatment is often unsuccessful in these patients.

Topical (intranasal) corticosteroids are used with the aim of reducing inflammation.
They are the most commonly prescribed drug in other chronic diseases of the nose

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

and sinuses, such as allergic rhinitis and chronic rhinosinusitis. Intranasal corticos-
teroid treatment can be delivered with sprays or drops and for different time periods.

Study characteristics
We included 34 randomised controlled trials (RCTs) with a total of 4452 participants
in this review. Most of the studies were relatively small, although the largest study
had 983 patients in total. All of the patients were either adults or adolescents (aged
between 12 and 18 years old) with non-allergic rhinitis. The studies looked at a range
of types, doses and methods of administration (e.g. spray, drops) of intranasal corti-
costeroids. Nine studies were sponsored by the pharmaceutical industry or had
commercial sponsors. One study was funded by the government. In several studies,
the pharmaceutical industry or commercial sponsor may have provided medications,
but the funding role was unclear. Funding was not reported in eight studies.

Key results

Intranasal corticosteroids compared with placebo

It is uncertain whether intranasal corticosteroids reduce patient-reported disease 5
severity in non-allergic rhinitis patients compared with placebo when measured at
up to three months. They may improve patient-reported disease severity compared
with placebo at up to four weeks, however evidence is of low certainty. Treatment with
intranasal corticosteroids probably increases the risk of epistaxis (nosebleed) but there
is no difference in the risk of other adverse effects. It is not possible to tell from this
review whether there is a difference between the different concentrations, delivery
methods or treatment plans of intranasal corticosteroids. There are no good-quality
studies assessing changes in quality of life with intranasal corticosteroids.

Intranasal corticosteroids compared with other treatments

There is not enough evidence to know whether intranasal corticosteroid treatment is
better, worse or the same as using other treatment strategies such as saline irrigation,
intranasal antihistamines, capsaicin or ipratropium bromide for non-allergic rhinitis.

Certainty of the evidence

Overall, the evidence for intranasal corticosteroids compared with placebo for most
outcomes  was either low-certainty (our confidence in the effect estimate is low)
or very low-certainty (our confidence in the effect estimate is very low). This was
because most studies were very small and used different methods to measure the
same outcome. This evidence is up to date to July 2019.

91
 Summary of findings

92
Intranasal corticosteroids compared to placebo for non-allergic rhinitis

Intranasal corticosteroids compared to placebo for non-allergic rhinitis

CHAPTER 5

Patient or population: adults and children > 12 with non-allergic rhinitis

Setting:   secondary/tertiary health care
Intervention: intranasal corticosteroids
Comparison: placebo
Outcomes Anticipated absolute Relative № of partici- Certainty Comments
effects* (95% CI) effect pants of the
Risk Risk with intra- (95% CI) (studies) evidence
with nasal corticoste- (GRADE)
placebo roids
Disease Fol- — SMD 0.74 lower — 131 Intranasal corticosteroids may improve patient-­
severity as low-up ≤ (1.15 lower to 0.33 (4 RCTs) low1 reported disease severity at a follow-up of up to 4
⊕⊕⊝⊝

mesured 4 weeks lower) weeks compared to placebo. The mean difference in

by disease severity score was 0.74 standard deviations
patient- lower (1.15 lower to 0.33 lower) with intranasal corti-
reported costeroids compared to placebo. This represents a
symptom medium effect size (Cohen 1988).
score Fol- — SMD 0.24 lower — 85 It is uncertain whether intranasal corticosteroids
(total nasal low-up > (0.67 lower to 0.20 (3 RCTs) very low2 improve patient-reported disease severity with a
⊕⊝⊝⊝

symptom 4 weeks higher) follow-up of more than 4 weeks compared to placebo,

score) because the certainty of the evidence is very low.
Change — SMD 0.15 lower — 1465 Intranasal corticosteroids may slightly improve pa-
from (0.25 lower to 0.05 (4 RCTs) low3 tient-reported disease severity change from base- line
⊕⊕⊝⊝

baseline lower) with a follow-up of up to 4 weeks compared

Fol- to placebo. The SMD of 0.15 represents a small ef-fect
low-up ≤ size. There are two large studies (Jacobs 2009; Webb
4 weeks 2002). Jacobs 2009 reports with a high degree of
certainty a small improvement in favour of intranasal
corticosteroids. Webb 2002 reports a less certain
clinically relevant improvement in favour of intranasal
corticosteroids. Jacobs 2009 has an adjusted SD
value (presented SD are most likely SEM).
 Significant adverse Study population RR 2.10 1174 There is probably a higher risk of epistaxis with intra-
event: epistaxis (31 per 65 per 1000 (1.24 to (4 RCTs) moderate4 nasal steroids compared to placebo.
⊕⊕⊕⊝

Follow-up: 2 weeks to 1000) (39 to 111) 3.57)

33 days
Disease-specific Just one study reported quality of life 49 (1 RCT) There is not enough information (1 study) to conclude
health-related quality (Lin 2017). Quality of life was better in the low5 whether there is a difference.
⊕⊕⊝⊝

of life intranasal corticosteroids group versus

Short Form 12 (SF- the placebo group, however while this
12v2) (range 0 to 800) difference was significant at a follow-up
Follow-up: 1 month to of 1 month (152.3 versus 145.6) it was
3 months barely noticeable at a follow-up of 3
months (148.4 versus 145.6).
Objective measure- Just 2 studies reported objective mea- 55 There is not enough information (2 studies with differ-
ment of airflow: peak surement of airflow (Malm 1981; Spector (2 RCTs) very low6 ent methods of measurement) to conclude whether
⊕⊝⊝⊝

flow rate (expiratory) 1980). However, they used different there is a difference.
Follow-up: 2 weeks to outcome measurements to measure
4 weeks outflow: rhinomanometry and expiratory
peak flow rate (PEFR). Neither found a
significant difference between groups:
rhinomanometry (Malm 1981) (SMD
-0.46, 95% CI -1.06 to 0.14; 44 partici-
pants); PEFR (Spector 1980) SMD 0.78,
95% CI -0.47 to 2.03; 11 participants).
Other adverse events Study population RR 0.99 1130 Intranasal corticosteroids probably result in little or no
Follow-up: 1 month to 454 per 450 per 1000 (0.87 to (3 RCTs) moderate7 difference in the risk of other adverse events com-
⊕⊕⊕⊝

6 weeks 1000 (395 to 509) 1.12) pared to placebo.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the
intervention (and its 95% CI).
CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; SD: standard deviation; SEM: standard error of the mean; SMD: standardised mean
difference
INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

93
5
94
GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a
possibility that it is substantially different.
CHAPTER 5

Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
1
Due to the small sample size we downgraded once for imprecision and once due to the risk of publication bias. The I2 value in this pooled analysis was 22%
so there was no reason to downgrade for heterogeneity.
2
We downgraded twice for serious imprecision due to the small sample size and because the confidence interval includes both meaningful benefit and
harm. We downgraded once for risk of publication bias due to the small sample size.
3
We downgraded twice for serious inconsistency because the I2 value is 96% and the confidence intervals for Jacobs 2009 and Webb 2002 do not
overlap. Jacobs 2009 has an unlikely SD value, which does not match the mean, n and P values. It is likely that the SD value presented should actually be a
standard error of the mean (SEM).
4
We downgraded once due to study limitations (risk of bias) because there were unclear blinding domains, which could have influenced the significant
adverse events (epistaxis) outcome. The I2value in this pooled analysis is 0% so there is no reason to downgrade for heterogeneity. We judged that there
were no other reasons to downgrade.
5
Due to the small sample size we downgraded once for imprecision and once due to the risk of publication bias.
6
We downgraded once for inconsistency (when the two studies are combined the I2 value is 67%). The two studies used different methods for measuring
objective airflow, which contributed to the heterogeneity. Due to the small sample size we downgraded once for imprecision and once due to the risk of
publication bias.
7
We downgraded once due to study limitations (risk of bias) as there were unclear blinding domains, which could have influenced the adverse events
outcome. The I2 value in the pooled analysis is 0% so there is no reason to downgrade for heterogeneity. We judged that there were no other reasons to
downgrade.
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

BACKGROUND

Description of the condition

Chronic rhinitis (allergic and non-allergic) affects up to 30% to 40% of the general
population (Bousquet 2008). Non-allergic rhinitis is diagnosed when anatomic, infec-
tious and allergic aetiologies are excluded and symptoms have been present for
more than 12 weeks. The symptoms include nasal congestion, clear rhinorrhoea,
sneezing and, less frequently, nasal itching. It is common, with an estimated preva-
lence of around 10% to 20% (Bachert 2008). Most epidemiological studies report
that 25% to 50% of chronic rhinitis patients can be categorised as having non-allergic
rhinitis (Fokkens 2002), with a worldwide estimated prevalence of 200 to 400 million
people (Bousquet 2008a). Most studies agree on a female predominance (Knudsen
2009; Molgaard 2007). A recent study has shown that quality of life is significantly
impaired in people with non-allergic rhinitis and this impairment is equal to that in
people with allergic rhinitis (Segboer 2018). Around 60% of non-allergic rhinitis patients
develop non-allergic asthma (Hellings 2017).

Within non-allergic rhinitis one can differentiate several phenotypes: environmental 5

(occupational, smoking), hormonal (e.g. pregnancy), gustatory, age (rhinitis of the
elderly), medication-induced and inflammatory (non-allergic rhinitis with eosinophilia
syndrome (NARES) or local allergic rhinitis) (Hellings 2017; Papadopoulos 2015). In
local allergic rhinitis, patients have the clinical characteristics of allergic rhinitis and
an allergen sensitisation but no systemic signs of atopy. NARES patients have high
numbers of eosinophils in their nasal mucosa and can have micro-polyposis, hyposmia
and signs of bronchial hyper-responsiveness in a limited way, comparable to patients
with chronic rhinosinusitis. The prevalence rates of these different phenotypes are
unknown.

Environmental (occupational (chemical) and smoking) rhinitis can be clearly linked to

an affecting agent. In close to 60% of cases, occupational rhinitis can be associated
with occupational asthma (Ameille 2013). Smoking is considered a specific irritant of
the nasal mucosa, which can cause non-allergic rhinitis (van Rijswijk 2005). Hormonal
rhinitis can occur during the menstrual cycle and puberty, due to hypothyroidism or
acromegaly, as well as during pregnancy, where it resolves postpartum. Gustatory
rhinitis is accompanied by oversecretion of nasal mucus in response to irritating gusta-
tory agents, usually spicy foods (Waibel 2008). Rhinitis of the elderly (senile rhinitis)
is encountered in the older generation and characterised by the presence of constant
rhinorrhoea and lack of other nasal complaints.

In the case of medication-induced rhinitis (rhinitis medicamentosa), several medica-

tions have been implicated (Varghese 2010). The most common is the misuse of
topical sympathomimetics (e.g. oxyor xylometazoline) for more than 10 days, resulting

95
CHAPTER 5

in dysregulation of the adrenergic receptors in the nasal mucosa and a relative increase
of the parasympathetic drive, leading to significant rhinorrhoea and nasal obstruction.
These symptoms cause the patients to continue using topical adrenergics, perpetu-
ating a vicious cycle. Treatment is usually focused on cessation of the affecting agent,
as well as support with intranasal corticosteroids.

In terms of the pathophysiological mechanisms, neurogenic, inflammatory and

idiopathic endotypes can be distinguished. Two phenotypes clearly belong to the
inflammatory endotype: local allergic rhinitis and non-allergic rhinitis with eosino-
philia syndrome (NARES). Within the neurogenic endotype, neurogenic dysbalance
(for example, senile rhinitis) and neurogenic inflammation (for example, idiopathic
rhinitis) can be differentiated.

Local allergic rhinitis is diagnosed when skin prick and serum specific IgE testing
are negative, however a nasal allergen provocation test is positive (Rondon 2012a).
A recent report attributed over a quarter of chronic rhinitis patients to local allergic
rhinitis (Rondon 2012b). NARES is considered in the presence of rhinitis symptoms,
no evidence of allergy and more than 20% eosinophilia on nasal smears (Ellis 2007).
Its pathophysiology is poorly understood, but is thought to involve a local, self-­
perpetuating nasal inflammation with eosinophilia (Groger 2012). Idiopathic rhinitis
has for a long time remained a diagnosis of exclusion, when the other causes of rhinitis
have been ruled out (Burns 2012). Its suggested pathophysiology includes chronic
inflammation of an antigenic or neurogenic nature (van Rijswijk 2005).

In explaining non-allergic rhinitis to patients, doctors have often referred to the concept
of nasal hyper-reactivity. For that reason, non-allergic rhinitis or idiopathic rhinitis was
also called vasomotor rhinitis in the past. However, recent literature shows us that
nasal hyper-reactivity is a common symptom in both allergic and non-allergic rhinitis.
The terminology of vasomotor rhinitis is therefore no longer used.

Treatment of non-allergic rhinitis includes trigger avoidance, topical and systemic

medications, and surgery. When rhinitis is caused by a known aetiologic factor, such
as smoking or chemical exposure, the mainstay of treatment is trigger avoidance.

Several medications are widely utilised in the treatment of non-allergic rhinitis,

including oral and topical nasal antihistamines, intranasal and (rarely) systemic corti-
costeroids, and anticholinergics (ipratropium bromide). Other medical options include
capsaicin, intranasal injection of botulinum toxin type A, intranasal saline rinse, local
and systemic sympathomimetics and cromolyn sodium. The exact mechanisms of
effect of these therapies in non-allergic rhinitis remain largely unknown.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Some medications are particularly useful in specific types of non-allergic rhinitis.

Specifically, ipratropium bromide is mostly used in the treatment of rhinitis of the
elderly, due to its alleviation of the main symptom, rhinorrhoea (van Rijswijk 2005).
Intranasal antihistamines are usually prescribed when sneezing is the main symptom
of non-allergic rhinitis (Schroer 2012). Capsaicin (8-methyl-N-vanillyl-6-nonenamide),
the active component of chili peppers, appears to have a therapeutic effect in idiopathic
rhinitis, based on several randomised controlled trials (van Rijkwijk 2003, Ciabatti
2009).

Surgical reduction can be considered to treat inferior turbinate hypertrophy, when

it contributes to nasal obstruction and mucosal hypersecretion in chronic rhinitis
(Garzaro 2012). Vidian neurectomy, causing denervation of the autonomic supply of
the nasal mucosa, can reduce the symptoms of rhinorrhoea and nasal obstruction
(Robinson 2006).

Description of the intervention

Topical (local) intranasal corticosteroids are administered as nasal sprays or drops.
Intranasal corticosteroids act locally on the nasal mucosa, eliciting anti-inflammatory 5
and immunosuppressant effects, while mostly avoiding the systemic side effects of
corticosteroids (Bruni 2009; Emin 2011; Mizrachi 2012).

Currently available intranasal corticosteroid preparations include the earlier generation

medications beclomethasone dipropionate, triamcinolone acetonide, flunisolide and
budesonide, and the newer preparations fluticasone propionate, fluticasone furoate
and mometasone furoate. They differ in their local potency, lipid solubility, bioavaila-
bility, and local and systemic side effects.

The local side effects of intranasal corticosteroids include epistaxis (5% to 10%), nasal
irritation (5% to 10%, including dryness, burning and stinging), headache, nasal septal
perforation (< 1%), candida infection of the nose and pharynx, and impaired wound
healing after recent nasal surgery or trauma (Merck 2012).

How the intervention might work

Corticosteroids have immunosuppressant and anti-inflammatory effects, modifying
and reducing inflammation through suppression of the synthesis of ­pro-­inflammatory
cytokines and pro-inflammatory enzymes, inhibiting lymphocyte proliferation and
chemotaxis (Mygind 2001).

The local pharmacology of intranasal corticosteroids is connected with absorption

characteristics (lipid solubility), topical potency (receptor-binding ability) and systemic
bioavailability (Benninger 2003). The delivery mechanism (sprays versus drops) can
also influence local drug concentration and its subsequent metabolism.

97
CHAPTER 5

In allergic rhinitis, optimal therapeutic efficacy can be achieved after daily use of intra-
nasal corticosteroids for two weeks (Bousquet 2008). However, it is unknown when
optimal therapeutic efficacy in non-allergic rhinitis can be achieved.

Intranasal corticosteroids are likely to work better for the inflammatory endotypes of
non-allergic rhinitis, i.e. NARES and LAR (Mygind 2001).

Why it is important to do this review

Establishing the clinical effectiveness of intranasal corticosteroids in non-allergic
rhinitis could have important clinical implications. Several well-conducted randomised
controlled trials have evaluated intranasal corticosteroids for non-allergic rhinitis. Most
of these studies have small numbers of participants and variations in the included
non-allergic rhinitis phenotypes, as well as variations in the dosages and schedule of
intranasal corticosteroid administration. However, there are no reported meta-analyses
on this topic.

This review aims to assess the evidence for the use of intranasal corticosteroids in
non-allergic rhinitis, to define the responsive subgroups and, specifically, to establish
the most advantageous dosing and scheduling regimens.

OBJECTIVES

To assess the effects of intranasal corticosteroids in the management of non-allergic

rhinitis.

METHODS

Criteria for considering studies for this review

Types of studies
We included studies with the following design characteristics:

• Randomised controlled trials (RCTs), including cluster-randomised and cross-over

trials (cross-over trials were only to be included if the data from the first phase
were available); and
• Patients were followed up for at least two weeks.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

We excluded studies with the following design characteristics:

• Randomised patients by side of nose (within-patient controlled) because it is
difficult to ensure that the effects of any interventions considered can be localised;
or
• Peri-operative studies.

Types of participants
Adults and children ≥ 12 years with all phenotypes of non-allergic rhinitis. We consider
patients 12 years of age and above to have the same phenotype as adults. We included
studies in which participants with perennial rhinitis were enrolled when it was possible
to extract data for those participants with non-allergic rhinitis.

We excluded studies that included a majority of patients with:

• llergic rhinitis;
A
• Infectious rhinitis;
• Acute or chronic rhinosinusitis;
• Auto-immune rhinitis; 5
• Rhinitis related to anatomical abnormalities.

Types of interventions
Intervention
We included all intranasal corticosteroids in nasal spray and nasal drops form, at any
dose and frequency, and for any duration.

First-generation intranasal corticosteroids:

• Beclomethasone dipropionate
• Triamcinolone acetonide
• Flunisolide
• Budesonide

Second-generation intranasal corticosteroids:

• Fluticasone furoate
• Fluticasone propionate
• Mometasone furoate
• Betamethasone sodium phosphate
• Ciclesonide

If other interventions (for example, decongestants) were used, these must have been
used equally in all treatment arms.

99
CHAPTER 5

Comparisons
The comparators were placebo or no intervention or other active treatments.

The main comparison pair was:

• Intranasal corticosteroids versus placebo

Other possible comparison pairs included:

• Intranasal corticosteroids versus saline irrigation
• Intranasal corticosteroids versus intranasal antihistamine
• Intranasal corticosteroids versus capsaicin
• Intranasal corticosteroids versus sodium cromoglycate
• Intranasal corticosteroids versus ipratropium

Types of outcome measures

Primary outcomes
• Disease severity as measured by patient-reported symptom score (such as a total
nasal symptom score (TNSS) or visual analogue scale (VAS))
• Significant adverse event: epistaxis

Secondary outcomes
• Disease-specific health-related quality of life (using disease-specific health-related
quality of life questionnaires scores such as the Rhinoconjunctivitis Quality of Life
Questionnaire (RQLQ and the Mini Rhinoconjunctivitis Quality of Life Questionnaire
(mini-RQLQ))
• Inspiratory peak flow levels, rhinomanometry or other objective measurements
of airflow
• Other adverse events: for example, local irritation/discomfort

Outcomes were measured at follow-up time points of ≤ 4 weeks and > 4 weeks.

Search methods for identification of studies

The Cochrane ENT Information Specialist conducted systematic searches for
randomised controlled trials and controlled clinical trials. There were no language,
publication year or publication status restrictions. The date of the search was 1 July
2019.

Electronic searches
The Information Specialist searched:

• he Cochrane ENT Register (searched via the Cochrane Register of Studies 1 July
T
2019)

100
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

• he Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 7)

T
(searched via the Cochrane Register of Studies 1 July 2019)
• PubMed (1946 to 1 July 2019)
• Ovid EMBASE (1974 to 1 July 2019)
• EBSCO CINAHL (1982 to 1 July 2019)
• Ovid CAB Abstracts (1910 to 1 July 2019)
• L ILACS (Latin American and Caribbean Health Science Information

database), lilacs.bvsalud.org (searched 1 July 2019)
• Web of Science (1945 to 1 July 2019)
• ClinicalTrials.gov (searched via the Cochrane Register of Studies and clinicaltrials.
gov 1 July 2019)
• World Health Organization (WHO) International Clinical Trials Registry Platform
(ICTRP), www.who.int/ictrp (searched 1 July 2019)

The Information Specialist modelled subject strategies for databases on the search
strategy designed for CENTRAL. Where appropriate, they were combined with subject
strategy adaptations of the highly sensitive search strategy designed by Cochrane for
identifying randomised controlled trials and controlled clinical trials (as described in 5
the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box
6.4.b. (Handbook 2011). Search strategies for major databases including CENTRAL
are provided in Appendix 1.

Searching other resources

We scanned the reference lists of identified publications for additional trials and
contacted trial authors where necessary. In addition, the Information Specialist
searched PubMed to retrieve existing systematic reviews relevant to this systematic
review, so that we could scan their reference lists for additional trials. The Information
Specialist also ran non-systematic searches of Google Scholar to retrieve grey litera-
ture and other sources of potential trials.

We did not perform a separate search for adverse effects of intranasal steroids. We
considered adverse effects described in the included studies only.

Data collection and analysis

Selection of studies
We merged the identified studies using the Covidence online reference management
software. We removed any duplicate records of the same report.

Two authors (AG and CS, a rhinology fellow and a junior otorhinolaryngology trainee,
respectively) independently examined the titles and abstracts of the studies and
removed obviously irrelevant reports. We then retrieved the full texts of potentially

101
CHAPTER 5

relevant articles. We linked multiple reports of the same study together. The same two
authors independently examined the full-text reports for compliance of the studies
with the eligibility criteria. We contacted the study authors, where appropriate, to clarify
study eligibility. The two authors then independently made final decisions on study
inclusion. Any disagreements on study inclusion were resolved by discussion. If neces-
sary, disagreement was resolved by arbitration of a third author (KS). We noted the
primary reason for exclusion.

Data extraction and management

Two authors (AG and CS) independently extracted the data with a predetermined data
collection form (Appendix 2). We piloted the form on a small number of studies to
identify any discrepancies in coding. If there were multiple reports of the same study,
each author collected data separately from each report and then we collated this into a
single study report. Disagreements were again resolved by discussion, with arbitration
by a third author (KS) if necessary.

For dichotomous outcomes, we extracted the numbers in each of the two outcome
categories in each of the intervention groups, or odds ratio, or risk accompanied by
measures of uncertainty (e.g. standard error, 95% confidence interval or an exact
P value). For continuous outcomes, we extracted the mean value of the outcome
measurements in each intervention group, respective standard deviation and number
of participants. If the data were presented in another format, we made appropriate
calculations and/or transformations according to the Cochrane Handbook for System-
atic Reviews of Interventions (Handbook 2011). We extracted ordinal outcomes and
outcomes presented as counts in the form reported in the original studies.

Assessment of risk of bias in included studies

AG and CS undertook assessment of the risk of bias of the included studies
independently, with the following taken into consideration, as guided by the Cochrane
Handbook for Systematic Reviews of Interventions (Handbook 2011):

• Sequence generation
• Allocation concealment
• Blinding
• Incomplete outcome data
• Selective outcome reporting and
• Other sources of bias

We used the Cochrane ‘Risk of bias’ tool in RevMan 5 (RevMan 2014), which involved
describing each of these domains as reported in the trial and then assigning a judge-
ment about the adequacy of each entry: ‘low’, ‘high’ or ‘unclear’ risk of bias.

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Measures of treatment effect

We calculated a weighted treatment effect across studies using RevMan 5 (RevMan
2014). For dichotomous outcomes, we calculated risk ratios (RR) after appropriate
conversions. For continuous outcomes, we calculated a mean difference (MD) or
a standardised mean difference (SMD) as appropriate. We analysed longer ordinal
scales (e.g. visual analogue scale (VAS) scores) as continuous data, using MD or
SMD. As suggested in the Cochrane Handbook for Systematic Reviews of Interven-
tions (Handbook 2011), we used standard rules of thumb in the interpretation of SMD
effect sizes (SMD, or Cohen’s effect size of < 0.41 = small, 0.40 to 0.70 = moderate,
> 0.70 = large) (Cohen 1988). We analysed short ordinal scales as dichotomous data
(using RR), combining adjacent scores together whenever it was possible to find an
appropriate cut-off point. We treated more frequent count data as continuous. We
expressed pooled treatment effects with their 95% confidence intervals (95% CI) for
all types of data.

Unit of analysis issues

We determined appropriate units of analysis from the included studies and presented
them in the results. We analysed cluster-randomised trials based on the level of alloca- 5
tion, i.e. clusters of patients. Cross-over trials were only included if the data from the
first phase were available.

Dealing with missing data

We recorded all missing data on the data collection form and reported this in the ‘Risk
of bias’ tables. Whenever possible, we contacted the original investigators to request
missing data and information for our risk of bias assessments.

Imputing total symptom scores

We planned to adopt the strategy outlined by Chong et al to deal with missing total
disease severity outcomes (Chong 2016). Where a paper did not present information
for the total disease severity in terms of patient-reported symptom scores but did
present data for the results of individual symptoms, we used the symptoms rhinor-
rhoea, blockage and sneezing to calculate a total symptom score. Where mean
final values or changes from baseline were presented in the paper for the individual
symptoms we summed these to calculate a ‘total symptom score’. We calculated
standard deviations for the total symptom score as if the symptoms were independent,
random variables that were normally distributed. We acknowledge that there is likely
to be a degree of correlation between the individual symptoms, however we used
this process because the magnitude of correlation between the individual symptoms
is not currently well understood (no evidence found). If the correlation is high, the
summation of variables as discrete variables is likely to give a conservative estimate
of the total variance of the summed final score. If the correlation is low, this method of
calculation will underestimate the standard deviation of the total score. However, the

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average patient-reported symptom scores have a correlation coefficient of about 0.5;

if this is also applicable to non-allergic rhinitis, the method used should have minimal
impact (Balk 2012). As this method of calculation does not take into account weighting
of different symptoms (no evidence found), we downgraded all the disease severity
outcomes for lack of use of validated scales whenever this occurred.

Assessment of heterogeneity
To assess the heterogeneity of effect size across pooled studies, we calculated the
I2 statistic in RevMan 5. We did not plan to perform a meta-analysis if heterogeneity
was considered substantial (50% to 90%) or considerable (75% to 100%), but because
the study Jacobs 2009 is one of the most well-known and largest studies on the topic,
we decided to include this study in the meta-analysis (with a random-effects model)
although this results in high (I2 = 96%) heterogeneity. The most likely reason for this
high heterogeneity is explained in detail in the Results section.

Assessment of reporting biases

We had planned to use a funnel plot to detect reporting biases if there were at least
10 studies included in the meta-analysis and to analyse the visual asymmetry of the
plot. However, none of our meta-analyses included more than 10 studies.

Data synthesis
We used RevMan 5 to perform a meta-analysis using the random-effects model if we
did not consider the heterogeneity of the included studies to be substantial or consid-
erable. We performed a meta-analysis of studies that were sufficiently homogenous
in terms of participants, treatments and outcome measures. When a meta-analysis
could not be performed due to the level of heterogeneity, we provided a narrative
analysis. We analysed the data on an intention-to-treat basis using the generic inverse
variance method. We made comparisons for all available outcomes between intranasal
corticosteroids and no therapy, intranasal corticosteroids and placebo, intranasal corti-
costeroids and other topical or systemic medications, intranasal corticosteroids and
two or more of the above therapies in combination, and between different intranasal
corticosteroids regimens (dose, frequency or duration comparisons, if available).

Subgroup analysis and investigation of heterogeneity

We performed subgroup analysis to compare the effects of intranasal corticosteroids:

• Different types of intranasal corticosteroids (type A versus type B)

The following subgroup analyses were planned but not conducted due to insufficient
data.

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• ifferent types of non-allergic rhinitis (e.g. rhinitis medicamentosa, pregnancy

D
rhinitis)
• Different doses of intranasal corticosteroids (dose A versus dose B, e.g. 200 μg
versus 400 μg/day budesonide)
• Different regimens of intranasal corticosteroids (regimen A versus regiment B,
e.g. once a day versus twice a day)
• Different delivery devices for intranasal corticosteroids (device A versus device B)

Sensitivity analysis
We carried out sensitivity analyses on the basis of the methodological diversity of the
included studies. We considered the following factors when repeating the analysis:

• isk of bias: excluding studies with high risk of bias (defined as four out of seven
R
domains deemed to have high risk)

GRADE and ‘Summary of findings’ table

Two authors (CS, AG) independently used the GRADE approach to rate the overall
certainty of evidence for each outcome using the GDT tool (https://gradepro.org/). The 5
certainty of evidence reflects the extent to which we are confident that an estimate
of effect is correct and we applied this in the interpretation of results. There are four
possible ratings: ‘high’, ‘moderate’, ‘low’ and ‘very low’. A rating of ‘high’ certainty
evidence implies that we are confident in our estimate of effect and that further
research is very unlikely to change our confidence in the estimate of effect. A rating
of ‘very low’ certainty implies that any estimate of effect obtained is very uncertain.

The GRADE approach rates evidence from RCTs that do not have serious limitations as
high certainty. However, several factors can lead to the downgrading of the evidence
to moderate, low or very low. The degree of downgrading is determined by the serious-
ness of these factors:

• tudy limitations (risk of bias)

S
• Inconsistency
• Indirectness of evidence
• Imprecision
• Publication bias

The ‘Summary of findings’ table presents only the outcomes for the main comparison,
intranasal corticosteroids versus placebo.

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RESULTS

Description of studies
See Characteristics of included studies; Characteristics of excluded studies.

Results of the search

The results of the search are presented in the study flow diagram in Figure 1. The
search retrieved 17,319 references. We identified no further references by screening
the reference lists of studies. We screened and excluded duplicates and obviously
irrelevant studies, leaving 6013 studies. After screening of the titles and abstracts of
these references, we discarded 5858 studies, leaving 155 references to assess for
eligibility. We assessed the full texts of these 155 references. We discarded 77 of these
references after full-text review.

Figure 1. Process for sifting search results and selecting studies for inclusion

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We formally excluded 43 studies with reasons recorded in the review (see Excluded

studies). The most common reason for exclusion was the lack of separate report of
the non-allergic rhinitis subpopulation in studies that initially enrolled patients with
perennial rhinitis or mixed rhinitis.

We did not identify any ongoing studies. One study is awaiting assessment
(NCT04002349). This study is a randomised, open-label clinical trial comparing both
nasal saline, intranasal corticosteroid, intranasal antihistamine and combination
therapy in non-allergic rhinitis patients. The expected completion date of the study is
31 March 2020 (see Characteristics of studies awaiting classification).

We included 34 studies in the systematic review. Out of these, we were able to include
data from 18 studies in our analyses.

Included studies
We included 34 studies in this review (Arikan 2006; Balle 1982; Behncke 2006; Boechat
2019; Blom 1997; Day 1990; Ellegård 2001; Guo 2015; Hallén 1997; Havas 2002; Hillas
1980; Incaudo 1980; Jacobs 2009; Jessen 1990; Kalpaklioglu 2010; Lin 2017; Löfkvist 5
1976;  Lundblad 2001;  Malm 1976;  Malm 1981;  Meltzer 1994;  Miller 1969;  O’Reilly
1991; Scadding 1995; Schulz 1978; Singh 2017; Song 2018; Spector 1980; Tantilip-
ikorn 2010; Tarlo 1977; Turkeltaub 1982; Varricchio 2011; Warland 1982; Webb 2002).
See Characteristics of included studies.

Design
Most of the included studies were randomised (Arikan 2006; Balle 1982; Behncke
2006; Blom 1997; Boechat 2019; Day 1990; Ellegård 2001; Guo 2015; Hallén 1997; Hillas
1980; Jacobs 2009; Jessen 1990; Kalpaklioglu 2010; Lin 2017; Lundblad 2001; Malm
1981; Meltzer 1994; Scadding 1995; Schulz 1978; Singh 2017; Song 2018; Spector
1980;  Tantilipikorn 2010;  Tarlo 1977;  Turkeltaub 1982;  Varricchio 2011;  Warland
1982; Webb 2002). Two studies were quasi-randomised (Havas 2002; Miller 1969).
Randomisation was unclear in four studies (Incaudo 1980;  Löfkvist 1976;  Malm
1976; O’Reilly 1991).

The majority of the studies used a parallel-group design (Arikan 2006;  Behncke
2006; Blom 1997; Boechat 2019; Day 1990; Ellegård 2001; Guo 2015; Hallén 1997; Havas
2002; Incaudo 1980; Jacobs 2009; Kalpaklioglu 2010; Lin 2017; Lundblad 2001; Meltzer
1994; Scadding 1995; Schulz 1978; Singh 2017; Song 2018; Spector 1980; Tantilipikorn
2010; Turkeltaub 1982; Varricchio 2011; Webb 2002). Ten studies had cross-over design
(Balle 1982; Hillas 1980; Jessen 1990; Löfkvist 1976; Malm 1976; Malm 1981; Miller
1969; O’Reilly 1991; Tarlo 1977; Warland 1982).

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Funding sources were reported in 11 studies, of which 10 were industry-sponsored

(Ellegård 2001; Hallén 1997; Hillas 1980; Jacobs 2009; Lin 2017; Lundblad 2001; Singh
2017;  Spector 1980;  Tantilipikorn 2010;  Webb 2002), and one was government-­
sponsored (Song 2018). In another five studies, the industry provided drugs for the
study, but no grant support (Balle 1982; Day 1990; Havas 2002; Löfkvist 1976; Malm
1976). In five studies, the industry was involved and may have provided medication,
but the funding role was unclear (Incaudo 1980; Malm 1981; Scadding 1995; Schulz
1978;  Turkeltaub 1982). Finally, funding was not reported in 12 studies (Arikan
2006; Behncke 2006; Blom 1997; Guo 2015; Jessen 1990; Kalpaklioglu 2010; Meltzer
1994; Miller 1969; O’Reilly 1991; Tarlo 1977; Varricchio 2011; Warland 1982). For the
other studies it was unclear whether there was any funding.

Conflicts of interest were not clearly reported. In 10 studies, at least one of the
authors was an employee of a pharmaceutical company (Day 1990;  Ellegård
2001; Incaudo 1980; Jacobs 2009; Malm 1981; Scadding 1995; Schulz 1978; Tantilip-
ikorn 2010; Turkeltaub 1982; Webb 2002). Other conflicts of interest were not reported.

Sample size
Samples sizes ranged from 15 (Balle 1982) to 983 (Webb 2002).

Setting
Most studies took place in secondary or tertiary referral hospital outpatient clinic
departments. The countries involved were Australia, Belgium, Brazil, Canada, China,
the Czech Republic, Denmark, Finland, France, Germany, Iceland, Ireland, Italy, the
Netherlands, New Zealand, Norway, Romania, Thailand, Turkey, Sweden, Switzerland,
the UK and the USA.

Participants
There were 4452 patients reported in 34 included studies. The correct number of
randomised patients is difficult to assess, given that many studies included both
allergic and non-allergic rhinitis patients and the total number randomised was
reported only for the combined population.

Overall, there were more females then males. In 17 studies where information was avail-
able 60% were female (Blom 1997; Ellegård 2001; Hallén 1997; Havas 2002; Incaudo
1980;  Jacobs 2009;  Jessen 1990;  Lin 2017;  Lundblad 2001;  Löfkvist 1976;  Malm
1976; Malm 1981; Miller 1969; Singh 2017; Spector 1980; Tantilipikorn 2010; Varricchio
2011). In the study Song 2018 the proportion male/female was comparable. In the
other studies, the exact proportions were not reported, or were reported for a combined
allergic and non-allergic rhinitis population; in most cases there were more females.
Interestingly, Incaudo 1980 was comprised only of male patients. Conversely, Ellegård

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2001 was a study of pregnancy rhinitis in females. Behncke 2006 studied rhinitis

symptoms in geriatric patients.

Several studies reported mean patient age, which was between 29 and 49 years. Age
range also varied by study, for example Boechat 2019 included elderly patients. The
overall range was from 9 years (Miller 1969) to 87 years (Boechat 2019). Most patients
were between 18 and 70 years of age.

Description of non-allergic rhinitis in included patients

The majority of studies used a conventional description of rhinitis, by which patients
with chronic perennial rhinitis had negative allergy testing. This included the descrip-
tion of non-allergic rhinitis as vasomotor rhinitis (Arikan 2006; Löfkvist 1976; Malm
1976; Miller 1969; Song 2018; Warland 1982) and non-allergic, non-infectious perennial
rhinitis (NANIPER) (Blom 1997). Only a few studies focused on specific subtypes of
non-allergic rhinitis: Hallén 1997 studied rhinitis medicamentosa, Jacobs 2009 investi-
gated a weather and temperature-sensitive subtype of vasomotor rhinitis, while Tantili-
pikorn 2010 focused on the irritant subtype due to air pollution, wind/temperature
triggers and strong odours. Boechat 2019 focused on senile rhinitis patients (≥ 60 5
years), with both allergic and non-allergic rhinitis. Webb 2002 subdivided the overall
non-allergic rhinitis population into NARES and non-NARES subtypes. Finally, Ellegård
2001  specifically studied pregnancy rhinitis. Interestingly, the majority of studies
purposefully excluded pregnant women from their populations. All patients had peren-
nial symptoms. In most studies, severity was rated as moderate or severe.

Interventions
Comparisons
Twenty-five studies compared intranasal corticosteroids with placebo (Arikan
2006;  Balle 1982;  Blom 1997;  Day 1990;  Ellegård 2001;  Hallén 1997;  Incaudo
1980;  Jacobs 2009;  Lin 2017;  Lundblad 2001;  Löfkvist 1976;  Malm 1976;  Malm
1981; Meltzer 1994; Miller 1969; O’Reilly 1991; Scadding 1995; Schulz 1978; Spector
1980;  Tantilipikorn 2010;  Tarlo 1977;  Turkeltaub 1982;  Varricchio 2011;  Warland
1982;  Webb 2002). In all but one of these studies, placebo was described as the
inactive vehicle of the intervention medication, or its ingredients were not described.
In Varricchio 2011, isotonic saline solution was used as placebo.

Among these, three studies also compared different doses of intranasal corticos-
teroids in a multiple-arm study (Blom 1997; Scadding 1995; Webb 2002), one study
compared different regimens of intranasal corticosteroids (Blom 1997), and one study
compared two different types of intranasal corticosteroids (Scadding 1995).

Two studies compared azelastine combined with an intranasal corticosteroid to

an intranasal corticosteroid alone (Guo 2015;  Song 2018). One study compared

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azelastine combined with fluticasone propionate to placebo (Singh 2017). Another

study compared intranasal corticosteroids with capsaicin (Havas 2002).

One study compared intranasal corticosteroids with ipratropium (Jessen 1990). Three
studies compared intranasal corticosteroids with intranasal antihistamine (Behncke
2006; Kalpaklioglu 2010; Song 2018). One study compared intranasal corticosteroids
versus saline, versus no treatment and versus intranasal corticosteroids combined
with saline (Lin 2017). Another study compared intranasal corticosteroids with sodium
cromoglycate (Hillas 1980). One study compared intranasal corticosteroids with
azelastine (Kalpaklioglu 2010). Finally, one study compared intranasal corticosteroids
with saline to saline alone (Boechat 2019).

Types of steroids
Fluticasone propionate was the most commonly used intranasal corticosteroid and was
the main intervention in 10 studies (Arikan 2006; Behncke 2006; Blom 1997; Ellegård
2001; Guo 2015; Hallén 1997; Meltzer 1994; Scadding 1995; Singh 2017; Webb 2002).
It was used in total daily doses (calculated as a sum of total dose for both nostrils) of
200 µg (Arikan 2006; Blom 1997; Ellegård 2001; Hallén 1997; Scadding 1995; Singh
2017; Webb 2002) or 400 µg daily (Blom 1997; Scadding 1995; Webb 2002). Singh
2017 and Guo 2015 used a combination of fluticasone propionate and azelastine. The
length of treatment varied from two weeks to three months. Arikan 2006 used treat-
ment for three months; Blom 1997, Blom 1997 and Ellegård 2001 for eight weeks; Guo
2015 for six weeks; Hallén 1997 and Singh 2017 for two weeks; Scadding 1995 for 12
weeks; and Webb 2002 for four weeks.

Beclomethasone dipropionate was used in seven studies (Jessen 1990;  Hillas

1980;  Löfkvist 1976;  Malm 1976;  O’Reilly 1991;  Scadding 1995;  Tarlo 1977). Daily
doses varied from 200 µg to 800 µg per day. Hillas 1980 used 400 µg daily for four
weeks. Jessen 1990 used 400 µg daily for two weeks. Löfkvist 1976 used 300 µg daily
for four weeks. Malm 1976 used daily doses of 200 µg, 400 µg and 800 µg for two
weeks. O’Reilly 1991 used 600 µg per day for 12 weeks. Finally, Scadding 1995 used
200 µg and 400 µg daily for 12 weeks.

Flunisolide nasal spray was used in six studies (Incaudo 1980; Schulz 1978; Spector
1980; Turkeltaub 1982; Varricchio 2011; Warland 1982). The daily doses ranged from
200 µg to 2 mg per day. Incaudo 1980 used 200 µg per day for six weeks; Schulz
1978  used 300 µg for six weeks;  Spector 1980  used 400 µg daily for four
weeks. Turkeltaub 1982 used 300 µg daily for 12 weeks. Varricchio 2011 used 2 mg
daily for eight weeks, which appears to be at least a five times higher dose compared
to the other four studies.

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Budesonide was used in five studies (Balle 1982;  Day 1990;  Havas 2002;  Malm
1981;  Song 2018). The daily doses ranged from 200 µg to 800 µg daily.  Balle
1982 used 200 µg and 500 µg daily for two weeks. Day 1990 used 400 µg daily for
four weeks. Havas 2002 used a total daily dose of 512 µg for two weeks. Finally, Malm
1981 used 50 µg, 200 µg and 800 µg daily for two weeks.

Fluticasone furoate was used in two studies (Jacobs 2009; Tantilipikorn 2010). Both
studies used 100 µg once daily for four weeks.

Triamcinolone acetonide was used in Kalpaklioglu 2010. A total daily dose of 220 µg
was used for two weeks.

Mometasone furoate was used in  Lundblad 2001  and  Boechat 2019.  Lundblad
2001 used a total daily dose of 200 µg for six weeks. Boechat 2019 used a total daily
dose of 200 µg for two weeks.

Finally, dexamethasone nasal spray was used in Miller 1969. A total daily dose of 672
µg or 1008 µg was used (patients used two to three times per day) for one month. 5
Steroid dosage
Different doses of the same intranasal corticosteroids were used in six studies in
addition to the placebo comparison (Balle 1982;  Blom 1997;  Malm 1976;  Malm
1981; Scadding 1995; Webb 2002). Balle 1982 used budesonide at daily doses of
200 µg and 400 µg in a cross-over study design. Blom 1997 (parallel-group study)
used fluticasone propionate respectively 200 µg once daily and twice daily in different
regimens: a) fluticasone propionate 200 µg once daily and placebo once daily for
eight weeks; b) fluticasone propionate 200 µg once daily and placebo once daily for
four weeks followed by fluticasone propionate 200 µg twice daily for four weeks; and
c) fluticasone propionate 200 µg twice daily for eight weeks. Malm 1976 used 200
µg, 400 µg and 800 µg daily doses of beclomethasone dipropionate in a cross-over
study design. Malm 1981, in comparison to the previous study, used budesonide at
daily doses of 50 µg, 200 µg or 800 µg, also in a cross-over study design.  Webb
2002 (parallel-group study) used fluticasone propionate respectively at 200 µg and 400
µg daily dosage. Finally, Scadding 1995 used both different doses of fluticasone and
another intranasal corticosteroid beclomethasone. Specifically, they used fluticasone
propionate 200 µg once daily, 200 µg twice daily and beclomethasone dipropionate
200 µg twice daily for 12 weeks.

Rescue medication
Some studies allowed for rescue medications to be used concurrently in all study
groups (Day 1990; Havas 2002; Lundblad 2001; Malm 1981; Spector 1980).

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Outcomes

Primary outcomes

Disease severity as measured by patient-reported symptom score

Thirty-four studies reported a patient-reported disease severity score ranging from
one symptom to a total nasal symptom score or an overall disease severity score.
These scores differed greatly in the method of reporting, ranging from a mean of
symptoms to individual scales for up to 10 symptoms. The summary scores were also
all constructed differently. A summary of the scales is shown in Table 1.

The individual symptom scores varied and included nasal obstruction, nasal conges-
tion, rhinorrhoea, post-nasal drip, sneezing, itchy nose, facial pain, anosmia, itchy eyes,
watery or red eyes, headache, cough, mucus production and sore or itchy throat. These
were most commonly measured on a scale ranging from 0 to 3 to 0 to 6, or a visual
analogue scale (VAS) ranging from 0 to 5 to 0 to 100.

We used the symptoms rhinorrhoea (secretion), congestion (obstruction) and sneezing

to calculate a total nasal symptom score in cases where only individual symptom
scores were reported.

The majority of studies reported an overall symptom score (Balle 1982;  Blom
1997;  Boechat 2019;  Day 1990;  Guo 2015;  Havas 2002;  Incaudo 1980;  Jacobs
2009; Kalpaklioglu 2010; Löfkvist 1976; O’Reilly 1991; Scadding 1995; Schulz 1978; Song
2018; Tantilipikorn 2010; Turkeltaub 1982; Varricchio 2011; Webb 2002). Most studies
combined individual symptom scores into a sum score of total nasal symptom score
(Blom 1997; Day 1990; Havas 2002; Jacobs 2009; Löfkvist 1976; O’Reilly 1991; Schulz
1978;  Tantilipikorn 2010;  Turkeltaub 1982;  Varricchio 2011;  Webb 2002).  Balle
1982 used a mean of individual symptom scores. Blom 1997 measured intensity of
nasal symptoms on a VAS from 0 to 10. Boechat 2019 and Song 2018 measured
a combined nasal symptom score on a VAS from 0 to 10. Incaudo 1980 assessed
overall severity of rhinitis on a scale of 1 to 4. Kalpaklioglu 2010 evaluated a total
nasal symptom score on a scale of 0 to 4. Finally, Scadding 1995 reported overall
assessment of symptoms by patients on a scale of 0 to 3, and at clinic visits on a
VAS of 0 to 10.

Significant adverse events: epistaxis

Eight studies reported on the significant adverse event ‘epistaxis’ (Arikan 2006; Incaudo
1980; Jacobs 2009; Lin 2017; Lundblad 2001; Malm 1981; Scadding 1995; Tantilipikorn
2010). In almost all studies this adverse event was reported as the number of cases
of epistaxis at the end of follow-up, either actively asked for by the investigator and/
or spontaneously reported by the patient or recorded daily in a diary or on a question

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form (Jacobs 2009). Scadding 1995 only mentioned “generally minor adverse events”

and reported no explicit numbers.

The risk of epistaxis was reported in five studies included in the meta-analysis (Incaudo
1980; Jacobs 2009; Lundblad 2001; Malm 1981; Tantilipikorn 2010).

Secondary outcomes

Disease-specific health-related quality of life

Six studies measured quality of life (Behncke 2006;  Boechat 2019;  Kalpaklioglu
2010; Lin 2017; Lundblad 2001; Song 2018). Behncke 2006 used the Rhinitis Quality
of Life Questionnaire (RQLQ) (but reported no numerical data on the non-allergic
rhinitis group separately). Boechat 2019 used the SNOT-22. Kalpaklioglu 2010 used the
mini-Rhinitis Quality of Life Questionnaire (mini-RQLQ) (but reported no numerical data
on the non-allergic rhinitis group separately). Lin 2017 used the SF-12v2 and Lundblad
2001 did not report on how quality of life was measured. Song 2018 used the SF12-v2
to measure quality of life. Boechat 2019 and Song 2018 were included in our analyses.
5
Inspiratory peak flow levels, rhinomanometry or other objective measure-
ments of airflow
Ten studies objectively measured nasal airflow (Boechat 2019; Ellegård 2001; Hallén
1997; Jessen 1990; Kalpaklioglu 2010; Malm 1981; O’Reilly 1991; Singh 2017; Spector
1980; Tarlo 1977). Boechat 2019 measured peak nasal inspiratory flow (PNIF) (L/
min).  Ellegård 2001  measured a blockage index ((PEF-nPEF)/PEF) and acoustic
rhinometry. Hallén 1997 measured rhinostereometry, acoustic rhinometry (MCA2
area) and PNIF (L/min). Jessen 1990 measured rhinomanometry during inclusion of
patients but it was not used to objectively measure airflow after treatment. Kalpaklioglu
2010 measured nPIFR (nasal peak inspiratory flow rate). Malm 1981 measured rhino-
manometry (in degrees). O’Reilly 1991 measured rhinomanometry using the Brom’s
method. Singh 2017 used the minimal cross-sectional area (MCA) before and after
cold dry air (CDA) provocation. Spector 1980 used the nasal peak expiratory flow rate
(PEFRn), the mouth peak expiratory flow rate (PEFRm) and the blockage index. Tarlo
1977 measured nasal airway resistance used the method of Taylor and Shivalkar.

Only three studies provided numerical data for objective airway measurements for
non-allergic rhinitis patients that we could use in our analysis (Boechat 2019; Malm
1981; Spector 1980). The other studies assessed another comparison than intranasal
corticosteroids versus placebo or reported no numerical data for the non-allergic
rhinitis subgroup.

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Other adverse events: local irritation, discomfort

Nineteen studies included ‘adverse events’ (besides epistaxis) as an outcome (Arikan
2006; Day 1990; Incaudo 1980; Jacobs 2009; Jessen 1990; Kalpaklioglu 2010; Lin
2017; Lundblad 2001; Malm 1976; Malm 1981; Miller 1969; O’Reilly 1991; Scadding
1995; Song 2018; Spector 1980; Tantilipikorn 2010; Tarlo 1977; Turkeltaub 1982; Varric-
chio 2011). In almost all studies these adverse events were reported as the number of
cases of adverse events at the end of follow-up, either actively asked for by the investi-
gator and/or spontaneously or recorded daily by the patient in a diary or on a question
form (Day 1990; Jacobs 2009). Of these studies four were included in the meta-anal-
ysis (Jacobs 2009; Lundblad 2001; Song 2018; Tantilipikorn 2010). The studies that
were not included in the meta-analysis either did not report data on non-­allergic rhinitis
patients separately, did not report numerical data or were excluded from the meta-­
analysis for other reasons (for example, too low or too high an intranasal corticosteroid
dosage or unclear dosage subgroup).

Excluded studies
In total we excluded 43 studies (see Characteristics of excluded studies).

Astafieva 2012 compared two types of intranasal corticosteroids, brand versus generic,

which was not a comparison included in our protocol and therefore we excluded this
study.

Celiker 2011 compared intranasal corticosteroids with radiofrequency ablation of the

inferior turbinate for nasal obstruction. It was excluded because the comparison intra-
nasal corticosteroids versus radiofrequency ablation was not defined in our protocol.

We excluded studies with high risks of bias such as Synnerstad 1996. Besides obvious
high risks of bias for allocation concealment, blinding of participants and personnel,
and blinding of outcome assessors, the study had minor issues with incomplete
outcome data, and some with selective outcome reporting (individual nasal symptoms
measured but not thoroughly reported, total nasal symptoms reported but not included
in methods). This study was supported by a grant from Astra Draco AB, Lund, Sweden,
and the second author worked for the company. The company provided budesonide
(Rhinocort). The study suggested that budesonide was better than beclomethasone.
There are significant grounds to suspect high risk of bias. Based on these observa-
tions, we decided to exclude this study.

The Small 1982 study (comparing beclomethasone with placebo in non-allergic rhinitis

patients) did not provide the results for the placebo group and was therefore excluded.

We also excluded 38 studies that were performed in patients with perennial rhinitis and
did not present results for the non-allergic rhinitis subgroup separately (Adamopoulos

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1995; Arbesman 1983; Balle 1982b; Basran 1995; Berger 2012; Bernstein 1997; Blair

1977;  Bunnag 1992;  Chatterjee 1974;  Dieges 1978;  Dockhorn 1999;  Gibson
1974; Hansen 1974; Harding 1976; Hartley 1985; Haye 1993; Jones 1979; Joubert
1983; Juniper 1993; Kakumanu 2003; Kivisaari 1998; Kohan 1989; Lahdensuo 1977; Lau
1990;  Lebowitz 1993;  Malmberg 1988;  McAllen 1969;  McAllen 1980;  Negreiros
1975;  Price 2013;  Rusnak 1981;  Scadding 1991;  Shaw 1979;  Svendsen 1989;  Sy
1979; Turner Warwick 1980; Webb 1977; Weckx 2001; Wight 1992). We contacted the
authors of the studies in an attempt to obtain these results, without success.

One excluded study was a meta-analysis with the only relevant study already included
in our review (Zucker 2019).

Besides the 43 excluded studies, two other studies did not present results for the
non-allergic rhinitis subgroup separately but also did not have any authors listed. These
studies were considered ‘discarded’.

Risk of bias in included studies

We included 34 studies in this review. Our judgements about risk of bias are presented 5
as a ‘Risk of bias’ graph in percentage form for all included studies combined (Figure
2). The risk of bias in individual studies in shown in a ‘Risk of bias’ summary (Figure 3).

Figure 2. ‘Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies

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Figure 3. ‘Risk of bias’

summary: review authors’
judgements about each
risk of bias item for each
included study

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Allocation
Most studies described a random component in the sequence generation process
but with no more information, so we judged them to have an unclear risk of bias.
The exceptions are  Havas 2002 and  Miller 1969, which had a high risk of bias
due to pseudo-randomisation and quasi-randomisation.  Incaudo 1980,  Löfkvist
1976, Malm 1976 and O’Reilly 1991 also have a high risk of bias because they did
not describe randomisation at all although the study type is very suggestive of a
randomised trial. Boechat 2019 (randomisation by a computer-generated code), Day
1990 (balanced and stratified randomisation), Lin 2017 (computer software) and Song
2018 (number table method) have a low risk of selection bias.

Allocation concealment was unclear in most studies, with the exception of Havas
2002, which had a high risk of bias (pseudo-randomisation),  Lin 2017  (had a
non-random component: day/order of admission) and Varricchio 2011 (allocation was
not concealed, single-blinded study). In addition, Incaudo 1980, Löfkvist 1976, Malm
1976 and O’Reilly 1991 also had a high risk of bias as they did not describe randomi-
sation at all although the study type is very suggestive of a randomised trial. Miller
1969 had a low risk of bias for allocation concealment as the authors described alloca- 5
tion concealment in detail (i.e. “over-printed on a tear-off portion of the label which
was attached to the case report form”).

Blinding
Most studies reported blinding of patients and physicians but did not give more infor-
mation on the blinding process so had an unclear risk of bias. Arikan 2006 had a
low risk of bias as one of the main outcomes (CT scoring) was at low risk because
of blinding of the radiologist. Boechat 2019, Havas 2002, Lin 2017, Singh 2017, Song
2018  and  Varricchio 2011  had high risk of bias for blinding either because of no
reporting of blinding and different treatment strategies per group making blinding
complicated, pseudo-randomisation, no randomisation or single-blinding of the study.

Incomplete outcome data

Nineteen studies had a low risk of attrition bias because data for all included partic-
ipants were reported. In 10 studies, the risk of attrition bias was high due to incom-
plete outcome data reporting or violation of the intention-to-treat protocol (Behncke
2006; Jessen 1990; Malm 1981; Meltzer 1994; O’Reilly 1991; Scadding 1995; Spector
1980; Tarlo 1977; Turkeltaub 1982; Warland 1982). In eight studies, the risk of attrition
bias was unclear because only a very small amount of data was not reported and this
had an unclear (and most likely low) effect on clinical outcome (Ellegård 2001; Hallén
1997; Hillas 1980; Jacobs 2009; Löfkvist 1976; Schulz 1978; Singh 2017; Webb 2002).

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Selective reporting
Fifteen studies had a low risk of selective reporting bias because all of the outcomes
described in the methods section could be found in the results. We were not able to
find a study protocol for any of the included studies.

In eight studies the risk of reporting bias was unclear due to incomplete presentation of
all outcomes (Balle 1982; Hillas 1980; Jessen 1990; Lin 2017; Löfkvist 1976; Scadding
1995;  Schulz 1978;  Webb 2002). In the remaining 12 studies the risk of selective
reporting bias was high due to major lack of reporting of significant outcomes, which
could influence the conclusions (Behncke 2006;  Blom 1997;  Ellegård 2001;  Guo
2015;  Lundblad 2001;  Malm 1976;  Meltzer 1994;  O’Reilly 1991;  Singh 2017;  Tarlo
1977; Warland 1982).

Other potential sources of bias

The risk of other bias was high in four studies (Incaudo 1980; Jessen 1990; Malm
1976; Spector 1980). Incaudo 1980 included only male patients. In Jessen 1990, it
was unclear if blinding was compromised for patients to report medication safety.
In addition, the scale up to “3 or 4 for severe symptoms” is vague. Finally, it was not
clear which groups the patients (5 of 24) co-treated with xylometazoline belonged to.
In Malm 1976, the cross-over study design had no wash-out period, leaving it possible
for there to be a carry-over effect. In Spector 1980, women of childbearing potential
were excluded, making the study biased.

Several studies received funding from a pharmaceutical company without clarifying

their role. Another extra bias in some studies resulted from limited ways of reporting
data, for example without mean and standard deviation. Only 15 studies had a low
risk of other potential sources of bias (Boechat 2019; Blom 1997; Ellegård 2001; Guo
2015; Havas 2002; Hillas 1980; Jacobs 2009; Kalpaklioglu 2010; Lin 2017; O’Reilly
1991; Schulz 1978; Song 2018; Tantilipikorn 2010; Varricchio 2011).

Effects of interventions
See Summary of findings table 1 for the main comparison: ‘Intranasal corticosteroids
versus placebo’.

Intranasal corticosteroids versus placebo

Thirteen studies (2045 participants) comparing intranasal corticosteroid treatment
with placebo provided data that could be used in our analyses (Arikan 2006; Balle
1982;  Blom 1997;  Day 1990;  Incaudo 1980;  Jacobs 2009;  Lundblad 2001;  Malm
1976; Malm 1981; Spector 1980; Tantilipikorn 2010; Turkeltaub 1982; Webb 2002).
Twelve included studies could not be used in the analyses (Ellegård 2001;  Hallén
1997;  Lin 2017;  Löfkvist 1976;  Meltzer 1994;  Miller 1969;  O’Reilly 1991;  Scadding
1995; Schulz 1978; Tarlo 1977; Varricchio 2011; Warland 1982).

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Different types of intranasal corticosteroids were used (budesonide, beclomethasone,

flunisolide, fluticasone propionate, fluticasone furoate, dexamethasone, mometasone
furoate).

Among the studies treatment dosage varied from 50 µg to 2000 µg daily. Most of the
studies that compared different dosages of intranasal corticosteroids used a cross-
over study design, with the exception of Blom 1997 and Webb 2002, which used a
parallel-group study design. In the cross-over studies the same patients were treated
with different dosages of intranasal corticosteroids, with a short (one-week) or no
wash-out, complicating a clear comparison between these dosage subgroups (Balle
1982; Malm 1976; Malm 1981). Only Balle 1982 showed a dosage effect for two nasal
symptom score outcomes. Malm 1976 and Malm 1981 showed no significant differ-
ence between the dosage subgroups. The two parallel-group studies both concluded
that there were no statistically significant differences among the different intranasal
corticosteroid dosage subgroups (Blom 1997;  Webb 2002). In the ­parallel-group
studies different dosage subgroups contained different patients but were compared
with the same control group. To prevent counting the same patients or controls
more than once, we decided to include one intranasal corticosteroids dosage in the 5
meta-analysis. The most common intranasal corticosteroid dosage was 200 µg. A
test for subgroup differences showed no significant difference (‘no dosage effect’)
between 200 µg and 400 µg. We therefore included studies in the meta-analysis with
an intranasal corticosteroid dosage range of 200 µg to 400 µg.

Treatment vehicles varied and included spray, aerosol, nebuliser, pressured canister
and atomised bottle. Frequency of usage varied from once daily to four times daily.

Disease severity, as measured by patient-reported total nasal symptom

score
Eleven studies presented data for disease severity using a number of different scales
that could be used in meta-analysis (Balle 1982;  Blom 1997;  Day 1990;  Incaudo
1980;  Jacobs 2009;  Malm 1976;  Malm 1981;  Spector 1980;  Tantilipikorn
2010; Turkeltaub 1982; Webb 2002). Table 1 shows the different scales used. Some
studies provided us with a total nasal symptom score (TNSS). In studies that did not
provide a total nasal symptom score, we calculated this score based on individual
rhinitis symptom scores, i.e. rhinorrhoea (secretion), congestion (obstruction) and
sneezing. Due to the differences in the scales used, we used a standardised mean
difference (SMD) in the analysis.

Outcomes were measured at up to four weeks follow-up in four studies and at more
than four weeks (six weeks to three months) follow-up in three studies. Outcomes
were also measured as change from baseline in another four studies.

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Up to four weeks follow-up

We were able to pool data from four studies that reported a patient-reported total
nasal symptom score (or individual scores that could be calculated into a total nasal
symptom score) with a follow-up of up to four weeks (Balle 1982; Malm 1976; Malm
1981;  Spector 1980). These studies showed that patients treated with intranasal
corticosteroids had lower total nasal symptom scores compared to placebo (SMD
-0.74, 95% confidence interval (CI) -1.15 to -0.33; 131 participants; 4 studies; I2 = 22%)
(Analysis 1.1) (low-certainty evidence). This represents a medium effect size (Cohen
1988). Spector 1980 was the only study that did not report an improvement of total
nasal symptom score with intranasal corticosteroids.

The heterogeneity in this analysis is mainly the result of Spector 1980. Removing this
study reduces the heterogeneity to 0%.

There were not enough data to carry out our planned subgroup analyses to assess
the differences between different dosages (see above), types, vehicles or frequencies
of intranasal corticosteroid treatment.

More than four weeks follow-up (six weeks to three months)

Three studies reported a patient-reported total nasal symptom score with a follow-up
of more than four weeks (Blom 1997; Incaudo 1980; Turkeltaub 1982). The follow-up
period varied between six weeks and three months.

These studies showed that patients treated with intranasal corticosteroids had no
difference in nasal symptom scores compared to placebo but the evidence is very
uncertain (SMD -0.24, 95% CI -0.67 to 0.20; 85 participants; 3 studies; I2 = 0%) (Analysis
1.2) (very low-certainty evidence).

Blom 1997 studied four different treatment regimens with different intranasal corti-
costeroid dosages. The authors concluded that there were no statistically significant
differences among the four treatment regimens in the investigators’ assessments of
symptoms and rhinoscopy at clinic visits.

There were not enough data to carry out our planned subgroup analyses to assess
the differences between different dosages (see above), types, vehicles or frequencies
of intranasal corticosteroid treatment.

Change from baseline, up to four weeks follow-up

Four studies reported on the change from baseline of a patient-reported total nasal
symptom score, with a follow-up of up to four weeks (Day 1990; Jacobs 2009; Tantili-
pikorn 2010; Webb 2002).

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These studies showed that patients treated with intranasal corticosteroids had no
difference in total nasal symptom scores compared to placebo (SMD -0.54, 95%
CI -1.18 to 0.10; 1465 participants; 4 studies; I2  = 96%) (Analysis 1.3) (low-certainty
evidence). This represents a medium effect size. We used a random-effects model
due to the high heterogeneity.

The very high heterogeneity in this analysis is mainly driven by  Jacobs 2009.
Removing this study reduces the heterogeneity to 0%. Without Jacobs 2009 there is
an improvement in favour of intranasal corticosteroids (SMD -0.23, 95% CI -0.37 to
-0.09) (without Jacobs 2009 we used a fixed-effect model because of the low hetero-
geneity). The Jacobs 2009 study reports a very unlikely standard deviation (SD) value
that does not match with the presented means, n and P values. The data would make
more sense if the standard deviation (SD) presented values were actually standard
error of the mean (SEM), which was confirmed by a re-analysis. As Jacobs 2009 is
one of the larger and also one of the most well-known and frequently cited studies, we
decided to keep the study included in the meta-analysis. Converting the as-presented
SD values into SEM values does change the outcome of this individual study (i.e. no
effect of intranasal corticosteroids), but it does not significantly change the overall 5
outcome of this comparison (‘Total nasal symptom score change from baseline, up
to four weeks follow-up’), which is in favour of intranasal corticosteroids (SMD -0.15,
95% CI -0.25 to -0.05; 1465 participants; 4 studies; I2 = 35%).

Webb 2002 studied two daily dosages (200 µg and 400 µg) in a parallel-group study,
with nearly the same effect on total nasal symptom score change from baseline. Only
the highest dosage (400 µg) from Webb 2002 was included in the meta-analysis.

Webb 2002  also reports an improvement in favour of intranasal corticosteroids,

however this is less certain than in Jacobs 2009. The amount of improvement is more
clinically relevant than in Jacobs 2009, i.e. around a 10% improvement in total nasal
symptom score. In general, the data from Webb 2002 seem to be far more reliable
than the data from Jacobs 2009.

Webb 2002 studied different daily dosages (200 µg and 400 µg) and concluded that
there were no statistically significant differences.

There were not enough data to carry out our planned subgroup analyses to assess
the differences between different dosages (see above), types, vehicles or frequencies
of intranasal corticosteroids treatment.

For the outcome total nasal symptom score change from baseline there were no
studies reporting a follow-up of more than four weeks.

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Twelve studies that did report nasal symptom score(s) could not be included in
the meta-analysis (Arikan 2006;  Meltzer 1994;  Miller 1969;  Lin 2017;  Lundblad
2001; Löfkvist 1976; O’Reilly 1991; Scadding 1995; Schulz 1978; Tarlo 1977; Varric-
chio 2011; Warland 1982). Arikan 2006 and Lundblad 2001 are, however, included in
the meta-analysis for other outcomes (adverse events). Miller 1969 and Varricchio
2011 are not included in the total nasal symptom score(s) meta-analysis because they
used an intranasal corticosteroid dosage higher than 200 µg to 400 µg daily. See Table
2 for a summary of the findings from these 12 studies for nasal symptom score(s).

Significant adverse events: epistaxis

The risk of epistaxis was reported in four studies included in the meta-analysis, two
with a follow-up of up to four weeks (Malm 1981; Tantilipikorn 2010) and two with a
follow-up of more than four weeks (Jacobs 2009; Lundblad 2001). Malm 1981 studied
different dosages of intranasal corticosteroids in a cross-over study design. The daily
dosage of 200 µg was included in the meta-analysis (see reasons above).

We decided to combine the four studies and not to separate them into up to four weeks
and more than four weeks follow-up. All studies showed a significantly higher risk of
epistaxis in the intranasal corticosteroids group compared to placebo (risk ratio (RR)
2.10, 95% CI 1.24 to 3.57; 1174 participants; 4 studies; I2  = 0%) (moderate-certainty
evidence). The absolute risk difference for epistaxis was 0.04 (Analysis 1.4), with a
number needed to treat to harm (NNTH) of 25 (95% CI 16.7 to 100).

Three of the studies included in the meta-analysis that reported on the risk of epistaxis
showed no significant difference between intranasal corticosteroids and placebo
(Jacobs 2009;  Malm 1981;  Tantilipikorn 2010).  For these studies the NNT, NNTB
(number needed to treat to benefit) and NNTH (number needed to treat to harm) are
as follows: Tantilipikorn 2010 had a NNT of 25, with NNTB 10 and NNTH 50. Jacobs
2009 had a NNT of 50, with NNTB 20 and NNTH 100. Malm 1981 had a NNT of 10, with
NNTB 6.25 and NNTH 14.29. Finally, Lundblad 2001 did show a significant difference
with a NNT of 14.29 (95% CI 7.69 to 100).

Three studies reported on epistaxis but were not included in the meta-analysis
because the study did not report numerical data for the non-allergic rhinitis subgroup
(Scadding 1995), due to lack of quality of the study (Lin 2017), or because no events
were observed in either group (Arikan 2006). Scadding 1995 reported “generally minor”
adverse events in the intranasal corticosteroids group and Lin 2017 reported two
cases of epistaxis in a total group of 22 patients treated with budesonide versus no
cases of epistaxis in the placebo group. Arikan 2006 reported no epistaxis in either
the intervention group or the control group.

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Disease-specific health-related quality of life

No studies except Lin 2017 reported numerical data on (health-related) quality of life
for non-allergic rhinitis patients. Lin 2017 used the Short Form 12 (SF-12v2) question-
naire to measure quality of life (scale range 0 to 800). This study was not included
in the analysis because of lack of quality of the study data (see reasons above). Lin
2017 reported a higher quality of life in the intranasal corticosteroids group versus the
placebo group after one month (152.3 versus 145.6); however, while this difference
was clear at one-month follow-up it was barely noticeable at three months follow-up
(148.4 versus 145.6) (low-certainty evidence).

Lundblad 2001 reported no numerical data on quality of life but did report narratively
that there was no significant difference in quality of life between the intranasal corti-
costeroids group and the placebo group.

Inspiratory peak flow levels, rhinomanometry or other objective measure-

ments of airflow
Only two studies provided data for objective airway measurements that we could
use in our analyses (Malm 1981; Spector 1980), one using peak flow expiratory rate 5
(Spector 1980) and one using rhinomanometry (Malm 1981). The study using peak
flow expiratory rate did not find a significant difference for flunisolide over placebo
(SMD 0.78, 95% CI -0.47 to 2.03; 11 participants) (Analysis 1.5). For rhinomanometry
there was also no significant difference (SMD -0.46, 95% CI -1.06 to 0.14; 44 partici-
pants) (Analysis 1.6) (Malm 1981). This evidence is of very low certainty.

Ellegård 2001  was not included in the meta-analysis as it compared intranasal

corticosteroids versus placebo in a single separate subgroup of non-allergic rhinitis
patients, i.e. participants with pregnancy rhinitis. Ellegård 2001 reported a blockage
index ((PEF-nPEF)/PEF) to objectify airflow after treatment. The mean blockage index
after eight weeks of treatment in the fluticasone group was 0.39 (SD 0.16) and the
mean blockage index in the placebo group was 0.41 (SD 0.15), therefore there was
no significant difference between the intranasal corticosteroids and placebo groups.

Hallén 1997 was not included in the meta-analysis as it compared intranasal corticos-

teroids versus placebo in a single separate subgroup of non-allergic rhinitis patients, i.e.
participants with rhinitis medicamentosa. Hallén 1997 reported both acoustic rhinom-
etry and PNIF after 13 days of treatment. The mean acoustic rhinometry outcome in
the intranasal corticosteroids group was 0.28 cm2 (SD 0.19) and the mean acoustic
rhinometry outcome in the placebo group was 0.03 cm2 (SD 0.17) (SMD -1.34, 95% CI
-0.35 to -2.33). The mean PNIF outcome in the intranasal corticosteroids group was
121.2 L/min (SD 69.0) and the mean PNIF outcome in the placebo group was 128.7 L/
min (SD 40.4) (SMD -0.13, 95% CI -0.75 to 1.00), i.e. there was no significant difference.

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O’Reilly 1991 was not included in the meta-analysis because it only reported P values
and there was too wide a variation between baseline and placebo values.

Tarlo 1977 was not included in the meta-analysis because it reported no numerical

data for the non-allergic rhinitis subgroup.

Jessen 1990 used rhinomanometry during the inclusion of patients but it was not
used to objectively measure airflow after treatment and could therefore not be used
in the meta-analysis.

Kalpaklioglu 2010 was included in the meta-analysis for the comparison of intranasal

corticosteroids versus ipratropium bromide.

The objective airflow measurements of Singh 2017 could not be included as they were
related to cold dry air exposure.

Other adverse events

The outcome ‘other adverse events’ was defined as adverse events other than
epistaxis, for example pharyngitis, nasal dryness/crusting and headache.

Three studies included in the meta-analysis reported on ‘other adverse events’ besides
epistaxis (Jacobs 2009; Lundblad 2001; Tantilipikorn 2010). We decided to combine the
three studies and not to make a separation into up to four weeks and more than four
weeks follow-up. Intranasal corticosteroids probably result in little or no difference in
the risk of other adverse events compared to placebo (RR 0.99, 95% CI 0.87 to 1.12;
1130 participants; 3 studies; I2 = 0%) (Analysis 1.7) (moderate-certainty evidence).

Lin 2017 was not included in the meta-analysis due to lack of quality of the study data
(see above). Miller 1969 was not included in the meta-analysis as it used a dosage
of dexamethasone of 672 µg to 1008 µg per day and only studies with an intranasal
corticosteroid dosage of 200 µg to 400 µg were included in the meta-analysis (see
above). Malm 1981 was not included in the meta-analysis as it was unclear in which
intranasal corticosteroid dosage subgroup the other adverse events occurred. Other
studies describing ‘other adverse events’ as an outcome in their ‘Materials and
methods’ sections did not report actual numbers/data in the ‘Results’ section or did
not report for the non-allergic rhinitis group separately and were therefore not included
in the review.

Lin 2017 was not included in the meta-analysis but reported seven cases of other
adverse events in a total group of 22 patients treated with budesonide versus no other
adverse events in the placebo group.

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Miller 1969 described two (non-epistaxis) adverse events in the intranasal corticos-

teroids group and two adverse events in the placebo group.

Malm 1981 reported four ‘other adverse events’ in the intranasal corticosteroids group
versus none in the placebo group.

Varricchio 2011 reported no clinically relevant adverse events in either the treatment

or control group.

Subgroups and phenotypes

Within the comparison of intranasal corticosteroids versus placebo there were not
enough data to perform a subgroup analysis for different subgroups/phenotypes of
non-allergic rhinitis. Ellegård 2001evaluated intranasal corticosteroids in pregnancy
rhinitis patients (see also under ‘Objective measurement of airflow’). Overall, the
study did not find a beneficial effect of intranasal corticosteroids over placebo. Hallén
1997 evaluated intranasal corticosteroids in rhinitis medicamentosa patients (see
also ‘Objective measurement of airflow’). They concluded that the symptom scores
for nasal stuffiness showed a marked reduction during the treatment period in both 5
groups, but there was a faster onset of symptom reduction after treatment with fluti-
casone propionate.

Intranasal corticosteroids versus saline

One four-armed study compared intranasal budesonide nasal spray 256 µg once daily
and nasal saline irrigation 100 mL of 3% saline per nostril combined with intranasal
budesonide nasal spray 256 µg once daily to nasal saline alone and no treatment (Lin
2017). This study was not included in the meta-analysis due to lack of quality of the
study data (see above).

Disease severity, as measured by patient-reported total nasal symptom

score
This study reported a total nasal symptom score using a visual analogue scale (VAS)
(unclear scale per individual symptom and unclear total range of symptoms).

There was a significant difference between budesonide (from VAS 5.91 to VAS 5.68
after three months) and saline (from VAS 5.96 to VAS 4.80 after three months) in favour
of saline (t-test, P < 0.05).

Significant adverse events: epistaxis

The risk of epistaxis was higher in the intranasal corticosteroids group (two partici-
pants with epistaxis) compared to the saline group (no participants with epistaxis).

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Disease-specific health-related quality of life

The quality of life measurement (SF-12v2: range 0 to 800) also showed a significant
effect (t-test, P < 0.05) in favour of saline (SF-12v2 increase from 146 at baseline to
151.30 after three months) compared to budesonide (SF-12v2 increase from 146 to
148.40).

Inspiratory peak flow levels, rhinomanometry or other objective measure-

ments of airflow
The study did not report objective measurements of nasal airflow.

Other adverse events

There were seven other adverse events in the budesonide treatment group (pharyngitis
and nasal dryness/crusting) and no other adverse events in the saline group.

Intranasal corticosteroids versus intranasal antihistamine

Three studies reported on intranasal corticosteroids versus an intranasal antihistamine
(Behncke 2006; Kalpaklioglu 2010; Song 2018). Kalpaklioglu 2010 and Song 2018 were
included in the meta-analysis. Kalpaklioglu 2010 compared triamcinolone acetonide
nasal spray 220 µg once daily to azelastine hydrochloride and Song 2018 compared
budesonide 200 µg two times per day to azelastine 200 µg two times per day.

Disease severity, as measured by patient-reported total nasal symptom

score
In Song 2018, there was a non-significant difference in combined nasal symptom VAS
score in favour of budesonide nasal spray (mean difference (MD) -0.25, 95% CI -0.69
to 0.19; 80 participants) (Analysis 2.1).

In Kalpaklioglu 2010, there was a non-significant difference in total nasal symptom

score mean change from baseline in favour of triamcinolone acetonide nasal spray
(MD -0.50, 95% CI -1.92 to 0.92; 63 participants) (Analysis 2.2). The study reports a
significant improvement in sneezing with triamcinolone in patients with non-allergic
rhinitis (P < 0.01), as well as conjunctivitis.

Significant adverse events: epistaxis

Epistaxis was not evaluated.

Disease-specific health-related quality of life

Kalpaklioglu 2010 assessed quality of life with the mini-Rhinoconjunctivitis Quality of
Life Questionnaire (RQLQ) but these results were not reported for non-allergic rhinitis
participants separately.

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Song 2018 assessed quality of life with the SF12-v2 questionnaire (a higher score
indicates better quality of life). There was a non-significant difference in favour of
azelastine in quality of life (MD -1.30, 95% CI -3.60 to 1.00; 80 participants) (Analysis
2.3).

Inspiratory peak flow levels, rhinomanometry or other objective measure-

ments of airflow
Kalpaklioglu 2010  also reported on the inspiratory peak flow rate (change from
baseline) and showed a small, non-significant difference in favour of triamcinolone
acetonide (MD -6.17, 95% CI -15.25 to 2.91; 63 participants) (Analysis 2.4).

Other adverse events

Song 2018 reported a higher risk of ‘other adverse events’ (such as dryness of the
nasal mucosa) in the budesonide group compared to azelastine (RR 2.00, 95% CI 0.19
to 21.18; 80 participants) (Analysis 2.5).

Behncke 2006 was not included in the meta-analysis because it reported no numerical

data for non-allergic rhinitis participants separately. This study does conclude that 5
there is no difference in effectiveness between intranasal corticosteroids and intra-
nasal antihistamines. The authors conclude that azelastine nasal spray and fluticasone
nasal spray improve RQLQ scores and rhinitis symptom scores in geriatric patients
with either allergic or non-allergic rhinitis.

Intranasal corticosteroids versus capsaicin

One study provided data for this comparison. Havas 2002 compared budesonide nasal
spray applied twice daily (256 µg daily dosage) to capsaicin 2.616 µg once weekly.

Disease severity, as measured by patient-reported total nasal symptom

score
There was a large significant difference in mean total nasal score in favour of capsaicin
(MD 1.60, 95% CI 0.03 to 3.16; 40 participants) (Analysis 3.1). A total nasal symptom
score was calculated as the mean sum of rhinorrhoea, congestion and sneezing (VAS
0 to 5 for each symptom, per side; range 0 to 30).

Significant adverse events: epistaxis

Epistaxis was not evaluated.

Disease-specific health-related quality of life

Quality of life was not evaluated.

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Inspiratory peak flow levels, rhinomanometry or other objective measure-

ments of airflow
Objective measurements of airflow were not evaluated.

Other adverse events

Other adverse events were not evaluated.

Intranasal corticosteroids versus sodium cromoglycate

One study provided data for this comparison (Hillas 1980). This study compared
sodium cromoglycate 2% six times daily to beclomethasone dipropionate 400 µg
daily. It reported no numerical data for the non-allergic rhinitis group separately and
was therefore not included in the meta-analysis.

Disease severity, as measured by patient-reported total nasal symptom

score
Intranasal corticosteroids relieved symptoms in 76.9% of patients versus 50% of
patients treated with sodium cromoglycate, a significant difference. The total symptom
score (mean of a total of seven symptoms that were scored on a range from 0 to 3) at
the end of treatment was 4.12 in participants treated with sodium cromoglycate and
2.37 in participants treated with intranasal corticosteroids, a significant difference.

Significant adverse events: epistaxis

The study reported that occasionally (no numerical data) patients using intranasal
corticosteroids had blood spotting while blowing their noses. This was not reported
in the group treated with sodium cromoglycate.

Disease-specific health-related quality of life

Quality of life was not evaluated.

Inspiratory peak flow levels, rhinomanometry or other objective measure-

ments of airflow
Objective measurements of airflow were not evaluated.

Other adverse events

No numerical data on other adverse events were reported, however some patients
experienced sneezing after using intranasal corticosteroids. No significant adverse
events were reported for cromoglycate sodium.

Intranasal corticosteroids versus ipratropium bromide

One study provided data for this comparison (Jessen 1990). This cross-over study
compared beclomethasone aerosol, twice daily (total daily dose 400 µg), with iprat-
ropium bromide 160 µg.

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Disease severity, as measured by patient-reported total nasal symptom

score
There was no significant difference between the treatments in total nasal symptom
score (MD -1.50, 95% CI -12.24 to 9.24; 48 participants) (Analysis 4.1).

Significant adverse events: epistaxis

Epistaxis was not evaluated.

Disease-specific health-related quality of life

Quality of life was not evaluated.

Inspiratory peak flow levels, rhinomanometry or other objective measure-

ments of airflow
The study used rhinomanometry during the inclusion of patients but it was not used
to objectively measure airflow after treatment.

Other adverse events

No other adverse events were evaluated. 5
Intranasal corticosteroids versus intranasal corticosteroids combined
with intranasal antihistamine
Three studies provided data for this comparison (Guo 2015; Singh 2017; Song 2018).

Guo 2015 compared fluticasone dipropionate nasal spray in an unknown dosage of

two sprays in each nostril once daily with fluticasone dipropionate nasal spray 100 µg
combined with azelastine in an unknown dosage in each nostril twice daily.

Singh 2017  reported no numerical data and was therefore not included in the
meta-analysis.

Song 2018 compared budesonide nasal spray 200 µg two times per day with budes-
onide nasal spray 200 µg two times per day combined with azelastine nasal spray
200 µg two times per day.

Disease severity, as measured by patient-reported total nasal symptom

score
There was a significant difference between INCS alone and INCS combined with intra-
nasal antihistamine for nasal symptom score (SMD 0.75, 95% CI 0.48 to 1.02; 242
participants).

Guo 2015 reported a small but significant difference in total nasal symptom score
(unclear scale and range) in favour of fluticasone dipropionate nasal spray combined

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with azelastine after six weeks of treatment (SMD 0.37, 95% CI 0.06 to 0.68; 162 partic-
ipants) (Analysis 5.1).

Song 2018 also reported a significant difference in total symptom VAS score (range 0
to 10) in favour of budesonide nasal spray combined with azelastine after eight weeks
of treatment (SMD 0.75, 95% CI 0.48 to 1.02; 80 participants) (Analysis 5.1).

Significant adverse events: epistaxis

Guo 2015 and Song 2018 did not report any cases of epistaxis in either treatment
group.

Disease-specific health-related quality of life

In Guo 2015, quality of life was not evaluated.

Song 2018 did evaluate quality of life by means of the SF12-v2 questionnaire (a higher
score indicating a better quality of life). It showed a significantly higher quality of life
in the group treated with budesonide combined with azelastine nasal spray compared
to budesonide nasal spray alone (MD -7.20, 95% CI -9.77 to -4.63; 80 participants)
(Analysis 5.2).

Inspiratory peak flow levels, rhinomanometry or other objective measure-

ments of airflow
In Guo 2015 and Song 2018 objective measurements of airflow were not evaluated.

Other adverse events

Two studies included in the meta-analysis reported on ‘other adverse events’ (Guo
2015; Song 2018). Both studies showed a nearly significant higher rate of other adverse
events in the combined intranasal corticosteroid and intranasal antihistamine group
(RR 0.26 95% CI 0.07 to 1.01; 242 participants; I2 = 15%) (Analysis 5.3).

Guo 2015 reported more adverse events (five reporting fatigue and bitter taste) in
the fluticasone dipropionate with azelastine group than in the fluticasone dipropi-
onate alone group (no adverse events) (RR 0.09, 95% CI 0.00 to 1.54; 162 participants)
(Analysis 5.3).

Song 2018 also reported more adverse events (dryness of nasal mucosa, dry throat
discomfort, bitter taste, slight erosion of nasal mucosa) in the budesonide with azelas-
tine group than in the budesonide alone group (RR 0.50, 95% CI 0.10 to 2.58; 80 partic-
ipants (Analysis 5.3).

Singh 2017 compared intranasal corticosteroids combined with azelastine to placebo

instead of intranasal corticosteroids. It could not be included in the meta-analysis

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because the total nasal symptom score was not reported numerically. Total nasal
symptom score and objective measurement of airflow were both related to cold dry air
provocation. The study did report that there were no statistically significant differences
between the two treatments.

Intranasal corticosteroids versus intranasal corticosteroids combined

with saline irrigation
One study provided data for this comparison (Lin 2017). This study was not included
in the meta-analysis due to lack of quality of the study data (see above). It compared
nasal saline irrigation (100 mL of 3% saline per nostril twice a day) with intranasal
budesonide nasal spray 256 µg once daily (two sprays per nostril per day, 64 µg per
spray), to intranasal budesonide alone.

Disease severity, as measured by patient-reported total nasal symptom

score
There was a significant difference between combination therapy (from VAS 6.18 to
VAS 4.48 after three months) and budesonide (from VAS 5.91 to VAS 5.68 after three
months) in favour of combination therapy (t-test, P < 0.05). 5
Significant adverse events: epistaxis
The combination therapy group had one patient with epistaxis, while the budesonide
group had two patients with epistaxis.

Disease-specific health-related quality of life

The quality of life measurement (SF-12v2) also showed a significant effect in favour
of combination therapy (increase from 146 at baseline to 152.9 after three months)
over budesonide (increase from 146 to 148.40) (t-test, P < 0.05).

Inspiratory peak flow levels, rhinomanometry or other objective measure-

ments of airflow
The study did not report on objective measurements of nasal airflow.

Other adverse events

The combined therapy group had eight participants with other adverse events (pharyn-
gitis, nasal dryness/crusting), while the budesonide group had seven participants with
other adverse events.

Intranasal corticosteroids with saline spray versus saline spray alone

One study provided data for this comparison (Boechat 2019). It compared mometa-
sone furoate 200 µg daily with isotonic saline spray to isotonic saline spray alone.

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Disease severity, as measured by patient-reported total nasal symptom

score
There was a non-significant difference between intranasal corticosteroid spray
combined with isotonic saline spray (VAS score 4.1 (SD 2.4)) and isotonic saline spray
alone (VAS score 5.4 (SD 2.1)) after two weeks (MD -1.30, 95% CI-2.97 to 0.37; 28
participants) (Analysis 6.1).

The pre-treatment VAS score for intranasal corticosteroid spray combined with isotonic
saline spray was 5.2 (SD 2.0) and for nasal spray alone was 5.3 (SD 2.5). Although the
combined treatment showed a better symptom improvement versus saline alone, the
reduction was non-significant (P = 0.056).

Significant adverse events: epistaxis

The study reported no adverse events.

Disease-specific health-related quality of life

The quality of life measurement (SNOT-22 questionnaire with a lower score indicating
a better quality of life) showed no significant difference between intranasal corti-
costeroid spray combined with isotonic saline spray (24.3 (SD 16.5)) and isotonic
nasal spray alone (32.3 (SD 15.2)) after two weeks (MD -8.0, 95% CI -19.75 to 3.75;
28 participants) (Analysis 6.2). Pre-treatment quality of life (SNOT-22) for intranasal
corticosteroid spray combined with isotonic saline spray was 30.0 (SD 15.2) and for
nasal spray alone was 38.1 (SD 19.9). The reduction was non-significant (P = 0.095).

Inspiratory peak flow levels, rhinomanometry or other objective measure-

ments of airflow
The peak nasal inspiratory flow (PNIF) measurements showed no significant differ-
ence between intranasal corticosteroid spray combined with isotonic saline spray (72.9
L/min (SD 25.5)) and isotonic nasal spray alone (82.1 L/min (SD 39.8)) after two weeks
(MD -9.20, 95% CI -33.96 to 15.56; 28 participants) (Analysis 6.3). Pre-treatment PNIF
for intranasal corticosteroid spray combined with isotonic saline spray was 77.1 (SD
25.8) and for nasal spray alone was 90.7 (SD 38.5). The reduction was non-significant
(P = 0.688).

Other adverse events

The study reported no adverse events.

DISCUSSION

Summary of main results

See Summary of findings table 1.

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We included 34 studies with a total of 4452 participants in this review, reporting on

our main comparison (intranasal corticosteroids versus placebo) and eight further
comparisons: intranasal corticosteroids versus saline, versus intranasal antihistamine,
versus capsaicin, versus cromoglycate sodium, versus ipratropium bromide, versus
intranasal corticosteroids and intranasal antihistamine, versus intranasal corticoster-
oids with saline and intranasal corticosteroids with saline versus saline alone. We were
able to analyse data from 18 studies for the eight different comparisons.

Intranasal corticosteroids versus placebo

We were only able to identify a significant number of studies (25) for the main compar-
ison, intranasal corticosteroids versus placebo; 13 of these studies could be included
in the meta-analysis. However, the evidence was limited by the fact that most studies
had only small numbers of patients and there was a high degree of variance in their
results. The two largest studies did show a significant improvement in symptom
scores (Jacobs 2009; Webb 2002). However, the study data in Jacobs 2009 are unlikely
to be credible. The study presented very unlikely standard deviation (SD) values, which
did not match the presented mean, n and P values, resulting in very high heterogeneity
of the data for the outcome ‘Total nasal symptom score, change from baseline’. Most 5
likely the SD values should have been standard error of the mean (SEM) values, as was
confirmed by re-analysis. The study authors did not reply to our questions about the
data. If the as-presented SD values are actually SEM, the overall effect size in favour
of intranasal corticosteroids for this comparison is only small.

There may be an improvement in patient-reported disease severity as measured by

a total nasal symptom score (TNSS) with intranasal steroids but we are uncertain
because we assessed the certainty of the evidence as low to very low due to high
imprecision and risk of publication bias due to small patient numbers. There were
too few data to draw conclusions on any differences according to type of intranasal
corticosteroids, dosage, vehicle used, frequency of usage or duration of treatment.

There is probably a higher risk of epistaxis with intranasal corticosteroids compared

to placebo (moderate-certainty evidence).

One study assessed quality of life (Lin 2017). This study showed that quality of life was
better in the intranasal corticosteroids group compared to the placebo group. However,
while this difference was significant at one-month follow-up it was barely noticeable
at three-month follow-up. Lin 2017 was not included in the meta-analysis because
of lack of quality of the study data. Firstly, the study presents unexpected data with
disappearance of benefit of intranasal corticosteroids with longer follow-up. Secondly,
including the study in the meta-analysis resulted in a high level of heterogeneity. Finally,
the SD values that are presented in the study do not match with presented means,

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n and P values. The data make more sense if the as-presented SD values should
actually be standard error of the mean (SEM), which was confirmed by a re-analysis.

As only two studies evaluated objective measurements of airflow and the data could
not be pooled due to the different methods used, we cannot draw conclusions on
this outcome. Neither study found a difference between intranasal corticosteroids
and placebo.

Intranasal corticosteroids probably result in little or no difference in the risk of other

adverse events compared to placebo (moderate-certainty evidence).

Other comparisons
For the following comparisons it is uncertain whether there are differences between
intranasal corticosteroids and the comparator group for any of the outcomes because
only one study assessed each comparison and in each case the certainty of the
evidence was very low: intranasal corticosteroids versus saline irrigation; intranasal
corticosteroids versus intranasal antihistamine;  intranasal corticosteroids versus
capsaicin; intranasal corticosteroids versus cromoglycate sodium; intranasal corti-
costeroids versus ipratropium bromide; intranasal corticosteroids versus intranasal
corticosteroids combined with intranasal antihistamines; intranasal corticosteroids
versus intranasal corticosteroids combined with saline irrigation; and intranasal corti-
costeroids with intranasal isotonic nasal spray versus isotonic nasal spray alone.

Three studies compared an intranasal corticosteroid with an intranasal corticosteroid

combined with an intranasal antihistamine. Two studies reported a significant differ-
ence in favour of intranasal corticosteroids combined with an intranasal antihistamine
versus intranasal corticosteroids alone (Guo 2015; Song 2018). The difference in favour
of the combined treatment strategy in these two studies was significant [pooled result
not shown in ‘Effects of interventions’]. The third study reported no statistically signif-
icant differences between the two treatments (Singh 2017).

Overall completeness and applicability of evidence

The types and dosages used in the studies were in keeping with manufacturers’
recommendations and are applicable to the population being studied. The phenotype/
endotype population of patients with non-allergic rhinitis studied most likely varied
among studies. As discussed in the Background, one would expect the inflammatory
non-allergic rhinitis endotypes (LAR/NARES) to benefit more from intranasal corti-
costeroids than the neurogenic or idiopathic endotypes.

Quality of life, which is one of the most important outcomes for patients, was only
included in three studies as an outcome measure (Boechat 2019; Lin 2017; Song 2018).

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There is too little information, therefore, to establish whether intranasal steroids have
an impact on patients’ quality of life.

Quality of the evidence

The certainty of the evidence (GRADE assessment) for our primary outcome, disease
severity as measured by patient-reported symptom score (total nasal symptom score),
was in general low because most studies had small participant numbers resulting in
high imprecision and high risk of publication bias. One of the only two studies with a
large number of participants was Jacobs 2009. Unfortunately this study contributed
to the very high heterogeneity in the study data because of unlikely standard deviation
values that were most likely to be standard error of the mean values.

It is likely that the variety of different intranasal corticosteroid treatment strategies

(type of intranasal corticosteroids, dosage, method of delivery), the differences in
included non-allergic rhinitis pheno- and endotypes and the differences in the ways of
measuring disease severity scores that were used contributed to the heterogeneity in
the study results. There was great variety in the methods used to measure symptom
severity scores and many scales were not validated. Not all studies defined non-allergic 5
rhinitis endotypes, for example presence or absence of inflammatory cells such as
eosinophils (NARES), which complicated subgroup analyses based on pheno- and
endotypes. A higher proportion of inflammatory cells (eosinophils) might improve the
chances of treatment effectiveness.

This low certainty of evidence is in contrast to the epistaxis adverse event outcome,
where we can be more certain that there is probably an increased risk in the intranasal
corticosteroids group compared to placebo (moderate-certainty evidence).

For quality of life and objective measurements of airflow there was not enough infor-
mation to draw conclusions (low-certainty evidence).

There was moderate-certainty evidence (large number of patients, low heterogeneity)

that intranasal corticosteroids probably result in little or no difference in the risk of
other adverse events compared to placebo.

Potential biases in the review process

The primary outcome total nasal symptom score consisted of different nasal
symptoms in different studies, measured on different measurement scales. When only
individual nasal symptom scores were reported but no total nasal symptom score, we
calculated a total nasal symptom scores for rhinorrhoea (secretion), nasal obstruction
(blockage) and sneezing: the most common symptoms used to calculate a total nasal
symptom score in the other included studies (Table 1). We decided not to include
itching, as a previous study by our research group has shown that ocular itch plays a

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less dominant role in non-allergic rhinitis compared to allergic rhinitis (Segboer 2018).
However, given that itching was included in the total nasal symptom score of a few
other studies, this may have resulted in a potential bias.

In some cases, the studies did not report enough information for us to analyse the
results further. Therefore for some studies we manually measured pixels from graphs
to calculate mean values and imputed standard deviations based on the P values
reported.

Some studies did include both allergic and non-allergic rhinitis participants but did
not provide (enough) separate data for non-allergic rhinitis participants to calculate a
mean and standard deviation (SD).

In the meta-analysis we included only studies with an intranasal corticosteroid dosage

range of 200 µg to 400 µg. The reason for this was to prevent double counting of the
same patients or controls (see Differences between protocol and review). This leads
to a potential bias in the review as the meta-analysis is limited to certain dosages.
However, only one study was excluded from the meta-analysis because of this dosage
limitation (Varricchio 2011).

Among studies the daily dosage of intranasal corticosteroids varied from 50 µg to

2000 µg. Most of the studies that compared different dosages of intranasal corticos-
teroids used a cross-over study design with the exception of Blom 1997 and Webb
2002, which used a parallel-group study design. In the cross-over studies the same
participants were treated with different dosages of intranasal corticosteroids, with a
short (one-week) or no wash-out, complicating a clear comparison between these
dosage subgroups (Balle 1982; Malm 1976; Malm 1981). Only Balle 1982 showed
a dosage effect for two nasal symptom score outcomes.  Malm 1976  and  Malm
1981 showed no significant difference between the dosage subgroups. The two paral-
lel-group studies both concluded that there were no statistically significant differences
between the different intranasal corticosteroid dosage subgroups (Blom 1997; Webb
2002). In the parallel-group studies the different dosage subgroups contained different
participants but were compared with the same control group. To prevent counting the
same patients or controls more than once, we decided to include one intranasal corti-
costeroid dosage in the meta-analysis. The most common intranasal corticosteroids
dosage was 200 µg. A test for subgroup differences showed no significant differ-
ence (no ‘dosage effect’) between 200 µg and 400 µg of intranasal corticosteroids.
We therefore included studies in the meta-analysis with an intranasal corticosteroid
dosage range of 200 µg to 400 µg.

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Agreements and disagreements with other studies or reviews

There are no previous published Cochrane Reviews on intranasal corticosteroids in
non-allergic rhinitis. There are, however, some position papers on non-allergic rhinitis,
such as Hellings 2017. This paper states that the inflammatory group (occupational
and drug-induced rhinitis) of non-allergic rhinitis patients may benefit from anti-in-
flammatory treatment such as nasal/oral corticosteroids. However, they conclude
that most randomised controlled trials evaluating local corticosteroids in non-allergic
rhinitis patients have shown a lack of efficacy. The PRACTALL report suggests that
intranasal corticosteroids could be effective in two phenotypes of non-allergic rhinitis,
i.e. NARES and possibly rhinitis medicamentosa, but it does not mention effectiveness
for other phenoor endotypes of non-allergic rhinitis (Papadopoulos 2015).

AUTHORS’ CONCLUSIONS

Implications for practice

For people with non-allergic rhinitis and clinicians 5

Overall, the certainty of the evidence for most outcomes in this review was low or very
low. It is unclear whether intranasal corticosteroids reduce patient-reported disease
severity in non-allergic rhinitis patients compared with placebo when measured at up
to three months. However, intranasal corticosteroids probably have a higher risk of
adverse effects such as epistaxis. There is a lack of evidence comparing intranasal
corticosteroids with other pharmacological treatments. It is unclear which is the best
type of intranasal corticosteroid to use with respect to type, concentration, vehicle
and how often to use it.

For those funding health care

When measured at up to three months, it is unclear whether intranasal corticosteroids
reduce patient-reported disease severity in non-allergic rhinitis patients compared
with placebo. However, they probably have a higher risk of adverse effects such as
epistaxis. Further research is needed: this could include large randomised controlled
trials comparing the effects of intranasal corticosteroids in different pheno- and
endotypes of non-allergic rhinitis and comparing different types, concentrations,
vehicles or frequencies of administration.

Implications for research

Evidence
As of July 2019, we have identified 34 studies that investigated the use of intranasal
corticosteroids in non-allergic rhinitis. The studies were generally small, included
different pheno-and endotypes of non-allergic rhinitis, and used different outcome

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measurements for patient-reported disease severity at up to four weeks. The evidence

identified indicates that there may be benefits in terms of patient-reported disease
severity when compared with placebo but the range of unvalidated instruments used,
along with heterogeneity in the study characteristics, made it difficult to draw definite
conclusions.

The reported evidence for adverse effects was of moderate certainty, i.e. there seems
to be a small but significant increased risk of epistaxis with intranasal corticosteroid
treatment.

More research on the use of intranasal corticosteroids in non-allergic rhinitis in the

form of large randomised controlled trials is important. The following aspects should
be considered when designing trials:

Population
• he different pheno- and endotypes of non-allergic rhinitis should be recognised
T
and trials should use stratified randomisation within these subgroups or focus
on one or other of the phenotypes. Care should be taken to adequately identify
the inflammatory endotypes (local allergic rhinitis and non-allergic rhinitis with
eosinophilia syndrome (NARES))
• Trials should be adequately powered and imbalances in prognostic factors (for
example, inflammatory or non-inflammatory endotypes) must be accounted for
in the statistical analysis
• Study participants should be diagnosed with non-allergic rhinitis using appropriate
diagnostic methods including clinical symptoms characteristic of (different pheno-
and endotypes of) non-allergic rhinitis with negative allergen sensitisation skin
prick test (SPT) and/or blood testing for allergen-specific IgE in serum (such as
ImmunoCAP or RAST) and proper rhinoscopy/nasal endoscopy

Intervention and comparison

• trial of intranasal corticosteroids compared with placebo could be considered
A
in patients with non-allergic rhinitis in primary care
• Investigators should consider the type, concentration, vehicle and frequency of
administration of intranasal corticosteroids used
• Investigators should consider comparing intranasal corticosteroids to other types
of treatment such as saline, intranasal antihistamines, capsaicin and ipratropium
bromide

Outcomes
• tudies should focus on outcomes that are important to patients with non-allergic
S
rhinitis (symptom scores, quality of life) and use validated instruments to measure
these, in particular using standard, validated, patient-reported disease severity

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scores and disease-specific health-related quality of life scores (e.g. the (mini)
Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ))
• The duration of the trial needs to be carefully considered. The current evidence
only includes trials that had up to a three-month treatment duration. A duration
of follow-up of 12 months is more likely to be meaningful given the chronicity of
the condition
• Trials and other high-quality studies should use consistent outcomes and adhere
to reporting guidelines, so that results can be compared across future trials. The
development of a standardised set of outcomes, or core outcome set, for non-
allergic rhinitis, agreed by researchers, clinicians and patients, would facilitate this
process

ACKNOWLEDGEMENTS

We would like to acknowledge the help of Jeremy Chee, Liyan Jia, Aidan Tan and
Yu-Tian Xiao in translating and extracting Chinese publication data; and Dr. Marijana
Geets-Kesic and Kristie Evenson for assistance with a Serbian study. 5
Thank you to Professor Carl Philpott for peer reviewing the manuscript and to Dee
Shneiderman for her consumer review.

This project was supported by the National Institute for Health Research, via Cochrane
Infrastructure, Cochrane Programme Grant or Cochrane Incentive funding to Cochrane
ENT. The views and opinions expressed therein are those of the authors and do not
necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the
Department of Health.

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REFERENCES TO STUDIES

Included studies

Arikan 2006
Arikan OK, Koc C, Kendi T, Muluk NB, Ekici A. CT assessment of the effect of flutica-
sone propionate aqueous nasal spray treatment on lower turbinate hypertrophy due
to vasomotor rhinitis. Acta Oto-Laryngologica 2006;126(1):37-42.

Balle 1982
Balle VH. The effect of budesonide in perennial rhinitis. European Journal of Respira-
tory Diseases. Supplement 1982;122:197-204.

Behncke 2006
Behncke VB, Alemar G, Kaufman DA, Eidelman FJ. Azelastine nasal spray and flutica-
sone nasal spray in the treatment of geriatric patients with rhinitis. Journal of Allergy
and Clinical Immunology 2006;2 Suppl 1:S263.

Blom 1997
Blom HM, Godthelp T, Fokkens WJ, KleinJan A, Mulder PG, Rijntjes E. The effect of
nasal steroid aqueous spray on nasal complaint scores and cellular infiltrates in the
nasal mucosa of patients with non-allergic, noninfectious perennial rhinitis. Journal
of Allergy and Clinical Immunology 1997;100(6 Pt 1):739-47.

Boechat 2019
Published and unpublished data
* Boechat JL. Re: RBR-498bnq The evaluation of the effectiveness of mometasone
furoate plus isotonic nasal saline in geriatric patients with rhinitis: a randomized clinical
trial. Email to C Segboer 8 July 2019.
Carvalho V, Olej B, De Moraes JR, Boechat JL. Mometasone furoate plus isotonic nasal
saline versus isotonic nasal saline alone in geriatric chronic rhinitis: an open-label,
active comparator, randomized trial. Allergy 2019;74(S106):376-853 [abstract TP0672].
RBR-498bnq. The effectiveness of mometasone furoate plus isotonic nasal saline
in the elderly with rhinitis. www.who.int/trialsearch/Trial2.aspx?TrialID=RBR-498bnq
(first received January 2018). [CENTRAL: CN-01900661; CRS: 10800361; CRSREP:
10800361]

Day 1990
Day JH, Andersson CB, Briscoe MP. Efficacy and safety of intranasal budeso-
nide in the treatment of perennial rhinitis in adults and children. Annals of Allergy
1990;64(5):445-50.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Ellegård 2001
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Hallén 1997
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Havas 2002
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Hillas 1980
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Incaudo 1980
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Jacobs 2009
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Löfkvist 1976
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Lundblad 2001
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Malm 1976
Malm L, Wihl JA. Intra-nasal beclomethasone dipropionate in vasomotor rhinitis. Acta
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Malm 1981
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Meltzer 1994
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Miller 1969
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Scadding 1995
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Schulz 1978
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Spector 1980
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Tarlo 1977
Tarlo SM, Cockcroft DW, Dolovich J, Hargreave FE. Beclomethasone dipropi-
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Warland 1982
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Webb 2002
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Excluded studies

Adamopoulos 1995
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Arbesman 1983
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Astafieva 2012
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rhinitis symptoms: the estimation of effectiveness, safety and clinical equivalence of
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генерика, содержащего флутиказона пропиона]. Lechashii Vrach 2012;9.

Balle 1982
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Berger 2012
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of mp29-02 (novel intranasal formulation of azelastine hydrochloride and fluticasone

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Bernstein 1997
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Blair 1977
Blair H, Butler AG. The treatment of perennial rhinitis with intranasal beclomethasone
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Bunnag 1992
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Celiker 2011
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Chatterjee 1974
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Dieges 1978
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Dockhorn 1999
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in combination for the treatment of rhinorrhea in perennial rhinitis. Annals of Allergy,
Asthma & Immunology 1999;4:349-59.

Gibson 1974
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145
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Hansen 1974
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Harding 1976
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Hartley 1985
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and tolerance of fluocortin butyl administered twice daily in adult patients with peren-
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Haye 1993
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Jones 1979
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Joubert 1983
Joubert JR. Flunisolide nasal spray in the treatment of perennial rhinitis. South African
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Juniper 1993
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Kakumanu 2003
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Kivisaari 1998
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146
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Kohan 1989
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Lahdensuo 1977
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Lau 1990
Lau SK, Wei WI, Van Hasselt CA, Sham CL, Woo J, Choa D, et al. A clinical comparison
of budesonide nasal aerosol, terfenadine and a combined therapy of budesonide and
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Lebowitz 1993
Lebowitz RA, Jacobs JB. Rhinomanometric and clinical-evaluation of triamcinolone
acetonide and beclomethasone dipropionate in rhinitis. American Journal of Rhinology
1993;7(3):121-4. 5
Malmberg 1988
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McAllen 1969
McAllen MK, Langman MJ. A controlled trial of dexamethasone snuff in chronic peren-
nial rhinitis. Lancet 1969;7602:968-71.

McAllen 1980
McAllen MK, Portillo PR, Parr EJ, Seaton A, Engler C. Intranasal flunisolide, placebo
and beclomethasone dipropionate in perennial rhinitis. British Journal of Diseases of
the Chest 1980;74(1):32-6.

Negreiros 1975
Negreiros EB, Filardi C. Preliminary observations on the intranasal use of beclometh-
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Price 2013
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147
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Rusnak 1981
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Scadding 1991
Scadding GK, Lund VJ, Holmstrom M, Darby YC. Clinical and physiological effects
of fluticasone propionate aqueous nasal spray in the treatment of perennial rhinitis.
Rhinology. Supplement 1991;11:37-43.

Shaw 1979
Shaw JD. Intra-nasal beclomethasone dipropionate in perennial rhinitis: a double-blind
study. Journal of Pharmacotherapy 1979;2(1):41-3.

Small 1982
Small P, Black M, Frenkiel S. Effects of treatment with beclomethasone dipropi-
onate in subpopulations of perennial rhinitis patients. Journal of Allergy and Clinical
Immunology 1982;70(3):178-82.

Svendsen 1989
Svendsen UG, Frølund L, Madsen F, Mygind N, Nielsen NH, Weeke B. Beclomethasone
dipropionate versus flunisolide as topical steroid treatment in patients with perennial
rhinitis. Clinical Otolaryngology and Allied Sciences 1989;14(5):441-5.

Sy 1979
Sy RK. Flunisolide intranasal spray in the treatment of perennial rhinitis. Archives of
Otolaryngology 1979;11:649-53.

Synnerstad 1996
Synnerstad B, Lindqvist N. A clinical comparison of intranasal budesonide with
beclomethasone dipropionate for perennial non-allergic rhinitis: a 12 month study.
British Journal of Clinical Practice 1996;50(7):363-6.

Turner Warwick 1980

Turner Warwick M. Double-blind trial comparing 2 dosage schedules of beclometha-
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months. Clinical Allergy 1980;10(3):239-51.

Webb 1977
Webb AK. Beclomethasone dipropionate aerosol in perennial rhinitis: preliminary
results of medical Research Council/Brompton Hospital Cooperative long-term study.
British Journal of Clinical Pharmacology 1977;4(Suppl 3):281S.

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Weckx 2001
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Wight 1992
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CHAPTER 5

Characteristics of studies

Characteristics of included studies

Arikan 2006

Methods Double-blind, parallel-group, randomised, placebo-controlled trial with 3

months duration of treatment
Participants Setting:  Otorhinolaryngology Head and Neck Surgery and Chest Disease
Departments, Faculty of Medicine, Kirikkale University, Turkey
Sample size:
Number randomised: 35 patients (20 in intervention, 15 in
control)
Number completed: 35 patients
Participant (baseline) characteristics:
Age: not reported
Gender: not reported
*No significant age or sex differences
Symptom duration: 1 to 8 years
Severity: N/A
Inclusion criteria: vasomotor rhinitis patients with bilateral inferior turbinate
hypertrophy suffering from chronic nasal obstruction, whose allergic skin
prick test and nasal cytologic examination for eosinophils were negative.
Exclusion criteria: previous sinonasal surgery, acute rhinosinusitis, nasal
polyps, clinically significant structural abnormalities, a history of hypersen-
sitivity to corticosteroids or food allergy, a need for regular use of inhaled
or systemic glucocorticosteroids for asthma and any systemic renal,
endocrine, cardiovascular, gastrointestinal or hematological diseases or
neuropsychiatric disorders, pregnant and lactating women; allergic rhinitis
(presence of three out of four of the following symptoms: nasal obstruction,
clear rhinorrhoea, repeated sneezing and itching of the nose for 1 year; and
allergic status as confirmed by radioallergosorbent tests and a skin prick
test using a range of common allergens).
Interventions Intervention group: fluticasone propionate (n = 20)
Dose: 50 µg, 1 puff each nostril (daily dose of 200 µg)
Frequency: twice daily (morning and evening)
Duration: 3 months
Vehicle: pressurised aerosol spray
Comparator group: placebo (vehicle) (n = 15)
Use of additional interventions: none
Outcomes 1. Nasal obstruction
VAS (0 to 10; 0 is better)
Measured prior to trial and after 1, 2 and 3 months of double-blind
treatment
Reported as before and after treatment
No numerical data provided
2. Adverse effects

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Table continued

Funding sources None

Declarations of None declared
interest
Notes Summary data not reported to allow inclusion in meta-analysis:
Outcomes reported as median, min, max and P value, so cannot
derive mean and SD to include in meta-analysis.
Study reports significantly greater relief of nasal obstruction with
fluticasone propionate versus placebo, however summary data
were not provided.

Risk of bias

Bias Authors’ Support for judgement

judgement
Random Unclear Random component in the sequence generation process:
sequence risk “patients with vasomotor rhinitis were randomly assigned to
generation receive a 3-month course of either an FP aqueous nasal spray
(selection bias) or a matching intranasal placebo spray”. The random sequence 5
generation is not further explained.
Allocation Unclear Not described
concealment risk
(selection bias)
Blinding of Low risk Double-blind study:
participants “Clinical evaluation was performed prior to the trial and after 1,
and personnel 2 and 3 months of double-blind treatment.”
(performance “Fifteen patients in the control group were treated with placebo
bias) FP, which was administered in the same fashion as the active
treatment.”
Blinding is not further described in detail.
Both treatments consisted of nasal spray making adequate
blinding possible. The outcomes consisted of a symptom-re-
lated questionnaire (outcome 1) completed by patients. The
CT assessment of turbinate size (outcome 2) was done by a
blinded radiologist. The symptom scores could have been influ-
enced by inadequate blinding (blinding not further described)
of the patients. The CT assessment is unlikely to have high risk
of bias.
Blinding of Low risk “The radiologist was blinded regarding the study medication.”
outcome
assessment
(detection bias)
Incomplete Low risk All participants that were randomised were reported in the
outcome data ‘Results’ section.
(attrition bias)

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CHAPTER 5

Table continued

Selective report- Low risk All outcomes that were pre-defined in ‘Materials and methods’
ing (reporting were reported in the ‘Results’ section.
bias)
Other bias Unclear Data not reported in means and SDs, but rather median, mean,
risk max and P values.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Balle 1982

Methods Double-blind, cross-over, randomised, placebo-controlled trial of 5 weeks total:

unclear run-in, 2 weeks treatment, 1 week wash-out, 2 weeks treatment
Participants Setting:  Departments of Otorhinolaryngology and Lung Medicine, Aalborg
hospital in Aalborg, Denmark
Sample size:
Number randomised: 36 perennial rhinitis, 15 non-allergic rhinitis
patients
Number completed: 36 perennial rhinitis, 15 non-allergic rhinitis
patients
Participant (baseline) characteristics:
Age: adults (specific age not described)
Gender: not described
Symptom duration: not described
Severity: not described
Inclusion criteria: patients with perennial rhinitis, with at least 2 of the 3 symp-
toms: nasal obstruction, rhinorrhoea, sneezing. Non-allergic rhinitis group was
defined by negative cutaneous allergy or RAST testing.
Exclusion criteria: diabetes, pregnancy, asthma, bronchitis
Interventions Intervention group: budesonide 200 µg daily (n = 15)
5
Dose: cross-over trial with 2 dosages of budesonide (200 µg and 400
µg daily)
Frequency: unclear
Duration: 2 weeks
Vehicle: not described
Comparator group: placebo (n = 15)
Use of additional interventions: none
Outcomes Total nasal symptom score (mean score of obstruction, rhinorrhoea and
sneezing)
Scale unclear, low indicates fewer symptoms
Presented as mean and SEM
Individual symptom scores
Measured, but not reported for non-allergic rhinitis subgroup only
Funding The role of the pharmaceutical company, AB Draco, besides providing the medi-
sources cation for the study, is not clarified.
Declarations None declared
of interest
Notes Cross-over trial with 2 dosages of budesonide (200 µg and 400 µg) versus
placebo. Dosage of 400 µg daily included in the meta-analysis. Single author
reports this RCT. Non-allergic rhinitis data (15 patients with non-allergic rhinitis)
available only for total nasal symptom score. Unclear scale.

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CHAPTER 5

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence Unclear risk Patients were randomly assigned: ‘Material and
generation (selection methods’: “They were randomly assigned to treatment
bias) with placebo, budesonide 200 µg or budesonide 400
µg.” The random sequence generation is not further
explained.
Allocation conceal- Unclear risk Not described
ment (selection bias)
Blinding of partici- Unclear risk ‘Abstract’: “double-blind cross-over study” and in ‘Materi-
pants and personnel als and methods’: “36 consecutive patients ... completed
(performance bias) a double-blind cross-over trial.”
Both treatments consisted of nasal spray making ade-
quate blinding possible.
Outcomes were patient symptom scores by the patient
and rhinoscopy by the investigator; these could have
been influenced by inadequate blinding.
Blinding of outcome Unclear risk Not described
assessment (detec-
tion bias)
Incomplete outcome Low risk All 36 patients included as described in ‘Materials and
data (attrition bias) methods’ are reported in the ‘Results’ section.
Selective reporting Unclear risk Individual symptom scores not described for non-aller-
(reporting bias) gic rhinitis subgroup separately.
Other bias Unclear risk Single author reports a RCT.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Behncke 2006

Methods Open-label, parallel-group randomised controlled trial with a 6-week study

period.
Participants Setting:  Otorhinolaryngology, Cleveland Clinic Florida, Weston, FL
Sample size:
Number randomised: 15 non-allergic rhinitis patients (negative
SPT), 3 allergic rhinitis
Number completed: 15 non-allergic rhinitis patients
Participant (baseline) characteristics:
Age: unclear
Gender: unclear
Symptom duration: 6-week study period
Severity: moderate-to-severe rhinitis
Inclusion criteria: 18 patients 65 years and older with a history of moder-
ate-to-severe rhinitis
Exclusion criteria: unclear
Interventions Intervention group: intranasal corticosteroids: fluticasone 2 sprays per nostril
daily (200 µg) (n = unclear)
Comparator group: intranasal antihistamine: azelastine: azelastine nasal
spray 2 sprays per nostril twice daily (1.1 mg) (n = unclear)
5
Use of additional interventions: none
Outcomes The primary outcome variable was quality of life as assessed by the Rhinitis
Quality of Life Questionnaire (RQLQ). Patients completed the RQLQ at baseline
and at week 3 and week 6. Patients also recorded symptoms and side effects
each day in a diary.
There is a stated significant improvement of symptom score from baseline,
however no definition/scale/range or numerical data for this symptom score.
Funding None
sources
Declarations of None declared
interest
Notes Study in geriatric patients
No numerical data for non-allergic rhinitis subgroup
Conclusion:
No difference in effectiveness between intranasal corticosteroids
and intranasal antihistamine.
Azelastine nasal spray and fluticasone nasal spray improved RQLQ
scores and rhinitis symptom scores in geriatric patients with either
allergic or non-allergic rhinitis.

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CHAPTER 5

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence Unclear risk Randomised: “Eligible patients were randomized to
generation (selec- treatment with either azelastine nasal spray 2 sprays
tion bias) per nostril bid (1.1 mg) or fluticasone 2 sprays per
nostril qd (200 µg) for a 6-week study period”. The
random sequence generation is not further explained.
Allocation conceal- Unclear risk No information
ment (selection
bias)
Blinding of partici- Unclear risk No information
pants and person-
nel (performance
bias)
Blinding of Unclear risk No information
outcome assess-
ment (detection
bias)
Incomplete High risk No numerical data on allergic or non-allergic rhinitis
outcome data subgroup.
(attrition bias)
Selective reporting High risk No numerical data on allergic or non-allergic rhinitis
(reporting bias) subgroup.
Other bias Unclear risk No information

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Blom 1997

Methods Double-blind, multi-centre, parallel-group, randomised, placebo-controlled trial

of 6 weeks total: 2 weeks run-in period, 8 weeks treatment
Participants Setting: outpatient Ear, Nose, and Throat Departments of the Leyenburg Hos-
pital in the Hague and the Dijkzigt University Hospital in Rotterdam,
the Netherlands
Sample size:
Number randomised: 65
Number completed: 65
Participant (baseline) characteristics:
Age: mean age 34 years (range 17 to 62 years)
Gender: 32 male, 33 female
Symptom duration: over 1 year
Severity: not described
Inclusion criteria: patients with NANIPER, with a history of nasal complaints
such as nasal obstruction, sneezing, and rhinorrhoea for a period of over 1
year; negative skin prick testing and Phadiatop. Periods of nasal discharge,
sneezing and congestion for an average of at least 1 hour per day for at least 5
days during a period of 14 days.
Exclusion criteria: allergic rhinitis, nasal or paranasal sinus infection, anatomic 5
disorders affecting nasal function (e.g. septal deviation, septal perforation, syn-
echia or bullous medial concha), pregnancy or lactation, systemic disorders,
and/or the use of medication affecting nasal function; nasal polyps; use of sys-
temic or inhaled corticosteroids, inhaled sodium cromoglycate or nedocromil
sodium or astemizole within the previous; inability of the patient to stop taking
medication affecting nasal function; a serious and/or unstable disease; nasal
surgery within the previous 6 weeks; abnormal laboratory results or abnormal
findings at physical examination.
Interventions Parallel-group study; 4 different treatment regimens:
a. Fluticasone propionate 200 µg once daily and placebo once daily for 8 weeks
b. Fluticasone propionate 200 µg once daily and placebo once daily for 4
weeks after which patients will be treated for 4 weeks longer with FP 200 µg
twice daily and placebo twice daily
c. Fluticasone propionate 200 µg twice daily and placebo twice daily for 8
weeks
d. Placebo twice daily for 8 weeks
Included in meta-analysis: fluticasone propionate (200 µg) twice daily for 8
weeks (n = 15)
Dose: a total daily dose of 400 µg for 8 weeks
Frequency: twice daily
Duration: 8 weeks
Vehicle: aqueous nasal spray
Comparator group: placebo twice daily for 8 weeks (n = 16)
Frequency: twice daily
Duration: 8 weeks
Use of additional interventions: none

161
CHAPTER 5

Table continued

Outcomes Individual symptoms:

Blockage
Sneezing
Rhinorrhoea
Measured by daily record chart used to measure symptoms. Inves-
tigators scored it on a scale (see below). Presented as increase in
percentage of symptom-free days.
Only mean data provided, but not SD.
Individual symptom scores:
Coughing
Mucus production
Eye irritation
Likely measured the same way as other individual symptoms.
No data reported.
Investigator scored individual symptoms:
Nasal blockage
Sneezing
Rhinorrhoea
Post-nasal drip
Measured on a scale of 0 to 3 (3 means worse).
No data reported.
Total nasal score (sum score of blockage, sneezing and rhinorrhoea)
Likely measured as sum score of 3 symptoms, and presented as
mean sum score for 1 week.
A more reliable VAS measure use in this meta-analysis instead.
Total symptom scores intensity of nasal symptoms
Measured on a VAS scale (0 to 10).
Time points: 2 weeks pre-treatment, 4 weeks after first batch of
treatment, 8 weeks after treatment.
Funding None
sources
Declarations None declared
of interest
Notes There are 2 measures of total nasal symptoms in this study that provide
numerical data. One is the mean sum score of blockage, sneezing and rhinor-
rhoea. The other one is intensity of nasal symptoms on a VAS. The latter is a
more established measurement, so we included this one in the meta-analysis.
Total symptom scores are measured at 4 weeks and at 8 weeks after treat-
ment. Symptom score measurement after 8 weeks of treatment is included in
the meta-analysis.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence Unclear risk Randomised study: eligible patients were randomised
generation (selection into 1 of 4 different treatment regimens: placebo
bias) administered twice daily for 8 weeks, FPANS (200 µg)
once daily and placebo once daily for 8 weeks, FPANS
(200 µg) once daily and placebo once daily for 4 weeks
followed by FPANS (200 µg) twice daily for 4 weeks, and
FPANS (200 µg) twice daily for 8 weeks. The random
sequence generation is not further explained.
Allocation conceal- Unclear risk Not described
ment (selection bias)
Blinding of partici- Unclear risk “A single-investigator, multicenter, double-blind, placebo
pants and personnel controlled study was done.” No further details regarding
(performance bias) blinding.
Both treatments consisted of nasal spray making ade-
quate blinding possible.
Outcomes: patient symptom scores by the patient and 5
biopsy/cytology by the investigator (single-investigator);
these outcomes could be influenced by inadequate
blinding.
Blinding of outcome Unclear risk Not described
assessment (detec-
tion bias)
Incomplete outcome Low risk All patients included as described in ‘Materials and
data (attrition bias) methods’ are reported in the ‘Results’ section.
Selective reporting High risk Outcomes not reported numerically or in figures: cough-
(reporting bias) ing, mucus production, eye irritation, terfenadine tablets
used, rhinoscopy.
Other bias Low risk Not described

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CHAPTER 5

Boechat 2019

Methods A randomised, open-label, active comparator trial, with 2 weeks treatment

Participants Setting:  outpatient allergy clinic at hospital, Universitario Antonio Pedro/
Universidade Federal Fluminense in the Metropolitan Region of Rio de
Janeiro, Brazil
Sample size:
Number randomised: 40 (20 to each treatment group, per treatment
group 14 non-allergic rhinitis patients, 28 non-allergic rhinitis patients
in total).
Number completed: 40 (28 non-allergic rhinitis patients in total).
Participant (baseline) characteristics:
Age: described for allergic and non-allergic rhinitis subgroups
together: varies between 60 and 87 years old (mean 71 years).
Gender: described for allergic and non-allergic rhinitis subgroups
together: 31 (75%) female participants.
Symptom duration: not described.
Severity: not explicitly described, however at least 2 chronic symp-
toms of rhinitis, congestion, rhinorrhoea, itching of the nose or sneez-
ing. Pre-treatment patients had combined nasal symptom scores of
5.0 to 5.8 on a 0 to 10 scale.
Inclusion criteria: at least 2 chronic symptoms of rhinitis, congestion, rhinor-
rhoea, itching of the nose or sneezing.
Exclusion criteria: primary or secondary immunodeficiency, mechanical
obstruction of upper airways and respiratory infection in the last 2 weeks.
Interven- Intervention group: intranasal steroid (mometasone furoate) + saline (n = 14)
tions Dose: 200 µg
Frequency: once a day
Duration: 2 weeks
Vehicle: nasal spray
Comparator group: isotonic nasal saline spray (n = 14), 4 times a day.
Use of additional interventions: no

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Table continued

Outcomes Individual symptoms:

Blocked nose
Itchy nose
Runny nose
Sneezing
Measured on a scale of 0 to 3 daily.
Mean change in symptom score from end of treatment to baseline
reported.
Data available for non-allergic rhinitis subgroup.
Combined symptom score
Combined nasal symptoms intensity score rated by a 10-point visual
analogue scale (VAS) at 2 weeks, with 0 indicating no symptoms and
10 the worst possible discomfort.
Measured pre-treatment and 2 weeks after treatment.
Data available for non-allergic rhinitis subgroup.
Peak nasal inspiratory flow
3 satisfactory maximal inspirations were obtained and the highest of
the 3 results was taken as the PNIF.
Measured pre-treatment and 2 weeks after treatment. 5
Measured in L/min.
Quality of life
SNOT-22 (sinonasal outcome test) questionnaire of quality of life.
SNOT-22 is the only questionnaire of quality of life in nasal chronic
problem that is validated in Brazilian Portuguese. This consists of
22 questions scored between 0 and 5, with higher scores meaning
greater problems. Data available for non-allergic rhinitis subgroup.
Measured pre-treatment and 2 weeks after treatment.
Adverse events
No adverse events (evaluated type of adverse events not described).
Funding Unclear/none reported
sources
Declarations None declared
of interest
Notes —

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CHAPTER 5

Risk of bias

Bias Authors’ judge- Support for judgement

ment
Random sequence gener- Low risk The randomisation scheme was generated using
ation (selection bias) a computer-generated code.
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants High risk Blinding of participants and personnel is not
and personnel (perfor- described. However, one patient group received
mance bias) 2 different nasal sprays while the other patient
group received only one type of nasal spray,
making blinding complicated.
Blinding of outcome Unclear risk Blinding of the person who evaluated the objec-
assessment (detection tive outcome (PNIF) is not described, nor the
bias) blinding of the patients (subjective outcomes
VAS and SNOT-22). However, one patient group
received two different nasal sprays while the
other patient group received only one type of
nasal spray, making blinding complicated at
least for the participants.
Incomplete outcome data Low risk All randomised patients completed the study.
(attrition bias)
Selective reporting Low risk All described outcomes of all included patients
(reporting bias) can be found in ‘Results’.
Other bias Low risk The authors declare no funding.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Day 1990

Methods Double-blind, parallel-group, randomised, placebo-controlled trial of 6 weeks

total: 2 weeks baseline, 4 weeks treatment
Participants Setting:  Kingston General Hospital, Ontario, Canada
Sample size:
Number randomised: 107 patients enrolled including children and
adults, of which 100 received treatment, and 99 were reported;
out of these, there were 23 patients with non-allergic rhinitis (10
treated with budesonide and 13 with placebo).
Number completed: 99
Participant (baseline) characteristics:
Age: described for allergic and non-allergic rhinitis subgroups
together: range 22 to 65 years (mean 41.9 years in budesonide,
and 45.9 years in placebo groups).
Gender: not described separately for allergic and non-allergic
rhinitis subgroups.
Symptom duration: at least 2 years
Severity: not described
Conclusion cannot be reached specifically about the non-allergic
rhinitis subgroup. 5
Inclusion criteria: perennial rhinitis over a period of at least 2 years, and cur-
rently not receiving therapy for rhinitis. Skin prick testing done either within
the last 6 months, or at baseline. In this review, only patients with non-allergic
rhinitis are included.
Exclusion criteria: pregnancy, tuberculosis, respiratory infection, additional
nasal disease, asthma requiring treatment with corticosteroids. In addition,
all other rhinitis medications were discontinued besides terfenadine. Immu-
notherapy was allowed as long as antigens relative to that time of year were
not involved.
Interventions Intervention group: budesonide (n = 10)
Dose: a total daily dosage of 400 µg
Frequency: 2 puffs per nostril each morning and each evening
Duration: 4 weeks
Vehicle: pressured canisters mounted in a nasal applicator
Comparator group: placebo (n = 13)
Use of additional interventions: terfenadine as rescue medication if symp-
toms became intolerable.

167
CHAPTER 5

Table continued

Outcomes Individual symptoms:

Blocked nose
Itchy nose
Runny nose
Sneezing
Measured on a scale of 0 to 3 daily.
Mean change in symptom score from end of treatment to baseline
reported.
Data available for non-allergic rhinitis subgroup
Combined symptom score
Measured and reported as above
Data available for non-allergic rhinitis subgroup
Global evaluation of efficacy
Measured by patient
At final clinic visit
Scale 0 (aggravated) to 4 (total control)
Data not available for non-allergic rhinitis subgroup
Adverse events
Data not available for non-allergic rhinitis subgroup
Funding None declared
sources
Declarations of None declared
interest
Notes —

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence gen- Low risk Randomisation was stratified according to age (6 to
eration (selection bias) 11 years, 12 to 18 years, above 18 years) and in the
oldest group also according to atopy. Authors report
balanced randomisation.
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants Unclear risk Double-blind, randomised, parallel-group design study.
and personnel (perfor- However, blinding is not described in further detail.
mance bias) Both treatments consisted of nasal spray making
adequate blinding possible. Subjective nasal scores
could have been influenced by inadequate blinding of
patients.
Blinding of outcome Unclear risk Double-blind, randomised, parallel-group design study.
assessment (detection However, blinding is not described in further detail.
bias)
Incomplete outcome Low risk Out of 107 randomised patients, 7 discontinued 5
data (attrition bias) the study before use of any medication and 1 in the
placebo group failed to follow-up. The authors do not
describe what they did with the data of the patient who
failed to return for follow-up. Given it was 1 patient
only out of a remaining 100, it is reasonable to con-
sider the effect to be small. Hence, we considered this
low risk for incomplete outcome data.
Selective reporting Low risk All described outcomes can be found in the results,
(reporting bias) though not all outcomes could be used for this review
a it focuses on non-allergic rhinitis.
Other bias Unclear risk The role of the pharmaceutical company AB Draco is
not clarified.

169
CHAPTER 5

Ellegård 2001

Methods Double-blind, parallel-group, randomised, placebo-controlled trial with 1-week

run-in, 8 weeks treatment, 16 weeks follow-up, total 24 weeks
Participants Setting:  28 maternity centres in the southern part of the County of Bohuslän
(Bohuslandstinget) and in the city of Göteborg, Sweden
Sample size:
Number randomised: 60 patients randomised; 26 (of 31) reported in
fluticasone group and 27 (of 29) reported in placebo group.
Number completed: 53
Participant (baseline) characteristics:
Age: 18 to 39 years
Gender: all females (given pregnancy rhinitis)
Symptom duration: at least 10 days
Severity: at least moderate, given requirement to demand treatment
Overall no difference with respect to age, number of children, weeks
of nasal congestion, gestational week and number of cigarette
smokers.
Inclusion criteria: Pregnancy rhinitis: pregnant women 18 to 39 years of age
with a treatment demanding nasal congestion for at least 10 days, without other
signs of respiratory tract infection.
Exclusion criteria: 1) corticosteroid treatment during the present pregnancy, or
a contra-indication for corticosteroids; 2) sodium cromoglycate 1 month before
entry; 3) medication with known influence on nasal mucosa, apart from local
decongestants, that were allowed for continuous use up to 6 weeks before entry;
4) serious or unstable concurrent disease; 5) anatomical abnormalities affecting
nasal breathing, nasal surgery during the present pregnancy or chronic nasal
symptoms before pregnancy; 6) purulent respiratory infection within 1 month
before entry; and 7) more than 1 fetus.
Interven- Intervention group: fluticasone propionate (n = 31 randomised, 26 reported)
tions Dose: 50 µg per actuation
Frequency: 2 actuations to each nostril in the morning (200 µg daily
dosage)
Duration: 8 weeks treatment
Vehicle: nasal spray
Comparator group: placebo (vehicle of the active spray) (n = 29 randomised, 27
reported)
Use of additional interventions: none

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Table continued

Outcomes Nasal congestion

Measured on a scale of 0 to 4; 0 = better
Reported for 8 weeks of treatment and 16 weeks of post-treatment
follow-up
In our analysis, we used data at the end of 8 weeks of treatment
Blockage index (BI)
Measured as BI=(PEF-nPEF)/PEF
Reported for 8 weeks of treatment and 16 weeks of post-treatment
follow-up
In our analysis, we used data at the end of 8 weeks of treatment
Acoustic rhinometry
Reported as 3 separate parameters: volume (cm3), MCA (cm2), dip 2
(cm2), however SDs could not be recalculated
Funding Göteberg Medical Society and GlaxoWellcome
sources
Declarations None declared
of interest
Notes This is the only study of intranasal corticosteroids in pregnancy rhinitis. Even 5
though it was industry sponsored, it found no effect of the studied medication.
Outcomes not included here due to lack of summary data or clinical: acoustic
rhinometry (full summary data not reported), anterior rhinoscopic assessment
of nasal secretions.

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Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence Unclear risk Randomised study: “The investigation was designed as
generation (selection a single-centre, placebo controlled, randomized, dou-
bias) ble-blind study with parallel groups.” Random sequence
generation is not further described.
Allocation conceal- Unclear risk Not described
ment (selection bias)
Blinding of partici- Unclear risk Double-blind study: “may be due to the fact that we
pants and personnel made a blind, placebo-controlled study”. “The investiga-
(performance bias) tion was designed as a single-centre, placebo controlled,
randomized, double-blind study with parallel groups.”
However, blinding is not described in further detail.
Both treatments consisted of nasal spray making ade-
quate blinding possible.
Subjective nasal scores could have been influenced by
inadequate blinding of patients. For a small amount also
reporting of nasal secretions and nasal crusts could
have been influenced by inadequate blinding of investi-
gators. Assessment of nPEF and PEF are less likely to be
influenced by inadequate blinding.
Blinding of outcome Unclear risk Not described, see above. Blinding of outcome assess-
assessment (detec- ment: patients are said to be blinded, but this is not
tion bias) further described. Blinding of the investigator is not
further described, it is said to be “double blinded”.
Incomplete outcome Unclear risk Not all results listed in ‘Methods’ are fully reported,
data (attrition bias) however most clinically important results are presented.
Selective reporting High risk 5 patients withdrawn from treatment group, 2 from
(reporting bias) placebo group.
Other bias Low risk Even though this was an industry-sponsored trial, it did
not show a beneficial effect of the studied medication.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Guo 2015

Methods Parallel-group randomised controlled trial with 6 weeks duration of treatment

Participants Setting:  Eye Otolaryngology Department, Eye Otolaryngology Hospital Affili-
ated to Fudan University, China
Sample size:
Number randomised: 162
Number completed: 154
Participant (baseline) characteristics:
Age: AZENS + FPNS (44.91 ± 6.77 years); FPNS only (42.43 ± 8.24
years)
Gender: N/A, no difference stated in paper
Symptom duration: AZENS + FPNS (2.70 ± 1.42 years); FPNS only
(3.01 ± 1.41 years)
Severity: AZENS + FPNS (nasal symptom score: 2.48 ± 0.40); FPNS
only (nasal symptom score: 2.50 ± 0.37)
Overall no difference for age, symptom duration and nasal symptom
score
Inclusion criteria:
• Patients between 30 to 60 years of age.
• Symptoms present for at least 9 months per year, with a history of at least 5
1 year.
• Primary symptom of nasal congestion; may be accompanied by sticky or
clear rhinorrhoea or sneezing.
• The symptom of nasal mucosal hyperaemia and congestion is mainly
caused by inferior turbinate enlargement.
• The nasal symptom score ≥ 2, and the patients have strong willingness to
improve the nasal symptom and have confidence in drug treatment.
Exclusion criteria:
• Nasal symptoms caused by allergy, typical symptoms of allergic rhinitis,
in patients once suffered from asthma or eczema, and allergen testing is
positive.
• Another cause of rhinitis (e.g. infectious or rhinitis medicamentosa).
• Anatomic abnormalities (e.g. deviated nasal septum or spur).
• Acute or chronic sinusitis, nasal polyps or the other space-occupying nasal
lesions.
• Use of nasal corticosteroids, decongestants, antihistamines or cold medi-
cine within one month.
• History of nasal surgery.

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Table continued

Interven- Intervention groups: fluticasone propionate nasal spray (FPNS): same as in

tions comparator group below; dosage unclear (n = 82 randomised, 78 treated, 5 lost
to follow-up)
Dose: no information provided
Frequency: FPNS 2 sprays each nostril, once a day
Duration: 6 weeks
Vehicle: nasal spray
Comparator group: azelastine nasal spray (AZENS) combined with FPNS
(n = 79 randomised, 76 received treatment as allocated, 3 lost to follow-up)
Dose: no information provided
Frequency: AZENS 2 sprays in each nostril, twice a day; FPNS 2
sprays each nostril, once a day
Duration: 6 weeks
Vehicle: nasal spray
Use of additional interventions: none
Outcomes 1. Total nasal symptom scores (no breakdown)
Measured pre-intervention, at 2 weeks and at 6 weeks (in the
meta-analysis reported at 6 weeks)
2. Satisfaction score
Binary outcome
Comprising a composite of ease of medication use, adverse
outcomes, cost, treatment efficacy
Funding None
sources
Declarations None declared
of interest
Notes Funding source not provided.
Total nasal symptom scores are measured at 2 weeks and at 6 weeks. Results
at 6 weeks are reported in the meta-analysis.

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Risk of bias

Bias Authors’ judge- Support for judgement

ment
Random sequence genera- Unclear risk Randomised controlled trial; however, there
tion (selection bias) was not sufficient information on sequence
generation.
Allocation concealment Unclear risk There was no information about allocation
(selection bias) concealment.
Blinding of participants and Unclear risk As the primary outcomes of nasal symptom
personnel (performance bias) scores and adverse events are both
self-reported outcome measures, and the
article had no information on blinding, there
was not sufficient information to make a
judgement.
Blinding of outcome assess- Unclear risk As the primary outcomes of nasal symptom
ment (detection bias) scores and adverse events are both
self-reported outcome measures, and the
article had no information on blinding, there
was not sufficient information to make a 5
judgement.
Incomplete outcome data Low risk 8 of 161 patients lost to follow-up, likely not
(attrition bias) significant.
Selective reporting (reporting High risk No protocol provided and all the reported
bias) outcomes were not prespecified in the
methods section of the article. Total nasal
symptom score calculation is not specified.
Other bias Low risk No other sources of bias were found in this
study.

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CHAPTER 5

Hallén 1997

Methods Double-blind, parallel-group, randomised, placebo-controlled trial with 14 days

duration of treatment
Participants Setting:  outpatient department of the ENT clinic at Sodersjukhuset, Stock-
holm, Sweden
Sample size:
Number randomised: 20 patients randomised; 10 per treatment
group, 19 patients reported
Number completed: 20 (results for 1 patient were excluded because
of a concurrent common cold during study period)
Participant (baseline) characteristics:
Age: mean age 33 years
Gender: 12 female and 8 male
Symptom duration: 2 years of topical decongestant use
Severity: not described
Inclusion criteria: patients with rhinitis medicamentosa, defined as overuse of
topical decongestants for at least 2 years, using their spray 1 to 15 times a day.
5 patients with documented allergies were NOT excluded.
Exclusion criteria: anatomic problems on rhinoscopy (not identified in any
patient).
Interventions Intervention group: fluticasone propionate (n = 10 randomised, 9 or 10 reported
(1 patient excluded without identification of group))
Dose: 50 µg per spray (200 µg per day total)
Frequency: 2 sprays into each nostril in the morning
Duration: 2 weeks treatment
Vehicle: aqueous nasal spray
Comparator group: placebo (vehicle of the active spray) (n = 10 randomised, 9
or 10 reported (1 patient excluded without identification of group))
Use of additional interventions: none
Outcomes 1. Nasal congestion
Measured on a VAS, 0 to 100
Reported for all days, 0 to 14 days
2. Rhinostereometry
Measure of nasal mucosal swelling: changes in the position of the
mucosal surface of the medial side of the head of the inferior concha
are registered in the plane of focus along the mm scale
3. Acoustic rhinometry (MCA 2 area)
Measured in cm2
4. PNIF
Measured in L/min
Funding GlaxoWellcome
sources
Declarations None declared
of interest

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Table continued

Notes 5 patients with documented allergies were NOT excluded.

No difference between AM (Figure4) and PM (Figure5) data, AM data included.
1 patient's results not reported, but it is not indicated which group they
belonged to, so most likely both groups had 10 patients.
The study was financially supported by Glaxo Wellcome AB, Molndal, Sweden.

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence generation Unclear risk “A parallel randomized, double-blind study”.
(selection bias) Random sequence generation was not further
described.
Allocation concealment (selec- Unclear risk Not described
tion bias)
Blinding of participants and Unclear risk “Double-blind study”, however blinding was not
personnel (performance bias) further described. Both treatments consisted
of nasal spray making adequate blinding 5
possible.
Outcome 1 (nasal airflow) as measured by
rhinostereometry, acoustic rhinometry and the
peak inspiratory flow meter, are unlikely to be
influenced by inadequate blinding.
Outcome 2 (symptom scoring) is more likely to
be influenced by inadequate blinding.
Blinding of outcome assess- Unclear risk Not described although it says it is a dou-
ment (detection bias) ble-blind study.
Incomplete outcome data Unclear risk The results from 1 patient were excluded
(attrition bias) because of a concurrent common cold during
the study period.
Selective reporting (reporting Low risk All outcomes described in ‘Methods’ are fully
bias) reported in ‘Results’.
Other bias Unclear risk The study was financially supported by Glaxo
Wellcome AB, Molndal, Sweden.

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CHAPTER 5

Havas 2002

Methods Double-blind, parallel-group, quasi-randomised (on odds and even basis)

controlled trial; 31 days total (3 days prior to treatment and 4 weeks of treat-
ment)
Participants Setting:  Department of Otolaryngology Head and Neck Surgery, Prince of
Wales Hospital, Sydney, Australia
Sample size:
Number randomised: 40
Number completed: 40
Participant (baseline) characteristics:
Age:
Budesonide group: males 40.3 years; females 37.0 years
Capsaicin group: males 41.5 years; females 41.0 years
Gender: 20 males, 20 females
Symptom duration: perennial
Severity: not reported
No significant difference for main examined symptoms (based on
figures)
Inclusion criteria: patients with perennial non-allergic rhinitis (IgE < 100 and
RAST negative) examined by the senior author. Nasal endoscopy used to
confirm rhinitis.
Exclusion criteria: any relevant antecedent history of rhinosinusitis or
antecedent nasal or sinus surgery. Presence on nasoendoscopy of nasal
septal deviation, nasal polyposis, rhinosinusitis and/or neoplasm. Smokers.
Interventions Intervention group: budesonide (n = 20)
Dose: 64 µg/dose), 2 puffs of the spray in each nostril, after
administration of lignocaine/phenylephrine (co-phenylcaine)
before the 1st treatment
Frequency: each AM and PM
Duration: 2 weeks
Vehicle: nasal spray
Comparator group: capsaicin (n = 20)
Dose: 70 μL, delivering 0.654 μg of capsaicin (capsaicin 71%,
dihydrocapsaicin 20.94% and nordihydrocapsaicin 4.94%), 2 puffs
into each nostril. Co-phenylcaine spray 10 minutes prior to
capsaicin first treatment.
Frequency: once weekly self-administration of 2 puffs of capsaicin
in each nostril weekly
Duration: 4 weeks
Vehicle: nasal spray
Use of additional interventions: co-phenylcaine spray before both
budesonide and capsaicin

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Table continued

Outcomes Individual symptom scores (headache, post-nasal drip, rhinorrhoea, nasal

blockage, sore throat, sneezing)
Assessed on a VAS (0 to 5; 0 = no symptoms), separately for each
side, 3 days prior to treatment and during last 3 days of treatment.
Aggregate total relief
Decrease of symptom scores after treatment: sum of relief scores
for all 6 symptoms.
Responders (improved versus worse or unchanged)
Funding None
sources
Declarations of None declared
interest
Notes Calculated a total nasal symptom score from means rhinorrhoea, blockage
and sneezing and calculated a pooled SD.
Disclosures: no financial interest with company supplying capsaicin.

Risk of bias
5
Bias Authors’ Support for judgement
judgement
Random sequence generation High risk Pseudo-randomisation: “they were pseudo-ran-
(selection bias) domized in two groups based on odds and
evens basis”.
Allocation concealment High risk Sequence generation was on an odds and evens
(selection bias) basis.
Blinding of participants and High risk High risk due to pseudo-randomisation.
personnel (performance bias)
Blinding of outcome assess- Unclear risk Not described
ment (detection bias)
Incomplete outcome data Low risk All outcomes described in ‘Methods’ are
(attrition bias) reported in ‘Results’.
Selective reporting (reporting Low risk No selective outcome reporting identified.
bias)
Other bias Low risk No other sources of bias identified.

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CHAPTER 5

Hillas 1980

Methods Double-blind, cross-over, randomised controlled trial with 4-week treatments,

wash-out not described. Cross-over, in 4 sequences: 1) sodium cromoglycate/
placebo/beclomethasone dipropionate/placebo; 2) beclomethasone dipropi-
onate/placebo/sodium cromoglycate/placebo; 3) placebo/sodium cromogly-
cate/placebo/beclomethasone dipropionate; and 4) placebo/beclomethasone
dipropionate/placebo/sodium cromoglycate)
Participants Setting:  Department of Medicine, University of Auckland School of Medicine,
Auckland, and Auckland Hospital Board, Auckland, New Zealand
Sample size:
Number randomised: 58 patients randomised, 52 patients analysed,
of which 21 were non-allergic rhinitis patients
Number completed: 52
Participant (baseline) characteristics:
Age: 13 to 58 years (mean age 29 years) for allergic and non-allergic
rhinitis groups
Gender: females: 29; males: 23 for allergic and non-allergic rhinitis
groups
Symptom duration: 1 to 45 years (mean 11 years)
Severity: severe
Inclusion criteria: 
only patients with severe chronic perennial rhinitis, usually without asthma,
were admitted to the trial. Almost all patients had been treated previously either
surgically or with drugs, or both.
Patients who received no relief from the sprays and were severely debilitated
by their symptoms were permitted to use antihistamine tablets, but were
requested to record the number taken each day.
Nasal infections, including those not clinically obvious but detected by the pres-
ence of increased numbers of neutrophils in nasal smears, were treated with a
short course of antibiotics before the trial.
Exclusion criteria: 
large polyps, mechanical obstruction, severe nasal infections, aspirin sensitiv-
ity, steroid dependence, use of continuous medication excepting oral contra-
ceptives, pregnant women and children under the age of 12.

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Table continued

Interventions Intervention group: sodium cromoglycate/Comparator group: beclometha-

sone dipropionate
Beclomethasone dipropionate (n = 21)
Dose: 50 µg/puff; 1 puff into each nostril
Frequency: 4 times per day (total daily dosage of 400 µg)
Duration: 4 weeks
Vehicle: aerosol
Beclomethasone dipropionate placebo (n = 21)
Dose: placebo
Frequency: 4 times per day
Duration: 4 weeks
Vehicle: aerosol
Sodium cromoglycate (n = 21)
Dose: 2%
Frequency: 6 times per day
Duration: 4 weeks
Vehicle: spray
Sodium cromoglycate placebo (n = 21)
Dose: placebo 5
Frequency: 6 times per day
Duration: 4 weeks
Vehicle: spray
Use of additional interventions: none
Outcomes Total nasal symptom score
Measured as a composite score of individual symptom scores of
sneezing, rhinorrhoea, nasal pruritis, blocked nose, itchy eyes, watery
eyes and red eyes
Measured on a scale of 0 to 3, where 0 = nil, 1 = mild, 2 = moderate
and 3 = severe
Reported as a mean of 4-week treatment period
Data not available for non-allergic rhinitis group separately
Individual symptom scores
Measured as above
Data not available for non-allergic rhinitis group separately
Symptomatic relief (responders)
Patients were asked whether the drug relieved their symptoms par-
tially or completely
Funding Medical Research Council of New Zealand, Fisons (Australia) Ltd, Essex Labo-
sources ratories, Australia and Schering Corporation
Declarations None declared
of interest

181
CHAPTER 5

Table continued

Notes Only data on responders versus no responders for non-allergic rhinitis sub-
group.
Wash-out period not described, potential spillover of treatment effect.
Industry-sponsored trial by 2 companies providing 2 different drugs. The study
shows no preference for one of the drugs, and therefore likely industry involve-
ment was unbiased.
Conclusion:
Beclomethasone dipropionate was significantly more effective in reliev-
ing symptoms than sodium cromoglycate (76.9% and 50% of the patients
improved respectively, P < 0.001). Both drugs were more active than placebos
but while beclomethasone dipropionate was very clearly more effective (P <
0.0005), sodium cromoglycate was only marginally better than its placebo (P <
0.05). Beclomethasone dipropionate was selected by 56% of the patients as the
best agent for continuing therapy.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear Patients were assigned randomly to the cross-over
tion (selection bias) risk sequence: “Patients were assigned randomly to
one of the above sequences.” However, random
sequence generation is not further described.
Allocation concealment Unclear Not described
(selection bias) risk
Blinding of participants and Unclear Double-blind trial, however blinding not further
personnel (performance bias) risk described. Both treatments consisted of nasal
spray making adequate blinding possible.
Outcomes were improvement, symptom scores and
drug preference. These could have been influenced
by inadequate blinding.
Blinding of outcome assess- Unclear Unclear, see above
ment (detection bias) risk
Incomplete outcome data Unclear 58 allergic rhinitis and non-allergic rhinitis patients
(attrition bias) risk were selected for the study and 52 were reported. 5
Selective reporting (reporting Unclear Not all outcomes are reported for the non-allergic
bias) risk rhinitis subgroup separately.
Other bias Low risk Industry-sponsored trial for both studied drugs,
however it is unlikely that one company would have
been favoured against the another.

183
CHAPTER 5

Incaudo 1980

Methods Double-blind, parallel-group, controlled trial with 2 weeks baseline, 6 weeks of

treatment. Randomisation was not described
Participants Setting:  Allergy Clinic, Departments of Pediatrics and Internal Medicine and
CIinicaI Investigation Center, Naval Regional Medical Center, and the
Akgy Department. Kaiser-Perrnanente Medical Center. San Diego, and
Syntex Corporation, Palo Alto
Sample size:
Number randomised: 56 patients; some analyses reported for 52
patients with skin prick testing results; out of these, there were a total
of 22 patient with non-allergic rhinitis
Number completed: 56 (of the 52 patients with skin prick test testing,
all were reported in ‘Results’)
Participant (baseline) characteristics:
Age: 19 to 62 (mean age 34.7)
Gender: all male
Symptom duration: at least 2 years
Severity: overall moderate severity: the patients chosen had symp-
toms severe enough to require medication on the majority of days
during the 3 months prior to the study
Overall no difference with respect to age, duration of symptoms or
concomitant medication use. Nasal congestion (P = 0.029) and a past
history of complicating nasal disorders were more frequent in the
flunisolide group. Conclusion cannot be reached specifically about
the non-allergic rhinitis subgroup.
Inclusion criteria: perennial rhinitis consisting primarily of nasal stuffiness,
rhinorrhoea or sneezing for a duration of at least 2 years. Non-allergic rhinitis
patients could be isolated from this study based on negative skin prick testing.
Exclusion criteria: nasal polyps
Interven- Intervention group: flunisolide (n = 11)
tions Dose: 0.025% flunisolide in aqueous propylene glycol/polyethylene
glycol. On average, 200 µg/day of flunisolide daily.
Frequency: 2 sprays in each nostril twice daily
Duration: 2 weeks baseline, 6 weeks treatment
Vehicle: coarse droplet spray via a pump-activated, non-Freon-pro-
pelled device
Comparator group: placebo (vehicle of the active spray) (n = 11)
Use of additional interventions: usual symptomatic medication in both groups
during baseline and double-blind periods of the study.

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Table continued

Outcomes Individual symptoms: sneezing, stuffy nose, runny nose, nose blowing,
post-nasal drip, measured on a scale of 1 to 4
Only P values reported: no difference between flunisolide and placebo
in non-allergic rhinitis subgroup
Data available for non-allergic rhinitis subgroup
Overall severity of rhinitis
Recalculated from Figure 1 of the article
Scale 1 (absent) to 4 (severe)
Disease control
Data reported as P values for allergic and non-allergic groups, or
cumulatively for both groups. Missing summary data cannot be
imputed.
Adverse events
Data available for non-allergic rhinitis subgroup
Significant benefit from flunisolide
Compares only those patients in the flunisolide group, therefore com-
parisons cannot be made with placebo
Funding None
sources 5
Declarations None declared
of interest
Notes Individual symptoms: sneezing, stuffy nose, runny nose, nose blowing, post-
nasal drip. For all individual symptoms, only P values are presented in Table III.
All P values are negative for non-allergic rhinitis group, but actual data cannot be
calculated from this table.
Study of perennial rhinitis including both allergic and non-allergic rhinitis
patients, but only males.
Co-intervention in the form of usual symptomatic medication was allowed to be
used by patients.
Company involvement unclear manufacturer?
Ethics approval not cited.

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CHAPTER 5

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- High risk “Thereafter, the patients were issued in a double
tion (selection bias) blind fashion either the active drug or the vehicle
control in identical plastic bottles.” “After the
study procedures were completed, the code was
broken.”
Allocation concealment High risk Randomisation not described
(selection bias)
Blinding of participants and Unclear risk Blinding is not further described. Both treatments
personnel (performance bias) consisted of nasal spray in identical bottles
making adequate blinding possible.
Outcomes were symptom scores/severity of rhi-
nitis symptoms and immunological studies. The
first outcome is likely to be influenced by inade-
quate blinding, the second outcome is unlikely to
be influenced by inadequate blinding.
Blinding of outcome assess- Unclear risk Not described, see above. Mainly symptom
ment (detection bias) scores assessed by patients could be influenced
by inadequate (unclear, not enough information)
blinding.
Incomplete outcome data Low risk Of 52 patients who had skin testing, all 52 are
(attrition bias) reported
Selective reporting (reporting Low risk All clinically relevant outcomes reported, although
bias) not all can be used for assessment of non-allergic
rhinitis only.
Other bias High risk The role of the pharmaceutical company Syntex
is not clarified. Also, only males were included in
this study.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Jacobs 2009

Methods Double-blind, parallel-group, randomised, placebo-controlled trial with 7to

14-day screening; 4-week treatment; follow-up phone call 3 to 5 days after
Participants Setting:  106 investigative centres in 6 countries (United States, Canada, Czech
Republic, Germany, Norway and Romania)
Sample size:
Number randomised: 699
Number completed: 660
Participant (baseline) characteristics:
Age:
12 to 18 years 33 (5%)
18 to 65 years 589 (84%)
65 to 75 years 59 (8%)
75 years 18 (3%)
Gender: female 479 (69%), male 220 (31%)
Symptom duration: symptomatic on the average of the last 8 record-
ings of rTNSS
Severity: at least moderate (4.5 out of 9 on the average of the last 8
recordings of rTNSS and 2 out of 3 for average reflective congestion
symptom) 5
Pooled patient demographics and baseline characteristics were
similar between the active and placebo groups
Inclusion criteria: vasomotor rhinitis (VMR) eligibility requirements included a
confirmed 2-year clinical history of perennial VMR, negative skin prick tests and
no history of responses to seasonal or perennial allergens, a positive response
to histamine skin testing, a normal sinus radiograph (to rule out infectious
sinusitis), and negative nasal cytology for eosinophils, defined as the absence of
eosinophils in nasal smears. In addition, a diagnosis of the VMR w/t (weather/
temperature) subtype was required, which required confirmation of disease
fluctuation with weather conditions by selection of weather/temperature change
as the predominant trigger for worsened rhinitis on the Vasomotor Rhinitis
Questionnaire.
Exclusion criteria: participants with rhinitis principally caused by airborne
irritant triggers (VMRir), allergic rhinitis, infectious disease or non-allergic rhinitis
with eosinophilic syndrome were excluded; and participants were required to
meet minimum symptom criteria and show persistence of their symptoms. Par-
ticipants were excluded if they had evidence of significant concurrent disease,
a clinically significant abnormal ECG, severe physical obstruction or septal
perforation of the nose, moderate-to-severe asthma, rhinitis medicamentosa,
upper respiratory tract infection, ocular disease (glaucoma, cataracts, or herpes
simplex), nasal or oropharyngeal candidiasis, history of adrenal insufficiency or
shingles, or a risk of developing chickenpox or measles during the study. Partic-
ipants could not use tobacco products. Pregnant women or those planning to
become pregnant were excluded.

187
CHAPTER 5

Table continued

Interven- Intervention group: fluticasone furoate (n = 353)

tions Dose: 110 µg
Frequency: once daily
Duration: 4 weeks
Vehicle: nasal spray
Comparator group: placebo (vehicle of the active spray) (n = 346)
Use of additional interventions: none
Outcomes 1. Change in daily reflective total nasal symptom score (rTNSS)
Participants rated congestion, rhinorrhoea, and post-nasal drip twice
daily on diary cards using a 4-point categorical scale ranging from 0
(symptom not present) to 3 (symptom hard to tolerate; interferes with
daily activities or sleeping)
Recorded as reflective symptom ratings (severity over the last 12
hours) and instantaneous symptom ratings (severity at the moment
of the assessment)
TNSS is the sum of the 3 symptom scores
Measured over treatment period (week 1 to 4)
2. Change in morning instantaneous TNSS
Measured as above
We chose to not report, as severity over 12 hours would be more
relevant than instantaneous symptoms
3. Change in individual symptom scores for congestion, rhinorrhoea and
post-nasal drip
Recorded as above
4. Overall response to therapy
For the entire treatment period
7-point categorical scale (significantly improved, moderately
improved, mildly improved, no change, mildly worse, moderately
worse, significantly worse)
We converted the first 3 orders of the scale into ‘responders’ and the
last 4 into ‘non-responders’ achieving a dichotomous outcome
5. Adverse events
Reported for headache, nasopharyngitis, epistaxis, pharyngo-laryn-
geal pain, diarrhoea, sinus headache, nausea, back pain, dysphonia
and vomiting
We decided to include any adverse events in the meta-analysis
Individual results were not significantly different
Funding GlaxoSmithKline
sources
Declarations None declared
of interest

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Table continued

Notes Study sponsored by GlaxoSmithKline.

Weather and temperature-sensitive vasomotor rhinitis.
One of the biggest and most well known (frequently cited) studies.
5% belongs to age 12 to 18 years.
Outcomes TNSS, individual symptoms, overall response and adverse events.
No significant difference between allergic and non-allergic rhinitis.

189
CHAPTER 5

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Randomised study: “To evaluate the efficacy
tion (selection bias) and safety of fluticasone furoate nasal spray in
subjects with VMRw/t, two global, multicenter,
randomized, double-blind, placebo-controlled
studies were conducted”. “Subjects were strat-
ified at randomization by country to account
for possible country-specific medical practice
differences and effects on study outcome.”
Random sequence generation is not further
described.
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and Unclear risk “Double-blind study” but blinding is not further
personnel (performance bias) described. Both treatments consisted of nasal
spray making adequate blinding possible.
Outcomes were symptom scores and adverse
events. These could have been influenced by
inadequate blinding.
Blinding of outcome assess- Unclear risk Not described, see above
ment (detection bias)
Incomplete outcome data Unclear risk Data available for 95% of patients.
(attrition bias)
Selective reporting (reporting Low risk All outcomes described in ‘Methods’ are fully
bias) reported in ‘Results’.
Other bias Unclear risk Company-sponsored study, but results do not
support the use of the medication.
The Jacobs 2009 study reports a very unlikely
standard deviation (SD) value that does not
match with the presented means, n and P values.
The data would make more sense if the standard
deviation (SD) presented values were actually
standard error of the mean (SEM), which was
confirmed by a re-analysis.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Jessen 1990

Methods Double-blind, double-dummy, cross-over, randomised controlled trial with 2

weeks treatment, 2 weeks wash-out, 2 weeks treatment; 3 weeks follow-up
after treatment
Participants Setting:  Department of Otolaryngology, University of Lund, Sweden
Sample size:
Number randomised: 31 patients randomised, 24 patients
reported
Number completed: 24
Participant (baseline) characteristics:
Age: 20 to 77 years (mean age 49 years)
Gender: 14 female, 10 male
Symptom duration: 0.5 to 30 years (mean 5.4 years)
Severity: at least moderate degree
Inclusion criteria: patients with the diagnosis of cholinergic non-allergic
rhinitis, with excessive nasal secretion for 0.5 to 30 years, and negative skin
prick test.
Exclusion criteria: asthma or nasal polyps; pregnancy; negative response to
ipratropium testing; negative skin prick testing; upper airway infection or use
of other relevant medication 2 weeks before the trial. 5
Interventions Intervention group: beclomethasone (n = 24)
Dose: 400 µg per day
Frequency: 2 puffs in the morning and evening to each nostril
Duration: 2 weeks treatment, 2 weeks wash-out, 2 weeks treat-
ment with comparator
Vehicle: aerosol
Comparator group: ipratropium (n = 24)
Dose: 160 µg
Co-treatment:
5 out of 24 patients were treated with 0.1% xylometazoline due
to high nasal airway resistance on rhinomanometry. It is unclear
which group these patients belonged to.
Use of additional interventions: none
Outcomes 1. Rhinomanometry
2. Secretions
Measured by patient on a scale of 0 for no symptoms to “3 or 4 for
severe symptoms”
Reported as cumulative score for 2 weeks
3. Sneezing
As above
4. Blockage
As above
5. Number of tissues used
6. Adverse events no data
Funding None
sources
Declarations of None declared
interest

191
CHAPTER 5

Table continued

Notes Scale somewhat ambiguous (“0 for no symptoms to “3 or 4 for severe symp-
toms”).
Symptom data presented for the period of 2 weeks. Given scale is up to 3-4,
and given numbers presented are in range of 6.1 to 19.8, we assume that
these are cumulative scores for 2 weeks (sum of scores).
Five of 24 patients had co-treatment with 0.1% xylometazoline. It is unclear
which group these patients belonged to.
Rhinomanometry data was not reported.
Patients report preference for drug; unclear how can they prefer if they are
blinded.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk “Double blind double dummy randomized cross-
tion (selection bias) over design”. Random sequence generation not
described.
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and Unclear risk “Double-blind study”; however, blinding not
personnel (performance bias) described in further detail. Both treatments con-
sisted of nasal spray making adequate blinding
possible.
Outcomes were symptom scores and prefer-
ence of treatment that could be influenced by
inadequate blinding. Assessment of eosinophilia
in nasal smears is a little bit less likely to be influ-
enced by inadequate blinding.
Blinding of outcome assess- Unclear risk Not described. See above.
ment (detection bias) 5
Incomplete outcome data High risk 31 patients randomised, but only 24 patients
(attrition bias) included: 5 excluded due to no benefit from
ipratropium and 2 found the trial regime too
time-consuming. This violates the intention-to-
treat protocol.
Selective reporting (reporting Unclear risk Most clinically relevant outcomes fully reported,
bias) however reported as means for each outcome.
Other bias High risk The study comments on patient preference for
medication and it is unclear how patients could
comment unless blinding was compromised.
Scale somewhat ambiguous (0 for no symptoms
to “3 or 4 for severe symptoms”).
Five of 24 patients had co-treatment with 0.1%
xylometazoline. It is unclear which group these
patients belonged to.

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CHAPTER 5

Kalpaklioglu 2010

Methods Single-blind, parallel-group, randomised controlled trial with 2 weeks duration of

treatment
Participants Setting:  tertiary care university hospital in Turkey
Sample size:
Number randomised: 63 patients with non-allergic rhinitis, additional
69 patients with allergic rhinitis, not considered in this analysis
Number completed: 63
Participant (baseline) characteristics:
Age: not reported separately for non-allergic rhinitis group
Gender: more female in the triamcinolone acetone nasal spray group
for both allergic and non-allergic rhinitis combined, however unclear if
this holds true for non-allergic rhinitis group only.
Symptom duration: not reported
Severity: at least moderate, given requirement to demand treatment
Overall no difference with respect to age, education, BMI, duration of
rhinitis, nasal operation, sinusitis. As noted above, there were more
females in the triamcinolone acetone nasal spray group for both aller-
gic and non-allergic rhinitis combined, however unclear if this holds
true for non-allergic rhinitis group only.
Inclusion criteria: history of at least 2 of the following symptoms: nasal itching,
sneezing, rhinorrhoea and/or nasal congestion, as described by the Allergic
Rhinitis and Its Impact on Asthma guidelines. Allergic rhinitis was defined as
nasal symptoms accompanied by SPT positivity with clinical relevance, whereas
non-allergic rhinitis was defined as nasal symptoms with negative SPTs.
Exclusion criteria: patients with nasal polyposis, infectious or occupational
rhinitis, major structural nasal abnormalities, current sinusitis and those who
were pregnant or lactating.
Interven- Intervention group: triamcinolone acetonide (n = 32)
tions Dose: 2 sprays/nostril (220 µg/day)
Frequency: once daily
Duration: 14 days
Vehicle: nasal spray
Comparator group: azelastine hydrochloride 0.1%, 2 sprays/nostril twice daily,
1.1 mg/day (n = 31)
Use of additional interventions: none

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Table continued

Outcomes 1. Total nasal symptom score (TNSS)

Measured on a scale of 0 to 4; 0 = better
Reported for 2 weeks after treatment
Reported as mean change from baseline
2. Individual nasal symptom scores (rhinorrhoea, congestion, itching, sneez-
ing, anosmia, conjunctivitis)
Measured on a scale of 0 to 4; 0 = better
Reported for 2 weeks after treatment
SDs and P values missing for non-allergic rhinitis group
However, text reports significant improvement of sneezing with triam-
cinolone in patients with non-allergic rhinitis (P < 0.01), as well as of
conjunctivitis (summary data not provided)
3. Peak nasal inspiratory flow (nasal peak inspiratory flow rate, nPIFR, in this
study)
The best of the 3 measurements was used for data analysis
4. Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36)
Not reported for non-allergic rhinitis subgroup separately
5. Mini–Rhinitis Quality of Life Questionnaire (mini-RQLQ)
Not reported for non-allergic rhinitis subgroup separately 5
6. Epworth Sleepiness Scale (ESS)
Not reported for non-allergic rhinitis subgroup separately
7. Adverse events
Not reported for non-allergic rhinitis subgroup separately
Funding None
sources
Declarations None declared
of interest
Notes Individual nasal symptom scores (rhinorrhoea, congestion, itching, sneezing,
anosmia, conjunctivitis): SDs and P values missing for non-allergic rhinitis
group. However, text reports significant improvement of sneezing with triamcin-
olone in patients with non-allergic rhinitis (P < 0.01), as well as of conjunctivitis
(summary data not provided).
Non-allergic rhinitis group not reported separately for: SF-36, mini-RQLQ and
adverse events.

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CHAPTER 5

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Randomised study: “randomized parallel-group
tion (selection bias) trial”, but random sequence generation not
further described.
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and Unclear risk Single-blind study, but likely participants blinded;
personnel (performance bias) not described in detail, however.
Symptom scores can be influenced in case of
inadequate blinding, assessment of nasal lavage
is less likely to have high risk of bias.
Blinding of outcome assess- Unclear risk Single-blind study and likely assessors not
ment (detection bias) blinded; not described in detail, however.
See above.
Incomplete outcome data Low risk All patients reported.
(attrition bias)
Selective reporting (reporting Low risk Most outcomes reported, however individual
bias) symptom SDs not reported.
Other bias Low risk No other risks of bias can be distinguished.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Lin 2017

Methods Parallel-group randomised controlled trial with 3 months duration

Participants Setting:  single-centre, university hospital in China
Sample size:
Number randomised: 101 patients non-allergic rhinitis (VMR)
patients were randomised, Group A control 24, Group B budesonide
25, Group C saline 25, Group D combination 27. Receiving treatment:
Group A 20, Group B 22, Group C 23, Group D 25
Number completed: 90
Participant (baseline) characteristics:
Age: (mean/SD) Group A: 40.8 ± 2.7; Group B: 41.2 ± 2.7; Group C:
43.9 ± 1.9; Group D: 43.6 ± 2.2
Gender: Group A: 13/11; Group B: 13/12; Group C: 14/11; Group D:
13/14 (male/female respectively)
Symptom duration: not reported
Severity: VAS (mean/SD): Group A: 6.00 ± 0.18; Group B: 5.91 ± 0.21;
Group C: 5.96 ± 0.17; Group D: 6.18 ± 0.17
Balanced in gender, age, VAS and SF-12v2
Inclusion criteria:
Patient living in Shanghai; age: 18 to 75 years; patients who present with symp- 5
toms and body signs of VMR; allergen skin prick test negative; allergen-specific
serum IgE negative (< 0.35 kU/L); blood eosinophil percentage < 5%; percentage
of eosinophil in nasal secretion smears < 5%.
Exclusion criteria: allergic rhinitis; acute/chronic inflammation of the respira-
tory tract; a history of nose surgery; a history of systemic use of corticosteroids
in the past 4 weeks; symptomatic deviation of nasal septum; cancer; patients
with contraindication of corticosteroid use; patients with contraindication of
hypertonic saline use; patients who participated in other clinical trials in the past
3 months; pregnant women.

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Table continued

Interven- Intervention group:

tions Group B (intranasal budesonide) (n = 25)
Dose (per spray and per day if available): 2 sprays per nostril per day
(64 µg per spray) = 256 µg/day
Frequency: every morning
Duration: 3 months (outcomes measured at 1 month, 2 months and 3
months)
Vehicle: nasal spray
Group D (nasal irrigation + intranasal budesonide) (n = 27)
Dose (per spray and per day if available): nasal irrigation: 100 mL of
3% saline per nostril; intranasal budesonide: same as Group B
Frequency: nasal irrigation: twice a day; intranasal budesonide: same
as Group B
Duration: outcomes are measured at 1 month and 3 months fol-
low-up
Vehicle: nasal irrigation: syringe; intranasal budesonide: nasal spray
Comparator group:
Group A (no treatment) (n = 20)
Group C (saline irrigation using 3% saline) (n = 25)
Use of additional interventions: none
Outcomes Primary outcomes:
Total nasal symptom scores in VAS
Significant adverse event epistaxis: number is reported
Secondary outcomes:
Quality of life is reported in SF-12v2
Other adverse events (pharyngitis, nasal dryness/crusting): numbers
are reported
Funding National Natural Science Foundation of China.
sources
Declarations None declared
of interest
Notes Only vasomotor rhinitis patients.
Unexpected data with disappearance of benefit of intranasal corticosteroids
with longer follow-up.
Results measured after 1 month, 2 months and after 3 months follow-up.
Funded by National Natural Science Foundation of China.

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Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Low risk Randomisation: “random sequence generated by
tion (selection bias) software”
Allocation concealment High risk P448 (in Chinese): “The allocation was performed
(selection bias) using random sequence generation software.
1~120 random sequence was generated and
assigned to each patient according to their order
of admission. Patients assigned to Number
1~30, 31~60, 61~90, 91~120 were respectively
allocated to Group A, B, C, and D.”
There is non-random component: day/order of
admission.
Blinding of participants and High risk Allocation concealment has a high risk of bias.
personnel (performance bias)
Blinding of outcome assess- High risk Blinding of participants and personnel was not
ment (detection bias) reported in this paper. However, considering that
the outcomes were primarily patient-reported, 5
blinding could not be achieved.
Incomplete outcome data Unclear risk The dropout of participants was 11/101 = 10.89%.
(attrition bias)
Selective reporting (reporting Unclear risk It is unknown whether there was selective
bias) reporting because the protocol for this trial is not
available.
Other bias Low risk No other risks of bias can be distinguished.

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CHAPTER 5

Lundblad 2001

Methods Double-blind, parallel-group, randomised, placebo-controlled trial with 2 weeks

screening, 6 weeks of treatment, 3 weeks follow-up after treatment
Participants Setting:  Department of Otorhinolaryngology, 16 sites (7 in Sweden, 3 in
Denmark, 3 in Finland and 3 in Norway)
Sample size:
Number randomised: 329
Number completed: 329
Participant (baseline) characteristics:
Age: 18 to 82 years (mean 42.8 years)
Gender: 167 males, 162 females
Symptom duration: mean duration of 9 years
Severity: at least moderate degree
Inclusion criteria: patients with nonspecific rhinitis symptoms of at least
moderate degree for at least 4 days per week during the month before entering
the study; a negative skin prick test to a standard test panel; a score of ≥ 2 for
rhinorrhoea or congestion and at least a moderate score during the month prior
to the trial for at least 1 hour daily and for at least 4 days per week.
Exclusion criteria: intolerance to aspirin or NSAIDs; significant septal deviations
or other structural deformities, nasal polyps; use of prohibited medications
(topical nasal, ocular or oral decongestants, nasal saline, shortor long-acting
antihistamines (for 24 to 72 hours); nasal atropine or ipratropium bromide,
ketotifen, azelastine and intranasal or ocular corticosteroids (for 1 to 2 weeks);
investigational drugs, high potency dermatological corticosteroids group III--IV
(Nordic classification), inhaled, oral, intravenous, rectal or intramuscular cortico-
steroids (for 1 to 3 months).
Interven- Intervention group: mometasone furoate (n = 167)
tions Dose: 200 µg
Frequency: once daily
Duration: 6 weeks
Vehicle: spray
Comparator group: placebo (constituents not described) (n = 162)
Use of additional interventions: as a rescue medication Clarityn (loratadine) 10
mg was dispensed by the physician at baseline and, if needed, at visits 3 and 4.

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Table continued

Outcomes 1. Subjective improvement (“subject’s overall evaluation of improvement”)

Reported as a dichotomous outcome (improved versus not improved)
Based on TNSS assessed via 4 symptoms: rhinorrhoea, nasal stuffi-
ness/congestion, nasal itching and sneezing, measured on a scale of
0 to 3
Possible scores from 0 to 12
Improvement defined as a reduction of at least 1 point in the overall
symptom score
Assessed during treatment
2. Objective improvement (“investigator’s overall evaluation of improve-
ment”)
Measured and reported as above
Unclear how specifically subjective improvement was distinguished
from investigator’s assessment of improvement
3. Therapeutic response
Reported as a scale of improvement, reported subjectively
Scale 1 to 5: 1 complete relief (virtually no symptoms present); 2
marked relief (symptoms greatly improved and, although present,
scarcely troublesome); 3 moderate relief; 4 slight relief; 5 treatment 5
failure
Here, we have combined “complete relief”, “marked relief” and “mod-
erate relief” into “responder” and “slight relief” and “treatment failure”
into “non-responder”
4. Relapse no numerical data reported, only P values
5. Quality of life no numerical data reported
6. Adverse outcomes
Reported as number of events
Individual numerical data reported for URTI, headaches, epistaxis,
sore throat
Funding Schering-Plough AB, Sweden
sources
Declarations None declared
of interest
Notes TNSS converted into “improvement” versus “failure” analysis, with sometimes
unclear methods of distinguishing between different outcome measures
derived from same original TNSS data.
Good data on adverse events, not on quality of life.
Study supported by Schering-Plough AB, Sweden.

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CHAPTER 5

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk “... a Nordic, multicenter, randomized, dou-
tion (selection bias) ble-blind, placebo-controlled study”.
Random sequence generation is not described.
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and Unclear risk Double-blind study, however blinding is not
personnel (performance bias) further described.
Improvement and quality of life assessment can
be influenced by inadequate blinding, as well as
report of adverse events.
Blinding of outcome assess- Unclear risk Not described, see above
ment (detection bias)
Incomplete outcome data Low risk Intention-to-treat analysis data available (all
(attrition bias) patients described in ‘Materials and methods’ are
reported in ‘Results’), even though per protocol
data also reported.
Selective reporting (reporting High risk Several sets of collected data not reported:
bias) quality of life, relapse and vitals data not reported
numerically.
Other bias Unclear risk Initially, total nasal symptom scores were col-
lected, however data were reported as subjective
and objective relief scores, leading to interpreta-
tion about original TNSS.
Study supported by Schering-Plough AB,
Sweden.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Löfkvist 1976

Methods Double-blind, cross-over, placebo-controlled trial with 4 weeks treatment, 1

week wash-out, 4 weeks placebo or in reverse order. Randomisation is unclear
Participants Setting:  university hospital in Lund, Sweden
Sample size:
Number randomised: 39
Number completed: 39
Participant (baseline) characteristics:
Age: 19 to 66 years (mean 39 years)
Gender: 19 males, 20 females
Symptom duration: half of the patients had had symptoms for more
than 10 years
Severity: not reported
Inclusion criteria: patients with a history of vasomotor rhinitis for many years,
who had perennial symptoms in the form of obstruction, nasal drip, sneezing
and nasal itching in varying degrees, and had negative allergy testing.
Exclusion criteria: nasal polyposis, obvious septum deviation, bronchial
asthma, pregnancy, or influenza-like disease.
Interven- Intervention group: beclomethasone dipropionate (n = 19)
tions Dose: 50 µg (300 µg daily dose)
5
Frequency: 3 times per day
Duration: 4 weeks
Vehicle: spray
Comparator group: placebo (constituents not described) (n = 20)
Use of additional interventions: none
Outcomes 1. Total nasal symptom score
Reported as a mean values and SD, in Figure 1 of the publication
Time points day 1, weeks 1 to 9
Assessed via 4 symptoms nasal catarrh, blockage, nasal itching and
sneezing, each measured on a scale of 0 to 3
Possible scores from 0 to 12
2. Individual nasal symptom scores
For nasal catarrh, blockage, nasal itching and sneezing, each mea-
sured on a scale of 0 to 3
Reported as a mean values and SD, in Figure 1 of the publication
Time points day 1, weeks 1 to 9
3. Patient’s subjective evaluation of therapeutic effect
Patients rated improvement after beclomethasone or placebo periods
Originally reported as “free of trouble”, “improved”, “unchanged” or
“worsened”
We converted this into “responder”, to include “free of trouble”,
“improved” and “non-responder”, to include “unchanged” or “wors-
ened”
Funding Glaxo Lakemedel AB, Sweden; Alfred Osterlund’s Stiftelse, Malmo, Sweden
sources

203
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Table continued

Declarations None declared

of interest
Notes Patients rated improvement after beclomethasone or placebo periods.
Originally reported as “free of trouble”, “improved”, “unchanged” or “worsened”,
converted into “responder”, to include “free of trouble”, “improved”, and “non-re-
sponder”, to include “unchanged” or “worsened”.

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- High risk Randomisation not described
tion (selection bias)
Allocation concealment High risk Randomisation not described
(selection bias)
Blinding of participants and Unclear risk Double-blind study, not further described.
personnel (performance bias) Nasal sprays were in identical packages so
blinding could have been possible.
Symptom scores could have been influenced by
inadequate blinding, cortisol levels not likely.
Blinding of outcome assess- Unclear risk See above
ment (detection bias)
Incomplete outcome data Unclear risk One patient withdrew due to influenza-simulating
(attrition bias) disease during beclomethasone treatment. It is
unclear what happened with this patient’s data.
Plasma cortisol levels reported for 19 patients
only.
Selective reporting (reporting Unclear risk Medical examination results not reported numer-
bias) ically, however given this is not an important
outcome, we judged the risk of bias as unclear.
Other bias Unclear risk Cross-over design with no clear signs of rando-
misation.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Malm 1976

Methods Double-blind, cross-over, placebo-controlled trial with 1 week prior to treatment,

2 weeks treatments x 4, given in 4 different sequences. No wash-out period.
Data only from 2nd week is used to minimise spill-over effect. Randomisation
not described
Participants Setting:  ENT Department, General Hospital, Malmo, Sweden
Sample size:
Number randomised: 21
Number completed: 21
Participant (baseline) characteristics:
Age: average 36 years (18 to 61 years)
Gender: 12 female, 9 male
Symptom duration: at least 1 year
Severity: not reported
Inclusion criteria: vasomotor rhinitis, as defined by symptoms of nasal block-
age, watery secretion and sneezing, and no relevant allergens found on history,
skin prick testing and provocation testing
Exclusion criteria: not described
Interven- Intervention group: beclomethasone dipropionate (n = 21)
tions Doses: (50 µg per puff) 200 µg daily, 400 µg daily, 800 µg daily (cross-
5
over study design)
Frequency: twice daily (200 µg) or 4 times daily (400 µg, 800 µg)
Duration: 2 weeks
Vehicle: Becotide aerosol used for asthma, with a special adaptor
Comparator group: placebo (constituents not described) (n = 21)
Use of additional interventions: not described
Outcomes 1. Individual symptom scores for nasal obstruction, rhinorrhoea, sneezing,
eye irritation
All symptoms ranked on a scale of 0 to 3
Data obtained from figure
2. Adverse effects transient irritation, sneezing, streaks off blood. No data
to perform analysis. No patient stopped study medication.
Funding Glaxo Lakemedel
sources
Declarations None declared
of interest

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Table continued

Notes Cross-over trial. Only overall summary data available for each inter-
vention.
Randomisation unclear.
Beclomethasone dipropionate 200 µg, 400 µg and 800 µg daily
versus placebo. 2-week treatments each, no wash-out period.
Patients assigned to 4 treatment sequences to go through all inter-
ventions in different orders.
Dosage of 400 µg daily included in meta-analysis.
Not clarified how many patients per treatment sequence.
Calculated a total nasal symptom score from means rhinorrhoea,
blockage and sneezing and calculated a pooled SD.
Remarkable decrease in symptom scores from baseline in Malm
1976 (60% decrease from baseline) and Malm 1981 (75% decrease
from baseline) studies.

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- High risk Randomisation not described
tion (selection bias)
Allocation concealment High risk Randomisation not described
(selection bias)
Blinding of participants and Unclear risk Double-blind study, not further described.
personnel (performance bias) Nasal sprays were in identical packages so
blinding could have been possible.
Symptom scores could have been influenced by
inadequate blinding, cortisol levels not likely.
Blinding of outcome assess- Unclear risk Not described, so see above
ment (detection bias)
Incomplete outcome data Low risk All patients completed the study.
(attrition bias)
Selective reporting (reporting High risk Summary data for each intervention group per
bias) treatment sequence not available.
Other bias High risk Cross-over design with no wash-out period.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Malm 1981

Methods Double-blind, cross-over, randomised controlled trial with 2 weeks run-in period;
2 weeks treatment; 1 week wash-out; 2 weeks treatment; 1 week wash-out; 2
weeks treatment; 1 week wash-out; 2 weeks treatment
Participants Setting:  university hospital in Lund, Sweden
Sample size:
Number randomised: 23 patients randomised
Number completed: 22
Participant (baseline) characteristics:
Age: 20 to 68 years (mean: 42 years)
Gender: 5 males, 17 females
Symptom duration: at least 1 year
Severity: not reported
Inclusion criteria: patients with perennial non-allergic rhinitis with 2 or more
of the symptoms of nasal obstruction, nasal secretion, sneezing attacks for at
least 1 year, and negative skin prick test.
Exclusion criteria: bronchial asthma or nasal polyposis.
Interven- Intervention groups: budesonide (n = 22)
tions Doses: 50 µg daily, 200 µg daily and 800 µg per day (cross-over study
design) 5
Frequency: 1 puff in each nostril, twice a day (morning and evening)
Duration: 2 weeks
Vehicle: pressurised aerosol
Comparator group: placebo (constituents not described) (n = 22)
Use of additional interventions: phenylpropanolamine as rescue medication
was allowed
Outcomes 1. Nasal obstruction
Measured by patient
Scale of 0 to 3 (0 is good)
Reported as mean ± SEM of at least 3 days of the patient’s symptom
score in each treatment period
2. Nasal secretion
As above
3. Sneezing
Measured by patient
Scale of 0 to 3 (0 is good: no sneezing = 0; 1 to 5 sneezes = 1 point; 6
to 15 = 2 points; more than 15 sneezes = 3 points)
Reported as above
4. Nasal airway resistance
Measured via rhinomanometry: nasal resistance parameter v2
Measured once at the end of the first week of the run-in period and
then on the day after each treatment period
Reported in degrees, 0 to 360 theoretically, wider angles correspond
to higher levels of resistance, low score is good
5. Treatment side effects
Funding AB Draco, a subsidiary of AB Astra
sources

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Table continued

Declarations None declared

of interest
Notes This is a cross-over trial.
Budesonide 50 µg, 200 µg and 800 µg daily versus placebo. 2-week
run-in, 2-week treatment each, 1-week wash-out period.
Dosage 200 µg daily included in the meta-analysis.
22 patients, however: 3 patients with no nasal obstruction and 1
patient with no sneezing attacks during the trial were excluded.
Another patient from the originally randomised patients was excluded
for social reasons.
Outcomes: nasal obstruction, nasal secretion, sneezing; patient-re-
ported, scale of 0 to 3, reported as mean ± SEM of at least 3 days of
the patient's symptom score in each treatment period.
Calculated a total nasal symptom score from means for rhinorrhoea,
blockage and sneezing and calculated a pooled SD.
Remarkable decrease in symptom scores from baseline in Malm
1976 (60% decrease from baseline) and Malm 1981 (75% decrease
from baseline) studies.
Involvement of AB Draco, a subsidiary of AB Astra, a pharmaceutical
company, is unclear.

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Comment: not described, but reports “prepara-
tion (selection bias) tions were given in randomized order”
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and Unclear risk Study reported as “double-blind”, blinding not
personnel (performance bias) further described.
Blinding of outcome assess- Unclear risk See above. As nasal sprays were compared, ade-
ment (detection bias) quate blinding could have been achieved.
For outcomes: rhinomanometry, nasal secretion/
smears and cortisol are less likely to be influ-
enced by inadequate blinding than symptom
scoring.
Incomplete outcome data High risk 22 patients were included for randomisation in
(attrition bias) a cross-over study design. 3 patients with no
nasal obstruction and 1 patient with no sneezing
attacks during the trial were excluded. Another
patient from the originally randomised patients
was excluded for social reasons. This has a risk
of attrition bias.
Selective reporting (reporting Low risk All described outcomes can be found in the
bias) results.
Other bias Unclear risk Involvement of AB Draco, a subsidiary of AB
Astra, a pharmaceutical company, is unclear.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Meltzer 1994

Methods Double-blind, multi-centre, parallel-group, randomised, placebo-controlled trial

with 4 weeks duration of treatment
Participants Setting:  Allergy and Asthma Research Centre, part of multi-centre trial
Sample size:
Number randomised: 286 non-allergic rhinitis patients
Number completed: 286 non-allergic rhinitis patients
Participant (baseline) characteristics:
Age: not reported
Gender: not reported
Symptom duration: at least 4 of 7 days prior to receiving study drug
Severity: nasal symptom scores of > 150 of 400 possible points for
sneezing, rhinorrhoea, nasal obstruction and post-nasal drip and, on
those 4 days the severity of at least 1 of the 4 symptoms must have
been at least 50 of 100 points
Inclusion criteria: 1) history of non-allergic rhinitis; 2) total serum immunoglob-
ulin E (IgE) level < 250 IU-ml; 3) negative SPT; 4) normal sinus radiograph.
Exclusion criteria: not defined, see inclusion criteria.
Interven- Intervention group: FPANS (fluticasone propionate) 100 µg or 200 µg twice
tions daily
5
Comparator group: placebo
Use of additional interventions: none
Outcomes Reduction of nasal symptom scores, particularly obstruction, overall assess-
ment of response to therapy: unclear definition, scale/range of nasal symptom
scores.
Funding None declared
sources
Declarations None declared
of interest
Notes No numerical data for non-allergic rhinitis group separately, only note that
FPANS in non-allergic rhinitis reduces total symptoms, improves individual
symptoms, mainly obstruction, and achieves significant overall improvement.

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CHAPTER 5

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Placebo-controlled, double-blind randomised trial
tion (selection bias) but randomisation not further described.
Allocation concealment Unclear risk Placebo-controlled, double-blind randomised trial
(selection bias) but randomisation not further described.
Blinding of participants and Unclear risk Blinding not described in detail
personnel (performance bias)
Blinding of outcome assess- Unclear risk Blinding not described in detail
ment (detection bias)
Incomplete outcome data High risk No numerical data on non-allergic rhinitis sub-
(attrition bias) group.
Selective reporting (reporting High risk No numerical data on non-allergic rhinitis sub-
bias) group.
Other bias Unclear risk No data available

Miller 1969

Methods Double-blind, cross-over, quasi-randomised (serial assignment into 2 groups)

controlled trial with 2 months total: 1 month on one treatment, then another
month on another. No wash-out period described
Participants Setting:  unclear, likely private office, USA
Sample size:
Number randomised: 90 patients randomised, 88 reported
Number completed: 88
Participant (baseline) characteristics:
Age: nearly all were adults, except 4 boys (9 to 14 years of age), 1 girl
of 17 years of age. Most patients were between 31 and 60 years of
age
Gender: 61 female, 27 male
Symptom duration: not reported
Severity: not reported
Inclusion criteria: vasomotor rhinitis, as defined by physical examination (reac-
tive non-allergic nasal membranes), skin testing where appropriate and absence
of allergic history.
Exclusion criteria: pregnancy, active tuberculosis, ocular herpes simplex,
acute or chronic infection, or other contraindication to adrenocortical hormone
therapy, use of medication for vasomotor rhinitis from 1 week before the trial
until the end of the trial.

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Table continued

Interven- Intervention groups: dexamethasone (n = 88)

tions Doses: 0.084 mg of dexamethasone per spray, 2 sprays in each
nostril (672 µg to 1008 µg of dexamethasone per day)
Frequency: 2 to 3 times per day
Duration: 1 month (no wash-out period)
Vehicle: aerosol container
Comparator group: placebo (inactive ingredients) (n = 88)
Use of additional interventions: none
Outcomes 1. Response to therapy
Measured on a scale: 100% = excellent; 75% to 99% = good; 50% to
74% = fair; < 50% = poor
Measured at 1 month after treatment
Data could be used for numerical analysis
2. Nasal obstruction
Measured by patient at 2 and 4 weeks after treatment
Scale 0 to 3, 0 is good
Reported as mean; SD recalculated based on P value
3. Discharge
Same as above 5
Data not included given P value not presented
4. Post-nasal drip
Same as above
Data not included
5. Sneezing
Same as above
Data not available
6. Anosmia
Same as above
Data not available
7. Side effects
Headache: data available
Funding None
sources
Declarations None declared
of interest
Notes No wash-out period in cross-over study.
Vasomotor rhinitis patients.
Only 1 patient had polyps, so decided that contamination was not an issue.
5 patients were below 18 years of age, but given that the majority appeared to
be over 12 we decided to include all patients.
Reported means for secretion, obstruction and post-nasal drip, however we
were not able to calculate a SD for secretion and post-nasal drip as the P value
was not reported, only the mean. So we can calculate a TNSS of obstruction,
secretion and post-nasal drip, but we cannot calculate a pooled SD, making this
outcome useless.

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CHAPTER 5

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- High risk Quasi-randomised (serial assignment into 2
tion (selection bias) groups): “The patients were divided into two
groups, in serial assignment, to a list of numbers
which designated the kind of medication to be
given”.
Allocation concealment Low risk Allocation concealed: “... were concealed by being
(selection bias) over-printed on a tear-off portion of the label
which was attached to the case report form”.
Blinding of participants and Unclear risk “Double-blind study” but blinding not further
personnel (performance bias) described.
Blinding of outcome assess- Unclear risk “Double-blind study” but blinding not further
ment (detection bias) described. Symptom scoring could have been
influenced by inadequate blinding, same as
symptoms by investigation.
Incomplete outcome data Low risk 2 patients from 90 were excluded: 1 due to not
(attrition bias) being able to identify group belonging, second
due to loss to follow-up. We think this exclusion
has a low chance of affecting overall outcomes.
Selective reporting (reporting Low risk All outcomes reported
bias)
Other bias Unclear risk SDs not reported, but could be recalculated using
P values.
No wash-out period.

212
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

O’Reilly 1991

Methods Double-blind, cross-over, controlled trial with 24 weeks total: 12 weeks on one
treatment, then another 12 weeks on another. No wash-out period described.
Randomisation not described
Participants Setting:  general ENT clinics at Whitechapel and Halton, UK
Sample size:
Number randomised: 23 patients randomised
Number completed: 16 reported (5 withdrew in placebo phase, 2 in
treatment phase because symptoms became intolerable)
Participant (baseline) characteristics:
Age: not described
Gender: not described
Symptom duration: not described
Severity: not reported
Inclusion criteria: patients with perennial rhinitis, defined as the presence
of nasal obstruction, paroxysmal sneezing and seromucinous rhinorrhoea.
Patients who had no positive skin prick test result to one or more allergens were
classified as non-allergic.
Exclusion criteria: patients with a personal or family history of atopy, positive
skin prick test to any of the common inhaled allergens, nasal polyps, nasal 5
sepsis, a deviated septum or abnormal sinus X-rays.
Interven- Intervention groups: beclomethasone dipropionate (n = 23)
tions Doses: 600 µg per day (4 puffs)
Frequency: 3 times per day
Duration: 12 weeks (no wash-out period)
Vehicle: not described
Comparator group: placebo (not described) (n = 23)
Use of additional interventions: none

213
CHAPTER 5

Table continued

Outcomes 1. Nasal obstruction

Measured on a scale of 0 to 5
Reported as P values only
2. Anterior rhinorrhoea
As above
3. Posterior rhinorrhoea
As above
4. Sneezing
As above
5. Facial pain
As above
6. Total nasal symptom score
Composite score for all 5 symptoms
Reported only as P values
7. Rhinomanometry
Using Brom’s method with the symptom scoring
Not reported given too wide a variation between baseline and placebo
values
8. Adverse reactions
Not specified
Funding None
sources
Declarations None declared
of interest
Notes No wash-out period.
7 out of 23 dropout rate.
Only P values reported, no means and SDs.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- High risk Randomisation not described
tion (selection bias)
Allocation concealment High risk Randomisation not described
(selection bias)
Blinding of participants and Unclear risk Double-blind study, however blinding was not
personnel (performance bias) further described. Symptom scoring and patient
preference could have been influenced by inade-
quate blinding.
Blinding of outcome assess- Unclear risk Double-blind study, however blinding was not
ment (detection bias) further described. Symptom scoring and patient
preference could have been influenced by inade-
quate blinding.
Incomplete outcome data High risk Out of 23 recruited patients, 5 withdrew in the
(attrition bias) placebo stage and 2 in the treatment stage
(30.4% missing data).
Selective reporting (reporting High risk Summary data not reported per group, and
5
bias) therefore verification of reported P values is
impossible.
Other bias Low risk No other risks of bias were distinguished.

215
CHAPTER 5

Scadding 1995

Methods Double-blind, parallel-group, randomised controlled trial with 2-week run-in

period, 12 weeks of treatment
Participants Setting:  36 centres in Western Europe
Sample size:
Number randomised: 516 patients with allergic and non-allergic
rhinitis were randomised (106 withdrawals before randomisation).
Number completed: 371 patients with allergic and non-allergic rhini-
tis were included in analysis, of which 188 were patients with non-al-
lergic rhinitis reported (50 with fluticasone propionate once daily, 49
with fluticasone propionate twice daily, 43 with beclomethasone, 46
with placebo).
Participant (baseline) characteristics:
Age: not described separately for non-allergic rhinitis group, range 10
to 83
Gender: percentage of females in the overall groups ranged 50% to
57% in different arms
Symptom duration: 5 or more of the 14-day period
Severity: moderate to severe (score of 2 or 3 on a 0 to 3 scale)
Not described for non-allergic rhinitis group separately, overall
homogenous for combined allergic and non-allergic rhinitis
Inclusion criteria: patients aged over 12 years with a history of moderate to
severe perennial rhinitis were recruited. Skin prick tests to common inhaled
perennial allergens (house dust, house dust mite, cat, dog, moulds) were per-
formed. Patients with negative skin prick test were classified as non-allergic.
Exclusion criteria: allergic rhinitis, invalid or insufficient diary record card data,
fewer than 2 symptoms of rhinitis at visit 1, insufficient symptoms in run-in, dis-
allowed concurrent medication, baseline nasal infection and non-compliance.
Interven- Intervention groups: fluticasone propionate once daily (n = 50)
tions Doses: 200 µg per dose
Frequency: once per day
Duration: 12 weeks
Vehicle: aqueous nasal spray
Comparator group: fluticasone propionate twice daily (n = 49)
As above, but twice a day
Comparator group: beclomethasone dipropionate (n = 43)
Doses: 200 µg per dose
Frequency: twice per day
Duration: 12 weeks
Vehicle: aqueous nasal spray
Comparator group: placebo (n = 46)
Frequency of treatment not described
Otherwise same as above
Use of additional interventions: none

216
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Table continued

Outcomes 1. Nasal blockage on waking

Measured by patient on a scale of 0 to 3 on a daily card, 3 is severe
2. Nasal blockage during the rest of the day
As above
3. Sneezing
As above
4. Rhinorrhoea
As above
5. Overall assessment of symptoms
As above
6. Overall assessment of symptoms at clinic visit
VAS, 0 to 10 cm, 10 = worst symptoms
7. Adverse events
No numerical data
Funding Glaxo Group Research ltd
sources
Declarations None declared
of interest
5
Notes Data not reported separately for non-allergic rhinitis group, but authors suggest
that tests for interaction between rhinitis category and treatment were carried
out and no interaction was found. Conclusion: their analysis suggests no differ-
ences based on allergic sensitisation.

217
CHAPTER 5

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Randomised trial, however random sequence
tion (selection bias) generation was not described.
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and Unclear risk Double-blind study, however blinding was not
personnel (performance bias) further described. Symptom scoring could have
been influenced by this; eosinophilia has less risk
of bias.
Blinding of outcome assess- Unclear risk Double-blind study, however blinding was not
ment (detection bias) further described. See above.
Incomplete outcome data High risk Of 516 initially randomised patients with peren-
(attrition bias) nial allergic and non-allergic rhinitis, only 371
were reported (attrition of 28.1%).
Selective reporting (reporting Unclear risk Outcomes were reported as percentage of symp-
bias) tom-free or no and mild symptom days, instead
of the recorded symptom scores. SDs were not
reported, but can be recalculated based on mean
and P values.
Other bias Unclear risk Funding of this multi-centre study is unclear. The
pharmaceutical company provided medications.
The corresponding author represents a pharma-
ceutical company.

218
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Schulz 1978

Methods Double-blind, parallel-group, randomised controlled trial with 2-week baseline, 6

weeks of treatment
Participants Setting:  Division of Clinical Immunology and Allergy, Montreal General Hospi-
tal, Montreal, Canada
Sample size:
Number randomised: 69 with allergic and non-allergic rhinitis (peren-
nial rhinitis) randomised
Number completed: 60 (9 patients terminated early and excluded
from analysis) (32 non-allergic rhinitis)
Participant (baseline) characteristics:
Age: 15 to 71 years
Gender: in the combined allergic and non-allergic rhinitis population:
29 males, 40 females. Distribution for non-allergic rhinitis group not
reported
Symptom duration: not reported
Severity: not described for non-allergic rhinitis group separately. In
the combined allergic and non-allergic rhinitis population, there were
no significant demographic or historical differences between treat-
ment groups. During the 2-week baseline period, however, patients 5
in the flunisolide group reported a greater number of hours with the
symptom “stuffy nose” than patients in the placebo group.
Inclusion criteria: perennial rhinitis, seasonal allergic rhinitis, including non-al-
lergic rhinitis.
Exclusion criteria: allergic rhinitis.
Interven- Intervention groups: flunisolide (n = 14)
tions Doses: 25 µg per spray, 2 sprays per nostril, 300 µg per day total for
both sides
Frequency: 3 times per day
Duration: 6 weeks
Vehicle: aqueous solution, via metered dose pump spray
Comparator group: placebo (n = 18)
Identical vehicle, without the flunisolide
Otherwise same as above
Use of additional interventions: none

219
CHAPTER 5

Table continued

Outcomes 1. Sneezing
Measured by patient on daily record chart
Duration (in hours) measured
2. Stuffy nose
As above
3. Runny nose
As above
4. Nose blowing
As above
5. Post-nasal drip
As above
6. TNSS
All 5 symptoms combined to determine overall duration of patients’
symptoms
Reported as percentage of days during which all 5 of the symptoms
lasted 1 hour or less and the percentage of days during which at least
1 of the 5 symptoms lasted 4 hours or more.
7. Overall effect of the test drug
Evaluated by patient at the end of treatment
Measured as total control, substantial but not complete control,
minor but definite control, no benefit and aggravated nasal symptoms
Only data available for non-allergic rhinitis group
Funding None
sources
Declarations None declared
of interest
Notes Most outcomes not available for non-allergic rhinitis group separately.
Only data for non-allergic rhinitis (Table 2) were overall effect of symptoms
(responder data) and this was recalculated into responder and non-responder
data.

220
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk “Randomized trial”, however random sequence
tion (selection bias) generation was not described.
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and Unclear risk “Double-blind”, however blinding was not further
personnel (performance bias) described. Symptom scoring could have been
influenced by this; plasma cortisol less likely.
Blinding of outcome assess- Low risk “Double-blind”, however blinding was not further
ment (detection bias) described. See above.
Incomplete outcome data Unclear risk Of 69 total enrolled patients, only 60 were
(attrition bias) reported for efficacy. Of these, 32 were patients
with non-allergic rhinitis. It is unclear how many
of the 9 non-reported patients were in the non-al-
lergic rhinitis subgroup. Adverse effect data were
reported for all 69 patients.
Selective reporting (reporting Unclear risk All results reported fully for overall group, only
5
bias) responder data reported for non-allergic rhinitis
group.
Other bias Low risk No other risks of bias could be distinguished.

Singh 2017

Methods Non-blinded, parallel-group, randomised clinical study with 2 weeks duration of

treatment
Participants Setting: the clinical EEC study and collection of biospecimens were con-
ducted at Inflamax Research (Mississauga, ON, Canada) and the
biospecimens were analysed at the University of Cincinnati
Sample size:
Number randomised: 30
Number completed: 30
Participant (baseline) characteristics:
Age: AzeFlu (44.91 ± 6.77 years); placebo (42.43 ± 8.24 years)
Gender: AzeFlu: female: 12, male: 8; placebo: female: 6, male
Symptom duration: unclear
Severity: unclear
Inclusion criteria: NAVMR based on symptoms and triggers; nasal symptoms
in response to a panel of non-allergic triggers, including CDA, in a NAVMR
questionnaire.
Exclusion criteria: positive test skin; mechanical obstruction; infection of the
nasal cavity.

221
CHAPTER 5

Table continued

Interven- Intervention group: AzeFlu (n = 20)

tions FDA-approved dosing regimen (1 spray in each nostril twice daily) at home
for 2 weeks. AzeFlu was supplied in a spray bottle containing a suspension of
azelastine hydrochloride (137 μg) and fluticasone propionate (50 μg) per spray
(0.137 mL).
The inactive ingredients included preservatives (alcohols, benzalkonium) and a
chelating agent (EDTA).
Comparator group: placebo (n = 10)
Placebo contained the same excipients as the AzeFlu preparation without the
active drug. During the study period, none of participants used concomitant
medications for NAVMR or medications that interact with AzeFlu.
Use of additional interventions: none
Outcomes 1. Total nasal symptom scores (after cold dry air provocation), before and after
treatment
2. Minimal cross-sectional area (MCA) (before and after cold dry air provoca-
tion) before and after treatment
Funding None
sources
Declarations None declared
of interest
Notes Outcome measures do not meet the definition as in the protocol, i.e. total nasal
symptom score and objective measurement of airflow are both related to cold
dry air provocation; despite that: should be reported in systematic review.
There is no statistically significant difference between AzeFlu and placebo for
the most important outcome, i.e. TNSS. Numerical data are not reported so
cannot be used in meta-analysis but should be reported in systematic review.

222
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Randomised trial. There was insufficient informa-
tion (selection bias) tion on sequence generation.
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and High risk As the primary outcomes of nasal symptom
personnel (performance bias) scores and adverse events are both self-reported
outcomes and the study is not blinded, this has a
high risk of bias.
Blinding of outcome assess- High risk See above
ment (detection bias)
Incomplete outcome data Low risk No loss to follow-up
(attrition bias)
Selective reporting (reporting High risk For the most important outcome TNSS the out-
bias) comes are not reported; the authors only state:
“The mean change in TNSS for the AzeFlu cohort
(vs. placebo cohort) was reduced, but did not
5
reach statistical significance. A similar numerical
trend was observed, albeit to a lesser extent,
for individual symptom scores of runny nose,
post-nasal drip, and nasal congestion.”
Other bias Unclear risk No other risks of bias could be distinguished.

223
CHAPTER 5

Song 2018

Methods Unclear blinded, parallel-group, randomised clinical study with 8 weeks treat-
ment
Participants Setting:  Department of Otolaryngology, Head and Neck Surgery, Affiliated
Hospital of Guizhou Medical Universtiy Guiyang, China
Sample size:
Number randomised: 120 (40 budesonide, 40 azelastine, 40
budesonide with azelastine)
Number completed: 120
Participant (baseline) characteristics:
Age: Group A (budesonide and azelastine) 42.4 ± 2.9 years; Group B
(budesonide) 41.6 ± 2.7 years; Group C (azelastine) 43.8 ± 1.9 years
Gender: general: male (M): 61, female (F): 59; Group A (budesonide
and azelastine): M/F: 21/19; Group B (budesonide): M/F: 18/22; Group
C (azelastine): M/F: 21/18
Symptom duration: not reported
Severity: baseline VAS: budesonide (VAS: 6.81 ± 1.61); azelas-
tine (VAS: 6.63 ± 1.85); budesonide with azelastine (VAS: 6.75 ±
1.48)
Inclusion criteria: typical symptoms and characteristics of vasomotor rhinitis;
negative skin prick test results; serum specific IgE (-); blood eosinophilia % < 5%;
nasal secretion eosinophilia %< 5%.
Exclusion criteria: allergic rhinitis, asthma, eczema, acute or chronic rhinosi-
nusitis, nasal tumour, systemic or any disease that might influence the result
of this study, usage of nasal, oral or systemic glucocorticoids, antihistamines,
leukotriene receptor inhibitors, various blood decongestant or theophylline in
last 3 months; involvement of any other clinical trials; allergy to glucocorticoid
or antihistamine drugs; pregnancy or breastfeeding; healthcare workers for the
study.
Interven- Intervention group: budesonide (n = 40)
tions Dose: 50 g/ puff, 2 puffs per nostril
Frequency: 2 times per day: total dosage 400 µg
Duration: 8 weeks
Vehicle: spray
Comparator groups:
Azelastine (n = 40)
Dose: 50g/ puff, 2 puffs per nostril
Frequency: 2 times per day: total dosage 400 µg
Duration: 8 weeks
Vehicle: spray
Budesonide with azelastine (n = 40)
Dose: 50 g/puff, 2 puffs per nostril
Frequency: 2 times per day: total dosage 400 µg
Duration: 8 weeks
Vehicle: spray
Use of additional interventions: none

224
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Table continued

Outcomes 1. Visual analogue scale (VAS): overall VAS score and VAS score for nasal
congestion, nasal itching, sneezing, rhinorrhoea
2. Score reduction index (SRI) = ((score before treatment-score after treat-
ment))/(score before treatment) x 100 (%): ≥ 80% = significant effectiveness;
30% to ~80% = effective; ≤ 30% = no effectiveness
3. Quality of life (SF-12v2)
4. Adverse events (in general, not specified)
Funding Science and technology plan of Guizhou province (Guizhou LH (2015) no. 7418).
sources
Declarations No information provided
of interest
Notes —

225
CHAPTER 5

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Low risk “120 patients with VMR were randomly grouped
tion (selection bias) by number table method’.
Allocation concealment Unclear risk No description of allocation concealment.
(selection bias)
Blinding of participants and High risk No blinding reported. However, the intervention
personnel (performance bias) in the treatment group is distinct from that in
the control group, therefore it is likely that the
self-reported outcomes have been influenced by
lack of blinding.
Blinding of outcome assess- High risk No blinding reported, however self-reported
ment (detection bias) outcomes are likely to be influenced by lack of
blinding.
Incomplete outcome data Low risk The number of patients reported in the outcomes
(attrition bias) was the same as that at baseline.
Selective reporting (reporting Low risk All outcomes stated in the ‘Methods’ were
bias) reported in the ‘Results’.
Other bias Low risk No co-intervention; baseline characteristics were
comparable;
government funding.

226
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Spector 1980

Methods Double-blind, parallel-group, randomised, placebo-controlled trial with 2-week

baseline period and a 4-week treatment
Participants Setting:  hospital and office patients in Denver, Colorado, USA
Sample size:
Number randomised: 20 patients randomised, 15 included in analy-
sis
Number completed: 15
Participant (baseline) characteristics:
Age: 15 to 66 years (mean: 35.1 years)
Gender: 10 males, 5 females
Symptom duration: at least 2 years
Severity: severe enough to require the use of medications more than
50% of the time and undesirable side effects from the usual medica-
tions (can be judged to be moderate or severe)
Summary data not reported, however recalculation of age, sex ratio,
baseline total symptom score, physician evaluation score not differ-
ent between groups
Inclusion criteria: 1) a history of perennial non-allergic rhinitis of at least 2 years
duration; 2) symptoms severe enough to require the use of medications more 5
than 50% of the time and undesirable side effects from the usual medications;
3) symptoms stable for at least 3 months prior to the study; 4) age 18 years or
older; and 5) no systemic or topical steroids used for at least 6 months prior to
the study.
Exclusion criteria: patients with nasal polyps who had symptoms of nasal
obstruction and women of child-bearing potential.
Interven- Intervention group: flunisolide (n = 7)
tions Dose: a solution containing 0.25% flunisolide, approximately 25 µg
flunisolide per spray, 2 sprays in each nostril (400 µg daily)
Frequency: 4 times per day
Duration: 4 weeks
Vehicle: plastic atomised bottle
Comparator group: placebo (vehicle only) (n = 8)
Use of additional interventions: patients were instructed not to change their
basic medication programme, which included a decongestant or antihistamine
or both.

227
CHAPTER 5

Table continued

Outcomes 1. Sneezing
Daily symptom diary
Duration (in hours) measured per day
2. Stuffiness
Same as above
3. Runny nose
Same as above
4. Nose blowing
Same as above
5. Post-nasal drip
Same as above
6. Adverse effects
No data provided
TNSS: patient evaluation, sum of 5 symptoms (sneezing, stuffiness, runny nose,
nose blowing and post-nasal drip) numerically assessed as absent (1), mild (2),
moderate (3) or severe (4)
7. Peak expiratory flow rate, nasal (PEFRn)
8. Peak expiratory flow rate, mouth (PEFRm)
9. Blockage index
(PEFRm-PEFRn)/PEFRm
Funding Study funded in part by Syntex Corporation. The authors’ relationship with the
sources funder is unclear.
Declarations None declared
of interest
Notes Women of childbearing potential excluded. Same study reported in Jones 1979,
which however, did not provide numerical data on symptom scores (only Figure
1 in article with no SDs or P values). We have decided to include Spector 1980
and not Jones 1979.
A PEFR was not obtained for all patients.

228
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Random sequence generation was not further
tion (selection bias) described.
Allocation concealment Unclear risk See above
(selection bias)
Blinding of participants and Unclear risk “Neither the patients nor personnel involved in
personnel (performance bias) the study knew the contents of the randomly
assigned bottles containing either flunisolide or
vehicle.”
Blinding not further described.
Blinding of outcome assess- Unclear risk See above. Patient symptom evaluation and phy-
ment (detection bias) sician evaluation could have been influenced.
Incomplete outcome data High risk 5 patient dropouts out of a total 20 randomised
(attrition bias) patients (25%). One explained by non-compliance,
the other 4 by lack of sufficient material for nasal
biopsies, however their clinical outcomes could
ideally have been reported. 5
The most clinically important outcome, TNSS, is
fully reported. PEFR (peak expiratory flow rate)
was not done/reported for all patients.
Selective reporting (reporting Low risk All outcomes are adequately reported.
bias)
Other bias High risk Funded in part by Syntex Corporation. It is
unclear if the authors have a relationship with the
funder.
Women of childbearing potential excluded.

229
CHAPTER 5

Tantilipikorn 2010

Methods Double-blind, parallel-group, randomised, placebo-controlled trial with 2-week

screening period, 4 weeks treatment, 3 to 5 days follow-up after treatment
Participants Setting:  multi-centre, 7 centres in Thailand
Sample size:
Number randomised: 102 total; fluticasone furoate (FFNS), n = 53,
placebo, n = 49
Number completed: 102
Participant (baseline) characteristics:
Age: 12 to 64 years; FFNS: 37.1 ± 12.78, range 12 to 58; placebo: 35.9
± 10.89, range 18 to 64
Gender: female (33), male (20)
Symptom duration: more than 2 years
Severity: average of 4.5 (maximum = 9) for the last 8 reflective TNSS
(rTNSS) assessments, an average of 2 (maximum = 3) for the last 8
reflective nasal congestion assessments and an 80% compliance
with their diary card entries over the span of their screening period.
Not significant for age, gender, compliance, trigger factors, mean
daily rTNSS, percentage of eosinophils in nasal smear. Participants in
the FFNS group spent 0.5 to 1.5 hours longer outside compared with
participants in the placebo group (unclear significance).
Inclusion criteria: participants to identify air pollution as the predominant
trigger that made their rhinitis symptoms worse, via completion of an irritant
rhinitis trigger questionnaire to select their predominant trigger from 3 types of
irritants (air pollution, wind/temperature triggers and strong odours). Inclusion
criteria also included a negative skin prick test to local seasonal and peren-
nial allergens, a positive histamine control skin prick test and a normal sinus
radiograph (Waters view) to rule out sinusitis. Randomisation criteria at Visit
2 required participants to have an average of ≥ 4.5 (maximum = 9) for the last
8 reflective TNSS assessments, an average of ≥ 2 (maximum = 3) for the last
8 reflective nasal congestion assessments and an 80% compliance with their
diary card entries over the span of their screening period.
Exclusion criteria: nasal obstruction, septal perforation, recent nasal surgery,
nasal infections; medications known to produce allergy symptoms, such as
congestion; use of face masks (e.g. used for protection from air pollution), con-
tinuous positive airflow pressure, saline nasal sprays and lavages, eye drop, and
local, herbal and homeopathic treatments.
Interven- Intervention group: fluticasone furoate (n = 53)
tions Dose: 110 µg (110 µg fluticasone furoate equals around 200 µg fluti-
casone propionate, budesonide of beclomethasone dipropionate)
Frequency: once daily
Duration: 4 weeks
Vehicle: not described
Delivery method: nasal spray
Comparator group: placebo (n = 49)
Use of additional interventions: none

230
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Table continued

Outcomes 1. Rhinorrhoea
Measured by patient on paper diary card, in AM and PM
4-point categorical scale of 0 to 3 (none, mild, moderate, severe)
Measured as instantaneous (i) and over previous 12 hours (reflective)
Instantaneous measured in AM, and reflective in both AM and PM
Measured during screening and treatment periods
2. Nasal congestion
Same as above
3. Post-nasal drip
Same as above
4. Eye itching/burning
Same as above
5. Eye tearing/watering
Same as above
6. Eye redness
Same as above
7. rTNSS reflective total nasal symptom score
Combined 3 reflective individual nasal symptom scores
Measured in AM and PM, which were averaged to arrive at the final 5
daily value (daily rTNSS)
Weekly data averaged
8. rTOSS reflective total ocular symptom score
Same as above, to derive daily rTOSS
9. AM iTOSS morning instantaneous predose TOSS
Obtained by summing of instantaneous pre-dose morning ocular
scores
10. Adverse effects
Epistaxis and any other adverse events
Funding GlaxoSmithKline
sources
Declarations None declared
of interest
Notes Some of the study authors were investigators for GlaxoSmithKline, while rest of
the authors were its employees. However, the study shows negative outcomes
and it is unlikely that the relationship with the company influenced the study
results.

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CHAPTER 5

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Randomised study: “Subjects who fulfilled the
tion (selection bias) randomization criteria were randomly assigned
in a 1:1 ratio to receive either FFNS 110 mcg
once daily or vehicle placebo nasal spray once
daily with the first dose being administered in the
clinic following device demonstration. Subjects
were stratified into two groups based on nasal
cytology: those with eosinophils constituting >5%
or <5% of nasal white blood cells.”
The sequence generation is not described.
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and Unclear risk Double-blind study, blinding is not further
personnel (performance bias) described.
Blinding of outcome assess- Unclear risk Double-blind study, blinding is not further
ment (detection bias) described.
Incomplete outcome data Low risk All patients reported
(attrition bias)
Selective reporting (reporting Low risk All outcomes reported
bias)
Other bias Low risk Some of the study authors were investigators for
GlaxoSmithKline, while the rest of the authors
were its employees. However, the study shows
negative outcomes and it is unlikely that the
relationship with the company influenced the
study results.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Tarlo 1977

Methods Double-blind, cross-over, randomised controlled trial with 6 weeks treatment,

6 months follow-up (BDA for 3 weeks and placebo for 3 weeks; the order of
administration was randomised)
Participants Setting:  Chest Allergy Clinic of St. Joseph’s Hospital in Hamilton
Sample size:
Number randomised: 26 patients with perennial rhinitis, 9 non-aller-
gic rhinitis
Number completed: 26
Participant (baseline) characteristics:
Age: ranged from 15 to 61 years (mean 34 years)
Gender: 16 male and 10 female
Symptom duration: rhinitis had been present for 2 to 20 years (mean
8.6 years)
Severity: not reported
In the week prior to the start of the inhalers, the mean daily values for
the symptom scores in the 26 patients was 4.5 for nasal congestion,
2.4 for rhinorrhoea, and 1.0 for sneezing (maximum 6 each). Both
taste and smell were absent or impaired in 9, and smell alone was
absent or impaired in 3. 5
Inclusion criteria: unclear
Exclusion criteria: not reported
Interven- Intervention group: BDA (beclomethasone dipropionate aerosol (BDA), 50 µg 4
tions times daily sprayed into each nostril) (n = unclear)
Comparator group: placebo: Freon propellant, same schedule (n = unclear)
Use of additional interventions: none

233
CHAPTER 5

Table continued

Outcomes Recording of symptoms on dairy cards: the diary card was similar to that used
by Norman and colleagues. Daily and nightly sneezing, nasal congestion and
rhinorrhoea were each recorded as 0 if absent, 1 if they lasted less than 30
minutes, 2 if between 30 minutes and 2 hours, and 3 if longer than 2 hours.
Taste and smell were recorded daily on the same card as normal, impaired or
absent.
NAIR (nasal airway resistance) was measured by a modification of the method
of Taylor and Shivalkar. A tight-fitting skin diver's mask was applied over the
patient's nose and eyes. This was connected to a pneumotachograph for mea-
suring flow and to a pressure transducer for measuring the transnasal pressure
between the inside of the mask and a mouthpiece held tightly between the teeth
and lips. Flow and pressure were recorded on the y and x axes, respectively, of
an x-y recorder, and NAlR was calculated from the slope of the tangent to the
pressure-flow curve at a flow of 0.4 L/set. Before the use of the inhalers was
started, NAIR was measured on 2 occasions. It was elevated (> 4 cm H,O/L/set)
on one occasion in 6 and on both occasions in 10; borderline (3 to 4 cm H,O/L/
sec) on one occasion in 4; normal (<b3 cm H,O/L/sec) on both occasions in 6.
Total nasal symptoms: the sum of the nasal symptom scores (sneezing, con-
gestion and rhinorrhoea, as well as the total) was measured during the third
week of treatment
Adverse events (no data for non-allergic rhinitis group separately), in general
reported as mild
Funding None
sources
Declarations None declared
of interest
Notes Limited numerical data for non-allergic rhinitis group separately.
Polyps were present in 8 and asthma in 6 patients. 16 patients showed some
evidence of increased IgE production. 9 patients had no signs of allergy and
perennial rhinitis.
Conclusions:
After 6 months 6/9 were successfully treated with intranasal corticosteroids
and 3/9 were unsuccessfully treated with intranasal corticosteroids.
General conclusion: results in those in whom a possible allergic component
could be identified were not different from those of the whole group.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Randomised but random sequence generation
tion (selection bias) not further described.
Allocation concealment Unclear risk Not specified
(selection bias)
Blinding of participants and Unclear risk Blinded but blinding not further described.
personnel (performance bias)
Blinding of outcome assess- Unclear risk Blinded but blinding not further described.
ment (detection bias) Symptom scoring could have been influenced.
Incomplete outcome data High risk Limited numerical data for non-allergic rhinitis
(attrition bias) group separately
Selective reporting (reporting High risk Limited numerical data for non-allergic rhinitis
bias) group separately
Other bias Unclear risk 8 patients had polyposis

235
CHAPTER 5

Turkeltaub 1982

Methods Double-blind, parallel-group, randomised, placebo-controlled trial with 2 weeks

pre-treatment, 12 weeks of treatment
Participants Setting:  hospital clinic, USA
Sample size:
Number randomised: unclear number of patients randomised to
non-allergic rhinitis only group; 75 patients with perennial rhinitis
randomised. Data reported for 33 patients in the non-allergic rhinitis
only group.
Number completed: 33 non-allergic rhinitis (unclear how many
non-allergic rhinitis patients randomised, 75 perennial rhinitis patients
randomised)
Participant (baseline) characteristics:
Age: not described
Gender: not described
Symptom duration: not described
Severity: “having year-round nasal symptoms severe enough to
require medication”, presumably moderate to severe
Reported as not different in terms of age, sex, duration and severity
of nasal symptoms, or prior history of chronic sinusitis, polyposis and
nasal surgery
Inclusion criteria: patients with seasonal or perennial rhinitis: having year-round
nasal symptoms severe enough to require medication, or who had a history of
being treatment failures and using a variety of over-the-counter and prescription
medication were selected for study. Specifically, non-allergic rhinitis patients
were those who tested negatively to ragweed, rye grass, Bermuda, Alternaria sp.
house dust, cat and dog.
Exclusion criteria: sinusitis, underlying nasal pathology resulting in fixed occlu-
sion of a nostril, or patients receiving medication for another indication, which
might suppress symptoms of perennial or seasonal rhinitis.
Interven- Intervention group: flunisolide (n = 20 after exclusions)
tions Dose: 25 µg per spray per nostril (300 µg daily)
Frequency: 3 times per day
Duration: 12 weeks
Vehicle: 20% propylene/15% polyethylene glycol
Comparator group: placebo (20% propylene/15% polyethylene glycol vehicle)
(n = 13 after exclusions)
Use of additional interventions: none
Outcomes 1. Total symptom score
Sum score of symptoms scores for sneezing, runny nose, stuffy
nose, eye itch and throat itch, each measured on a 0 to 6 scale. To
this was added the number of tablets and nasal sprays required to
control nasal symptoms for the preceding 12-hour period.
Possible scores from 0 to 40
2. Adverse effects
Measured for allergic and non-allergic rhinitis groups together
Cannot be recalculated for non-allergic rhinitis only

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Table continued

Funding Syntex Corporation

sources
Declarations None declared
of interest
Notes Unconventional total nasal symptom score calculation.
15 patients excluded from perennial rhinitis group in efficacy assessment.
Involvement of Syntex Corporation (a pharmaceutical company) is unclear.

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Random allocation for perennial rhinitis patients;
tion (selection bias) random sequence generation was not described.
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and Unclear risk Study described as “double-blind”, however
personnel (performance bias) blinding was not further described. 5
Blinding of outcome assess- Unclear risk Study described as “double-blind”, however
ment (detection bias) blinding was not further described; symptom
scoring could have been influenced.
Incomplete outcome data High risk 15 patients in perennial rhinitis group (comprised
(attrition bias) of perennial allergic and non-allergic rhinitis
patients) were not included in the analysis of
efficacy, even though they were included in the
analysis of side effects.
Selective reporting (reporting Low risk All described outcomes (in perennial rhinitis
bias) group) can be found in the results, even though
only symptom scores can be separated for the
non-allergic rhinitis group only, and other out-
comes are reported cumulatively for both allergic
and non-allergic rhinitis perennial rhinitis groups.
Other bias Unclear risk Involvement of Syntex Corporation (a pharma-
ceutical company) is unclear.

237
CHAPTER 5

Varricchio 2011

Methods Single-blind (patients not blinded), parallel-group, randomised, placebo-con-

trolled trial with 8 weeks duration of treatment
Participants Setting:  2 hospitals in Naples, Italy
Sample size:
Number randomised: 60
Number completed: 60
Participant (baseline) characteristics:
Age: 21 to 63 years (mean 42.8 years)
Gender: 39 male, 21 female
Symptom duration: unclear
Severity: unclear
Not significant for age, gender, nasal score, turbinate hypertrophy,
nasal cytology
Inclusion criteria: patients with diagnosis of non-allergic rhinitis based on
history of nasal symptoms (including sneezing, rhinorrhoea and nasal obstruc-
tion typically dependent on exposure to triggers such as odours, irritants,
weather changes), presence of inflammatory cells on nasal smear, and negative
SPT according to validated criteria.
Exclusion criteria: acute or chronic upper respiratory infections, anatomic nasal
defects, documented sensitisation (skin prick testing done to confirm), using
intranasal or oral corticosteroids, nasal or oral decongestants, anti-leukotrienes,
and intranasal or oral antihistamines during the previous 4 weeks, or had a
history of chronic epistaxis, immunodeficiency, or hypersensitivity to flunisolide.
Interven- Intervention group: flunisolide (n = 30)
tions Dose: 0.5 mg/ml, 2 mL (1 mg) at each application, twice a day (total 2
mg per day) = 2000 µg/day
Frequency: twice a day
Duration: 8 weeks
Vehicle: Rinowash nebuliser
Comparator group: placebo (isotonic saline solution) (n = 30)
Use of additional interventions: none
Outcomes 1. Total symptom score:
4 items (nasal itching, sneezing, rhinorrhoea and nasal obstruction)
assessed on a scale of 0 to 3
Possible scores from 0 to 12
Lower score indicates better outcome
Assessed on day 1 and 8 weeks
2. Adverse events
Unclear how assessed (only narrative results reported)
Funding None
sources
Declarations None declared
of interest
Notes Comparisons made both between groups, as well as change of baseline.
Very high dose of flunisolide 2 mg per day. Other studies used 200 µg to 400 µg
per day.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Randomly assigned; random sequence genera-
tion (selection bias) tion was not described.
Allocation concealment High risk Allocation was not concealed from patients;
(selection bias) single-blinded study.
Blinding of participants and High risk Single-blind study: patients were not blinded.
personnel (performance bias)
Blinding of outcome assess- Unclear risk Assessing physicians were blinded, patients
ment (detection bias) not; no more details on blinding of physicians.
Symptom scoring by patients.
Incomplete outcome data Low risk All patients enrolled in the study completed the
(attrition bias) 8-week trial.
Selective reporting (reporting Low risk All data reported.
bias)
Other bias Low risk No others potential biases could be distin-
guished. 5
Warland 1982

Methods Double-blind, cross-over, randomised, placebo-controlled trial with 4 weeks per

treatment, 2-week interval between 2 treatment periods
Participants Setting:   University of Bergen, Norway
Sample size:
Number randomised: 34 patients suffering from perennial rhinitis, 22
allergic rhinitis patients, 12 vasomotor rhinitis patients
Number completed: 12 vasomotor rhinitis patients reported
Participant (baseline) characteristics:
Age: mean 32.5 (range 16 to 76)
Gender: 14 males, 20 females
Symptom duration: mean 5.9 years
Severity: 1 slight, 24 moderate, 9 severe
Inclusion criteria: unclear.
Exclusion criteria: patients who were pregnant, who were suffering from
nasal obstruction due to nasal polyps, or who were taking corticosteroids were
excluded from the trial.
Interven- Intervention groups: flunisolide nasal solution: 200 µg per day (n = unclear)
tions Comparator group: placebo (n = unclear)
Use of additional interventions: none

239
CHAPTER 5

Table continued

Outcomes Daily record of overall severity of symptoms on a scale from 0 to 3

Sneezing, runny nose, nose blowing and post-nasal drip per individual nasal
symptom on a scale from 0 to 4.
Condition of nasal mucosa and quantity and aspect of nasal secretions.
Conclusion: a statistically significant difference in favour of flunisolide nasal
solution
Vasomotor rhinitis: total effect: 0/12, substantial effect: 3/13, minor effect: 3/12
Funding None
sources
Declarations None declared
of interest
Notes Flunisolide nasal solution seems to be effective in both allergic rhinitis as vaso-
motor rhinitis, although is seems to be more effective in an allergic state.
Limited separate data for non-allergic rhinitis subgroup versus allergic rhinitis
subgroup.
No numerical data for non-allergic rhinitis subgroup for one of the outcomes
from our protocol.

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Randomised study; unclear random sequence
tion (selection bias) generation
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and Unclear risk Double-blind, no more details on blinding
personnel (performance bias)
Blinding of outcome assess- Unclear risk Double-blind, no more details on blinding; scoring
ment (detection bias) of symptoms could be influenced
Incomplete outcome data High risk Limited numerical data for vasomotor rhinitis
(attrition bias) patients only
Selective reporting (reporting High risk Limited numerical data for vasomotor rhinitis
bias) patients only
Other bias Unclear risk No other risks of bias could be distinguished

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Webb 2002

Methods Double-blind, double-dummy, parallel-group, randomised, placebo-controlled

trial with 7 days screening, 28 days treatment
Participants Setting:  clinic patients, Allergy and Asthma Research Associates, USA.
Reported as integrated data from 2 multi-centre trials and 1 sin-
gle-centre trial
Sample size:
Number randomised: 983
Number completed: 651
Participant (baseline) characteristics:
Age: range 12 to 83 years; mean 41 to 43 years
Gender: % males 34% to 39% in 3 treatment groups
Symptom duration: more than 1 year
Severity: as above
Ethnicity: 93% to 96% Caucasian
No differences between groups for age, gender, ethnicity, duration of
symptoms, % NARES and baseline TNSS (overall, in NARES and in
non-NARES)
Inclusion criteria: perennial non-allergic rhinitis, negative skin tests to all geo-
graphically relevant allergens. Symptom severity 150 on TNSS on at least 4 of 7 5
days immediately preceding randomisation
Exclusion criteria: other rhinitis medications (e.g. antihistamines)
Interven- Parallel-group study:
tions a. Fluticasone propionate 200 µg daily
b. Fluticasone propionate 400 µg daily
Included in meta-analysis:
Fluticasone propionate 400 µg daily (n = 325)
Doses: 400 µg daily
Frequency: twice daily
Duration: 28 days
Vehicle: aqueous solution
Device: aqueous nasal spray
Comparator group: placebo (n = 326)
Vehicle without active ingredient
Otherwise same as above
Use of additional interventions: none

241
CHAPTER 5

Table continued

Outcomes 1. Nasal obstruction

Diary card each evening
Time points: baseline, 2 and 4 weeks
VAS, 0 to 100 mm
2. Post-nasal drip
As above
3. Rhinorrhoea
As above
4. TNSS
Sum of individual scores
2 studies used 3 symptoms (nasal obstruction, post-nasal drip, and
rhinorrhoea) 0 to 300 score for TNSS
Third study used 4 symptoms (nasal obstruction, post-nasal drip,
rhinorrhoea and sneezing) 0 to 400 score for TNSS
Only patients with a combined score of 150 on the first 2 studies and
200 of the third study were randomised.
For this combined report, only 3 symptoms were used to calculate
TNSS (nasal obstruction, post-nasal drip and rhinorrhoea)
Possible scores are 0 to 300
Funding SmithKline Beecham Corporation doing business as GlaxoSmithKline
sources
Declarations None declared
of interest
Notes Integrated data from 2 multi-centre trials and 1 single-centre trial: report of 3
individual studies pulled together (done by pharmaceutical company).
Included the same outcome separately for NARES and non-NARES groups: only
mean value of TNSS change from baseline presented, without SD or P value, so
cannot include in meta-analysis.
Sponsored by a grant from SmithKline Beecham Corporation doing business as
GlaxoSmithKline.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Randomised, double-blind trial. Random
tion (selection bias) sequence generation was not described.
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and Unclear risk Blinding was not described in further detail
personnel (performance bias)
Blinding of outcome assess- Unclear risk See above. Symptom scoring could have been
ment (detection bias) influenced.
Incomplete outcome data Low risk “In all, 95% of patients completed the proto-
(attrition bias) col-specified 28 days of treatment, with 2% of
any treatment group being withdrawn for lack of
efficacy.”
This percentage is low enough that it likely did
not affect the results in a major way.
Selective reporting (reporting
bias)
Unclear risk Individual symptom scores measured but only
TNSS reported.
5
Other bias High risk Individual symptom scores measured, but only
TNSS reported and 4 employees of the company
are authors.

AZENS: azelastine nasal spray

BDA: beclomethasone dipropionate aerosol
BMI: body mass index
ECG: electrocardiogram
FDA: (US) Food and Drug Administration
FFNS: fluticasone furoate nasal spray
FP: fluticasone propionate
FPANS: fluticasone propionate aqueous nasal spray
FPNS: fluticasone propionate nasal spray
MCA: minimal cross-sectional area
N/A: not available
NANIPER: non-allergic, non-infectious perennial rhinitis
NARES: non-allergic rhinitis with eosinophilia syndrome
NAVMR: non-allergic vasomotor rhinitis
NSAID: non-steroidal anti-inflammatory drug
PEF: peak expiratory flow
PEFR: peak expiratory flow rate
PNIF: peak nasal inspiratory flow
RAST: radioallergosorbent
RCT: randomised controlled trial
RQLQ: Rhinoconjunctivitis Quality of Life Questionnaire
rTNSS: reflective total nasal symptom score
rTOSS: reflective total ocular symptom score

243
CHAPTER 5

SD: standard deviation

SEM: standard error of the mean
SNOT-22: Sinonasal Outcomes Test 22
SPT: skin prick test
TNSS: reflective total nasal symptom score
TOSS: total ocular symptom score
URTI: upper respiratory tract infection
VAS: visual analogue scale
VMR: vasomotor rhinitis

CHARACTERISTICS OF EXCLUDED STUDIES

Adamopoulos 1995
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Arbesman 1983
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Astafieva 2012
Reason for exclusion COMPARISON: this study compared 2 types of intranasal corticosteroids,
brand versus generic. This was not included in our protocol.

Balle 1982
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Berger 2012
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Bernstein 1997
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Blair 1977
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Bunnag 1992
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Celiker 2011
Reason for exclusion COMPARISON: this study compared intranasal corticosteroids with radiofre-
quency ablation. This comparison was not included in our protocol.

Chatterjee 1974
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Dieges 1978
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Dockhorn 1999
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Gibson 1974
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Hansen 1974
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup

244
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Harding 1976
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Hartley 1985
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup

Haye 1993
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Jones 1979
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Joubert 1983
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Juniper 1993
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Kakumanu 2003
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Kivisaari 1998
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Kohan 1989
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup 5
Lahdensuo 1977
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Lau 1990
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Lebowitz 1993
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Malmberg 1988
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
McAllen 1969
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
McAllen 1980
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Negreiros 1975
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Price 2013
Reason for exclusion The authors were contacted, but suggested “the subpopulation
studied with NAR is too small from which to draw any meaningful conclusions
Rusnak 1981
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Scadding 1991
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Shaw 1979
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup

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CHAPTER 5

Small 1982
Reason for exclusion No data were provided in the results for the placebo group
Svendsen 1989
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Sy 1979
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Synnerstad 1996
Reason for exclusion This was a parallel-group, open-label (non-blinded) randomised study of
budesonide versus beclomethasone dipropionate nasal sprays. In addition to obvious high risk of bias
for allocation concealment, blinding of participants and personnel, and blinding of outcome assessors,
the study had issues with incomplete outcome data, and some issues with selective outcome reporting
(individual nasal symptoms measured but not thoroughly reported, total nasal symptoms reported but
not included in methods). This study was supported by a grant from Astra Draco AB, Lund, Sweden, and
the second author worked for the company. The company provided budesonide (Rhinocort). The study
suggested that budesonide was better than beclomethasone. There are significant grounds to suspect
high risk of bias. Based on these observations combined with incomplete and selective outcome data
reporting little to no valuable numerical or descriptive outcome data, we decided to exclude this study.

Turner Warwick 1980

Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Webb 1977
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Weckx 2001
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Wight 1992
Reason for exclusion Neither numerical nor narrative data available for non-allergic rhinitis subgroup
Zucker 2019
Reason for exclusion Meta-analysis with the only relevant study already included in our review

Characteristics of ongoing studies

NCT04002349
Methods Randomised, parallel-group clinical trial
Participants Non-allergic rhinitis patients
Interventions Placebo (0.9% natural saline spray), budesonide nasal spray (Rhino-
cort), levocabastine nasal spray, combined treatment
Outcomes Unclear
Starting date 1 July 2019
Contact information Principal investigators: Luo Zhang MD; Yifan Meng, PhD
Beijing Tongren Hospital, Beijing, China
Email: [email protected]; [email protected]
Notes Estimated study completion date: 31 March 2020

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

DATA AND ANALYSES

Comparison 1. Intranasal corticosteroids versus placebo

Outcome or Subgroup Studies Partic- Statistical Method Effect Estimate

ipants
1.1 Total nasal symptom 4 131 Std. Mean Difference (IV, -0.74 [-1.15, -0.33]
score, follow-up ≤ 4 weeks Random, 95% CI)
1.1.1 Budesonide 2 74 Std. Mean Difference (IV, -0.83 [-1.30,
Random, 95% CI) -0.35]
1.1.2 Flunisolide 1 15 Std. Mean Difference (IV, 0.11 [-0.90, 1.13]
Random, 95% CI)
1.1.3 Beclomethasone 1 42 Std. Mean Difference (IV, -0.96 [-1.60, -0.32]
dipropionate Random, 95% CI)
1.2 Total nasal symptom 3 85 Std. Mean Difference (IV, -0.24 [-0.67, 0.20]
score, follow-up > 4 weeks Random, 95% CI)
1.2.1 Fluticasone propi- 1 31 Std. Mean Difference (IV, -0.17 [-0.87, 0.54]
onate Random, 95% CI)
1.2.2 Flunisolide 2 54 Std. Mean Difference (IV, -0.28 [-0.84, 0.27] 5
Random, 95% CI)
1.3 Total nasal symptom 4 1465 Std. Mean Difference (IV, -0.54 [-1.18, 0.10]
score (change from base- Random, 95% CI)
line), follow-up ≤ 4 weeks
1.3.1 Fluticasone furoate 2 794 Std. Mean Difference (IV, -0.62 [-1.72, 0.47]
(110 µg fluticasone Random, 95% CI)
furoate equals around 200
µg FP, BUD or BDP)
1.3.2 Budesonide 1 20 Std. Mean Difference (IV, -0.74 [-1.65, 0.17]
Random, 95% CI)
1.3.3 Fluticasone propi- 1 651 Std. Mean Difference (IV, -0.24 [-0.40,
onate Random, 95% CI) -0.09]
1.4 Significant adverse 4 1174 Risk Difference (M-H, Fixed, 0.04 [0.01, 0.06]
event: epistaxis 95% CI)
1.4.1 Fluticasone furoate 2 801 Risk Difference (M-H, Fixed, 0.02 [-0.00, 0.05]
(110 µg fluticasone 95% CI)
furoate equals around 200
µg FP, BUD or BDP)
1.4.2 Budesonide 1 44 Risk Difference (M-H, Fixed, 0.05 [-0.07, 0.16]
95% CI)
1.4.3 Mometasone 1 329 Risk Difference (M-H, Fixed, 0.07 [0.01, 0.13]
furoate 95% CI)
1.5 Objective measure- 1 11 Std. Mean Difference (IV, 0.78 [-0.47, 2.03]
ment of airflow: peak flow Random, 95% CI)
rate (expiratory)

247
CHAPTER 5

Table continued

1.6 Objective measure- 1 44 Std. Mean Difference (IV, -0.46 [-1.06, 0.14]
ment of airflow: rhinoma- Fixed, 95% CI)
nometry
1.7 Other adverse events 3 1130 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.87, 1.12]
1.7.1 Fluticasone furoate 2 801 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.81, 1.16]
(110 µg fluticasone furoate
equals around 200 µg FP,
BUD or BDP)
1.7.2 Mometasone furoate 1 329 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.87, 1.19]

248
INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

249
CHAPTER 5

250
INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

251
CHAPTER 5

Comparison 2. Intranasal corticosteroids versus intranasal antihistamine

Outcome or Subgroup Studies Partic- Statistical Method Effect Estimate

ipants
2.1 Total nasal symptom 1 80 Mean Difference (IV, Fixed, -0.25 [-0.69, 0.19]
score, follow-up > 4 weeks 95% CI)
2.1.1 Budesonide 1 80 Mean Difference (IV, Fixed, -0.25 [-0.69, 0.19]
95% CI)
2.2 Total nasal symptom 1 63 Mean Difference (IV, -0.50 [-1.92, 0.92]
score (change from base- Random, 95% CI)
line), follow-up ≤ 4 weeks
2.2.1 Triamcinolone 1 63 Mean Difference (IV, -0.50 [-1.92, 0.92]
acetonide Random, 95% CI)
2.3 Quality of life (SF- 1 80 Mean Difference (IV, Fixed, -1.30 [-3.60, 1.00]
12v2) 95% CI)
2.3.1 Budesonide 1 80 Mean Difference (IV, Fixed, -1.30 [-3.60, 1.00]
95% CI)
2.4 Objective measure- 1 63 Mean Difference (IV, -6.17 [-15.25, 2.91]
ment of airflow: inspi- Random, 95% CI)
ratory peak flow rate
(change from baseline)
2.4.1 Triamcinolone 1 63 Mean Difference (IV, -6.17 [-15.25, 2.91]
acetonide Random, 95% CI)
2.5 Other adverse events 1 80 Risk Ratio (M-H, Fixed, 2.00 [0.19, 21.18]
95% CI)
2.5.1 Budesonide 1 80 Risk Ratio (M-H, Fixed, 2.00 [0.19, 21.18]
95% CI)

252
INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

253
CHAPTER 5

Comparison 3. Intranasal corticosteroids versus capsaicin

Outcome or Subgroup Studies Partic- Statistical Method Effect Estimate

ipants
3.1 Total nasal symptom 1 40 Mean Difference (IV, Fixed, 1.60 [0.03, 3.16]
score, follow-up ≤ 4 weeks 95% CI)
3.1.1 Budesonide 1 40 Mean Difference (IV, Fixed, 1.60 [0.03, 3.16]
95% CI)

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Comparison 4. Intranasal corticosteroids versus ipratropium bromide

Outcome or Subgroup Studies Partic- Statistical Method Effect Estimate

ipants
4.1 Total nasal symptom 1 48 Mean Difference (IV, Fixed, -1.50 [-12.24, 9.24]
score, follow-up ≤ 4 weeks 95% CI)
4.1.1 Beclomethasone 1 48 Mean Difference (IV, Fixed, -1.50 [-12.24, 9.24]
95% CI)

5
Comparison 5. Intranasal corticosteroids (INCS) versus INCS + intranasal antihistamine

Outcome or Subgroup Studies Partic- Statistical Method Effect Estimate

ipants
5.1 Total nasal symptom 2 242 Std. Mean Difference (IV, 0.75 [0.48, 1.02]
score, follow-up > 4 weeks Fixed, 95% CI)
5.1.1 Fluticasone propio- 1 162 Std. Mean Difference (IV, 0.37 [0.06, 0.68]
nate (dosage unclear) Fixed, 95% CI)
5.1.2 Budesonide 1 80 Std. Mean Difference (IV, 1.85 [1.32, 2.38]
Fixed, 95% CI)
5.2 Quality of life (SF12- 1 80 Mean Difference (IV, Fixed, -7.20 [-9.77, -4.63]
v2) 95% CI)
5.2.1 Budesonide 1 80 Mean Difference (IV, Fixed, -7.20 [-9.77, -4.63]
95% CI)
5.3 Other adverse events 2 242 Risk Ratio (M-H, Fixed, 0.26 [0.07, 1.01]
95% CI)
5.3.1 Fluticasone propio- 1 162 Risk Ratio (M-H, Fixed, 0.09 [0.00, 1.54]
nate (dosage unclear) 95% CI)
5.3.2 Budesonide 1 80 Risk Ratio (M-H, Fixed, 0.50 [0.10, 2.58]
95% CI)

255
CHAPTER 5

256
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

5
Comparison 6. Intranasal corticosteroids + saline versus saline

Outcome or Subgroup Studies Partic- Statistical Method Effect Estimate

ipants
6.1 Total nasal symptom 1 28 Mean Difference (IV, Fixed, -1.30 [-2.97, 0.37]
score, follow-up ≤ 4 weeks 95% CI)
6.1.1 Mometasone 1 28 Mean Difference (IV, Fixed, -1.30 [-2.97, 0.37]
furoate 95% CI)
6.2 Quality of life (SNOT- 1 28 Mean Difference (IV, Fixed, -8.00 [-19.75, 3.75]
22) 95% CI)
6.2.1 Mometasone 1 28 Mean Difference (IV, Fixed, -8.00 [-19.75, 3.75]
furoate 95% CI)
6.3 Objective measure- 1 28 Mean Difference (IV, Fixed, -9.20 [-33.96,
ment of airflow: peak 95% CI) 15.56]
nasal inspiratory flow
6.3.1 Mometasone 1 28 Mean Difference (IV, Fixed, -9.20 [-33.96,
furoate 95% CI) 15.56]

257
CHAPTER 5

258
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

ADDITIONAL TABLES

Table 1. Summary of patient-reported disease severity scores

Study ID Symptoms Score for each Summation Notes

measured symptom (total range)
Arikan 2006 Nasal obstruction Measured on a Completed No summary data
VAS: 0 to 10, 0 is prior to trial and reported to allow
better at 1, 2 and 3 inclusion in the
months (range meta-analysis for
0 to 10); as only this outcome
one symptom
no summation
needed
Balle 1982 1. Obstruction Scale unclear, low Total scores Unclear scale for
2. Rhinorrhoea indicates fewer (for the last individual symp-
3. Sneezing symptoms 7 days of a toms
2-week treat-
ment period)
represented 5
the means of
scores for the
3 symptoms
(range unclear)
Blom 1997 A. Total nasal score A. Measured on a A. Presented We used B as
(sum score of block- scale of 0 to 3 (3 as mean sum a total nasal
age, sneezing and means worse) score of 3 symptom score
rhinorrhoea) B. Measured on a symptoms for because a VAS is
1. Blockage VAS: 0 to 10 (0 is 1 week (range a more estab-
2. Sneezing better) 0 to 3) lished measure-
3. Rhinorrhoea B. Measured ment
B. Overall inten- at 2 weeks
sity of total nasal pre-treatment, 4
symptoms Does not weeks after first
consist of individual batch of treat-
symptoms ment, 8 weeks
after treatment
(range 0 to 10);
overall intensity,
therefore no
summation of
symptoms

259
CHAPTER 5

Table continued

Symptoms Score for each Summation

Study ID Notes
measured symptom (total range)
Boechat Combined nasal Measured on a Measured —
2019 symptom score VAS scale of 0 to pre-intervention
(after emailing 10 (10 is worse) and at 2 weeks
author):
1. Nasal blockage
2. Sneezing
3. Nasal itching
4. Rhinorrhoea
Behncke Total nasal symptom Unclear Unclear —
2006 score, unclear defi-
nition
Day 1990 1. Blocked nose Measured on a Mean change in —
2. Itchy nose scale of 0 to 3 (0 total combined
3. Runny nose is better) symptom score
4. Sneezing (range 0 to 3)
from end of
treatment to
baseline (week
4 versus week
0)
Ellegård Congestion Measured on a Reported after We evaluated
2001 scale of 0 to 4 (0 8 weeks of the data at the
is better) treatment and end of 8 weeks
16 weeks of of treatment as
post-treatment this was the most
follow-up common method
(range 0 to 4); of measurement
as only one among other
symptom no studies
summation
needed
Guo 2015 Total nasal symptom Scale unclear Measured —
score; no breakdown pre-intervention
in individual symp- and at 2 weeks;
toms range and sum-
mation unclear

260
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Table continued

Symptoms Score for each Summation

Study ID Notes
measured symptom (total range)
Hallén 1997 Nasal congestion Measured on a Reported for No differences
VAS of 0 to 100 (0 all days, 0 to between morning
is better) 14 days, in the and evening data.
morning and Reported morning
in the evening data at day 13.
(range 0 to
100); as only
one symptom
no summation
needed
Havas 2002 1. Rhinorrhoea Measured on Sum of mean We did not use the
2. Nasal blockage a VAS of 0 to 5 values of reported aggre-
3. Sneezing (0 = no symp- rhinorrhoea, gate relief score,
4. Headache toms), separately nasal blockage but instead calcu-
5. Post-nasal drip for each side and sneezing lated a total nasal
6. Sore throat (range 0 to 30); symptom score
measurement out of rhinorrhoea, 5
at end of treat- nasal blockage
ment and sneezing
(mean values and
SDs per symptom
were provided)
Hillas 1980 Total nasal symptom Both measured Total nasal No separate
score on a scale of 0 to symptom score: data reported
1. Sneezing 3 (0 = nil, 1 = mild, reported as a for non-allergic
2. Rhinorrhoea 2 = moderate and mean of 4-week rhinitis, only
3. Nasal pruritis 3 = severe) treatment responder/non-re-
4. Blocked nose period sponder data
5. Itchy eyes
6. Watery eyes
7. Red eyes
Incaudo Overall severity of Measured daily on Reported mean We did not use the
1980 rhinitis a scale of 1 to 4 (0 at end of week reported individual
is better) 2, 4, 6 and 8 rhinitis symptoms
(range 0 to 4) to calculate a total
nasal symptom
score, as only
P values were
reported

261
CHAPTER 5

Table continued

Symptoms Score for each Summation

Study ID Notes
measured symptom (total range)
Jacobs 1. Congestion Measured twice TNSS is sum of We used daily
2009 2. Rhinorrhoea daily on diary the 3 symptom reflective TNSS
3. Post-nasal drip cards using a scores (range 0 and not morning
4-point categori- to 9). Change in instantaneous
cal scale ranging TNSS (range 0 TNSS
from 0 (symptom to 9) from end
not present) to 3 of treatment
(symptom hard to (week 4) to
tolerate; interferes baseline.
with daily activi-
ties or sleeping)
Jessen 1990 1. Nasal secretion All 3 symptoms Reported as Unclear whether
2. Sneezing were measured sum score of maximum scale
3. Nasal blockage daily on a scale 2-week treat- was 3 or 4
of 0 to 3/4 (0 is ment period
better) (range 0 to
126/168)
Kalpaklioglu 1. Rhinorrhoea Scale of 0 to 4 (0 Most likely —
2010 2. Congestion is better) although not
3. Itching explicitly cited
4. Sneezing sum of all indi-
5. Anosmia vidual symp-
6. Conjunctivitis toms. Reported
for 2 weeks
after treatment.
Reported as
mean change
from baseline.
Lin 2017 1. Nasal obstruction Unclear scale Unclear total —
2. Nasal itch range of symp-
3. Rhinorrhoea toms
4. Sneezing

262
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Table continued

Symptoms Score for each Summation

Study ID Notes
measured symptom (total range)
Lundblad 1. Rhinorrhoea Measured on a Range 0 to 12; Converted into
2001 2. Nasal stuffiness/ scale of 0 to 3 (0 reported most dichotomous
congestion is better) likely as sum outcome:
3. Nasal itching at the end of improved versus
4. Sneezing treatment unimproved.
Improvement
defined as a
reduction of at
least 1 point
in the overall
symptom score.
No numerical data
on original TNSS,
so not included in
meta-analysis for
this outcome
Löfkvist 1. Nasal catarrh Measured on a Range 0 to 12 No numerical 5
1976 2. Blockage scale of 0 to 3 (0 data on original
3. Nasal itching is better) TNSS, therefore
4. Sneezing not included in
meta-analysis.
There are data on
‘non-responder/
improvement/
responder’
Malm 1976 1. Nasal obstruction Measured on a TNSS not We calculated
2. Rhinorrhoea scale of 0 to 3 (0 reported, but a total nasal
3. Sneezing is better) calculated for symptom score
4. Eye irritation meta-analysis: out of rhinorrhoea,
sum of mean nasal blockage
values of nasal and sneezing
obstruction, (mean values and
rhinorrhoea SDs per symptom
and sneezing were provided) for
(range 0 to 9); the dosages 200
measurement µg, 400 µg and
at end of treat- 800 µg
ment)

263
CHAPTER 5

Table continued

Symptoms Score for each Summation

Study ID Notes
measured symptom (total range)
Malm 1981 1. Nasal obstruction Measured on a TNSS not We calculated
2. Nasal secretion scale of 0 to 3 (0 reported, but a total nasal
3. Sneezing is better) calculated for symptom score
Reported as meta-analysis: out of rhinorrhoea,
mean ± SEM of sum of mean nasal blockage
at last 3 days values of nasal and sneezing
of the patients obstruction, (mean values and
symptom score rhinorrhoea and SDs per symptom
in each treatment sneezing (range were provided)
period for nasal 0 to 9) for the dosages
obstruction and 50 µg, 200 µg and
secretion. For 800 µg
sneezing: scale of
0 to 3 (0 is good:
no sneezing = 0;
1 to 5 sneezes = 1
point; 6 to 15 = 2
points; more than
15 sneezes = 3
points)
Meltzer Nasal symptom Unclear Unclear Unclear
1994 score, unclear defi-
nition
Miller 1969 1. Nasal obstruction Measured by Not reported We were unable
2. Discharge patient at 2 and 4 to calculate a SD
3. Post-nasal drip weeks after treat- for rhinorrhoea
4. Sneezing ment on a scale of (secretion) and
0 to 3 (0 is better) post-nasal drip as
the P values for
these symptoms
were not reported,
therefore not
included in
meta-analysis for
this outcome
O’Reilly 1991 1. Nasal obstruction Measured on a Composite Only P values
2. Anterior rhinor- scale of 0 to 5 (0 score for all reported, there-
rhoea is better) 5 symptoms, fore not included
3. Posterior rhinor- range 0 to 25 in meta-analysis
rhoea for this outcome
4. Sneezing
5. Facial pain

264
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Table continued

Symptoms Score for each Summation

Study ID Notes
measured symptom (total range)
Scadding A. 1. Nasal blockage A. Measured by A. Range 0 No data reported
1995 on waking patient on a scale to 12 for non-allergic
2. Nasal blockage of 0 to 3 on a daily B.1. Range 0 rhinitis subgroup
during the rest of card (0 is better) to 3 separately, there-
the day B. 1. Measured by B.2. Range 0 fore not included
3. Sneezing patient on a scale to 10 in meta-analysis.
4. Rhinorrhoea of 0 to 3 on a daily The study states
B. 1. Overall assess- card (0 is better) that there were
ment of symptoms 2. VAS, 0 to 10 no differences
by patient cm (10 = worst between allergic
2. Overall assess- symptoms) and non-allergic
ment of symptoms rhinitis patients
at clinic visit
Schulz 1978 1. Sneezing Duration in hours All 5 symptoms No data reported
2. Stuffy nose per symptom combined to for non-allergic
3. Runny nose measured determine rhinitis subgroup
4. Nose blowing overall duration separately for this 5
5. Post-nasal drip of patients’ outcome, there-
symptoms. fore not included
Reported as in meta-analysis.
percentage of There are data
days during on ‘responder/
which all 5 of non-responder’.
the symptoms
lasted 1 hour
or less and the
percentage of
days during
which at least
one of the 5
symptoms
lasted 4 hours
or more
Singh 2017 — — — Not included in
meta-analysis
as TNSS data
are reported in
relationship to
cold dry air provo-
cation

265
CHAPTER 5

Table continued

Symptoms Score for each Summation

Study ID Notes
measured symptom (total range)
Song 2018 A. Overall VAS Measured on a Range (0 to 10), —
B. Individual VAS: 0 to 10, 0 is measurement
symptom VAS: better at week 8
1. Congestion
2. Sneezing
3. Itching
4. Rhinorrhoea
Spector 1. Sneezing Patient evaluation, Range (5 to 20), —
1980 2. Stuffiness sum of 5 symp- measurement
3. Runny nose toms numerically at week 4
4. Nose blowing assessed as
5. Post-nasal drip absent (1), mild
(2), moderate
(3), or severe (4);
range 1 to 4
Tantilipikorn 1. Rhinorrhoea 4-point categor- Combined Compared data
2010 2. Nasal congestion ical scale of 0 3 reflective from week 4 to
3. Post-nasal drip to 3 (none, mild, individual nasal baseline to arrive
4. Eye itching/ moderate, severe), symptom at change from
burning measured by scores (range baseline TNSS.
5. Eye tearing/ patient on paper 0 to 9) We included the
watering diary card, in AM Measured in reflective TNSS
6. Eye redness and PM, as instan- AM and PM, (rTNSS) in the
taneous (i) and which were meta-analysis, not
over previous 12 averaged to the instantaneous
hours (reflective). arrive at the TNSS (iTNSS).
Instantaneous final daily value
score measured in (daily rTNSS)
AM, and reflective
in both AM and
PM measured
during screening
and treatment
periods
Tarlo 1977 Individual rhinitis 0 if absent, 1 if Total nasal No separate data
symptoms: they lasted less symptoms: for non-allergic
1. Daily and nightly than 30 minutes, the sum of the rhinitis subgroups
sneezing 2 if between 30 nasal symptom
2. Nasal congestion minutes and 2 scores (sneez-
3. Rhinorrhoea hours, and 3 if ing, congestion,
Total nasal symp- longer than 2 and rhinor-
toms hours rhoea, as well
as the total)

266
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Table continued

Symptoms Score for each Summation

Study ID Notes
measured symptom (total range)
Turkeltaub 1. Sneezing Measured on 0 Sum score Unusual method
1982 2. Runny nose to 6 scale (0 is of symptoms of measurement
3. Stuffy nose better) scores for of TNSS
4. Eye itch sneezing,
5. Throat itch runny nose,
stuffy nose,
eye itching and
throat itching
measured
post-treatment,
each measured
on 0 to 6 scale
(range 0 to
30). To this
was added
the number
of tablets and 5
nasal sprays
required to
control nasal
symptoms for
the preceding
12-hour period;
possible scores
range from 0
to 40
Varricchio 1. Nasal itching Measured on 0 Range 0 to 12; Reported TNSS as
2011 2. Sneezing to 3 scale (0 is assessed on continuous data
3. Rhinorrhoea better) day 1 and at 8 and change from
4. Nasal obstruction weeks baseline. We have
included the first
approach
Warland Overall severity of Overall severity of — —
1982 symptoms symptoms: scale
Individual rhinitis from 0 to 3
symptoms: Individual nasal
1. Sneezing symptoms: scale
2. Runny nose from 0 to 4
3. Nose blowing
4. Post-nasal drip

267
CHAPTER 5

Table continued

Symptoms Score for each Summation

Study ID Notes
measured symptom (total range)
Webb 2002 1. Nasal obstruction Measured on a Range 0 to 300, TNSS reported
2. Post-nasal drip VAS, 0 to 100 (0 is measured at as change from
3. Rhinorrhoea better) both 2 weeks baseline.
and 4 weeks Combination of 3
studies

TNSS: total nasal symptom score

iTNSS: instantaneous total nasal symptom score
rTNSS: reflective total nasal symptom score
SD: standard deviation

Table 2. Nasal symptom scores: studies not included in meta-analysis

Study Findings
Arikan Concluded that treatment with fluticasone propionate provided significantly
2006 greater relief from the symptom of nasal obstruction compared with placebo over
the entire 3-month treatment period. Patients’ subjective assessments of nasal
obstruction after medical treatment correlated with the results of objective testing.
Lin 2017 This study was not included in the meta-analysis because of lack of quality of the
study data. Firstly, the study presents unexpected data, with disappearance of the
benefit of intranasal corticosteroids with longer follow-up. Secondly, including the
study in the meta-analysis resulted in a high level of heterogeneity. The SD values
that are presented in the study do not match with the presented means, n and P
values. The data make more sense if the as-presented SD values should actually
be standard error of the mean (SEM), which was confirmed by a re-analysis. As
the authors did not reply to our question regarding the above, we decided to not
include this study in the meta-analysis. The study did show a beneficial effect
of intranasal corticosteroids over placebo, however this effect disappeared with
longer follow-up.
Meltzer This study was not included in the meta-analysis for this outcome as it did not
1994 report numerical data for the non-allergic rhinitis subgroup. They did conclude that
fluticasone propionate reduces total symptoms, improves individual symptoms
(mainly obstruction) and achieves a significant overall improvement in non-allergic
rhinitis compared to placebo.
Miller 1969 Reported a statistically significant difference in symptoms in favour of intranasal
corticosteroids (it did not report P values for rhinorrhoea and post-nasal drip so we
were not able to calculate a SD).
Lundblad Reported no numerical data on original TNSS, so it could not be included in the
2001 meta-analysis for this outcome. It did report data that could be translated into
proportions of ‘responders/non-responders’. The study did not find significant
differences between intranasal corticosteroids and placebo. The study converted
TNSS into a dichotomous outcome: improved versus unimproved. Improvement
was defined as a reduction of at least 1 point in the overall symptom score. No
numerical data on original TNSS was provided, therefore this study was not
included in the meta-analysis for this outcome.

268
 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

Table continued

Löfkvist This study was not included in the meta-analysis as no data on TNSS were
1976 reported. The study did report data on ‘responders/non-responders’ with 29/39
responders in the intranasal corticosteroids group and 12/39 responders in the
placebo group, favouring intranasal corticosteroids with an odds ratio (OR) of 0.44
(95% confidence interval (CI) 0.24 to 0.64).
O’Reilly This study was not included in the meta-analysis as only P values were reported.
1991 Patients reported subjective symptom scores on a scale of 0 to 5 for nasal
obstruction, anterior rhinorrhoea, posterior rhinorrhoea, sneezing and facial pain.
When the composite scores for all 5 symptoms were compared, there was a signif-
icant difference between beclomethasone dipropionate and baseline (P = 0.01)
and beclomethasone dipropionate and placebo (P = 0.02) in favour of beclometha-
sone dipropionate.
Scadding This study on 2 types of intranasal corticosteroids versus placebo in perennial
1995 rhinitis patients (allergic and non-allergic rhinitis) reported a number of individual
rhinitis symptoms and an overall assessment of symptoms, but no separate data
on non-allergic rhinitis patients were presented. However, the study does state
that there were no differences between allergic and non-allergic rhinitis. This study
reported a significant improvement with intranasal corticosteroids versus placebo
in perennial allergic rhinitis, with fluticasone propionate aqueous nasal spray (200 5
µg) as effective as beclomethasone dipropionate µg twice daily.
Schulz This study was not included in the meta-analysis as no data on TNSS were
1978 reported. The study did report data on responders/non-responders with 6 of 14
responders in the intranasal corticosteroids group and 8 of 18 responders in the
placebo group with an OR of 0.02 (95% CI 0.33 to 0.36), therefore not a significant
difference.
Tarlo 1977 This study was not included in the meta-analysis for this outcome as it did not
report enough numerical data for the non-allergic rhinitis subgroup. They con-
cluded that after 6 months 6 of 9 non-allergic rhinitis patients were successfully
treated with intranasal corticosteroids and 3 of 9 non-allergic rhinitis patients were
unsuccessfully treated with intranasal corticosteroids. They concluded that their
results (in favour of intranasal corticosteroids over placebo) in those in whom a
possible allergic component could be identified were not different from those of
the whole group.
Varricchio This study was not included in the meta-analysis because we decided to only
2011 include studies with an intranasal corticosteroid dosage of 200 µg to 400 µg. This
study uses an intranasal corticosteroid dosage of 2000 µg. The study did report a
significant improvement in nasal symptoms in non-allergic rhinitis after an 8-week
treatment period with intranasal flunisolide.
Warland This study was not included in the meta-analysis for this outcome because it did
1982 not report numerical data for the non-allergic rhinitis subgroup. They concluded
that flunisolide nasal solution seems to be effective in both allergic rhinitis and
vasomotor rhinitis patients, although it seems to be more effective in an allergic
state.

SD: standard deviation

TNSS: total nasal symptom score

269
 APPENDICES

270
Appendix 1. Search strategies
CENTRAL PubMed EMBASE (Ovid)
CHAPTER 5

1 MESH DESCRIPTOR Rhinitis EXPLODE ALL AND #1 “Rhinitis”[Mesh] 1 exp rhinitis/

CENTRAL:TARGET #2 rhinit* 2 rhinit*.tw.
2 (rhinit*):AB,EH,KW,KY,MC,MH,TI,TO AND CEN- #3 (NARES or NAR or LAR or 3 (NARES or NAR or LAR or NANIPER).tw.
TRAL:TARGET NANIPER) 4 1 or 2 or 3
3 NARES or NAR or LAR or NANIPER AND CEN- #4 (#1 OR #2 OR #3) 5 exp steroid/
TRAL:TARGET #5 “Anti-Inflammatory Agents”[Mesh] 6 exp glucocorticoid/
4 #1 OR #2 OR #3 #6 “Anti-Inflammatory Agents, 7 exp hydroxycorticosteroid/
5 MESH DESCRIPTOR Steroids EXPLODE ALL AND Non-Steroidal”[Mesh] 8 exp antiinflammatory agent/
CENTRAL:TARGET #7 (#5 NOT #6) 9 exp nonsteroid antiinflammatory agent/
6 MESH DESCRIPTOR Glucocorticoids EXPLODE #8 (STEROID* or CORTICOSTE- 10 (STEROID* or CORTICOSTEROID* or GLUCOCORTI-
ALL AND CENTRAL:TARGET ROID* or GLUCOCORTICOID* or COID* or CORTICOID* or BECLOMETHASONE or BECLA-
7 MESH DESCRIPTOR Hydroxycorticosteroids CORTICOID* or BECLOMETHASONE MET or BECLOCORT or BECOLMETASONE or BETAMETH-
EXPLODE ALL AND CENTRAL:TARGET or BECLAMET or BECLOCORT ASONE or BETAMETASONE or BETADEXAMETHASONE
8 MESH DESCRIPTOR Anti-Inflammatory Agents or BECOLMETASONE or BETA- or FLUBENISOLONE or CELESTO or BECOTIDE or
EXPLODE ALL AND CENTRAL:TARGET METHASONE or BETAMETASONE BECONASE or VANCENASE or ALANASE or NASALIDE or
9 MESH DESCRIPTOR Anti-Inflammatory Agents, or BETADEXAMETHASONE or NASAREL).tw.
Non-Steroidal EXPLODE ALL AND CENTRAL:TAR- FLUBENISOLONE or CELESTO or 11 (FLUNISOLIDE or NASALIDE or NASAREL or RHINALAR
GET BECOTIDE or BECONASE or VANCE- or FLUTICASONE or FLONASE or FLOUNCE or FLIXONASE
10 #8 NOT #9 NASE or ALANASE or NASALIDE or or MOMETASONE or NASONEX or TRIAMCINOLONE or
11 (STEROID* or CORTICOSTEROID* or GLUCOCOR- NASAREL) NASACORT or “TRI NASAL” or ARISTOCORT or VOLON or
TICOID* or CORTICOID* or BECLOMETHASONE or #9 “Hydroxycorticosteroids”[Mesh] AVAMYS).tw.
BECLAMET or BECLOCORT or BECOLMETASONE #10 “Glucocorticoids”[Mesh] 12 (HYDROCORTISONE or CORTISOL or DEXAMETH-
or BETAMETHASONE or BETAMETASONE or #11 “Steroids”[Mesh] ASONE or DEXAMETASONE or HEXADECADROL or
BETADEXAMETHASONE or FLUBENISOLONE or #12 (FLUNISOLIDE or NASALIDE or DECADRON or DEXACORT or DEXASONE or HEXADROL
CELESTO or BECOTIDE or BECONASE or VANCE- NASAREL or RHINALAR or FLUTI- or METHYLFLUORPREDNISOLONE or MILLICORTEN or
NASE or ALANASE or NASALIDE or NASAREL):AB,E- CASONE or FLONASE or FLOUNCE ORADEXON or BUDESONIDE or HORACORT or PULMI-
H,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET or FLIXONASE or MOMETASONE or CORT or RHINOCORT).tw.
12 (FLUNISOLIDE or NASALIDE or NASAREL or RHI NASONEX or TRIAMCINOLONE or 13 8 not 9
 NALAR or FLUTICASONE or FLONASE or FLOUNCE NASACORT or “TRI NASAL” or ARIS- 14 5 or 6 or 7 or 10 or 11 or 12 or 13
or FLIXONASE or MOMETASONE or NASONEX or TOCORT or VOLON or AVAMYS) 15 4 and 14
TRIAMCINOLONE or NASACORT or “TRI NASAL” #13 (HYDROCORTISONE or COR- 16 exp topical drug administration/
or ARISTOCORT or VOLON or AVAMYS):AB,EH,K- TISOL or DEXAMETHASONE or 17 exp nebulizer/
W,KY,MC,MH,TI,TO AND CENTRAL:TARGET DEXAMETASONE or HEXADECAD- 18 exp vaporizer/
13 (HYDROCORTISONE or CORTISOL or DEXA- ROL or DECADRON or DEXACORT 19 exp intranasal drug administration/
METHASONE or DEXAMETASONE or HEXADECAD- or DEXASONE or HEXADROL or 20 (spray or aerosol or powder or inhal* or solution or
ROL or DECADRON or DEXACORT or DEXASONE or METHYLFLUORPREDNISOLONE turbuhaler or intranasal* or intra next nasal or topical* or
HEXADROL or METHYLFLUORPREDNISOLONE or or MILLICORTEN or ORADEXON drops).tw.
MILLICORTEN or ORADEXON or BUDESONIDE or or BUDESONIDE or HORACORT or 21 16 or 17 or 18 or 19 or 20
HORACORT or PULMICORT or RHINOCORT):AB,E- PULMICORT or RHINOCORT) 22 15 and 21
H,KW,KY,MC,MH,TI,TO AND CENTRAL:TARGET #14 (#7 OR #8 OR #9 OR #10 OR #11
14 #5 or #6 or #7 or #10 or #11 or #12 or #13 OR #12 OR #13)
15 #4 and #14 #15 (spray or aerosol or powder or
16 MESH DESCRIPTOR Administration, Topical inhal* or solution or turbuhaler or
EXPLODE ALL AND CENTRAL:TARGET intranasal* or intra next nasal or
17 MESH DESCRIPTOR Nebulizers and Vaporizers topical* or drops)
EXPLODE ALL AND CENTRAL:TARGET #16 “Administration, Intrana-
18 MESH DESCRIPTOR Administration, Intranasal sal”[Mesh]
EXPLODE ALL AND CENTRAL:TARGET #17 “Nebulizers and Vaporiz-
19 (spray or aerosol or powder or inhal* or solution ers”[Mesh]
or turbuhaler or intranasal* or intra next nasal or #18 “Administration, Topical”[Mesh]
topical* or drops ):AB,EH,KW,KY,MC,MH,TI,TO AND #19 (#15 OR #16 OR #17 OR #18)
CENTRAL:TARGET #20 (#4 AND #14 AND #19)
20 #16 OR #17 OR #18 OR #19
21 #15 AND #20
Web of Science (Web of Knowledge) CINAHL (EBSCO) Trial registers
INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

271
5
 Table continued

272
#1 TS=rhinit* S20 S14 AND S19 ICTRP
#2 TS=(NARES or NAR or LAR or NANIPER) S19 S15 OR S16 OR S17 OR S18 rhinitis AND steroids OR rhinitis AND corticosteroid OR
CHAPTER 5

#3 #2 OR #1 S18 TX spray or aerosol or powder rhinitis AND corticoid OR rhinitis AND glucocorticoid OR
#4 TS=(STEROID* or CORTICOSTEROID* or GLUCO- or inhal* or solution or turbuhaler rhinitis AND fluticasone
CORTICOID* or CORTICOID* or BECLOMETHASONE or intranasal* or intra next nasal or ClinicalTrials.gov
or BECLAMET or BECLOCORT or BECOLMETA- topical* or drops (rhinitis) AND (steroids OR CORTICOSTEROID OR GLU-
SONE or BETAMETHASONE or BETAMETASONE S17 (MH “Administration, Intranasal”) COCORTICOID OR CORTICOID OR FLUTICASONE OR
or BETADEXAMETHASONE or FLUBENISOLONE or S16 (MH “Nebulizers and Vaporiz- hydrofluoroalkane OR ciclesonide OR butorphanol OR
CELESTO or BECOTIDE or BECONASE or VANCE- ers”) beclomethasone)
NASE or ALANASE or NASALIDE or NASAREL) S15 (MH “Administration, Topical+”) ClinicalTrials.gov (via CRS)
#5 TS=(FLUNISOLIDE or NASALIDE or NASAREL S14 S4 AND S13 1 ((rhinit* or NARES or NAR or LAR or NANIPER)):AB,EH,K-
or RHINALAR or FLUTICASONE or FLONASE or S13 S5 OR S6 OR S9 OR S10 OR S11 W,KY,MC,MH,TI,TO AND INSEGMENT
FLOUNCE or FLIXONASE or MOMETASONE or OR S12 2 (STEROID* or CORTICOSTEROID* or GLUCOCORTI-
NASONEX or TRIAMCINOLONE or NASACORT or S12 HYDROCORTISONE or COR- COID* or CORTICOID* or BECLOMETHASONE or BECLA-
“TRI NASAL” or ARISTOCORT or VOLON or AVAMYS) TISOL or DEXAMETHASONE or MET or BECLOCORT or BECOLMETASONE or BETAMETH-
#6 TS=(HYDROCORTISONE or CORTISOL or DEXA- DEXAMETASONE or HEXADECAD- ASONE or BETAMETASONE or BETADEXAMETHASONE
METHASONE or DEXAMETASONE or HEXADECAD- ROL or DECADRON or DEXACORT or FLUBENISOLONE or CELESTO or BECOTIDE or
ROL or DECADRON or DEXACORT or DEXASONE or or DEXASONE or HEXADROL or BECONASE or VANCENASE or ALANASE or NASALIDE or
HEXADROL or METHYLFLUORPREDNISOLONE or METHYLFLUORPREDNISOLONE NASAREL ):AB,EH,KW,KY,MC,MH,TI,TO AND INSEGMENT
MILLICORTEN or ORADEXON or BUDESONIDE or or MILLICORTEN or ORADEXON 3 (FLUNISOLIDE or NASALIDE or NASAREL or RHINALAR
HORACORT or PULMICORT or RHINOCORT ) or BUDESONIDE or HORACORT or or FLUTICASONE or FLONASE or FLOUNCE or FLIXONASE
#7 #6 OR #5 OR #4 PULMICORT or RHINOCORT or MOMETASONE or NASONEX or TRIAMCINOLONE or
#8 TS=(spray or aerosol or powder or inhal* or solu- S11 FLUNISOLIDE or NASALIDE or NASACORT or “TRI NASAL” or ARISTOCORT or VOLON or
tion or turbuhaler or intranasal* or intra next nasal or NASAREL or RHINALAR or FLUTI- AVAMYS):AB,EH,KW,KY,MC,MH,TI,TO AND INSEGMENT
topical* or drops) CASONE or FLONASE or FLOUNCE 4 (HYDROCORTISONE or CORTISOL or DEXAMETH-
#9 #8 AND #7 AND #3 or FLIXONASE or MOMETASONE or ASONE or DEXAMETASONE or HEXADECADROL or
NASONEX or TRIAMCINOLONE or DECADRON or DEXACORT or DEXASONE or HEXADROL
NASACORT or “TRI NASAL” or ARIS- or METHYLFLUORPREDNISOLONE or MILLICORTEN or
TOCORT or VOLON or AVAMYS ORADEXON or BUDESONIDE or HORACORT or PULMI-
S10 STEROID* or CORTICOSTE- CORT or RHINOCORT ):AB,EH,KW,KY,MC,MH,TI,TO AND
ROID* or GLUCOCORTICOID* or INSEGMENT
 CORTICOID* or BECLOMETHASONE 5 #2 OR #3 OR #4
or BECLAMET or BECLOCORT or 6 #1 AND #5
BECOLMETASONE or BETAMETHA- 7 nct:AU AND INSEGMENT
SONE or BETAMETASONE or BETA- 8 #7 AND #6
DEXAMETHASONE or FLUBENIS-
OLONE or CELESTO or BECOTIDE
or BECONASE or VANCENASE or
ALANASE or NASALIDE or NASAREL
S9 S7 not S8
S8 (MH “Antiinflammatory Agents,
Non-Steroidal+”)
S7 (MH “Antiinflammatory Agents+”)
S6 (MH “Glucocorticoids”)
S5 (MH “Steroids+”)
S4 S1 OR S2 OR S3
S3 TX NARES or NAR or LAR or
NANIPER
S2 TX rhinit*
S1 (MH “Rhinitis+”)
INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

273
5
CHAPTER 5

Appendix 2. Summary of the data collection form

We extracted the following characteristics using a data collection form.

• eneral information: publication type, year, country, author contact details.

G
• S tudy eligibility: type of study, participants, types of interventions, comparisons
and outcomes.
• S tudy methods: design, unit of allocation, start and end dates, duration of
participation, ethical approval, funding, possible conflicts of interest.
• Participants: population description, setting, inclusion and exclusion criteria,
method of recruitment, informed consent, total number randomised, clusters
(if applicable), baseline imbalances, withdrawals and exclusions, age, sex, race/
ethnicity, severity of illness, comorbidities, previous nasal and sinus surgery, other
relevant socio-demographics, measured and reported subgroups.
• Intervention and comparison groups: intranasal corticosteroids and comparison
type, number randomised to group, duration of treatment, timing, delivery,
providers, co-interventions, economic information, resource requirements,
integrity of delivery, compliance.
• Outcomes: type of outcome, time points measured, time points reported, unit of
measurement, scale, assumed risk estimate, power.
• ‘Risk of bias’ assessment: random sequence generation, allocation concealment,
blinding of participants and personnel, blinding of outcome assessment,
incomplete outcome data, selective outcome reporting, other bias.
• Data and analysis: comparison, outcome, subgroup, time points, results, number of
missing participants, reason missing, number of participants moved from another
group, reason for move, unit of analysis, statistical method.
• O ther information: key conclusions of the study, references to other relevant
studies.

CONTRIBUTIONS OF AUTHORS

Christine Segboer (CS), Artur Gevorgyan (AG), Klementina Avdeeva (KA), Supinda
Chusakul (SC), Jesada Kanjanaumporn (JK), Songklot Aeumjaturapat (SA), Laurens
Reeskamp (LR), Wytske Fokkens (WJF), Kornkiat Snidvongs (KS).

WJF, AG, CS and LR were responsible for drafting the review, selecting the studies,
data extraction and analysis, and drafting the final manuscript. WJF conceived the
idea and participated in drafting the review and the final manuscript. KA partici-
pated in data extraction and analysis and drafting the final manuscript. SC, JK and
SA participated in reviewing the review manuscript and giving expert opinions. KS
participated in selecting the studies, data extraction and analysis, and reviewing the
review manuscript.

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

DECLARATIONS OF INTEREST

• Christine Segboer: none known.

• Artur Gevorgyan: Artur Gevorgyan has received speaker fees in 2017 from Takeda
Canada, Abbott, Meda Pharmaceuticals and Mylan. Meda and Mylan are related
to Dymista nasal spray. Takeda is related to Omnaris.
• Klementina Avdeeva: none known.
• Supinda Chusakul: none known.
• Jesada Kanjanaumporn: none known.
• Songklot Aeumjaturapat: none known.
• Laurens Reeskamp: none known.
• Wytske Fokkens: WJ Fokkens has received private sector support for research
and/or clinical trials related to the treatment of allergic and non-allergic rhinitis
from Chordate (2018/19), as well as public sector research support from the EU,
and for studies not related to allergic and non-allergic rhinitis from GSK (2017-19),
Sanofi (2016-19) and Novartis (2018-19). WJ Fokkens has also received a speaker
fee from Sanofi (2018-19).
• Kornkiat Snidvongs: none known. 5

SOURCES OF SUPPORT

Internal sources
• No sources of support supplied

External sources
• National Institute for Health Research, UK. Infrastructure funding for Cochrane
ENT

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CHAPTER 5

DIFFERENCES BETWEEN PROTOCOL AND REVIEW

In the protocol the outcome ‘other adverse events’ was defined as local irritation/
discomfort. While performing the review it became clear that widening the definition
of ‘other adverse events’ to all other adverse events besides epistaxis (for example,
pharyngitis, nasal dryness/crusting and headache) would result in more information.

Although we did not plan to perform a meta-analysis if heterogeneity was considered

substantial (50% to 90%) or considerable (75% to 100%), we made one exception.
We carried out pooling in the presence of very high heterogeneity in the case of the
comparison ‘Total nasal symptom score (change from baseline)’ as result of the study
Jacobs 2009. The problems with Jacobs 2009 that are responsible for the high heter-
ogeneity are described in detail above. This study is, however, one of the largest of
the studies on this topic and very well known. For that reason we decided to retain it
in the meta-analysis.

We calculated a total nasal symptom score (sum of mean symptom scores) and
pooled SD (SQRT (SDa2+ SDb2+ SDc2)) from the individual symptoms of ‘rhinorrhoea/
secretions’, ‘congestion/obstruction’ and ‘sneezing’ when studies only provided us
with individual symptom scores. When assessing the individual symptoms that were
used to calculate a total nasal symptom score in the other included studies (Table 1),
these three symptoms were the most common. One could consider also including
‘itch’ (Hellings 2017); however, previous studies have shown that ocular itch plays a
less dominant role in non-allergic rhinitis patients compared to allergic rhinitis patients
(Segboer 2018). In addition, Malm 1976 would have been the only study for which we
could also have included ‘itch’ to calculate a total nasal symptom score. Miller 1969
was the only study that also reported ‘post-nasal drip’ as an extra symptom that we
could have included in a calculated total nasal symptom score; however, as we were
not able to calculate a pooled standard deviation from this study, we were not able to
calculate a total nasal symptom score from rhinorrhoea, congestion and post-nasal
drip, which would otherwise have been justifiable.

Among studies treatment daily dosage varied from 50 µg to 2000 µg. Most of the
studies that compared different dosages of intranasal corticosteroids used a cross-
over study design with the exception of Blom 1997 and Webb 2002, which used a
parallel-group study design. In the cross-over studies the same participants were
treated with different dosages of intranasal corticosteroids, with short (one-week)
or no washout, complicating a clear comparison between these dosage subgroups
(Balle 1982; Malm 1976; Malm 1981). Only Balle 1982 showed a dosage effect for
two nasal symptom score outcomes. Malm 1976 and Malm 1981 showed no signifi-
cant difference between the dosage subgroups. The two parallel-group studies both
concluded that there were no statistically significant differences between the different

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 INTRANASAL CORTICOSTEROIDS FOR NON‐ALLERGIC RHINITIS

intranasal corticosteroid dosage subgroups (Blom 1997; Webb 2002). In the paral-
lel-group studies the different dosage subgroups contained different participants but
were compared with the same control group. To prevent counting the same partici-
pants or controls more than once, we decided to include one intranasal corticosteroid
dosage in the meta-analysis. The most common intranasal corticosteroid dosage
was 200 µg. A test for subgroup differences showed no significant difference (‘no
dosage effect’) between 200 µg and 400 µg of intranasal corticosteroids. We therefore
included studies in the meta-analysis with an intranasal corticosteroid dosage range
of 200 µg to 400 µg.

In the protocol, under electronic searches we planned to search KoreaMed, PakMed-

inet, IndMed and ISRCTN. However, the Cochrane ENT Information Specialist has
deemed that these sources are not worth searching for the majority of reviews. These
searches were not performed and were therefore not reported in the Search methods
for identification of studies section.

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CHAPTER 6
Capsaicin for non-allergic
rhinitis
 A. Gevorgyan 1
C.L. Segboer 1
R. Gorissen
C.M. van Drunen
W.J. Fokkens
1
Shared first authorship. CL Segboer and A Gevorgyan contributed equally to this work

Cochrane Database Syst Rev. 2015 Jul; 14(7)

CHAPTER 6

ABSTRACT

Background
There are many forms of rhinitis. Patients are diagnosed with non-allergic rhinitis when
anatomic, infectious and allergic aetiologies have been excluded. The symptoms,
including nasal congestion, blockage or obstruction, clear rhinorrhoea, sneezing and,
less frequently, nasal itching, can range from mild to debilitating. It affects between
25% and 50% of patients with rhinitis. Several medications are widely used in the
treatment of non-allergic rhinitis, including oral and topical nasal antihistamines, intra-
nasal and (rarely) systemic corticosteroids, and anticholinergics. Capsaicin, the active
component of chili peppers, delivered intranasally, is considered a treatment option
for non-allergic rhinitis.

Objectives
To assess the effectiveness of capsaicin in the management of non-allergic rhinitis
compared with no therapy, placebo or other topical or systemic medications, or two
or more of the above therapies in combination, or different capsaicin regimens.

Search methods
We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the
Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 5); PubMed;
EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and
additional sources for published and unpublished trials. The date of the search was
24 June 2015.

Selection criteria
Randomised controlled trials in adult patients with non-allergic rhinitis comparing
intranasal capsaicin with no therapy, placebo or other topical or systemic medications,
or their combinations.

Data collection and analysis

We used the standard methodological procedures expected by The Cochrane
Collaboration.

Main results
We included four studies (five publications) involving 302 participants with idiopathic
non-allergic rhinitis. All the included studies described patients with moderately severe,
idiopathic non-allergic rhinitis who were between the ages of 16 and 65. Studies had
follow-up periods ranging from four to 38 weeks. The overall risk of bias in the studies
was either high or unclear (two studies had overall high risk of bias, while two others
had low to unclear risk of bias). Using the GRADE system we assessed the evidence

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 CAPSAICIN FOR NON-ALLERGIC RHINITIS

as being of low to moderate quality. A meta-analysis was not possible, given lack of
similarity of the reported outcomes.

Two studies compared capsaicin with placebo. One study reported that capsaicin
resulted in an improvement of overall nasal symptoms (a primary outcome) measured
on a visual analogue scale (VAS) of 0 to 10. There was a mean difference (MD) of -3.34
(95% confidence interval (CI) -5.24 to -1.44), MD -3.73 (95% CI -5.45 to -2.01) and MD
-3.52 (95% CI -5.55 to -1.48) at two, 12 and 36 weeks post-treatment, respectively.
Another study reported that, compared to placebo, capsaicin (at 4 µg/puff) was more
likely to produce overall symptom resolution (reduction in nasal blockage, sneezing/
itching/coughing and nasal secretion measured with a daily record chart) at four weeks
post-treatment (a primary outcome). The risk ratio (RR) was 3.17 (95% CI 1.38 to 7.29).

One study compared capsaicin to budesonide (an intranasal corticosteroid). This

study found that patients treated with capsaicin had a better overall symptom score
compared to those treated with budesonide (MD 2.50, 95% CI 1.06 to 3.94, VAS of 0 to
10). However, there were no differences in the individual symptom scores for headache,
postnasal drip, rhinorrhoea, nasal blockage, sneezing and sore throat assessed during
the last three days of a four-week treatment.
6
One study compared two different regimens of capsaicin administration: five treat-
ments in one day versus five treatments given every two to three days during two
weeks. Using daily record charts, the study reported significant improvement of
individual symptom scores for rhinorrhoea in patients treated five times per day,
however numerical data were not presented. There were no improvements in the
other outcomes: rhinorrhoea, nasal obstruction, sneezing and overall nasal symptoms,
measured on a VAS.

Finally, one of these studies also compared three doses of capsaicin (to placebo).
Patients treated with a 1 µg versus 4 µg per puff dose of capsaicin had a worse daily
record chart overall symptom score resolution (RR 0.63, 95% CI 0.34 to 1.16).

Only one study attempted to measure adverse effects (a primary outcome), however
due to methodological issues with the assessment we are unable to draw any
conclusions.

We sought to include other secondary outcomes (e.g. quality of life measures, treat-
ment dropouts, endoscopic scores, turbinate or mucosal size, cost of therapy), but
none of these were measured or reported in the included studies.

281
CHAPTER 6

Authors’ conclusions
Capsaicin may be an option in the treatment of idiopathic non-allergic rhinitis. It is given
in the form of brief treatments, usually during the same day. It appears to have benefi-
cial effects on overall nasal symptoms up to 36 weeks after treatment, based on a
few, small studies (low-quality evidence). Well-conducted randomised controlled trials
are required to further advance our understanding of the effectiveness of c ­ apsaicin in
non-allergic rhinitis, especially in patients with non-allergic rhinitis of different types
and severity, and using different methods of capsaicin application.

PLAIN LANGUAGE SUMMARY

Capsaicin for non-allergic rhinitis

Review question
Is capsaicin applied into the nose (intranasal) effective in the management of
non-allergic rhinitis compared with no therapy, placebo or other topical or systemic
medications?

Background
Rhinitis means inflammation of the nose. It affects 30% to 40% of the general popula-
tion. There are many forms of rhinitis: rhinosinusitis (or simply sinusitis), allergic
rhinitis and non-allergic rhinitis. Non-allergic rhinitis is diagnosed in patients who have
negative tests for allergies and also do not have sinusitis. The symptoms include
congestion of the nose, a blocked or obstructed sensation in the nose that causes
difficulty breathing, clear nasal discharge (runny nose), sneezing and nasal itching.
There are several subtypes of non-allergic rhinitis: occupational (from exposure to
chemicals), smoking, gustatory (related to eating food or drinking fluid), hormonal
(from changes in hormone levels in the body), pregnancy, senile or elderly (mostly
affecting the older population), medication-induced (for example, from overuse of
decongestant nasal sprays) and local allergic (local allergy in the nose, while skin or
blood allergy tests are negative). The most common subtype of non-allergic rhinitis is
‘idiopathic’ or ‘vasomotor’ rhinitis, which results from imbalance of the neural (nerve)
system that manages the function of the nose. The mechanisms of many of these
subtypes remain unknown. Non-allergic rhinitis affects about 25% to 50% of patients
with rhinitis and is therefore very common.

Capsaicin is the active ingredient of chili peppers. It has medicinal properties and is
used elsewhere in medicine, for example for neuralgias (nerve pain) and psoriasis
(a skin disease). The side effects of using capsaicin in the nose include irritation,
burning, sneezing and coughing, however there are no known long-term side effects
of c
­ apsaicin use. Capsaicin is given in the form of brief treatments, usually during the

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 CAPSAICIN FOR NON-ALLERGIC RHINITIS

same day. It works by down-regulating transient receptor potential vanilloid (TRPV)

receptor expression on C-sensory fibres. TRPV represents special ion channels
involved in the sensations of pain, cold, hotness, tastes, pressure and vision. C fibres
help to conduct some of these sensations. There is ongoing research into the effects
of capsaicin on these mechanisms and its clinical uses.

Study characteristics
We included four studies involving 302 patients with idiopathic non-allergic rhinitis. All
the included studies described patients with moderately severe idiopathic non-allergic
rhinitis, who were between the ages of 16 and 65. The studies had a follow-up ranging
from four to 38 weeks after treatment.

Key results
Individually, the studies reported that the overall function of the nose in patients with
non-allergic rhinitis improved when treated with capsaicin compared to placebo.
Capsaicin also seems to work better than another common type of nasal medica-
tion, budesonide (a steroid). The best knowledge that we have on capsaicin treatment
supports giving it five times in one day, and to use doses of at least 4 micrograms in
each puff. We could not combine the results together. The included studies did not
have sufficient information to allow us to draw a conclusion about side effects. We also 6
wanted to include other outcomes (e.g. quality of life measures, treatment dropouts,
endoscopic scores, turbinate or mucosal size, cost of therapy), but none of these were
measured or reported in the included studies.

Quality of the evidence

Overall, we judged the quality of the evidence to be of low to moderate quality. The
evidence is up-to-date to June 2015.

Conclusions
Given that many other options do not work well in non-allergic rhinitis, capsaicin is a
reasonable option to try under physician supervision.

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CHAPTER 6

SUMMARY OF FINDINGS FOR THE MAIN COMPARISON

Table 1 Capsaicin compared to placebo for non-allergic rhinitis

Capsaicin compared to placebo for non-allergic rhinitis

Patient or population: non-allergic rhinitis
Settings: tertiary university hospital
Intervention: capsaicin
Comparison: placebo
Outcomes Illustrative comparative Rel- No of Quality of Comments
risks* (95% CI) ative partici- the evi-
Assumed Corresponding effect pants dence
risk risk (95% (studies) (GRADE)
CI)
Placebo Capsaicin
Overall The mean The mean — 24 ⊕⊕⊕⊝ A lower
nasal overall overall nasal (1 RCT) moderate1,2 score indi-
symptom nasal symptom cates better
score symptom score 36 weeks overall
36 weeks score 36 post-treatment nasal
post-treat- weeks in the interven- symptoms
ment post-treat- tion group was
ment was 3.52 lower (5.55
6.778 lower to 1.48
lower)
Daily Study population RR 3.17 104 ⊕⊕⊝⊝ The bigger
record 115 per 366 per 1000 (1.38 to (1 RCT) low3 the number
chart 1000 (159 to 841) 7.29) per 1000,
symptom the more
Moderate
resolution patients
4 weeks 115 per 366 per 1000 would have
post-treat- 1000 (159 to 841) resolution
ment (cap- of their
saicin 4 μg/ symptoms
puff versus
placebo)
Treatment- Not Not reported — — — —
related reported
adverse
events
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided
in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed
risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio

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 CAPSAICIN FOR NON-ALLERGIC RHINITIS

Table continued

GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in
the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the
estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1
Small sample size (40 patients total).
2
Single study.
3
Pseudo-randomisation was performed on an odds and evens basis.

BACKGROUND

Description of the condition

Non-allergic rhinitis is a term that includes rhinitis of several aetiologies. Patients are
diagnosed with non-allergic rhinitis when anatomic, infectious and allergic aetiologies
have been excluded. The symptoms include nasal congestion, blockage or obstruction,
clear rhinorrhoea, sneezing and, less frequently, nasal itching. These symptoms can
be intermittent or persistent and can range from mild to debilitating (Schroer 2012). 6
Although studies on quality of life in non-allergic rhinitis are scarce, extrapolation of
knowledge from studies in allergic rhinitis, as well as unpublished data in non-allergic
rhinitis, testify to the significant impact of non-allergic rhinitis symptoms on patients’
quality of life (Bousquet 2008; Gelardi 2008; Meltzer 1999).

Non-allergic rhinitis and allergic rhinitis have similar symptoms. Allergic rhinitis is
excluded by negative findings of allergy history, skin prick testing and measurement of
serum-specific IgE antibodies. The Allergic Rhinitis and its Impact on Asthma (ARIA)
initiative, in collaboration with the World Health Organization, has developed guidelines
for the diagnosis and treatment of allergic rhinitis (Bousquet 2008).

Non-allergic rhinitis also needs to be differentiated from acute and chronic rhinosinus-
itis with or without nasal polyps (CRSwNP and CRSsNP, respectively), an inflammation
of the nose and paranasal sinuses due to infectious or inflammatory aetiology. Chronic
rhinosinusitis is characterised by nasal obstruction, congestion or blockage, anterior
or posterior rhinorrhoea, facial pressure or pain, and reduction or loss of smell. Several
guidelines for the diagnosis and management of acute and chronic rhinosinusitis have
been developed, including the European Position Paper on Rhinosinusitis and Nasal
Polyps (EPOS 2012), the clinical practice guideline on adult sinusitis by the American
Academy of Otolaryngology – Head and Neck Surgery (Rosenfeld 2007), and the
Canadian clinical practice guidelines for acute and chronic rhinosinusitis (Desrosiers
2011).

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Chronic rhinitis (allergic and non-allergic) affects up to 30% to 40% of the general
population (Bousquet 2008). Most epidemiological studies report that 25% to 50%
of rhinitis patients can be categorised as having non-allergic rhinitis (Fokkens 2002).
Most studies agree on a female predominance of non-allergic rhinitis (Knudsen
2009; Molgaard 2007).

Non-allergic rhinitis can be subclassified based on different aetiologies: occupational

(chemical), smoking, gustatory, hormonal, senile (rhinitis of the elderly), atrophic,
medication-induced (including rhinitis medicamentosa), local allergic rhinitis, non-
allergic rhinitis with eosinophilia syndrome (NARES) and idiopathic (vasomotor or
non-allergic, non-infectious perennial allergic rhinitis (NANIPER)). However, the patho-
physiology of non-allergic rhinitis remains largely unknown (Van Gerven 2012).

Occupational (chemical) and smoking rhinitis can be clearly linked to an affecting

agent. In close to 60% of cases, occupational rhinitis can be associated with occupa-
tional asthma (Ameille 2013). Smoking is considered a specific irritant of the nasal
mucosa, which can cause non-allergic rhinitis (van Rijswijk 2005). Gustatory rhinitis
is accompanied by oversecretion of nasal mucus in response to irritating gustatory
agents, usually spicy foods (Georgalas 2012). Hormonal rhinitis can occur during
the menstrual cycle and puberty, due to hypothyroidism or acromegaly, as well as
during pregnancy, where it resolves postpartum. Rhinitis of the elderly (senile rhinitis)
is encountered in the older generation and characterised by the presence of constant
rhinorrhoea and lack of other nasal complaints.

In the case of rhinitis medicamentosa, several medications have been implicated

(Varghese 2010). The most common is the misuse of topical sympathomimetics (e.g.
oxy- or xylometazoline) for more than 5 to 10 days, resulting in disregulation of the
adrenergic receptors in the nasal mucosa and in a relative increase of the parasympa-
thetic drive, leading to significant rhinorrhoea and nasal obstruction. These symptoms
cause patients to continue using topical adrenergics, perpetuating a vicious cycle.
Treatment is usually focused on cessation of the affecting agent, as well as support
with intranasal or, rarely, oral corticosteroids.

Local allergic rhinitis is diagnosed when skin prick and serum-specific IgE testing
are negative, however a nasal allergen provocation test is positive (Rondon 2012).
A recent report attributed over a quarter of chronic rhinitis patients to local allergic
rhinitis (Rondon 2012). NARES is considered in the presence of rhinitis symptoms, no
evidence of allergy and the presence of more than 20% eosinophilia on nasal smears
(Ellis 2007). Its pathophysiology is poorly understood, but is thought to involve a local,
self perpetuating nasal inflammation with eosinophilia (Groger 2012).

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Idiopathic rhinitis has for a long time remained a diagnosis of exclusion, when the other
causes of rhinitis have been ruled out (Burns 2012). Idiopathic rhinitis has been referred
to as vasomotor rhinitis, NANIPER, non-infectious, non-allergic rhinitis (NINAR) and
intrinsic rhinopathy. It is diagnosed based on the patient’s complaints and exclusion
of other types of rhinitis. Some patients in this group predominantly have conges-
tion, whereas others may have unexplained rhinorrhoea as the main symptom. The
latter group has been previously called vasomotor rhinitis. Nasal hyper-reactivity is
a common and characteristic feature of patients with chronic rhinitis, and can be
elicited by cold dry air provocation (van Rijswijk 2005). Several mechanisms have
been proposed to explain idiopathic rhinitis, including chronic inflammation, imbal-
ance of parasympathetic and sympathetic neural systems, and activation of the non-
adrenergic, non-cholinergic or peptidergic systems with involvement of C sensory
fibres.

Treatment of non-allergic rhinitis includes trigger avoidance, topical and systemic

medications, and surgery. When rhinitis is caused by a known aetiologic factor, such
as smoking or chemical exposure, the mainstay of treatment is trigger avoidance.

Several medications are widely utilised in the treatment of non-allergic rhinitis,

including oral and topical nasal antihistamines, intranasal and (rarely) systemic corti- 6
costeroids, and anticholinergics (ipratropium bromide). Other medical options include
capsaicin, intranasal injection of botulinum toxin type A, intranasal saline rinse, local
and systemic sympathomimetics and cromolyn sodium. The exact mechanisms of
the effect of these therapies in non-allergic rhinitis remain largely unknown.

Some medications are particularly useful in specific types of non-allergic rhinitis.

Specifically, ipratropium bromide is mostly used in the treatment of rhinitis of the
elderly, due to its alleviation of the main symptom, rhinorrhoea (van Rijswijk 2005).
Intranasal antihistamines are usually prescribed when sneezing is the main symptom
of non-allergic rhinitis (Schroer 2012). Capsaicin (8-methyl-N-vanillyl-6-nonenamide),
the active component of chili peppers, appears to have a therapeutic effect in idiopathic
rhinitis, based on several randomised controlled studies. This therapy is usually tried
after failed treatment with intranasal corticosteroids (van Rijswijk 2005).

Surgical reduction can be considered to treat inferior turbinate hypertrophy, when

it contributes to nasal obstruction and mucosal hypersecretion in chronic rhinitis
(Garzaro 2012). Vidian neurectomy, causing denervation of the autonomic supply of
the nasal mucosa, can reduce the symptoms of rhinorrhoea and nasal obstruction
(Robinson 2006).

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Description of the intervention

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the active component of chili peppers,
plants of the genus Capsicum. Along with other related compounds, it belongs to a
group of chemicals identified as capsaicinoids. Capsaicin produces a burning sensa-
tion when a tissue comes into contact with it. This occurs via binding to transient
receptor potential vanilloid 1 (TRPV-1) receptor, an ion-channel type receptor, which
can be stimulated by heat and physical abrasion. Binding of capsaicin to it results
in a similar burning sensation. As a topical medication, capsaicin has been used for
neuralgias and psoriasis. Several similar compounds are currently being tested in
clinical trials.

Intranasal capsaicin is currently considered one of the treatment options for

non-­allergic rhinitis. Capsaicin is also one of the active ingredients (along with
eucalyptus oil) in Sinus Buster, an over-the-counter nasal spray available in the United
States (Bernstein 2011). The dose and frequency of intranasal capsaicin application
have varied significantly in studies. Doses of capsaicin have ranged from 0.1 to 100
mg per application, given through one or several actuations of the spray depending
on the capsaicin preparation in a particular study (Blom 1997/1998; Ciabatti 2009; van
Rijswijk 2003). The regimen of capsaicin treatment has also ranged widely from five
times during the same day, to three times per day for three days, to once daily for five
days, or once every two to three days for seven treatments. The local pharmacology
of capsaicin in the nose is poorly understood. It is metabolised in the liver.

The side effects of intranasal capsaicin application include irritation, burning, sneezing
and coughing. There are no known long-term side effects of capsaicin use.

Intranasal capsaicin is currently available in many countries, including Austria, Belgium,

Germany, Mexico, The Netherlands, Sweden, UK and USA.

How the intervention might work

Capsaicin affects the unmyelinated peptidergic sensory C fibres of the nasal mucosa,
which are highly sensitive to it (Stjarne 1989). It is hypothesised that repeated high
doses of capsaicin lead to degeneration of these nerve fibres. Unmyelinated sensory C
fibres play a role in neurogenic reflex mechanisms in the nasal mucosa, both local and
central. Stimulation of these sensory fibres by nonspecific stimuli can lead to a local
reflex in the nasal mucosa with a release of neuropeptides (C-peptide, CGRP, VIP). At
the same time, capsaicin does not affect the number of inflammatory cells in the nasal
mucosa long-term (Blom 1997/1998). The same study also did not show a difference
in neuronal tissue density as expressed by synaptophysin or neurofilament staining.

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Although these mechanisms are not considered definitive, several studies have
demonstrated a significant improvement of nasal symptoms after topical adminis-
tration of capsaicin (Lacroix 1991; van Rijswijk 2003).

Interestingly, intranasal capsaicin has also been studied in allergic rhinitis. However,
a Cochrane review on capsaicin in allergic rhinitis in adults did not find an evidence of
intranasal capsaicin effect (Cheng 2006).

Why it is important to do this review

Establishing the clinical efficacy of capsaicin in non-allergic rhinitis could have impor-
tant clinical implications. Only a few randomised controlled trials have evaluated the
effectiveness of capsaicin in non-allergic rhinitis. Most of these studies have small
numbers of participants, as well as variations in the dosing and schedule of capsaicin
administration. There are no reported meta-analyses on this topic.

This review aims to assess the evidence for the use capsaicin in non-allergic rhinitis
and specifically to establish the most advantageous dosing and scheduling regimens.

OBJECTIVES 6
To assess the effectiveness of capsaicin in the management of non-allergic rhinitis
compared with no therapy, placebo or other topical or systemic medications, or two
or more of the above therapies in combination, or different capsaicin regimens.

METHODS

Criteria for considering studies for this review

Types of studies
Randomised and quasi-randomised controlled trials (RCTs), including cluster-
randomised and cross-over trials, irrespective of publication status, date of publication
or language.

Types of participants
Inclusion criteria
Adult patients with all types of non-allergic rhinitis in any setting. The types of
non-­allergic rhinitis included were idiopathic (vasomotor or non-allergic, non-infectious
perennial allergic rhinitis), occupational (chemical), smoking, gustatory, hormonal,
senile (rhinitis of the elderly), atrophic, medication-induced (including rhinitis medic-
amentosa), local allergic rhinitis and non-allergic rhinitis with eosinophilia syndrome

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(NARES). We defined patients over 16 years of age as adults. We included studies

involving only a subset of non-allergic rhinitis patients of interest if these data could
be used in the analysis. We included studies of perennial rhinitis, if it was possible to
isolate outcomes for patients with non-allergic rhinitis.

Exclusion criteria
Patients with allergic rhinitis (history of allergy, skin prick testing or serum-specific IgE
antibodies, or following ARIA guidelines), infectious aetiology, acute or chronic rhinosi-
nusitis (following EPOS 2012, Canadian (Desrosiers 2011) or American (Rosenfeld
2007) guidelines on sinusitis), autoimmune rhinitis (presence of autoimmune markers)
or rhinitis related to anatomical abnormalities.

Types of interventions
Intervention
Intranasal capsaicin at any dose, frequency and duration. Studies of capsaicin with
a co-intervention were to be included and we planned to use sensitivity analysis to
assess the impact of their inclusion.

Comparisons
No therapy, placebo or other topical or systemic medications, or two or more of the
above therapies in combination, or different capsaicin regimens (dose, frequency or
duration).

Types of outcome measures

We analysed the following outcomes in the review, but they were not used as a basis
for including or excluding studies.

Primary outcomes
• Overall symptom score (e.g. global symptom scores, daily record chart score)
• Individual symptom scores (e.g. nasal congestion, rhinorrhoea, sneezing, nasal
itching), measured by visual analogue scale (VAS)
• Adverse events

Secondary outcomes
• Quality of life measures (e.g. via appropriate validated questionnaires for rhinitis)
• Treatment failure, dropouts, non-compliance with treatment, or unplanned switch
to or addition of another medication
• Objective measurements: nasal peak expiratory flow (NPEF), peak nasal inspiratory
flow (PNIF), anterior or posterior rhinomanometry, and acoustic rhinometry

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• Additional outcomes
· Endoscopic score
· Analysis of nasal secretions
· Turbinate or mucosal size
· Analysis of nasal mucosal biopsy
· Haematological, biochemical and urinary parameters
· Costs of therapy

We sought any follow-up period, as available in the included studies.

Search methods for identification of studies

The Cochrane Ear, Nose and Throat Disorders Group’s Trial Search Co-ordinator
conducted systematic searches for randomised controlled trials and controlled clinical
trials. There were no language, publication year or publication status restrictions. The
date of the search was 24 June 2015.

Electronic searches
The Trial Search Co-ordinator searched:

• The Cochrane Register of Studies (CRS) ENT Disorders Group Trials Register 6
(searched 24 June 2015);
• The Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 5);
• PubMed (1946 to 24 June 2015);
• Ovid EMBASE (1974 to 2015 week 25);
• Ovid CAB Abstracts (1910 to 2015 week 24);
• EBSCO CINAHL (1982 to 24 June 2015);
• Ovid AMED (1985 to 24 June 2015);
• LILACS (searched 24 June 2015);
• KoreaMed (searched 24 June 2015);
• IndMed (searched 24 June 2015);
• PakMediNet (searched 24 June 2015);
• Web of Knowledge, Web of Science (1945 to 24 June 2015);
• ClinicalTrials.gov (searched via the CRS 24 June 2015);
• ICTRP (searched 24 June 2015);
• Google Scholar (searched 24 June 2015);
• Google (searched 24 June 2015).

Subject strategies for databases were modelled on the search strategy designed for
CENTRAL. Where appropriate, they were combined with subject strategy adaptations
of the highly sensitive search strategy designed by The Cochrane Collaboration for
identifying randomised controlled trials and controlled clinical trials (as described in
the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box

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6.4.b. (Handbook 2011). Search strategies for major databases including CENTRAL
are provided in Appendix 1.

Searching other resources

We scanned the reference lists of identified publications for additional trials and
contacted trial authors where necessary. In addition, the Trial Search Co-ordinator
searched PubMed, TRIPdatabase, The Cochrane Library and Google to retrieve existing
systematic reviews relevant to this systematic review, so that we could scan their
reference lists for additional trials. We searched for conference abstracts using the
Cochrane Ear, Nose and Throat Disorders Group Trials Register.

Data collection and analysis

Selection of studies
We merged the identified studies using EndNote X2 reference management software
(Thomson Reuters, New York, NY, USA). We removed duplicates records of the same
report. Two authors (AG and CS, a rhinology fellow and a junior otorhinolaryngology
trainee, respectively) independently examined the titles and abstracts of the studies
to remove obviously irrelevant reports. We then retrieved the full texts of potentially
relevant articles. We linked multiple reports of the same study together. The same two
authors independently examined the full-text reports for compliance of studies with the
eligibility criteria. We contacted the study authors, where appropriate, to clarify study
eligibility. Then, the two authors independently made final decisions on study inclusion.
Disagreement on study inclusion was resolved by discussion. If necessary, we planned
that disagreement would be resolved by arbitration by a third author (CMvD), but this
was not required. We noted the primary reason for exclusion.

Data extraction and management

Two authors (AG and CS) independently extracted the data with a predetermined
data collection form (Appendix 2). We piloted the form on a small number of studies
to identify any discrepancies in coding. If multiple reports of the same study existed,
each author collected data separately from each report and then collated this into
a single study report. We resolved disagreements by discussion. If necessary, we
planned that disagreements would be resolved by arbitration by a third author (CMvD),
but this was not required.

For dichotomous outcomes, we extracted the numbers in each of the two outcome
categories in each of the intervention groups, or odds ratio, or risk accompanied by
measures of uncertainty (e.g. standard error, 95% confidence interval or an exact
P value). For continuous outcomes, we extracted the mean value of the outcome
measurements in each intervention group, the respective standard deviation and
the number of participants. If the data were presented in another format, we made

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appropriate calculations or transformations (or both) according to the  Cochrane

Handbook for Systematic Reviews of Interventions (Handbook 2011). We extracted
ordinal outcomes and outcomes presented as counts in the form reported in the
original studies.

Assessment of risk of bias in included studies

AG and CS undertook assessment of the risk of bias of the included trials independently,
with the following taken into consideration, as guided by the Cochrane Handbook for
Systematic Reviews of Interventions (Handbook 2011):

• Sequence generation
• Allocation concealment
• Blinding
• Incomplete outcome data
• Selective outcome reporting and
• Other sources of bias

We used the Cochrane ‘Risk of bias’ tool in RevMan 5 (RevMan 2014), which involved
describing each of these domains as reported in the trial and then assigning a judge-
ment about the adequacy of each entry: ‘low’, ‘high’ or ‘unclear’ risk of bias. 6
Measures of treatment effect
We calculated a weighted treatment effect across studies using RevMan 5 (RevMan
2014). For dichotomous outcomes, we calculated risk ratios (RR) after appropriate
conversions. For continuous outcomes, we calculated a mean difference (MD) or a
standardised mean difference (SMD) as appropriate. We analysed longer ordinal scales
(e.g. VAS scores) as continuous data, using MD or SMD. We planned to analyse short
ordinal scales as dichotomous data (using RR), combining adjacent scores together
whenever it was possible to find an appropriate cut-off point. For rare count data, we
planned to calculate rate ratios based on the original data. We planned to treat more
frequent count data as continuous. We planned to convert time-to-event data into
hazard ratios. We did not carry out the above-mentioned planned analyses due to lack
of data. We had planned to express pooled treatment effects with their 95% confidence
intervals (95% CI) for all types of data.

Unit of analysis issues

We determined appropriate units of analysis from the included studies and presented
them in the results. We analysed cluster-randomised trials based on the level of
allocation, i.e. clusters of patients. For cross-over trials without a washout period, we
planned to analyse data from the first treatment period. For cross-over trials with a
washout period, we used summary results of a paired t-test analysis of participant-spe-
cific differences between experimental and control intervention measurements to

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incorporate into the meta-analysis. If participant-specific differences were not

reported, we only provided a narrative report of the cross-over trial.

Dealing with missing data

We recorded all missing data on the data collection form and reported this in the ‘Risk
of bias’ table. Whenever possible, we contacted the original investigators to request
missing data. We planned for three scenarios for missing data for primary outcomes,
however these were not required. In the first scenario, we would have calculated the
results without the missing data. In the second scenario, we would have assumed
data for primary outcomes to be missing at random, and we would have carried
the last observation forward for the missing value. In the third scenario, we would
have assumed data for the primary outcome to be not missing at random, and we
would have assumed the missing values to have a poor outcome. For secondary
outcomes, we would have calculated the results without the missing data. We would
have performed sensitivity analyses to assess for changes in overall results based on
the assumptions of these scenarios.

Assessment of heterogeneity
To assess the heterogeneity of effect size across pooled studies, we calculated
the I2 statistic in RevMan 5. We did not perform a meta-analysis if we considered
heterogeneity substantial (50% to 90%) or considerable (75% to 100%) according to
the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011).

Assessment of reporting biases

We planned to use a funnel plot to detect reporting biases when there were at least 10
studies included in the meta-analysis, and we planned to analyse the visual asymmetry
of the plot. This was not required because fewer than four studies were included. If
there were small studies identified with larger treatment effects, we had planned to
perform a sensitivity analysis excluding these studies. This also was not required.

Data synthesis
We planned to use RevMan 5 to perform a meta-analysis using the random-effects
model if we did not consider the heterogeneity of the included studies substantial or
considerable. We intended to perform a meta-analysis for studies that were sufficiently
homogenous in terms of participants, treatments and outcome measures. When a
meta-analysis could not be performed due to the level of heterogeneity, we provided
a narrative analysis. We analysed the data on an intention-to-treat basis and using the
generic inverse variance method. We made comparisons for all available outcomes
between capsaicin and placebo, capsaicin and other topical or systemic medications,
and between different capsaicin regimens (dose, frequency or duration comparisons,
if available). We planned but ultimately were unable to make comparisons between

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capsaicin and no therapy, and capsaicin and two or more of the above therapies in
combination, due to lack of data.

Subgroup analysis and investigation of heterogeneity

We intended to perform subgroup analyses to compare the effects of capsaicin:

• I n different types of non-allergic rhinitis;

• In different severities of non-allergic rhinitis;
• At different time points after treatment;
• In non-allergic rhinitis diagnosed in primary versus secondary or tertiary care
settings;
• In patients who did or did not have surgery prior to treatment;
• Comparing delivery forms of capsaicin (spray versus drops);
• Comparing different schedules of capsaicin delivery;
• Comparing different doses of capsaicin delivery.

Sensitivity analysis
We intended to carry out sensitivity analyses on the basis of the methodological diver-
sity of the included studies. We considered the following factors when repeating the
analysis: 6
• isk of bias: excluding studies with high risk of bias (defined as four out of seven
R
domains deemed to have high risk);
• E xcluding industry-sponsored studies;
• E xcluding studies with significant author financial and other conflict of interest;
• Excluding studies with co-intervention administered simultaneously with capsaicin;
• Analysis by study design: parallel versus cross-over studies;
• S tatistical model of analysis (fixed-effect versus random-effects model);
• Assumptions about missing data (considering the scenarios outlined above).

GRADE and ‘Summary of findings’ table

We used the GRADE approach to rate the overall quality of evidence. The quality of
evidence reflects the extent to which we are confident that an estimate of effect is
correct and we applied this in the interpretation of results. There are four possible
ratings: high, moderate, low and very low. A rating of high quality of evidence implies
that we are confident in our estimate of effect and that further research is very unlikely
to change our confidence in the estimate of effect. A rating of very low quality implies
that any estimate of effect obtained is very uncertain.

The GRADE approach rates evidence from RCTs that do not have serious limitations
as high quality. However, several factors can lead to the downgrading of the evidence

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to moderate, low or very low. The degree of downgrading is determined by the serious-
ness of these factors:

• tudy limitations (risk of bias);

S
• Inconsistency;
• Indirectness of evidence;
• Imprecision; and
• Publication bias.

We included ‘Summary of findings’ (SOF) tables, constructed according to the recom-

mendations described in Chapter 10 of the Cochrane Handbook for Systematic Reviews
of Interventions (Handbook 2011).

RESULTS

Description of studies
See Characteristics of included studies; Characteristics of excluded studies.

Results of the search

The results of the search are presented in the study flow diagram in Figure 1. The
search retrieved 319 references. We identified two more records from the references
of retrieved studies. We initially screened for duplicates and obviously irrelevant studies
and discarded 143 references, leaving 178. After screening the titles and abstracts of
these references, we further excluded 172 studies, leaving six references. We assessed
the full texts of these references. We excluded one of these references due to the
treatment arm being contaminated by co-treatment. We included five references in the
systematic review, representing a total of four studies (two references were describing
different outcomes of the same study population). We additionally identified one study
as ongoing (NCT02288156) (see Characteristics of ongoing studies). There are no
‘awaiting assessment’ studies.

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Figure 1. Process for sifting search results and selecting studies for inclusion

Included studies
We included four studies in the review. Of the five references to these studies,
two described the same study and patient population with different outcome
measures (Blom 1997/1998). Two studies compared capsaicin to placebo (Blom
1997/1998; Ciabatti 2009). One study compared two treatment regimens of capsai­cin:
five treatments in one day versus five treatments given every two to three days during

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two weeks (van Rijswijk 2003). The study by Ciabatti, in addition to comparing capsa-
icin with placebo, also compared three different doses of capsaicin to each other.
Finally, the Havas 2002 study compared capsaicin with budesonide.

Design
Blom 1997/1998  and  van Rijswijk 2003  were both randomised studies.  Ciabatti
2009 and Havas 2002 were quasi-randomised. All four studies used a parallel-group
design.

None of the studies reported their funding source or any conflicts of interest.

Sample sizes
Sample sizes ranged from 30 (van Rijswijk 2003) to 208 (van Rijswijk 2003).

Setting
Blom 1997/1998 and van Rijswijk 2003 took place in tertiary university hospitals in the
Netherlands, Ciabatti 2009 in a similar setting in Italy. The setting for Havas 2002 was
a Department of Otolaryngology – Head and Neck Surgery in Australia.

Participants
There were 302 patients in total in the four included studies, of which 165 (54.46%)
were males. Patient age was reported in three studies (Blom 1997/1998;  Havas
2002; van Rijswijk 2003). In Blom 1997/1998 and van Rijswijk 2003, patient age ranged
from 16 to 65 and the mean age was 36 years. The mean age in the Havas 2002 study
was 40.3 years for males and 37.0 years for females in the budesonide group, and
41.5 years for males and 41.0 years for females in the capsaicin group. The Ciabatti
2009 study did not report patient age.

Description of non-allergic rhinitis in included patients

All studies included similar patients with a history of nasal complaints such as
nasal obstruction, sneezing and rhinorrhoea for a period of more than one year, with
symptoms for at least one hour per day and for at least five days during a period of
14 days preceding the study. The patients were described as having idiopathic rhinitis
(Ciabatti 2009; van Rijswijk 2003) and NANIPER (Blom 1997/1998; Havas 2002), the
previously used term for idiopathic rhinitis. Specific excluded types of non-allergic
rhinitis were smoking, pregnancy, hormonal and rhinitis medicamentosa. All patients
had perennial symptoms. Severity could be assessed in two studies as moderate or
severe based on symptom scores (Blom 1997/1998; van Rijswijk 2003). We identified
no studies that examined patients with other types of non-allergic rhinitis.

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Interventions
Capsaicin spray was used in all four included studies. One study used a dose of 15
µg/puff/nostril in the form of seven treatments every two to three days, to a total of
106.9 µg (Blom 1997/1998). The second study used two puffs into each nostril, each
containing 0.654 µg of capsaicin (capsaicin 71%, dihydrocapsaicin 20.94% and nordi-
hydrocapsaicin 4.94%), administered once weekly for four weeks, totalling 10.46 µg per
treatment (Havas 2002). The third study used a dose of 8.25 µg/puff and compared
regimens of five sprays applied in one day (once every hour for five hours) versus
application every two to three days for a total of five applications to a total of 82.5 µg
per study for both sides (van Rijswijk 2003). The fourth study used 1 µg, 2 µg and 4
µg/puff three times a day for three consecutive days (nine applications), amounting
to 72 µg per entire treatment for both sides (Ciabatti 2009).

As a placebo, Blom 1997/1998 used NaCl, van Rijswijk 2003 used the capsaicin solvent

and Ciabatti 2009 did not describe the consistency of the placebo used.

In Havas 2002, the comparison group was budesonide aqueous nasal corticosteroid
spray, 64 µg per dose, in the form of two puffs of the spray in each nostril in the
morning and evening for two weeks.
6
A co-intervention in the form of xylometazoline hydrochloride and lidocaine-based
sprays was used in two studies, Blom 1997/1998 and van Rijswijk 2003, 15 minutes
before capsaicin application (in the van Rijswijk 2003 study before the first capsaicin
application of the day). In Havas 2002, a co-intervention with lignocaine/phenylephrine
(co-phenylcaine) spray was used before the first treatment. No co-interventions were
described in Ciabatti 2009.

Outcomes
Primary outcomes
All four studies reported symptoms as an outcome. These were reported as a daily
record chart of several nasal symptoms or an overall nasal symptom score, or
individual symptoms scores measured by a VAS. The results were reported either
narratively or as a change over time, or resolution of symptoms, or improved versus
worse over time.

Ciabatti 2009 measured the side effects of capsaicin application in the form of nasal
blockage, itching/sneezing and coughing, though these symptoms also constitute
actual symptoms of non-allergic rhinitis, and hence differentiation between them as
side effects of capsaicin or as symptoms of non-allergic rhinitis would be difficult. No
further information was provided by this study to make such a determination.

None of the other included studies reported adverse events.

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Secondary outcomes
Quality of life measures and treatment failure, dropouts, non-compliance with treat-
ment or unplanned switch to or addition of another medication were not reported in
any of the included studies.

One study measured the levels of leukotrienes C4/D4/E4, prostaglandin D2 and tryptase
in nasal lavage, blood and urine chemistry, as well as expression of CD1, CD3, CD25,
CD68, IgE, MBP, chymase, tryptase, synaptophysin and neurofilament in the epithelium
and lamina propria of the inferior turbinate (Blom 1997/1998). One study measured
smell, nasal patency and mucosal sensitivity (van Rijswijk 2003).

None of the studies reported nasal peak expiratory flow (NPEF), anterior or posterior
rhinomanometry, endoscopic score, turbinate or mucosal size or costs of therapy.

Missing data
We contacted all authors of the included publications with a request to provide
summary data (means and standard deviations (SDs)) for the intervention groups
for clinically relevant outcomes. The contacted authors were unable to provide the
missing data for the included studies.

Follow-up
The study that compared capsaicin with placebo followed patients for 36 weeks
post-treatment (Blom 1997/1998). The study that compared two regimens of capsaicin
treatment followed patients for 38 weeks (van Rijswijk 2003). The study that compared
several doses of capsaicin and capsaicin with placebo followed patients for four weeks
before and four weeks after treatment (Ciabatti 2009). Finally, the study comparing
capsaicin with budesonide followed the patients for a total of 31 days (three days
before and four weeks after treatment) (Havas 2002).

Excluded studies
We excluded only one full-text study (Bernstein 2011). This was a randomised, placebo­-
-controlled, double-blind, parallel study of 21 days total duration (seven days pre­-­
treatment and 14 days during treatment), which compared Sinus Buster (a homeo-
pathic preparation of Capsicum annuum and Eucalyptol) with placebo (filtered water).
The participants were patients with non-allergic rhinitis and mixed rhinitis between 18
and 60 years of age. The mixed rhinitis patients were defined as having one or more
clinically relevant positive skin prick test (wheal ≥ 3 mm in diameter with surrounding
erythema compared with saline control in conjunction with a positive histamine
control) to a panel of aeroallergens that correlated with clinical symptoms and signif-
icant upper respiratory symptoms induced by chemical irritants, strong odours,
weather or temperature changes. The study did not report outcomes separately for
the non-allergic rhinitis and mixed rhinitis cohorts, however the authors provided us

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with the data for the non-allergic rhinitis cohort only. The main reason for the exclu-
sion of the cohort of purely non-allergic rhinitis patients in this study from the present
systematic review was the potential for unaccounted for effects of the co-intervention,
Eucalyptol, which was present only in the Sinus Buster and not in the placebo group.
In addition, the study used a ‘homeopathic’ dose of capsaicin.

Risk of bias in included studies

Judgements about risk of bias are presented as a ‘Risk of bias’ graph in percentage
form for all included studies combined (Figure 2). Risk of bias in individual studies is
shown in a ‘Risk of bias’ summary figure (Figure 3).

Figure 2. ‘Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies

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Figure 3. ‘Risk of bias’ summary: review authors’ judgements about each risk of bias item for each
included study

Allocation
Only one study described random sequence generation and we judged it to have a low
risk of selection bias (van Rijswijk 2003). In this study, computer-generated randomi-
sation was prepared in blocks of eight randomly permuted allocations. Another study
did not specify (Blom 1997/1998), while two others had high risk of bias for random
sequence generation (Ciabatti 2009; Havas 2002). Havas 2002 randomised patients
based on an odds and evens basis, while Ciabatti 2009 randomised according to the
patients’ date of visit. These two techniques are methods of quasi-randomisation,
hence opening the opportunity for lack of concealment; we therefore judged them as
having high risk of bias.

Allocation concealment was not specified by any of the included studies.

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Blinding
The studies by Blom 1997/1998 and van Rijswijk 2003 were described as double-blind
and hence we assessed their risk of bias for blinding as low. The studies by Havas
2002 and Ciabatti 2009 did not specify the method of blinding and we judged them to
have an unclear risk of bias of detection bias (blinding of outcome assessment) and a
high risk of performance bias (blinding of participants and personnel).

Incomplete outcome data

We assessed Blom 1997/1998, Ciabatti 2009 and Havas 2002 as having low risk of
bias for incomplete outcome data, given all patients were accounted for at the end
of the study. One patient in Blom 1997/1998 could not complete capsaicin treatment
due to influenza with fever. We judged that this patient’s withdrawal before treatment
would not affect the results of the study, and hence we judged the risk of bias to be
low. In Havas 2002 and Ciabatti 2009, for each outcome all patients were accounted
for. In van Rijswijk 2003, there was no specific mention of whether all patients were
accounted for at the end of the study, and therefore we considered this as an unclear
risk of bias.

Selective reporting
Blom 1997/1998 suffered from selective reporting of outcomes. Specifically, daily 6
record chart data were not fully reported, while VAS data were reported only as a figure
(figure 2 in the article). Levels of leukotrienes, prostaglandins, tryptase, blood and urine
chemistry were not reported numerically.

Ciabatti 2009 measured, but did not report, daily record chart outcomes measured at
four weeks prior to treatment, as a baseline comparison between the groups.

We considered these two studies to have high risk of bias for selective reporting of
outcomes.

Havas 2002 and van Rijswijk 2003 reported all measured outcomes and we considered

them to have a low risk of bias.

Other potential sources of bias

In Ciabatti 2009, the measured adverse events (nasal blockage, itching/sneezing and
coughing) could also be considered symptoms of disease. The study does not clarify
when these outcomes were reported by patients. Obviously, if this was immediately
after application of the intranasal medications, these symptoms could be consid-
ered side effects of capsaicin administration. However, these symptoms, except for
coughing, are usual symptoms of non-allergic rhinitis, and reporting them in the days
after medication application means that they cannot be differentiated as symptoms

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of the disease or side effects of the medication. Due to this uncertainty, we deemed
this study to have a high risk of bias for other potential sources of bias.

The study by  van Rijswijk 2003  was a cluster-randomised trial using computer-­
generated randomisation in blocks of eight randomly permuted allocations. ‘Table
3’ of that study shows the baseline characteristics for both treatment regimens of
capsaicin (five treatments in one day versus five treatments given every two to three
days during two weeks). We did not identify any other issues that could result in bias
in this study, and we judged it to be at low risk of other potential sources of bias.

We considered the other two studies to have a low risk of bias for this parameter (Blom
1997/1998; Havas 2002).

EFFECTS OF INTERVENTIONS

See: Summary of findings for the main comparison: Capsaicin compared to placebo
for non-allergic rhinitis; Summary of findings 2: Capsaicin compared to budesonide
for non-allergic rhinitis; Summary of findings 3: Five capsaicin treatments in one day
compared to daily capsaicin treatment for five days for non-allergic rhinitis.

We were unable to identify similar data from the included studies for pooling, hence
we did not carry out a meta-analysis.

Comparison 1: Capsaicin versus placebo

See Summary of findings table 1.

Two studies (in three publications) compared capsaicin with placebo (Blom
1997/1998; Ciabatti 2009). Blom 1997/1998 accounts for the same study, reporting
various outcomes in two publications, with the first one reporting clinically relevant
outcomes and the latter reporting molecular outcomes. These two publications used
a capsaicin dose of 15.28 µg per puff per nostril, one puff per treatment, in the form of
seven treatments every two to three days. A total of 213.79 µg of capsaicin was applied
during the entire treatment to both nasal cavities. The study by Ciabatti 2009 used 1
µg, 2 µg and 4 µg/puff three times a day for three consecutive days (nine applications),
to a total of 72 µg for both sides.

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Primary outcomes

Overall symptom score

Blom 1997/1998 used a daily record chart to measure symptoms of nasal blockage,
clear discharge (runny nose), sneezing, coughing, mucus production and eye irrita-
tion. Post-treatment numerical data for each treatment group were not presented,
however the authors reported that no significant difference was found for the individual
symptoms as well as for the mean sum-score before, during or after therapy.

The same study measured overall nasal symptoms using a visual analogue scale (VAS)
from 0 to 10 and reported it in figure 2 of their publication. From this figure, we recal-
culated the mean and standard deviation (SD) for each time point. The respective data
and forest plots for post-treatment weeks two, 12 and 36 are presented in Analysis
1.1, Analysis 1.2 and Analysis 1.3. The capsaicin group had a statistically significant
improvement at all three post-treatment time points (week two: mean difference (MD)
-3.34, 95% confidence interval (CI) -5.24 to -1.44; week 12: MD -3.73, 95% CI -5.45 to
-2.01; week 36: MD -3.52, 95% CI -5.55 to -1.48). We considered the quality of this
evidence to be moderate for this outcome.

Ciabatti 2009 employed a daily record chart for symptom scores (nasal blockage, 6
sneezing/itching/coughing and nasal secretion). The outcome was persistence of
symptoms at four weeks post-treatment in a non-responder analysis. We converted
the data instead into a responder analysis. Three different concentrations of capsa-
icin were compared to placebo. The respective data on symptom resolution are
presented in Analysis 1.4, Analysis 1.5 and Analysis 1.6 for the 1 µg, 2 µg and 4 µg
dose c­ omparisons with placebo. The 4 µg dose of capsaicin per puff was the only one
that had a statistically significant effect over placebo (risk ratio (RR) 3.17, 95% CI 1.38 to
7.29) (Analysis 1.6). We considered the quality of evidence to be low for this outcome.

Ciabatti 2009  was the only study that deliberately compared different doses of
capsai­cin as well as placebo. Capsaicin doses ranged between 1 µg, 2 µg and 4 µg
per puff. These allowed three sets of comparisons: between 1 µg and 2 µg, between
1 µg and 4 µg, and between 2 µg and 4 µg.

Outcomes were measured four weeks after treatment via daily record chart scores for
nasal blockage, sneezing/itching/coughing and nasal secretion, and were presented
as persistence of symptoms. We converted the data into resolution of symptoms
(retaining responder/non-responder analysis). The results are presented in Analysis
4.1, Analysis 4.2 and Analysis 4.3, and demonstrate statistically significant differences
when comparing 4 µg versus 1 µg per puff doses of capsaicin, with the former faring
better (RR 0.63, 95% CI 0.34 to 1.16). We considered the quality of evidence to be low

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for this outcome. Side effects were also measured and these have been addressed
above in the capsaicin versus placebo comparison section.

Both Blom 1997/1998 and Ciabatti 2009 employed a daily record chart. However, given

the lack of numeral representation of data in Blom 1997/1998, we could not perform
a meta-analysis.

Individual symptom scores

Blom 1997/1998  recorded individual symptoms on the daily record chart and
reported that no significant difference was found for the individual symptoms, as
well as the mean sum-score before, during or after therapy. Ciabatti 2009 reported
overall symptoms only in the form of a daily record chart and provided no information
regarding individual symptoms.

Treatment-related adverse events as reported in trials

Ciabatti 2009 also compared treatment side effects, which included nasal blockage,
itching/sneezing and coughing. However, given these parameters are symptoms of
the disease itself, it would be difficult to differentiate whether these symptoms are a
result of capsaicin application or the disease, unless it is specified when exactly these
symptoms were measured. If they took place immediately after capsaicin application,
they could certainly be interpreted as a side effect of capsaicin. Given there was no
clarification on this, we omitted these reported side effects from our analysis. Blom
1997/1998 only reported that there were no adverse events, but no real data were
presented.

Secondary outcomes

Quality of life measures

Quality of life measures were not reported for this comparison.

Treatment failure, dropouts, non-compliance with treatment, or unplanned

switch to or addition of another medication
In Blom 1997/1998, one patient could not complete capsaicin treatment due to influ-
enza with fever. We judged that this patient’s withdrawal before treatment would
not affect the results of the study, and hence we judged the risk of bias to be low.
In Ciabatti 2009, all patients completed the treatment.

Objective measurements
Blom 1997/1998 measured the levels of leukotrienes C4/D4/E4, prostaglandin D2 and
tryptase in the nasal lavage. The authors reported that no significant difference in
time trend between the two treatment groups occurred during treatment, however
numerical data were not presented.

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Blom 1997/1998 also measured the expression of CD1, CD3, CD25, CD68, IgE, MBP
(i.e. BMK13 antibody), chymase, tryptase, synaptophysin and neurofilament, and found
no statistically significant differences between the groups. Given the lack of clinical
relevance of these results, we did not recalculate the numerical data.

Additional outcomes
Additional outcomes were not reported for this comparison.

Comparison 2: Capsaicin versus budesonide

See Summary of findings table 2.

In Havas 2002, capsaicin (“full strength capsaicin”, two puffs into each nostril, each
dose 70 µL, delivering 0.654 µg of capsaicin) was compared with budesonide aqueous
nasal corticosteroid spray (64 µg per dose, in the form of two puffs of the spray into
each nostril in the morning and evening for two weeks). Treatments were carried
out for four weeks, and the outcomes were measured during the last three days of
treatment.

Primary outcomes 6
Overall symptom score
In Havas 2002, aggregate scores were calculated from a combination of individual
symptom scores. Aggregate scores during the fourth week of treatment were better
in the capsaicin group compared to budesonide (MD -2.46, 95% CI -4.28 to -0.63; VAS
0 to 5) (Analysis 2.1). Aggregate relief scores represented total score change from
baseline for all symptoms. Once again, combining the results for both genders per
treatment group, the aggregate relief score was overall better with capsaicin versus
budesonide (MD 2.50, 95% CI 1.06 to 3.94) (Analysis 2.2). We considered the quality
of evidence to be low for this outcome.

Individual symptom scores

In Havas 2002, nasal obstruction was reported using a responder/non-responder
approach in the results of the study. There was no significant difference found between
the two groups (Analysis 2.3). Individual symptoms were recorded using a 0 to 5
VAS score. All results were presented separately for males and females in the form
of means and upper 95% confidence interval (CI) in figures. We used these figures
to calculate the estimated mean and upper 95% CI for males and females separately
per each treatment group, then summarised this as cumulative mean and SD for both
males and females per treatment group, according to Higgins 2011. There were no
differences between budesonide and capsaicin for headache (Analysis 2.4), postnasal

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drip (Analysis 2.5), rhinorrhoea (Analysis 2.6), nasal blockage (Analysis 2.7), sneezing
(Analysis 2.8) or sore throat (Analysis 2.9).

Treatment-related adverse events as reported in trials

Adverse events were not reported for this comparison.

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 CAPSAICIN FOR NON-ALLERGIC RHINITIS

Secondary outcomes

Quality of life measures

Quality of life measures were not reported for this comparison.

Treatment failure, dropouts, non-compliance with treatment, or unplanned

switch to or addition of another medication
These outcomes were not reported for this comparison.

Objective measurements
Objective measurements were not reported for this comparison.

Additional outcomes
Additional outcomes were not reported for this comparison.

Comparison 3: Different regimens of capsaicin administration

See Summary of findings table 3.

Building on a previous study (Blom 1997/1998), van Rijswijk 2003 compared two treat- 6

ment regimens of capsaicin: five treatments in one day versus five treatments given
every two to three days during two weeks. During provocation, 0.27 ml of a 0.1 mmol/l
capsaicin solution was used (a total of 16.49 µg).

Primary outcomes

Overall symptom score

In van Rijswijk 2003, overall nasal symptoms were presented as medians in a figure,
without respective measures of variation to allow for calculations of effect size.

Individual symptom scores

Using daily record charts, van Rijswijk 2003 reported significant improvement of rhinor-
rhoea in patients treated five times per day. There were no improvements in other
parameters. However, numerical data were not presented per each measured time
point to allow for further analysis.

Rhinorrhoea, nasal obstruction, sneezing and overall nasal symptoms were measured
on a VAS. The study noted that a significant improvement was observed in both
groups. The difference in the time trend was reported to be significant.

The time trend for decrease of rhinorrhoea symptoms was reported to be n ­ on-­­­
sign­ificant, however treatment with capsaicin five times per day was reported to result

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in better improvement of rhinorrhoea. For nasal obstruction, the time trend to decrease
of symptoms was reported to be significant. The time trend to decrease of sneezing
was not significant, and neither was the difference in the absolute VAS levels between
the groups. Neither numerical data nor graphs were provided to allow for calculation
of effect size per time point.

Treatment-related adverse events as reported in trials

Adverse events were not reported for this comparison.

Secondary outcomes

Quality of life measures

Quality of life measures were not reported for this comparison.

Treatment failure, dropouts, non-compliance with treatment, or unplanned

switch to or addition of another medication
There were no dropouts reported for this comparison.

Objective measurements
In van Rijswijk 2003, the mean University of Pennsylvania Smell Identification Test
(UPSIT) scores were not different at the beginning of the study. At 12 weeks post-­
treatment, the UPSIT score continued to be no different between the groups (Analysis
3.1). We considered the quality of evidence to be moderate for this outcome.

There was no difference between the groups in cold dry air hyper-reactivity, TMMCA1
and TMMCA2 measures of acoustic rhinometry, peak nasal inspiratory flow (PNIF),
mucosal sensitivity to capsaicin, mucosal sensitivity to touch (for both epicritic and
protopathic sensitivity), heart rate, or systolic and diastolic blood pressure at any time
point.

Additional outcomes
Additional outcomes were not reported for this comparison.

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ADDITIONAL SUMMARY OF FINDINGS

Capsaicin compared to budesonide for non-allergic rhinitis

Capsaicin compared to budesonide for non-allergic rhinitis

Patient or population: patients with non-allergic rhinitis
Settings: tertiary university hospital
Intervention: capsaicin
Comparison: budesonide
Outcomes Illustrative comparative risks* Rel- No of par- Quality Comments
(95% CI) ative ticipants of the
Assumed Corresponding effect (studies) evi-
risk risk (95% dence
CI) (GRADE)
Budesonide Capsaicin
Nasal Study population RR 1.11 40 ⊕⊕⊝⊝ Higher
obstruction 90 per 100 100 per 100 (0.93 to (1 study) low1,2,3 number
during the (84 to 100) 1.31) indicates
4th week of more
Moderate
treatment patients
Number of 90 per 100 100 per 100 respond-
responders (84 to 100) ing to
Follow-up: 4 capsaicin 6
weeks compared
to those
respond-
ing to
budesonide
Aggregate The mean The mean — 40 ⊕⊕⊝⊝ Higher
relief score aggregate aggregate relief (1 study) low1,2,3 scores indi-
during the relief score score during cate more
4th week of during the the 4th week relief of
treatment 4th week of of treatment in symptoms
Follow-up: 4 treatment in the intervention
weeks the control group was
group was 2.5 higher
3.65 (1.06 to 3.94
higher)
Treatment- Not reported Not reported — — — —
related
adverse
events
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided
in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed
risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio

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Table continued

Capsaicin compared to budesonide for non-allergic rhinitis

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of
effect.
Moderate quality: Further research is likely to have an important impact on our confidence in
the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the
estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1
Pseudo-randomisation was performed on an odds and evens basis.
2
Small sample size (40 patients total).
3
Single study.

Five capsaicin treatments in one day compared to daily capsaicin treatment for five days for
non-allergic rhinitis

Five capsaicin treatments in one day compared to daily capsaicin treatment for five days for
non-allergic rhinitis
Patient or population: patients with non-allergic rhinitis
Settings: tertiary university hospital
Intervention: 5 capsaicin treatments in 1 day
Comparison: daily capsaicin treatment for 5 days
Outcomes Illustrative comparative Rel- No of par- Quality Comments
risks* (95% CI) ative ticipants of the
Assumed Corresponding effect (studies) evidence
risk risk (95% (GRADE)
CI)
Daily 5 capsaicin
capsaicin treatments in
treat- 1 day
ment for
5 days
Smell The mean The mean smell — 30 ⊕⊕⊕⊝ Higher
testing smell testing in the (1 study) moder- score
University of testing intervention ate1 indicates
Pennsylvania in the groups was better
Smell Identi- control 3 higher smell sen-
fication Test groups (1.5 lower to 7.5 sation
(UPSIT) was higher)
Scale from: 0 29 units
to 40
Follow-up: 12
weeks

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Table continued

Treat- Not Not reported — — — —

ment-related reported
adverse
events
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided
in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed
risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of
effect.
Moderate quality: Further research is likely to have an important impact on our confidence in
the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the
estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Small sample size (30 total).

1

DISCUSSION 6
Summary of main results
We were unable to pool the data from the included studies into a meta-analysis. This
would have been possible only with daily record chart symptom score data. However,
due to the lack of numerical data from the Blom 1997/1998 publication, pooling of
daily record chart data was not possible.

All studies included patients with the classic non-allergic rhinitis subtype of idiopathic
rhinitis (previously called NANIPER). In this aspect, populations in the included studies
were quite uniform. Three studies examined the effects of capsaicin versus placebo;
one compared different doses of placebo to each other (within the same placebo-­
controlled study), and one further study examined the regimen of capsaicin applica-
tion. Finally, another study compared capsaicin with budesonide, an intranasal corti-
costeroid. Outcome measures were mostly clinically based, and most studies included
a measure of patients’ symptoms in the form of a daily record chart or visual analogue
scale (VAS) score. Several studies also attempted to measure objective parameters
of nasal function (e.g. airflow, smell, etc). Finally, Blom 1997/1998 investigated the
molecular aspects of the effect of capsaicin in non-allergic rhinitis.

The reporting of results in the included studies was suboptimal. In several instances,
summary data were not presented in narrative, tabular or graphic form, and hence
could not be included in the current review.

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Comparing capsaicin with placebo and using the clinically meaningful data that could
be extracted from the studies, one study reported a statistically significant improve-
ment in overall nasal symptoms as measured on a VAS at post-treatment weeks two,
12 and 36 (Blom 1997/1998). Another study reported a statistically significant improve-
ment of daily record chart symptom scores at four weeks with 4 µg of capsaicin per
puff, but not with 1 µg or 2 µg per puff (Ciabatti 2009).

The included studies reported no significant differences between the groups for
several measures: daily record chart (Blom 1997/1998), levels of leukotrienes C 4/D4/
E4, prostaglandin D2 and tryptase in the nasal lavage (Blom 1997/1998), expression of
CD1, CD3, CD25, CD68, IgE, MBP (i.e. BMK13 antibody), chymase, tryptase, synapto-
physin and neurofilament (Blom 1998), or side effects in the form of nasal blockage,
itching, sneezing and coughing (Ciabatti 2009).

Comparing different doses of capsaicin, Ciabatti 2009 demonstrated that 4 µg per

puff of capsaicin was more effective than 1 µg per puff. Given that no other studies
made direct dose comparisons, pooling of data was not possible.

van Rijswijk 2003  compared two different regimens of capsaicin application: five
treatments in one day, one hour apart versus five treatments given every two to three
days during two weeks. They reported significant improvements of rhinorrhoea in
the group treated five times in one day. However, there was no significant difference
between the groups for the other measured symptoms, despite there being a reported
improvement in the time trend for resolution of some symptoms. There were also no
significant differences in smell, nasal airflow, mucosal sensitivity testing, or heart rate
and blood pressure.

Comparing capsaicin to budesonide, an intranasal corticosteroid, aggregate scores

and aggregate relief scores were better with capsaicin, while there was no significant
difference for all other symptoms.

Overall, the data from individual studies indicate that capsaicin may significantly
improve overall nasal symptoms either measured on a VAS or as a responder deriva-
tive of daily record chart symptom scores. Higher doses of capsaicin are better than
low doses, with no significant increase in side effects with doses up to 4 µg per puff.
However, even higher doses were used in Blom 1997/1998 and van Rijswijk 2003.
Application of capsaicin five times during the same day appears to be non-inferior to
application once every two to three days to a total of five doses. In addition, capsai­cin
seems to be more effective than budesonide when overall relief of symptoms is
considered.

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Overall completeness and applicability of evidence

The lack of the opportunity to pool data from several studies does not allow us to draw
a strong conclusion regarding the effectiveness of capsaicin in non-allergic rhinitis.
Individual studies appear to suggest that cumulative nasal symptoms (overall nasal
symptoms, daily record chart, overall response to treatment) are better when treated
with capsaicin compared to placebo or intranasal corticosteroids. Subgroup analysis
indicates that higher doses of capsaicin may result in improvement in the proportion
of responders, without significantly increasing side effects. No conclusions can be
drawn from this review regarding the effects of capsaicin in non-allergic rhinitis of
different types or severity, or with different forms of delivery of capsaicin.

The findings of this review apply to patients with idiopathic rhinitis, given that the
included studies involved patients with this specific type of non-allergic rhinitis
(idiopathic rhinitis, NANIPER, vasomotor rhinitis or intrinsic rhinopathy). Studies
excluded specific types of non-allergic rhinitis, including those relating to smoking,
pregnancy, hormonal changes, rhinitis medicamentosa or senile rhinitis. None of
the studies included a mixed group of patients with non-allergic rhinitis of various
aetiologies.

Interestingly, the ratio of men in the included studies was 54.46% of all patients, while 6
most epidemiological studies report a larger proportion of affected females. We
believe that the discrepancy of gender distribution in our study compared to larger
epidemiological ones can be explained by the relatively small number of included
patients.

Considering the limitations of the data presented, further studies are required to build
upon the currently available evidence and further describe the role of capsaicin in the
treatment of non-allergic rhinitis.

Quality of the evidence

The quality of studies included in this review is low to moderate (see Summary of
findings table 1; Summary of findings table 2; Summary of findings table 3). Specifi-
cally, quality was low to moderate for comparisons between capsaicin and placebo,
low for comparisons between capsaicin and budesonide, moderate for comparisons
of capsaicin treatment regimens and low for comparisons of capsaicin doses. The
limitations included the small sample sizes of the included studies, the availability of
only a single study for each comparison and pseudo-randomisation of some studies.

Many of the studies suffered from either selective reporting of results or reporting that
did not allow the isolation of summary data for treatment groups. Given that none of
the authors contacted could provide further summary data, in several instances we
had to recalculate these data from figures. The most consistent evidence is presented

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for measures of overall nasal symptoms (measured using a VAS or daily record chart,
or summarised as a responder/non-responder analysis). Overall, the risk of bias was
low to unclear.

Potential biases in the review process

We excluded one study including 42 patients from this review (Bernstein 2011). This
included patients with both non-allergic rhinitis and mixed rhinitis. The latter was
defined as having one or more clinically relevant positive skin prick test (wheal ≥ 3
mm in diameter with surrounding erythema compared with saline control in conjunc-
tion with a positive histamine control) to a panel of aeroallergens that correlated with
clinical symptoms and significant upper respiratory symptoms induced by chemical
irritants, strong odours, weather or temperature changes. Total nasal symptom score
(TNSS) was considered as the primary endpoint and individual symptoms were consid-
ered as secondary endpoints, while the Rhinitis Quality of Life Questionnaire (RQLQ)
was considered an additional endpoint, and automated olfactometry was considered
a part of the safety analysis. Considering this mixed group of patients, ICX72 (Sinus
Buster, containing homeopathic doses of capsaicin), resulted in a significant improve-
ment over placebo in TNSS change from baseline, and an improvement in nasal
congestion, sinus pain, sinus pressure and headache at five, 10, 15 and 30 minutes,
as well as at 60 minutes for nasal congestion and sinus pain.

We were able to get in touch with the authors of the study, who were able to isolate
from the study’s population a group of nine patients with non-allergic rhinitis: four
treated with ICX72 (i.e. Sinus Buster) and five treated with placebo. Re-analysing the
available data, we found no significant differences in TNSS, individual symptom scores
or the RQLQ and its individual components.

We ultimately decided to not include this study in the review, because the treatment
arm alone was contaminated by eucalyptus co-treatment. The latter is known to stimu-
late cold receptors in the nose and hence can alter the perception of the effect of
capsaicin alone (Behrendt 2004). In addition, the study only used a homeopathic dose
of capsaicin and this dose could not be identified by the study authors.

Another potential point of bias could be the data obtained from the studies. Most data
were not presented numerically, therefore we had to recalculate some of the data from
the narrative text or from figures, as we were unable to obtain raw or summary data
from study authors.

In the case of figures, we calculated pixels from the baseline (x-axis) to a known point
on the y-axis to determine the scale, followed by a calculation of individual pixels for
each data point (e.g. mean or standard deviation (SD) or CI). Given that this calculation
may not be completely precise, there is potential for an additional bias, however we

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 CAPSAICIN FOR NON-ALLERGIC RHINITIS

cannot strongly assume that the bias would benefit either the treatment or control
group, as it would be random.

Another potential bias is that one of our lead authors (WJF) is also the lead author
of two of the five included studies, Blom 1998 and van Rijswijk 2003. The first study
(published as Blom 1997/1998) was the first randomised controlled trial (RCT) on
capsaicin in non-allergic rhinitis, while the second one established no differences when
patients were treated with capsaicin every two to three days for a total of five days
versus administration of all treatments in one day. In order to avoid any bias, another
author (CMvD) was brought in to participate in study selection and data analysis.
While WJF conceived the idea for the review and participated in drafting the protocol
and the final manuscript, she had no participation in study selection or data analysis.

Agreements and disagreements with other studies or reviews

There are no other systematic reviews or meta-analyses on non-allergic rhinitis.

We identified an interesting conference abstract describing a RCT that compared

capsaicin with ipratropium bromide for vasomotor rhinitis (Cuilty-Siller 1996). The
outcomes measures were nasal resistance and airflow measured by rhinomanometry.
It was not possible to conclude from the abstract whether one or the other medication 6
was more effective in treating vasomotor rhinitis. We were unable to obtain raw data
or a full-text publication from the authors.

Lacroix 1991 described the effects of capsaicin in 16 patients with non-allergic rhinitis

and 17 controls. In non-allergic rhinitis patients, capsaicin resulted in significant
improvement of individual nasal symptoms (obstruction, rhinorrhoea and sneezing)
up to six months after application.

Marabini 1991 reported on the effects of capsaicin in patients with known vasomotor

rhinitis. Patients recorded their symptoms over one month. Capsaicin reduced the
symptom scores of nasal obstruction and nasal secretion, as well as overall symptom
scores.

These two studies, Lacroix 1991 and Marabini 1991, conducted prior to the first RCT
on capsaicin, provided grounds for further investigation, and overall agree with the
results of the RCTs, even though the effects are less pronounced than in the RCTs.

Sanico 1998 measured the effects of capsaicin in patients with non-allergic rhinitis,

patients with allergic rhinitis and healthy controls. Immediately after application,
­capsaicin produced burning, lacrimation and rhinorrhoea, which were not different in
the three groups. This study did not, however, provide any meaningful clinical infor-
mation about the long-term post-treatment effects of capsaicin.

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CHAPTER 6

As already indicated, the study by Bernstein 2011, performed in a mixed group of

patients with both non-allergic rhinitis and mixed rhinitis, showed an effect of Sinus
Buster over placebo. However, recalculations for the non-allergic rhinitis group alone
did not show any statistically significant changes.

AUTHORS’ CONCLUSIONS

Implications for practice

Capsaicin may be included in the treatment of idiopathic non-allergic rhinitis. It appears
to have beneficial effects on overall nasal symptoms up to 36 weeks after treatment,
based on the results of individual studies. It is given in a form of brief treatments,
usually during the same day. The overall quality of evidence in the included studies
is low to moderate.

Intranasal capsaicin is used only in a handful of countries, so it is beneficial for

individual practitioners to know that capsaicin preparations of at least 4 µg per puff
provide a benefit over placebo with no documented short-term side effects. Despite the
lack of availability of capsaicin in pharmacies in many countries, it can be prepared by
hospital pharmacies or upon request, and may provide clinics with another treatment
option for non-allergic rhinitis. In other countries, capsaicin is available as over-the-
counter combination homeopathic preparations, such as Sinus Buster in the United
States or Nasol in Canada. Given the homeopathic doses of capsaicin and the inclu-
sion of other active ingredients, it is hard to judge whether these preparations are
effective and this review certainly did not aim to address them. We also do not have
conclusive evidence regarding the risk of harm. The most common immediate side
effects include burning, lacrimation, rhinorrhoea and cough, however long-term risks
of harm are unknown.

Given the overall scarcity of options in the treatment of non-allergic rhinitis, capsaicin
is a viable option in those with idiopathic non-allergic rhinitis.

Implications for research

Pooling of results for a meta-analysis was not possible in this review, due to the
scarcity of randomised controlled trials and lack of uniform presentation of data.
Well-conducted randomised controlled trials are required to further advance our
understanding of the effectiveness of capsaicin in non-allergic rhinitis. Many aspects
require further study, including the effect of capsaicin in patients with non-allergic
rhinitis of different types and severity, and the effect of different methods of delivery
of capsaicin. Standardisation of the reporting of clinically meaningful data, including
patient-reported outcomes (symptom scores, validated questionnaires), as well as

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objective measurements, will help to paint a more comprehensive picture of the effects
of capsaicin in this condition.

ACKNOWLEDGEMENTS

We acknowledge Prof. Jonathan Bernstein for providing raw data from their study.

This project was supported by the National Institute for Health Research, via Cochrane
Infrastructure, Cochrane Programme Grant or Cochrane Incentive funding to the
Cochrane ENT Group. The views and opinions expressed therein are those of the
authors and do not necessarily reflect those of the Systematic Reviews Programme,
NIHR, NHS or the Department of Health.

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CHARACTERISTICS OF STUDIES

Characteristics of included studies

Blom 1997/1998

Methods Allocation: randomised, double-blind, placebo-controlled; 42 weeks duration

(36 weeks post-treatment)
Design: parallel-group study
Participants Number: 35 patients were randomised; 25 patients were included after exclu-
sion criteria applied
Age: 16 to 64 years
Gender: 16 males, 9 women
Setting: tertiary university hospital in The Netherlands
Eligibility criteria:
Patients with NANIPER (history of nasal complaints such as nasal obstruction,
sneezing and rhinorrhoea for a period of over 1 year) with symptoms at least 1
hour per day for at least 5 days during a period of 14 days
Symptom duration: perennial
Severity: at least moderate or severe based on daily record chart or symptom
scores on VAS
Exclusion criteria: allergic rhinitis, positive SPT, positive serum IgE, nasal or
paranasal sinus infection, nasal surgery within the previous 6 weeks, history
of nasal polyps, anatomical nasal disorders, pregnancy, lactation, systemic
disorders, smoking, use of systemic or inhaled corticosteroids, inhaled sodium
cromoglycate, nedocromil sodium, or astemizole within the previous month,
inability of the patient to stop taking medication affecting nasal function, a
serious and/or unstable disease, abnormal blood work or urine analysis, or
abnormal findings at physical examination
Interven- Intervention group: capsaicin
tions n = 14
• 0.1 mmol/L, consisted of pelargonic acid vanillylamide dissolved in 3 ml
alcohol (96%) and diluted in 1 L NaCI solution (0.9%), applied in the form of
a spray (“puff”)
• Dose: 0.5 ml solution was sprayed in each nostril (0.15 mg capsaicin)
• Frequency: every 2 or 3 days for a total of 7 treatments in 2 weeks
• 1 patient could not complete treatments due to influenza
Comparator group: placebo
n = 11
• Sodium chloride solution (0.9%)
Use of additional interventions: co-intervention in both groups 15 minutes prior
to intervention:
• 3 applications of xylometazoline hydrochloride 0.1% (Otrivin® nebuliser) in
each nostril
• 3 applications (10 mg/puff) of lidocaine base (100 mg/ml) (Xylocaine® 10%
spray) in each nostril

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 CAPSAICIN FOR NON-ALLERGIC RHINITIS

Table continued

Outcomes Daily record chart (DRC), 6 items total: nasal blockage, clear nasal discharge,
sneezing, coughing, green/yellow or brown mucus production and eye irritation.
• 4 items (nasal blockage, clear nasal discharge, sneezing and coughing) on
a 0 to 3 scale
• 2 items (green/yellow or brown mucus production and eye irritation) on a 0
to 1 scale
• Lower score indicates better outcome
Overall nasal symptoms (VAS, 0 to 10)
Levels of leukotrienes C4/D4/E4, prostaglandin D2 and tryptase in nasal lavage
Blood and urine chemistry
Expression of CD1, CD3, CD25, CD68, IgE, MBP, chymase and tryptase in the
epithelium and lamina propria (Blom 1997/1998)
Expression of synaptophysin and neurofilament
Funding Funding: not reported
sources
Declarations None declared
of interest
Notes Some results not reported for DRC.
This article, along with Blom 1998, is from the same study.
Participants lost to follow-up: 1 patient could not complete treatment due to
influenza. 6
Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Unclear risk Not described
tion (selection bias)
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and Low risk Quote: “This study was performed in a dou-
personnel (performance bias) ble-blind placebo-controlled fashion.”
Blinding of outcome assess- Low risk Quote: “This study was performed in a dou-
ment (detection bias) ble-blind placebo-controlled fashion.”
Incomplete outcome data Low risk 1 patient could not complete capsaicin treatment
(attrition bias) due to influenza with fever. We judged that this
patient’s withdrawal before treatment would not
affect the results of the study, and hence we
judged the risk of bias to be low.
Selective reporting (reporting High risk DRC results are not fully reported
bias) VAS results reported only in “figure 2”.
Other bias Low risk None identified

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CHAPTER 6

Ciabatti 2009

Methods Allocation: quasi-randomised study (patient assigned according to the date of

their visit); 8 weeks total (4 weeks before and 4 weeks after treatment)
Design: parallel-group study
Participants Number: 208 patients randomised
Age: not reported
Gender: 115 males, 93 females
Setting: tertiary university hospital in Italy
Eligibility criteria:
Patients with idiopathic rhinitis (history of nasal breathing obstruction, sneezing,
coughing, rhinorrhoea and nasal itching for ≥ 1 year) with duration of symptoms
≥ 1 hour per day for at least 5 days during the 14 days preceding the day of the
first visit and no beneficial effect of nasal corticosteroid spray (for a period of at
least 6 weeks)
Symptom duration: perennial
Severity: not reported
Exclusion criteria: allergic rhinitis, nasal surgery within the previous 6 weeks,
history of nasal polyps, anatomical disorder affecting nasal function, pregnancy,
lactation, systemic disorders, smoking, use of systemic or inhaled corticoste-
roids, inhaled sodium cromoglycate, nedocromil sodium, or astemizole within
the previous month, inability of the patient to stop taking medication affecting
nasal function, a serious and/or unstable disease, abnormal blood work or urine
analysis, or abnormal findings at physical examination
Baseline characteristics: baseline differences not reported
Interven- Intervention group A: capsaicin 1 µg/puff
tions n = 52
Intervention group B: capsaicin 2 µg/puff
n = 52
Intervention group C: capsaicin 4 µg/puff
n = 52
Intervention group D: placebo 0 µg/puff
n = 52
Capsicum oleous nasal spray 1 µg/puff (70 ml/puff) or other doses, respec-
tively, 1 puff/nostril was administered 3 times a day, at 30-minute intervals, for 3
consecutive days
Placebo: consistency not described
Use of additional interventions: none
Outcomes Daily record chart (DRC), 5 items total: nasal blockage, sneezing, itching,
coughing, green/yellow mucus production
• 4 items on a 0 to 3 scale, and 1 item on a 0 to 1 scale
• Total score 0 to 7; lower score indicates better outcome
• Outcomes reported as resolution (DRC score = 0) and persistence (DRC
score ≥ 1)
Adverse events
Nasal blockage, itching/sneezing, coughing
Funding Not reported
sources

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Table continued

Allocation: quasi-randomised study (patient assigned according to the date of

Methods their visit); 8 weeks total (4 weeks before and 4 weeks after treatment).
Design: parallel-group study.
Declarations None declared
of interest
Notes Adverse events are also symptoms of disease, therefore would be difficult to
differentiate.
Participants lost to follow-up: none

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- High risk Patients assigned according to the date of their
tion (selection bias) visit (quasi-randomisation).
Allocation concealment High risk Likely high risk, as specific measures to ensure
(selection bias) allocation concealment were not described in this
quasi-randomised study.
Blinding of participants and High risk Likely high risk, given the quasi-randomised study
personnel (performance bias) design and the lack of co-intervention with an 6
anaesthetic to conceal the effect of capsaicin.
Blinding of outcome assess- Unclear risk Not described
ment (detection bias)
Incomplete outcome data Low risk All patients accounted for in every outcome.
(attrition bias)
Selective reporting (reporting High risk Pre-treatment DRC recorded but not reported.
bias)
Other bias High risk Studied adverse events are also symptoms of
disease, hence differentiation would be difficult.

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Havas 2002

Methods Allocation: quasi-randomised study (on odds and even basis); 31 days total (3
days prior to treatment and 4 weeks of treatment)
Design: parallel-group study
Participants Number: 40 patients randomised
Age:
• Budesonide group: males 40.3 years; females 37.0 years
• Capsaicin group: males 41.5 years; females 41.0 years
Gender: 20 males, 20 females
Setting: Department of Otolaryngology – Head and Neck Surgery in Australia
Eligibility criteria:
Patients with perennial non-allergic rhinitis (IgE < 100 and RAST negative) exam-
ined by the senior author
Symptom duration: perennial
Severity: not reported
Exclusion criteria: any relevant antecedent history of rhinosinusitis or anteced-
ent nasal or sinus surgery. Presence on nasoendoscopy of nasal septal devia-
tion, nasal polyposis, rhinosinusitis and/or neoplasm. Smokers
Interven- Intervention group: capsaicin (each dose containing 70 µL, delivering 0.654
tions µg of capsaicin: capsaicin 71%, dihydrocapsaicin 20.94% and nordihydrocap-
saicin 4.94%), 2 puffs into each nostril. Co-phenylcaine spray 10 minutes prior
to capsaicin first treatment. Then once weekly self administration of 2 puffs of
capsaicin in each nostril weekly for 4 weeks
Comparator group: budesonide (64 micrograms/dose), 2 puffs of the spray in
each nostril qAM and qPM for 2 weeks, after administration of lignocaine/phen-
ylephrine (co-phenylcaine) before the 1st treatment
Outcomes 1. Symptom sheet (VAS), assessed separately for each side, 3 days prior to
treatment and during last 3 days of treatment:
• Headache
• PND
• Rhinorrhoea
• Nasal blockage
• Sore throat
• Sneezing
2. Aggregate total relief (decrease of symptom scores after treatment: sum of
relief scores for all 6 symptoms)
3. Improved versus worse (or unchanged)
Funding Disclosures: no financial interest with company supplying capsaicin
sources
Declarations None declared
of interest
Notes Participants lost to follow-up: none declared

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 CAPSAICIN FOR NON-ALLERGIC RHINITIS

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- High risk Pseudo-randomisation was performed on an
tion (selection bias) odds and evens basis.
Allocation concealment High risk High risk due to pseudo-randomisation.
(selection bias)
Blinding of participants and High risk High risk due to pseudo-randomisation.
personnel (performance bias)
Blinding of outcome assess- Unclear risk Not described
ment (detection bias)
Incomplete outcome data Low risk All outcomes reported
(attrition bias)
Selective reporting (reporting Low risk No selective outcome reporting identified.
bias)
Other bias Low risk No other sources of bias identified.

van Rijswijk 2003

Methods Allocation: randomised, double-blind, double-dummy; 310 days (38 weeks

post-treatment)
6
Design: parallel-group study
Participants Number: 30 patients randomised
Age: 16 to 65 years (mean age, 36 years)
Gender: 14 males, 16 females
Setting: tertiary university hospital in The Netherlands
Eligibility criteria:
Patients with idiopathic rhinitis (history of nasal complaints such as nasal
obstruction, sneezing and/or rhinorrhoea for a period of over 1 year) with
periods of nasal discharge, sneezing and congestion for an average of at least
1 hour per day for at least 5 days during a period of 14 days and with no benefit
from nasal corticosteroid spray for a period of at least 6 weeks)
Symptom duration: perennial
Severity: at least moderate or severe based on daily record chart or symptom
scores on VAS
Exclusion criteria: allergic rhinitis, positive SPT, positive serum IgE, nasal or
paranasal sinus infection, nasal surgery within the previous 6 weeks, history
of nasal polyps, anatomical nasal disorders, pregnancy, lactation, systemic
disorders, smoking, use of systemic or inhaled corticosteroids, inhaled sodium
cromoglycate, nedocromil sodium, or astemizole within the previous month,
inability of the patient to stop taking medication affecting nasal function, a
serious and/or unstable disease, abnormal blood work or urine analysis, or
abnormal findings at physical examination
Baseline characteristics: baseline differences not reported

329
CHAPTER 6

Table continued

Allocation: randomised, double-blind, double-dummy; 310 days (38 weeks

Methods post-treatment)
Design: parallel-group study
Interven- Intervention group: first treated with capsaicin 5 times on a single day at 1-hour
tions intervals. After 2 weeks, they received a total of 5 treatments with dummy
placebo once every 2nd or 3rd day
n = 15
Comparator group: first received dummy placebo 5 times on a single day at
1-hour intervals. This was followed 2 weeks later by a total of 5 treatments with
capsaicin once every 2nd or 3rd day
n = 15
Capsaicin: (0.1 mmol/l) consisted of 30.3 mg pelargonic acid vanillylamide
dissolved in 3 ml alcohol (96%) and diluted in 1 L NaCl solution (0.9%)
Placebo: capsaicin solvent only
Dose: 0.27 ml of solution (3 applications) sprayed into each nostril with a
metered nasal spray (0.09 ml per actuation, coefficient of variation 4%)
Use of additional interventions: co-intervention in both groups 15 minutes prior
to intervention:
• 3 applications of xylometazoline hydrochloride 0.1% (Otrivin® nebuliser) in
each nostril
• 3 applications (10 mg/puff) of lidocaine base (100 mg/ml) (Xylocaine® 10%
spray) in each nostril
Outcomes Daily record chart (DRC), 5 items total: nasal blockage, clear nasal discharge,
sneezing, coughing, green/yellow mucus production. 4 items on a 0 to 3 scale,
and 1 item on a 0 to 1 scale. Lower score indicates better outcome
Nasal symptoms, measured by VAS (0 to 10): overall nasal symptoms, rhinor-
rhoea, nasal obstruction, sneezing
Smell measured by UPSIT
Cold dry air hyper-reactivity
Nasal patency measured by acoustic rhinomanometry
Nasal patency measured by PNIF
Mucosal sensitivity to capsaicin
Mucosal sensitivity to touch – epicritic and protopathic sensitivity
Blood pressure and heart rate
Funding Not reported
sources
Declarations None declared
of interest
Notes Numerical data not reported for many outcomes and time points.
Participants lost to follow-up: none

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 CAPSAICIN FOR NON-ALLERGIC RHINITIS

Risk of bias

Bias Authors’ Support for judgement

judgement
Random sequence genera- Low risk Randomised, double-blind study. Description
tion (selection bias) provided of how this was done.
Allocation concealment Unclear risk Not described
(selection bias)
Blinding of participants and Low risk Quote: “This study was performed in a dou-
personnel (performance bias) ble-blind randomized fashion.”
Blinding of outcome assess- Low risk Quote: “This study was performed in a dou-
ment (detection bias) ble-blind randomized fashion.”
Incomplete outcome data Unclear risk Not reported
(attrition bias)
Selective reporting (reporting Low risk All outcomes reported, though not always in
bias) straightforward ways.
Other bias Low risk No other sources of bias identified.

DRC: daily record chart

IgE: immunoglobulin E
NaCI: sodium chloride
NANIPER: non-allergic, non-infectious perennial allergic rhinitis 6
PND: post-nasal drip
PNIF: peak nasal inspiratory flow
qAM: every morning
qPM: every afternoon/evening
RAST: radioallergosorbent test
SPT: skin prick test
UPSIT: University of Pennsylvania Smell Identification Test
VAS: visual analogue scale

331
CHAPTER 6

Characteristics of excluded studies

Bernstein 2011

Reason for exclusion 1. Population: patients with both allergic and non-allergic rhinitis. After
communicating with the study’s author, it was possible to isolate only
patients with non-allergic rhinitis. However, we excluded this study for
the following reasons:
2. Eucalyptol co-intervention in the capsaicin treatment group only
a. Eucalyptus is known to result in temporary alleviation of nasal symp-
toms alone and affects cold receptors in the nose
b. Despite a “homeopathic” dose of capsaicin, given a strong reaction
to Eucalyptol, we can reasonably suspect that blinding of patients
would have been difficult to achieve

Characteristics of ongoing studies

NCT02288156

Study name ‘Elaboration of patient-friendly treatment strategy with capsaicin nasal spray
in patients with idiopathic rhinitis’
Methods Randomised, parallel-group, double-blind trial
Participants Inclusion criteria:
Aged 18 to 65 years; both genders
Idiopathic rhinitis patients with at least 2 persistent (> 12 weeks) rhinological
symptoms (nasal discharge, sneezing, nasal congestion) for an average of at
least 1 hour per day
Idiopathic rhinitis patients with a total nasal symptoms score (TNS) of 5 or
more on a visual analogue scale (VAS)
Interventions Capsaicin nasal spray 0.01 mM (2 puffs/nostril/day) over 4 weeks
Capsaicin nasal spray 0.001 mM (2 puffs/nostril/day) over 4 weeks
Capsaicin nasal spray 0.1 mM (5/day administered on a single day) (current
treatment)
Placebo

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 CAPSAICIN FOR NON-ALLERGIC RHINITIS

Table continued

Outcomes Primary outcome measure:

Change in VAS for major nasal symptoms (week 4). Patients score their main
nasal complaints from 0 to 10 on a scale, with 0 meaning no complaints and
10 meaning the worst complaints. This is done at baseline and after 4 weeks
of treatment
Secondary outcome measures:
Change in VAS for individual nasal symptoms (week 4). Patients score all
kinds of nasal symptoms from 0 to 10 on a scale, with 0 meaning no com-
plaints and 10 meaning the worst complaints. This is done at baseline and
after 4 weeks of treatment
Change in therapeutic response in all treatment regimes (week 4)
Evaluation of the therapeutic response (TRE) on a scale from 1 (= no relief of
symptoms) to 5 (= total relief of symptoms)
Change of nasal hyper-reactivity in all treatment modalities (week 4)
Evaluation of appearance of adverse events in all treatment groups (week 4
and 12)
Evaluation of recurrence of symptoms in all treatment modalities (week 4, 12
and 26)
Starting date January 2015 (completion date estimated December 2017)
Contact Sofie Mees ([email protected]); Emily Dekimpe
information ([email protected])
Principal investigator: Prof. Dr. Peter Hellings, UZ Leuven 6
Notes —

DATA AND ANALYSES

Comparison 1 Capsaicin versus placebo

Outcome or Subgroup Studies Partic- Statistical Method Effect

ipants Estimate
1.1 Overall nasal symptoms 2 weeks 1 24 Mean Difference (IV, -3.34
post-treatment [VAS, 0-10] Fixed, 95% CI [VAS, 0-10]) [-5.24,-1.44]
1.2 Overall nasal symptoms 12 1 24 Mean Difference (IV, -3.73
weeks post-treatment [VAS, 0-10] Fixed, 95% CI [VAS, 0-10]) [-5.45,-2.01]
1.3 Overall nasal symptoms 36 1 24 Mean Difference (IV, -3.52
weeks post-treatment [VAS, 0-10] Fixed, 95% CI [VAS, 0-10]) [-5.55,-1.48]
1.4 Daily record chart symptom 1 104 Risk Ratio (M-H, Fixed, 1.50
resolution at 4 weeks post-treatment 95% CI) [0.58, 3.91]
(capsaicin 1 μg/puff versus placebo)
1.5 Daily record chart symptom 1 104 Risk Ratio (M-H, Fixed, 2.00
resolution at 4 weeks post-treatment 95% CI) [0.81, 4.93]
(capsaicin 2 μg/puff versus placebo)
1.6 Daily record chart symptom 1 104 Risk Ratio (M-H, Fixed, 3.17
resolution at 4 weeks post-treatment 95% CI) [1.38, 7.29]
(capsaicin 4 μg/puff versus placebo)

333
CHAPTER 6

334
CAPSAICIN FOR NON-ALLERGIC RHINITIS

335
CHAPTER 6

Comparison 2 Capsaicin versus budesonide

Outcome or Subgroup Studies Partic- Statistical Method Effect

ipants Estimate
2.1 Aggregate score during the 4th 1 40 Mean Difference (IV, -2.46
week of treatment [VAS, 0-5] Fixed, 95% CI [VAS, 0-5]) [-4.28,
-0.63]
2.2 Aggregate relief score during the 1 40 Mean Difference (IV, 2.50
4th week of treatment Fixed, 95% CI) [1.06, 3.94]
2.1 Aggregate score during the 4th 1 40 Mean Difference (IV, -2.46
week of treatment [VAS, 0-5] Fixed, 95% CI [VAS, 0-5]) [-4.28,
-0.63]
2.2 Aggregate relief score during the 1 40 Mean Difference (IV, 2.50
4th week of treatment Fixed, 95% CI) [1.06, 3.94]
2.5 Postnasal drip during the 4th 1 40 Mean Difference (IV, -0.50
week of treatment [VAS, 0-5] Fixed, 95% CI [VAS, 0-5]) [-1.32, 0.33]
2.6 Rhinorrhoea during the 4th week 1 40 Mean Difference (IV, -0.25
of treatment [VAS, 0-5] Fixed, 95% CI [VAS, 0-5]) [-0.99, 0.48]
2.7 Nasal blockage during the 4th 1 40 Mean Difference (IV, -1.19
week of treatment [VAS, 0-5] Fixed, 95% CI [VAS, 0-5]) [-2.45, 0.06]
2.8 Sneezing during the 4th week of 1 40 Mean Difference (IV, -0.15
treatment [VAS, 0-5] Fixed, 95% CI [VAS, 0-5]) [-0.74, 0.43]
2.9 Sore throat during the 4th week of 1 40 Mean Difference (IV, -0.44
treatment [VAS, 0-5] Fixed, 95% CI [VAS, 0-5]) [-1.04, 0.15]

336
CAPSAICIN FOR NON-ALLERGIC RHINITIS

337
CHAPTER 6

338
CAPSAICIN FOR NON-ALLERGIC RHINITIS

339
CHAPTER 6

Comparison 3 Different regimens of capsaicin administration

Outcome or Subgroup Studies Partici- Statistical Method Effect

pants Estimate
3.1 UPSIT at 12 weeks post-treatment 1 30 Mean Difference (IV, 3.00
Fixed, 95% CI) [-1.50, 7.50]

Comparison 4 Different doses of capsaicin

Outcome or Subgroup Studies Partici- Statistical Method Effect

pants Estimate
4.1 Daily record chart symptom 1 104 Risk Ratio (M-H, Fixed, 0.75 [0.35,
resolution at 4 weeks post-treatment 95% CI) 1.63]
(capsaicin 1 μg versus 2 μg/puff)
4.2 Daily record chart symptom 1 104 Risk Ratio (M-H, Fixed, 0.47 [0.24,
resolution at 4 weeks post-treatment 95% CI) 0.95]
(capsaicin 1 μg versus 4 μg/puff)
4.3 Daily record chart symptom 1 104 Risk Ratio (M-H, Fixed, 0.63 [0.34,
resolution at 4 weeks post-treatment 95% CI) 1.16]
(capsaicin 2 μg versus 4 μg/puff)

340
CAPSAICIN FOR NON-ALLERGIC RHINITIS

341
CHAPTER 6

APPENDICES

Appendix 1 Search strategies

CENTRAL PubMed EMBASE (Ovid) CINAHL
(EBSCO)
#1 MeSH descriptor: #1 “Rhinitis”[Mesh] 1 exp rhinitis/ S1 (MH “Rhini-
[Rhinitis] explode all #2 rhinit*[Title/Abstract] 2 “rhinit*”.tw. tis+”)
trees #3 (NARES or NAR or LAR or 3 (NARES or S2 TX rhinit*
#2 rhinit* NANIPER[Title/Abstract]) NAR or LAR or S3 TX NARES or
#3 NARES or NAR or #4 (#1 OR #2 OR #3) NANIPER).tw. NAR or LAR or
LAR or NANIPER #5 “Capsaicin”[Mesh] 4 (Capsaicin* or NANIPER
#4 #1 OR #2 OR #3 #6 (Capsaicin* or Pepper or Pepper or Axsain or S4 S1 OR S2
#5 MeSH descriptor: Axsain or Zacin or Capsicum Zacin or Capsicum OR S3
[Capsaicin] explode or Capsidol or Zostrix or or Capsidol or S5 (MH “Capsa-
all trees Capzasin or Gelcen or Katrum Zostrix or Capza- icin”)
#6 (Capsaicin* or or Capsin or Capsacinoid*[Ti- sin or Gelcen or S6 TX Capsaicin*
Pepper or Axsain or tle/Abstract]) Katrum or Capsin or Pepper or
Zacin or Capsicum #7 (sinus[Title/Abstract]) AND or Capsacinoid*). Axsain or Zacin
or Capsidol or buster[Title/Abstract] tw. or Capsicum
Zostrix or Capzasin #8 (#5 OR #6 OR #7 OR #8) 5 exp capsaicin/ or Capsidol or
or Gelcen or Katrum #9 (#4 AND #8) 6 (sinus adj6 Zostrix or Capza-
or Capsin or Capsa- buster).tw. sin or Gelcen or
cinoid* or sinus next 7 1 or 2 or 3 Katrum or Capsin
buster) 8 4 or 5 or 6 or Capsacinoid*
#7 #5 or #6 9 7 and 8 S7 TX sinus and
#8 #4 and #7 buster
S8 S5 OR S6
OR S7
S9 S4 AND S8
Clinicaltrials.gov Web of Science AMED (Ovid) ICTRP
(via the Cochrane
Register of Studies)

342
 CAPSAICIN FOR NON-ALLERGIC RHINITIS

Table continued

rhinitis AND (Cap- #1 TS=rhinit* 1 exp rhinitis/ rhinitis and Cap-

saicin* OR Pepper #2 TS=(NARES or NAR or LAR 2 “rhinit*”.tw. saicin or rhinitis
OR Axsain OR Zacin or NANIPER) 3 (NARES or and pepper or
OR Capsicum OR #3 #2 OR #1 NAR or LAR or rhinitis and
Capsidol OR Zostrix #4 TS=(Capsaicin* or Pepper NANIPER).tw. axsain or rhinitis
OR Capzasin OR or Axsain or Zacin or Capsi- 4 (Capsaicin* or and capsicum
Gelcen OR Katrum cum or Capsidol or Zostrix or Pepper or Axsain or or rhinitis and
OR Capsin OR Cap- Capzasin or Gelcen or Katrum Zacin or Capsicum capsidol or rhi-
sacinoid*) or Capsin or Capsacinoid*) or Capsidol or nitis and zostrix
#5 TS=(sinus AND buster) Zostrix or Capza- or rhinitis and
#6 #5 OR #4 sin or Gelcen or capzasin or rhi-
#7 #6 AND #3 Katrum or Capsin nitis and gelcen
or Capsacinoid*). or rhinitis and
tw. katrum or rhinitis
5 exp capsaicin/ and capsin or
6 (sinus adj6 rhinitis and cap-
buster).tw. sacinoid
7 1 or 2 or 3
8 4 or 5 or 6
9 7 and 8

6
Appendix 2 Summary of the data collection form
We extracted the following characteristics using the data collection form.

• eneral information: publication type, year, country, author contact details.

G
• S tudy eligibility: type of study, participants, types of interventions, comparisons
and outcomes.
• S tudy methods: design, unit of allocation, start and end dates, duration of
participation, ethical approval, funding, possible conflicts of interest.
• Participants: population description, setting, inclusion and exclusion criteria,
method of recruitment, informed consent, total number randomised, clusters
(if applicable), baseline imbalances, withdrawals and exclusions, age, sex, race/
ethnicity, severity of illness, comorbidities, other relevant socio-demographics,
measured and reported subgroups.
• Intervention and comparison groups: capsaicin and comparison type, number
randomised to group, duration of treatment, timing, delivery, providers, co-
interventions, economic information, resource requirements, integrity of delivery,
compliance.
• Outcomes: type of outcome, time points measured, time points reported, unit of
measurement, scale, assumed risk estimate, power.

343
CHAPTER 6

• ‘ Risk of bias’ assessment: random sequence generation, allocation concealment,

blinding of participants and personnel, blinding of outcome assessment,
incomplete outcome data, selective outcome reporting, other bias.
• Data and analysis: comparison, outcome, subgroup, time points, results, number of
missing participants, reason missing, number of participants moved from another
group, reason for move, unit of analysis, statistical method.
• O ther information: key conclusions of the study, references to other relevant
studies.

CONTRIBUTIONS OF AUTHORS

AG, CG and RG were responsible for drafting the protocol, selecting the studies, data
extraction and analysis, and drafting the final manuscript. CMvD participated in study
selection, data analysis and drafting the final manuscript. WJF conceived the idea and
participated in drafting the protocol and the final manuscript.

DECLARATIONS OF INTEREST

Wytske Fokkens received private sector support for research and/or clinical
trials related to treatment of allergic and non-allergic rhinitis from Allergopharma,
GlaxoSmithKline (GSK) and Bioinpsire, as well as public sector research support from
InterUniversity Attraction Poles (Belgium), ZonMW (The Netherlands), and Global
Allergy and Asthma European Network (EU). WJ Fokkens has also received royalties
for legal consultation/expert witness testimony for Stallergens. WJF is also the lead
author of two of the five included studies, Blom 1997/1998 and van Rijswijk 2003.

Cornelis M van Drunen has received grants form GSK, ALK, Allergopharma, the
European Union (GA2LEN, BM4SIT) and the Dutch (NWO) and Flemish Government
(FMO) in the field of (non)-allergic rhinitis and chronic rhinosinusitis.

Artur Gevorgyan was supported by the 2013 Clinical Fellowship of the European
Academy of Allergy and Clinical Immunology.

Christine Segboer: no potential conflict of interest.

Rob Gorissen: no potential conflict of interest.

No funds have been received by the authors of the review that relate directly to
capsaicin.

344
SOURCES OF SUPPORT

Internal sources
• None, Other.

The authors received no specific support for this study

External sources
• National Institute for Health Research, UK.

Infrastructure funding for the Cochrane ENT Group

DIFFERENCES BETWEEN PROTOCOL AND REVIEW

We decided to define patients over 16 years of age as adults (Types of participants).

This was dictated by the fact that most studies had a cut-off of 16 years for definition
of an adult. Given that we were unable to obtain further information about the included
studies from the authors, we were also unable to exclude those patients aged between
16 and 18 years.

The specific types of non-allergic rhinitis included are now listed in  Types of
participants.

We have included a ‘Summary of findings’ table and described the method used in
the Methods section.

We have specified that quasi-randomisation is acceptable in included studies (Types

of studies).

Index Terms

Medical Subject Headings (MeSH)

Anti-Inflammatory Agents [*therapeutic use]; Budesonide [therapeutic use]; Capsaicin
[administration & dosage; *therapeutic use];

Randomized Controlled Trials as Topic; Rhinitis [*drug therapy]

MeSH check words

Adolescent; Adult; Aged; Humans; Middle Aged
CHAPTER 7
Inhibition of
capsaicin-driven nasal
hyper-reactivity by
SB-705498, a TRPV-1
antagonist
 C.T. Holland
C.M. van Drunen
J.C. Denyer
K. Smart
C.L. Segboer
I. Terreehorst
A. Newlands
M. Beerahee
W.J. Fokkens
D.C. Tsitoura

Br J Clin Pharmacol. 2014 May; 77(5):777-88

CHAPTER 7

ABSTRACT

Aims
To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD)
of intranasal SB‐705498, a selective TRPV-1 antagonist.

Methods
Two randomized, double‐blind, placebo‐controlled, clinical studies were performed: (i)
an intranasal SB‐705498 first time in human study to examine the safety and PK of five
single escalating doses from 0.5 to 12 mg and of repeat dosing with 6 mg and 12 mg
twice daily for 14 days and (ii) a PD efficacy study in subjects with non‐allergic rhinitis
(NAR) to evaluate the effect of 12 mg intranasal SB‐705498 against nasal capsaicin
challenge.

Results
Single and repeat dosing with intranasal SB‐705498 was safe and well tolerated. The
overall frequency of adverse events was similar for SB‐705498 and placebo and no
dose‐dependent increase was observed. Administration of SB‐705498 resulted in less
than dose proportional AUC (0,12 h) and Cmax, while repeat dosing from day 1 to day 14
led to its accumulation. SB‐705498 receptor occupancy in nasal tissue was estimated
to be high (>80%). Administration of 12 mg SB‐705498 to patients with NAR induced
a marked reduction in total symptom scores triggered by nasal capsaicin challenge.
Inhibition of rhinorrhoea, nasal congestion and burning sensation was associated with
2‐ to 4‐fold shift in capsaicin potency.

Conclusions
Intranasal SB‐705498 has an appropriate safety and PK profile for development in
humans and achieves clinically relevant attenuation of capsaicin‐provoked rhinitis
symptoms in patients with NAR. The potential impact intranasal SB‐705498 may have
in rhinitis treatment deserves further evaluation.

What is already known about this subject

• Transient receptor potential vanilloid 1 (TRPV-1) is an ion channel expressed on
peripheral nerves, activated by several physical, chemical and biological factors.
• In the nose, overstimulation of TRPV-1‐expressing sensory nerves may lead
to nasal hyper‐reactivity and development of rhinitis symptoms in sensitive
individuals.
• Targeting TRPV-1 may offer the potential to control medical conditions

characterized by sensory neuronal hyper‐responsiveness, including the nasal
hyper‐reactivity that underlies non‐allergic rhinitis (NAR).

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 INHIBITION OF CAPSAICIN-DRIVEN NASAL HYPER-REACTIVITY BY SB-705498

What this study adds

• his study provides an insight on the early clinical evaluation of SB‐705498, a
T
selective TRPV-1 antagonist, as a potential intranasal therapeutic modality for
NAR.
• T he safety and pharmacokinetic (PK) profile of intranasal SB‐705498 was
established in humans and an agonist‐antagonist intranasal dose–response
capsaicin challenge was initiated to provide evidence of pharmacology in the
target patient population.
• Intranasal SB‐705498 could be developed as a potential new blocker of nasal
hyper‐reactivity in rhinitis patients.

INTRODUCTION

Rhinitis is a common condition that affects up to 30% of adults and 40% of children
and poses a significant economic burden to the world population (1-3). A regular patho-
physiological feature of rhinitis is nasal hyper‐responsiveness. Nasal hyper‐respon-
siveness is characterized by exaggerated nasal sensory and reflexogenic responses
to environmental factors, such as weather changes, household chemicals, pollution
or strong odours, that result in generation of symptoms of rhinorrhoea, nasal conges-
tion, sneezing and itch (4, 5). Nasal hyper‐responsiveness is often a consequence of
allergic inflammation, as allergic mediators affect directly the sensory nasal nerves 7
and reduce their threshold potential for activation (4). Nasal hyper‐responsiveness is
also the cardinal feature of non‐allergic rhinitis (NAR), a disease entity thought to be
driven by over‐reactivity of nasal sensory nerves or over‐interpretation of normally
transmitted signals by the CNS response centres (6). Blocking the sensory neuronal
pathways involved in nasal hyper‐responsiveness has been proposed as a novel form
of treatment for difficult to treat rhinitis patients. This concept is supported by clinical
data demonstrating that cold dry air or hypertonic saline triggered nasal hyper‐respon-
siveness is inhibited after anaesthetization or desensitization of the nasal sensory
fibres (4, 7).

TRPV-1 (also known as VR1, vanilloid/capsaicin receptor, OTRPC1) (8) is a sensory

nerve receptor, a member of a super‐family of structurally related transmembrane ion
channels, known to serve a multitude of cellular roles, including many facets of sensory
transduction (9, 10). TRPV-1 is activated by several physiological stimuli including
capsaicin, heat, low pH, osmotic stress and by endogenous inflammatory mediators,
such as histamine, prostaglandins and lipoxygenases (9, 11). TRPV-1 is expressed on
afferent sensory nerves, particularly on non‐myelinated C‐fibre nociceptors, and is
present in the airways. In the upper airways expression of TRPV-1 has been confirmed
on the trigeminal sensory neurones that innervate the epithelium and subepithelium
of nasal mucosa (12). The expression of TRPV-1 has been found enhanced in chronic

349
CHAPTER 7

inflammation (13). Several lines of experimental evidence indicate that TRPV-1 is a key

player in the excitability of airway sensory neurons and TRPV-1 sensitive nerves have
been shown to contribute in the development of lower and upper airway hyper‐respon-
siveness, bronchoconstriction and cough (14, 15). This suggests that TRPV-1 may be
a primary target for pharmacological intervention for a range of respiratory disorders.

To assess if TRPV-1 antagonism can prevent nasal hyper‐responsiveness and there-

fore become a promising therapeutic modality for NAR, SB‐705498, a potent and
selective TRPV-1 antagonist (16, 17), has been developed for intranasal administration.
SB‐705498 is a known inhibitor of the multiple modes of TRPV-1 activation. Treat-
ment with oral SB‐705498 has been applied successfully in models of neuropathic
and inflammatory pain (18). In a pre‐clinical rhinitis model, intranasal as well as oral
administration of SB‐705498 has been shown to block the capsaicin‐evoked nasal
secretions (19). In this rhinitis model 10‐fold lower doses of intranasal SB‐705498 were
required to achieve the same efficacy as the orally dosed compound. Furthermore,
intranasal SB‐705498 has a good safety and pre‐clinical toxicology profile that allowed
initiation of clinical studies.

In this article we describe a first time in human (FTIH) study to characterize the safety
and PK profiles of intranasal SB‐705498 in healthy volunteers and a pharmacody-
namics (PD) study to evaluate its effects against capsaicin‐provoked nasal reactivity
in subjects with NAR.

METHODS

The FTIH study to determine the safety, tolerability and PK of single and repeat dosing
with intranasal SB‐705498 in healthy volunteers was conducted at Hammersmith
Medicines Research, London, UK (GlaxoSmithKline protocol: VR1111610; clintrials.
gov: NCT00907933). The PD study to evaluate the effect of intranasal SB‐705498
on capsaicin‐evoked nasal reactivity in patients with NAR was conducted at Acade-
misch Medisch Centrum, Amsterdam, the Netherlands (GlaxoSmithKline protocol:
VR1111925; clintrials.gov: NCT01439308).

Clinical study populations

FTIH study
Non‐smoking male and female healthy volunteers aged 18–60 years with no previous
history of nasal disorders were included in the study. A total of 14 and 30 healthy
volunteers participated in the single and repeat dose arm of the study respectively.

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 INHIBITION OF CAPSAICIN-DRIVEN NASAL HYPER-REACTIVITY BY SB-705498

PD study
Forty‐one male and female, non‐smoking NAR patients aged 18–55 years with no
other concomitant disorders participated in the study. All patients had a diagnosis of
NAR >1 year, as determined by the presence of perennial rhinitis symptoms triggered
by environmental provocateurs (i.e. weather changes, irritants, air pollution etc.) for
at least 9 months of the year. All NAR patients were required to have normal levels of
total plasma IgE and negative allergen‐specific skin or serum IgE tests.

All study participants provided written, informed consent to participate in the studies.
Local Ethics Committees provided formal approval for the studies which were
conducted in accordance with all known regulatory requirements and the guiding
principles of the Declaration of Helsinki (20).

Clinical study designs

FTIH study
This study had two‐arms. First the safety, tolerability and PK of five single ascending
doses of intranasal SB‐705498 (0.5, 1.5, 3, 6, and 12 mg) were evaluated in healthy
volunteers following a randomized, double‐blind, placebo‐controlled, five period,
incomplete block crossover design. The incomplete block design was intended to
make the study more manageable for participants and more time efficient. Success-
fully screened subjects were randomized to receive a single intranasal dose of either
SB‐705498 or placebo in each treatment period, and over the course of the study each 7
subject received five out of the six possible treatments, each once only. In each treat-
ment period subjects attended the unit approximately 24 h before dosing and remained
resident for 24 h post‐dosing. A follow‐up phone call was made 7 to 10 days later. At
the end of each treatment period all available blinded safety and PK data were reviewed
to allow dose escalation. Treatment periods were separated by a 7 day washout.

After the safety of single dosing was established a randomized, double‐blind, placebo‐
controlled, parallel group study was initiated to evaluate the safety, tolerability and PK
of 6 and 12 mg of intranasal SB‐705498 administered twice daily for 14 days. New
healthy volunteers were recruited for this arm of the study. Eligible subjects attended
the study 24 h before the first dosing (day −1) and remained resident for approxi-
mately 36 h post‐dosing. Subjects left the unit with a diary card and sufficient study
medication to continue self‐administration until day 7, when they returned to the unit
for review of diary information and adherence and to get new medication supplies to
continue self‐administration until day 13. On day 13 subjects returned to the unit again
and remained resident for approximately 48 h after their last dosing for assessments
and collection of PK samples. A follow‐up phone call was made 7–10 days after the
final dose.

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PD study
This was a randomized, double‐blind, placebo‐controlled, parallel group study to
evaluate the effect of a single intranasal administration of 12 mg SB‐705498 on
­capsaicin‐evoked nasal reactivity in patients with NAR. PK and safety were also
assessed. Subjects with NAR went through an initial screening to assess their eligi-
bility for enrolment in the study and confirm their responsiveness to a single, unilat-
eral, intranasal challenge with 50 μg capsaicin. Only subjects who developed a total
symptom score (TSS) ≥3 in response to the capsaicin challenge entered the treatment
phase of the study. On the dosing day 1 h after administration of SB‐705498 or placebo,
all patients underwent a baseline unilateral, intranasal vehicle control challenge and
subsequently received three unilateral, intranasal challenges with incremental doses
of capsaicin (2.5 μg, 12.5 μg and 50 μg). Clinical symptoms were assessed and nasal
secretions were collected after each challenge. Patients were followed‐up by telephone
48 h after treatment.

Justification of dose selection

The selection of doses for the FTIH and PD studies was based on the estimated
SB‐705498 dose–response from a guinea pig rhinitis PD model over the oral dose
range 3 to 30 mg kg−1 (19). The estimated ED50 parameter (10 mg kg−1) in the guinea
pig was converted to the corresponding drug levels of 1.4 μg ml−1 (EC50) in the nasal
turbinates using clearance data obtained in guinea pigs after intravenous and intra‐
nasal dosing and blood to nasal tissue partition (in house data). The EC50 value in the
guinea pig turbinates was then scaled to corresponding equivalent drug levels (EC50)
in human turbinates based on the known human clearance parameter of the drug and
free drug fraction and assuming similar blood to nasal tissue partition as in the guinea
pig. As described below, an estimation of a total intranasal dose of 12 mg (6 mg/nostril)
would be required in humans to achieve intranasal concentrations corresponding to
those found to be effective in the guinea pig. It was predicted that the intranasal dose
of SB‐705498 12 mg (6 mg in each nostril) would lead to high receptor occupancy (∼
>80%) at the target nasal tissues. This estimate took into account the binding affinity
of SB‐705498 at the human TRPV-1 receptor (pKb = 7.5 in house data), an assumed
volume of human nasal tissue of 20 ml (21) and an intranasal bioavailability of the
drug of approximately 20% after intranasal dosing. The intranasal bioavailability in
humans was approximated from preclinical data in the dog where the drug was given
intranasally with and without charcoal (unpublished data on file, GlaxoSmithKline,
Stevenage, UK). The charcoal block test is a standard and useful method to estimate
the tissue bioavailability following topical administration (such as inhaled or intranasal
route) of the drug compared with oral administration. Co‐administration of charcoal
with the drug prevents its oral absorption resulting in minimal systemic availability of
the administered drug. The predicted nasal tissue and systemic exposure in humans
with doses of intranasal SB‐705498 up to 12 mg were within the safety margins derived
from preclinical safety studies.

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Safety assessments
Adverse events were recorded throughout the FTIH and PD studies. The investigator
graded adverse event intensity (mild, moderate or severe) and relationship with study
drug. Body temperature, vital signs, 12‐lead electrocardiogram (ECG), nasal tolerability
(nasal symptom scoring by visual analogue scale [VAS], nasal endoscopy (performed
in the FTIH only) and visual nasal examination were evaluated at several time points
post‐dosing. Furthermore, there was repeat assessment of laboratory safety para-
meters, including plasma progesterone, adrenocorticotrophic hormone and cortisol
concentrations (because administration of SB‐705498 to rat or dog at high doses
above the no adverse effect level (NOAEL) has been associated with vacuolation and
hypertrophy of some hormone producing organs, most notably the adrenal cortex,
but also the ovaries and testes).

PK assessment
In the FTIH, blood samples were collected for PK analysis pre‐dose, 15 and 30 min
and 1, 2, 4, 8, 12 and 24 h post each single dosing. In the 14 days repeat dosing
arm, samples were taken at the same times relative to dosing on day 1 and day 14,
and additional samples were taken 36 and 48 h after the last dose received on day
14. In the PD study blood samples were collected pre‐dose, 30 min and 1, 2, 3 and
4 h post‐dosing. Plasma was analyzed for parent drug by high performance liquid
chromatography/tandem mass spectrometry using a TurboIonspray interface and
multiple reaction monitoring (22, 23). The method had a lower limit of quantification 7
(LLQ) of 2.5 ng ml−1 using a 50 μl aliquot of human plasma over a linear calibration
range of 2.5 to 2000 ng ml−1. Quality control (QC) samples, prepared at three different
analyte concentrations and stored with study samples, were analyzed with each batch
of samples against separately prepared calibration standards. For the analysis to
be acceptable, no more than one‐third of the QC results were to deviate from the
nominal concentration by more than 15% and at least 50% of the results from each
QC concentration were to be within 15% of nominal. All applicable analytical runs met
all predefined run acceptance criteria.

SB‐705498 PK parameters were derived from the initial time–concentration data by

standard non‐compartmental analysis using WinNonLin Pro (Version 4.1; Pharsight
Products, Cary, NC, USA). The following parameters were assessed: AUC(0,t), AUC
from time 0 to 4 h, from time 0 to 12 h and from time 0 to 24 h post‐dose (AUC(0,4 h),
AUC(0,12 h), AUC(0,24 h)), maximum observed plasma concentration (Cmax) and time
to maximum observed plasma concentration (tmax).

PD assessments
Intranasal capsaicin challenge
In the PD study the nasal response to unilateral, intranasal capsaicin challenge was
assessed and the effect of prior treatment with intranasal SB‐705498 vs. placebo

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analyzed. In brief, patients blew their nose to clear any secretions and both nostrils
were then washed 20 times in 1 min with 0.9% saline (10 ml). The lavage fluid was
discarded and the nostrils were dried. Initially, a baseline assessment of the response
to a unilateral intranasal vehicle control challenge was made by spraying saline into the
right nostril using a metered pump device (25 μl or 50 μl per actuation). Subsequently
the response to capsaicin challenge was evaluated by spraying a single (at screening)
or incremental capsaicin doses (2.5 μg, 12.5 μg and 50 μg) into the right nostril using
a metered pump device. The number of actuations was determined by the dose of
capsaicin required. Challenges with saline or each dose of capsaicin were separated
by an interval of 20 min during which a series of assessments were made.

At 1, 5, and 9 min after each challenge, patients were asked to grade the intensity
of symptoms of burning sensation, rhinorrhoea, lacrimation and nasal congestion
as follows: 0 = none; 1 = mild; 2 = moderate and 3 = severe. The individual scores
were summed to produce a TSS. Patients also completed a 10 cm long VAS for nasal
congestion, rhinorrhoea, lacrimation and burning sensation.

Peak nasal inspiratory flow (PNIF) was measured using an InCheck PNIF meter
(Clement Clarke International Ltd, Harlow, United Kingdom) 15 min after each challenge.
Three inspiratory efforts were made and the highest measure was recorded.

Statistical analysis
FTIH study
Sample sizes were based on logistic feasibility. In the single dose arm dose proportio­
nality using Cmax and AUC was assessed using a power model and analysis of variance
(anova). In the repeat dose arm, a statistical analysis was performed on AUC(0,12 h)
and Cmax (after morning dosing) to evaluate the accumulation ratio. A mixed effect
model was fitted with dose (categorical variable), day and dose by day interaction as
fixed effects and repeated measures analysis was carried out on day using subject as
a blocking effect. Day 14 was compared with day 1 in order to estimate the accumu-
lation ratio for each treatment group.

PD study
An unblinded adaptive sample size re‐estimation was planned for when 20 patients
had completed the study to determine whether to terminate the study for futility or
efficacy. Due to a high rate of recruitment, it was conducted after 37 patients had
been dosed but the analysis used data from only 20 patients. Following the interim
analysis the planned number of patients (n = 40) were subsequently recruited. Treat-
ment differences and ratios (SB‐705498 12 mg vs. placebo) of adjusted means were
analyzed for TSS and nasal secretion weights using a repeated measures anova. A
Bayesian analysis was conducted to derive the posterior probability distributions
for total nasal secretion weights, mean TSS and average VAS measures for nasal

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 INHIBITION OF CAPSAICIN-DRIVEN NASAL HYPER-REACTIVITY BY SB-705498

congestion, rhinorrhoea, lacrimation and burning sensation. The probabilities were

derived using a mixed effects model (fitted for the frequentist analysis). However,
a Student’s t cumulative distribution function was used to obtain the probabilistic
statements, assuming a non‐informative prior. The difference between SB‐705498
12 mg and placebo for change from baseline in PNIF was analyzed using a repeated
measures anova.

Dose ratio analysis

A quantitative approach was performed in the PD study to evaluate the effect of single
dose SB‐705498 (antagonist) in the presence of incremental challenge with capsaicin
(agonist) to estimate the shift in dose–response. Clinical endpoints corrected for saline
baseline were evaluated including average TSS, components of TSS (nasal congestion,
lacrimation, burning sensation, and rhinorrhoea), VAS scores for individual compo-
nents (nasal congestion, lacrimation, burning sensation, rhinorrhoea) and PNIF. The
standard parallel line assay method was applied to each of the clinical endpoints (24).
With this method, an overall anovais carried out and tests of significance performed
on the regression slope, linearity of dose–response and evidence of parallelism. For
each clinical endpoint, the dose–response was compared only for the agonist and
in the presence of the drug (antagonist). This comparison was done by estimation
of the potency ratio (with associated 95% confidence intervals [CIs]), which corre-
sponds to the inverse of the ratio for the doses that produce equivalent responses in
the two treatment groups for each endpoint. This analysis was performed using PLA 7
Version 2.0 software (Stegmann Systems, Rodgan, Germany) for parallel line and
parallel logistics assays. This software includes a suite of transformation functions
for the response variables to account for any heteroscedasticity. Individual datasets
for each clinical endpoint for both studies were fitted to the appropriate model with a
detailed statistical output of the overall dose ratio analysis. Dose ratio estimates for
each clinical endpoint and associated 95% CIs are graphically presented.

Results

Participants
FTIH study
Fourteen healthy volunteers (HVT) with mean age 32.9 (23–52) years and thirty HVT
with mean age 28.5 (21–48) years were randomized in the single and repeat dose
arms of the study respectively. All subjects completed the study. The populations were
predominantly Caucasian (11 subjects [79%] in the single dose arm and 24 subjects
[80%] in the repeat dose arm) and male (11 subjects [79%] and 22 subjects [73%],
respectively).

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PD study
Forty‐one patients (26 females and 15 males) were randomized (SB‐705498 12 mg:
19 patients; placebo: 22 patients). All completed, except one patient who received
SB‐705498 12 mg and withdrew because of an adverse event (intermittent hyperten-
sion). Mean (range) ages were 40.1 (19–57) years in the SB‐705498 group and 34.0
(18–55) years in the placebo group.

Safety and tolerability results

FTIH study
Single and repeat dosing with intranasal SB‐705498 was well tolerated at all dose
levels tested. No serious adverse events were reported in the study and no dose
relationship in the incidence of adverse events was observed. Subjects who received
single administration of 1.5 mg intranasal SB‐705498 presented a slightly greater
incidence of drug‐related adverse events. However, this finding was not repeated at
higher doses and therefore it was not considered clinically relevant. All adverse events
were transient and of mild/moderate intensity. The most frequently reported adverse
events were headache and oropharyngeal pain (Table 1). Clinically significant changes
for vital signs, cardiac monitoring, body temperature, and standard haematology and
biochemistry tests (including plasma progesterone, adrenocorticotrophic hormone
and cortisol concentrations) were not detected. Furthermore, there were no consistent
or dose dependent signs of nasal irritancy with clinical significance, as assessed by
individual scoring of nasal symptoms, nasal endoscopy and visual nasal examination,
after either single or repeat intranasal SB‐705498 administration.

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Table 1. Summary of adverse events reported by more than one subject in the FTIH study

Part 1 Part 2
Placebo SB‐705498 Placebo SB‐705498
Adverse event 0.5 mg 1.5 mg 3 mg 6 mg 12 mg 6 mg 12 mg
n = 11 n = 12 n = 12 n = 11 n = 12 n = 12 n = 10 n = 10 n = 10
n (%) n (%) n (%) n(%) n(%) n (%) n (%) n(%) n(%)
Any event 2 (18) 1 (8) 5 (42) 5 (45) 4 (33) 2 (17) 5 (50) 4 (40) 3 (30)
Any event judged 1 (9) 0 2 (17) 1 (9) 0 1 (8) 5 (50) 4 (40) 3 (30)
drug‐related*
Headache 2 (18) 1 (8) 1 (8) 2 (18) 0 0 3 (30) 1 (10) 2 (20)
Oropharyngeal 0 0 3 (25) 0 0 1 (8) 1 (10) 1 (10) 1 (10)
pain
Upper respiratory 0 0 0 2 (18) 1 (8) 0 0 1 (10) 2 (20)
tract infection
Abdominal pain 0 1 (8) 0 1 (9) 0 0 0 0 0
Nasal congestion 0 0 0 1 (9) 1 (8) 0 0 0 0

*Assesments of relationship were made prior to unblinding and, therefore, events could be judged
related to placebo.

PD study
Administration of intranasal SB‐705498 was well tolerated by NAR patients. Twenty‐ 7
two patients reported adverse events: 11 (58%) had received SB‐705498 and 11 (50%)
had received placebo (Table 2). The most frequently reported event was cough, which
was reported by five (26%) patients who received SB‐705498 compared with two (9%)
patients who received placebo. No serious adverse events were reported. One patient
was withdrawn from the study because of intermittent hypertension of mild intensity
that occurred 26 min after dosing with SB‐705498 12 mg. The hypertension resolved
approximately 2 h later. No clinically significant abnormalities in vital signs, 12‐lead
ECG, body temperature, nasal examination or clinical laboratory tests were observed.
Nasal capsaicin challenge did not appear to cause other events than the expected
nasal reactivity.

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Table 2. Adverse events reported by more than one patient in the PD study

Placebo SB‐705498 12 mg

Adverse event n = 22 n = 19
n (%) n (%)
Any event 11 (50) 11 (58)
Cough 2 (9) 5 (26)
Headache 3 (14) 3 (16)
Fatigue 3 (14) 2 (11)
Sneezing 3 (14) 1 (5)
Throat irritation 2 (9) 1 (5)
Feeling cold 0 2 (11)
Lacrimation increased 1 (5) 1 (5)
Nausea 2 (9) 0
Upper airway obstruction 2 (9) 0

Pharmacokinetic results
FTIH study
Following intranasal administration, SB‐705498 was fairly rapidly absorbed in HVT
achieving maximum plasma concentration at 1–2 h post‐dose (Table 3) and had
slow distribution and elimination. This rate of absorption remained largely unaffected
after repeat administration (Table 4) with plasma concentrations of SB‐705498
declining slowly (Figure 1). Repeat administration led to higher plasma concentra-
tions of SB‐705498 compared with those achieved after single intranasal dosing
(Figure 1). Generally, SB‐705498 systemic exposure increased with dose escalation
from 0.5 mg to 12 mg. However, the results of the power model suggest that the
increase in systemic exposure was less than dose proportional in terms of AUC(0,12 h)
(slope: 0.753 ng ml−1 h mg−1, 90% CI 0.644, 0.862) and Cmax (slope: 0.826 ng ml−1 mg−1,
90% CI 0.730, 0.921). Repeat intranasal administration of 6 and 12 mg SB‐705498
for 14 days was associated with systemic drug accumulation. Values of AUC(0,24 h)
and Cmax increased 2–3‐fold on day 14 compared with day 1.

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 INHIBITION OF CAPSAICIN-DRIVEN NASAL HYPER-REACTIVITY BY SB-705498

Table 3. Derived PK parameters [geometric mean (95% confidence interval)] after single dosing
in the FTIH study

Part 1
SB‐705498 dose
0.5 mg 1.5 mg 3 mg 6 mg 12 mg
n = 12 n = 12 n = 11 n = 12 n = 12
AUC(0,t) NC 152.8 249.8 440.6 903.6
(ng ml−1 h) (121.0, 193.0) (100.7, 619.4) (346.2, 560.9) (617.8, 321.7)
Cmax (ng ml−1) 4.7 22.2 33.1 43.0 86.4
(3.3, 6.6) (18.2, 27.1) (20.1, 54.7) (33.5, 55.2) (64.4, 115.9)
tmax (h)* 1.0 1.0 2.0 2.0 2.0
[0.5, 2.0] [1.0, 8.0] (0.25, 4.02) (1.00, 4.00) (1.00, 8.00)

*Presented as median [range]. AUC(0,t), area under the plasma concentration–time curve from-
time zero to time t; Cmax, maximum plasma concentration; NC, Non‐calculable due to non‐quantifi-
able concentrations; tmax, time to Cmax.

Table 4. Derived PK parameters [geometric mean (95% confidence interval)] after repeat dosing
in the FTIH study

Part 2
SB‐705498 6 mg SB‐705498 12 mg
Day 1 a.m. Day 14 a.m. Day 1 a.m. Day 14 a.m.
n = 10 n = 10 n = 10 n = 10
7
AUC(0,24 h) 634.5 1522.1 1601.3 3416.3
(ng ml−1 h) (307.8, 1308.0) (628.3. 3687.4) (1296.7, 1977.5) (2280.0, 5118.8)
Cmax (ng ml−1) 38.2 (15.6, 93.4) 90.3 (39.5, 206.4) 102.1 (76.1, 137.0) 196.3 (125.3, 307.7)
tmax (h)a 2.0 (NC, 4.1) 2.0 (0.5, 4.0) 2.0 (0.5, 4.03) 3.0 (0.3, 12.0)

a
 Presented as median (range) AUC(0,24 h), area under the plasma concentration–time curve from
time zero to 24 h; Cmax, maximum plasma concentration; NC, Non‐calculable due to non‐quantifi-
able concentrations; tmax, time to Cmax.

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Figure 1. Mean (SD) plasma concentrations of SB‐705498 after twice daily intranasal dosing on day
1 and day 14.
day 1 12 mg twice daily;
day 14 12 mg twice daily

PD study
PK analysis of blood samples from NAR patients confirmed that maximum
plasma concentrations were achieved at 3 h post‐dose. Geometric mean Cmax was
77.7 ng ml−1 (95% CI 54.1, 111.5) and AUC(0,t) was 140.5 ng ml−1 h (95% CI 91.5, 215.9).

Pharmacodynamic results
PD study
Administration of a single dose of 12 mg intranasal SB‐705498 to patients with NAR
prior to intranasal challenge with capsaicin resulted in a decrease of the capsaicin‐
provoked symptoms, including burning sensation, rhinorrhoea, nasal congestion
and lacrimation (Figure 2A). At baseline, following challenge with saline control, both
SB‐705498 and placebo groups reported similar symptoms. The TSS adjusted mean
(95% CI) values were 1.45 (1.03, 1.86) for the placebo and 1.21 (0.75, 1.68) for the
SB‐705498 group. However, the TSS induced by all doses of capsaicin were markedly
reduced in the SB‐705498 treated group compared with placebo. Specifically, after
challenge with 2.5 μg capsaicin, the adjusted mean (95% CI) values of TSS were 4.16

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 INHIBITION OF CAPSAICIN-DRIVEN NASAL HYPER-REACTIVITY BY SB-705498

(3.35, 4.97) in the placebo and 2.97 (2.08, 3.87) in the SB‐705498 group. After challenge
with 12.5 μg capsaicin, the TSS values were 6.01 (5.10, 6.93) and 4.76 (3.74, 5.78),
respectively, and after challenge with 50 μg capsaicin, the TSS values were 7.14 (6.04,
8.24) and 5.90 (4.969, 7.12) respectively. Bayesian analyses of mean TSS concluded
that the probability that SB‐705498 treatment led to some inhibition of challenge
response (>0%) compared with placebo was P > 0.9 for all capsaicin doses.

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Figure 2. (A) Boxplots showing the effect of treatment with intranasal SB‐705498 or placebo on total
symptom scores (TSS) in patients with NAR. Square and circle symbols represent mean, horizontal
line within the box represents median, lower and upper edges of box represent the 25th and 75th values
percentiles, respectively. The 5th and 95th percentiles, not shown graphically, were, respectively,:
▫SB‐705498 12 mg: saline 0 and 5; 2.5 μg capsaicin dose 0.67 and 7.67; 12.5 μg capsaicin dose 1.33
and 10.00; 50 μg capsaicin dose 2.67 and 11.30. Placebo: saline 0 and 3.67; 2.5 μg capsaicin dose
1.33 and 6.3; 12.5 μg capsaicin dose 2.67 and 8.67; 50 μg capsaicin dose 4.0 and 10.3.
(B) Boxplots showing the effect of treatment with intranasal SB‐705498 or placebo and peak nasal
inspiratory flow (PNIF) in patients with NAR. Square and circle symbols represent mean; horizontal
line within the box represents median; lower and upper edges of box represent the 25th and 75th values
percentiles respectively. The 5th and 95th percentiles, not shown graphically, were respectively:
▫SB‐705498 12 mg: saline 40 and 230; 2.5 μg capsaicin dose 45 and 200; 12.5 μg capsaicin dose 0
and 150; 50 μg capsaicin dose 0 and 150. Placebo: saline 45 and 200; 2.5 μg capsaicin dose 50 and
200; 12.5 μg capsaicin dose 50 and 190; 50 μg capsaicin dose 40 and 190.
●●, placebo
, SB‐705498 12 mg

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 INHIBITION OF CAPSAICIN-DRIVEN NASAL HYPER-REACTIVITY BY SB-705498

Assessment of VAS scores for individual symptoms triggered by capsaicin

indicated that all recorded symptoms were affected by treatment with SB‐705498.
Figure 3 illu­strates the effect of treatment with SB‐705498 compared with placebo on
burning sensation provoked by incremental capsaicin challenge. Burning sensation
was of particular PD importance for the development of intranasal SB‐705498, as
capsai­cin‐induced burning sensation is mediated directly by TRPV-1 engagement in
sensory neurones (25) and therefore evaluation of its inhibition is a direct measure
related to target TRPV-1 inhibition.

Figure 3. Boxplots showing the effect of treatment with intranasal SB‐705498 or placebo on burning
sensation, assessed by visual analogue scale (VAS). Square and circle symbols represent mean,
horizontal line within the box represents median, lower and upper edges of box represent the 25th and
75th values percentiles, respectively. The 5th and 95th percentiles, not shown graphically, were, respec-
tively,: SB‐705498 12 mg: saline 0 and 8.3; 2.5 μg capsaicin dose 4.33 and 63.3; 12.5 μg capsaicin
dose 7 and 96.67; 50 μg capsaicin dose 21.67 and 95. Placebo: saline 0 and 28.67; 2.5 μg capsaicin
dose 3.3 and 73.0; 12.5 μg capsaicin dose 9 and 90; 50 μg capsaicin dose 9.67 and 99.3.
●●, placebo
, SB‐705498 12 mg

The dose ratio analyses carried out on the TSS and VAS scores (nasal congestion,
rhinorrhoea and burning sensation) confirmed that the shifts in the relative potency
between placebo and SB‐705498 treated subjects were parallel. The parallel shift in
the dose–response is consistent with the competitive mechanism of inhibition of
TRPV-1 activation by the drug, which has also been demonstrated previously in in
vitro cellular assays (17). Detailed evaluation of the shift in the capsaicin‐induced
TSS dose–response following SB‐705498 administration showed a mean change of
2.8‐fold in relative potency (Figure 4). For individual VAS scores a 2‐ to 4‐fold change
in relative potency was observed on average (Figure 4).

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Figure 4. Forest plot depicting relative dose potency (mean and 95% CI) for clinical symptoms
in patients with NAR. A ratio greater than 1 signifies a positive clinical endpoint response signal

Before administration of treatment, PNIF values were slightly greater in the placebo
group than in the SB‐705498 group; these differences were maintained after dosing
with capsaicin (Figure 2B). A statistical analysis of the change from baseline indicated
that challenge with increasing capsaicin dose resulted in some decrease (worsening)
in PNIF values in both treatment arms. Treatment with SB‐705498 compared with
placebo, resulted in a minimal effect on PNIF values (mean change from baseline)
which was more obvious after challenge with the lower doses of capsaicin.

DISCUSSION

The results of this study support the concept that selective blockade of TRPV-1 stimu-
lation in the nose can reduce nasal hyper‐responsiveness and development of rhinitis
symptoms triggered by exogenous agents provoking sensory nerve excitability. This is
the first study to explore and describe the safety, PK and PD efficacy of a novel intra-
nasal formulation of SB‐705498 in healthy volunteers and patients with NAR. Single
and twice daily repeat intranasal administration of SB‐705498, at doses up to 12 mg,
was found to be safe overall and well tolerated. Treatment with intranasal SB‐705498
showed target‐specific local PD activity against nasal hyper‐reactivity provoked by
capsaicin challenge.

Because of the central role of TRPV-1 in multi‐modal activation of sensory nerves,

TRPV-1 antagonism has attracted significant interest as a target for the treatment
of a wide range of disorders characterized by enhanced neural excitability, including

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 INHIBITION OF CAPSAICIN-DRIVEN NASAL HYPER-REACTIVITY BY SB-705498

neurological, gastrointestinal, urinary and respiratory conditions. However, to date

the foremost application of TRPV-1 antagonists has been in the treatment of pain. At
least 11 TRPV-1 antagonists have been identified and assessed for safety and tolera-
bility following systemic or oral administration (17). From these, five compounds have
already progressed into ‘proof of concept’ studies to provide early efficacy readouts
in patients with neuropathic or inflammatory pain. The GSK TRPV-1 antagonist
SB‐705498 was initially developed as a novel oral analgesic. SB705498 blocked effec-
tively in vitro the activation of TRPV-1 by capsaicin, low pH and temperature (16, 17).
In healthy volunteers single dosing with oral SB‐705498 up to levels within the safety
margin set by preclinical toxicology, was well tolerated and associated with a signif-
icant reduction of capsaicin‐evoked skin flare and a lesser effect on thermal pain
sensation (22). Furthermore in the same study, oral SB‐705498 produced a marked
decrease on the flare and hyperalgesia elicited by UVB‐irradiation of skin, implying that
TRPV-1 antagonism may exert an effect on neurogenic inflammation. The degree of
SB‐705498 PD efficacy on skin symptoms was correlated with the levels of systemic
drug exposure which suggested that high oral SB‐705498 doses would be necessary
to achieve adequate restriction of nociceptive activity (22). Single oral administration
of SB‐705498 in healthy volunteers (22) up to 400 mg, resulted in tmax of 2 h (0.75–4 h)
and terminal phase elimination half‐life of 54 h (35–93 h) that corresponded with a low
oral clearance of approximately 9 l h−1.

The clinical development of oral TRPV-1 antagonists has been recently confounded 7
by the finding that their administration carries the risk of eliciting hyperthermia. Signif-
icant, acute increase in body temperature has been observed in preclinical species, as
well as in humans and has already led to discontinuation of the development of several
potent TRPV-1 inhibitor compounds (26-29). Oral SB‐705498 administration to guinea
pigs has been shown to result in mild body temperature increase at 30 mg kg−1 (0.6°C),
and 100 mg kg−1 (0.8°C) but not at 10 mg kg−1, a dose which elicits an analgesic activity
in the guinea pig (unpublished, in house data). Also, in a GSK clinical trial in subjects
with dental pain single administration of oral SB‐705498, at doses of 400–1000 mg
(1.18–6.55 μg ml−1 (Cmax)), led to a potential trend towards a slight transient increase
in body temperature 2 h after dosing (ClinicalTrials.gov Identifier: NCT00281684). The
mechanisms underlying the effect of TRPV-1 antagonists on body temperature are not
entirely clear, but they appear to arise from inhibition of TRPV-1 signalling on afferents
innervating the viscera (30, 31). In most studies the induced hyperthermia seems to
be dependent on the levels of systemic exposure. In the context of rhinitis treatment,
it was thought that local application of a TRPV-1 inhibitor in the nose could achieve
effective local TRPV-1 blockade with doses much lower than those needed to achieve
the same effect following oral drug administration. This would reduce decisively the
likelihood of treatment‐related systemic adverse effects, including hyperthermia. It was
therefore of interest to explore an intranasal formulation of SB‐705498, as this would
allow topical delivery at the site of action and thereby minimize the systemic exposure.

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The challenge was to select a dose of SB‐705498 that would maximize its pharma-
cology in the nasal tissue when administered topically. In addition, direct correlation
of systemic drug concentrations with the corresponding pharmacodynamics in target
nasal tissues would not be appropriate mainly due to uncertainty in the kinetics of the
drug effect in the nasal turbinates. However, as described earlier in this manuscript,
based on translation of findings from a PD guinea pig rhinitis model a maximum
intranasal dose of 12 mg SB‐705498 was selected for evaluation in the clinic. This
dose was expected to achieve a high level of receptor occupancy after taking into
account the human systemic exposure and the assumption of nasal bioavailability
of the drug based on preclinical data. The charcoal block test in the dog has been
shown to be a good predictor for assessing local drug deposition in humans (32, 33).
Following intranasal administration about 20% of the SB‐705498 dose is estimated
to be available in the nasal tissues and absorbed across the nasal mucosa, while the
remainder is expected to be swallowed and absorbed across the gastrointestinal tract.
If complete drug absorption occurred in the nasal tissues, then 20% of the 12 mg of
SB‐705498 (e.g. approximately 2 mg) administered in this PD study could be antici-
pated in the nasal tissues and fluid in a maximum aqueous volume of approximately
20 ml (SB‐705498 tissue concentration of 2 mg 20 ml–1) (21). If nasal ciliary clearance
(t1/2 of 15 min) is taken into consideration (34), even one tenth of the estimated nasal
tissue concentration would still be associated with high receptor occupancy.

The SB‐705498 PK findings in the intranasal FTIH study were consistent with the
predictions based on the PK data from the FTIH study with oral SB‐705498 (22) and
the nasal deposition values described above. The marked increase in plasma concen-
trations of SB‐705498 after repeat intranasal dosing compared with single dosing was
predictable based on the long terminal phase elimination half‐life of approximately 54 h
observed in a previous study where the drug was administered orally (22). As expected
from the predicted systemic exposure, single and repeat administration of intranasal
SB‐705498 up to 12 mg was not associated with increase in body temperature in any of
the study participants or with any other significant treatment‐emergent AEs. In terms
of PD efficacy, the results of our study indicated that the reduction of capsaicin‐evoked
rhinitis symptoms following administration of intranasal SB‐705498 in patients with
NAR is consistent with effective local TRPV-1 antagonism. The differences in capsa-
icin‐induced TSS between the SB‐705498 12 mg and placebo group remained similar
across all capsaicin doses used and were in the range of 1.19–1.25, suggesting a
uniform response by the antagonist SB‐705498 to all capsaicin challenges conducted
in the study. Some outlier TSS points were observed in the group of patients treated
with SB‐705498, but the most conservative approach was taken and these data were
included in the statistical analysis. From a clinical perspective, it is difficult to comment
at this stage if there are patients with particular characteristics who may not respond
adequately to SB‐705498, because the total number of participants per arm in the
study was limited. Most likely, the data reflect the normal spectrum of variability in

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the response to capsaicin, as well as to drug, as outliers with high TSS were noted
following saline challenge, and an outlier with a much lower TSS was seen in the
SB‐705498 treated group after challenge with 12.5 μg capsaicin. An improvement in
TSS of at least 1 unit represents a shift from one assessment grade to a lower grade,
(e.g. from moderate to mild) and therefore, a change >1 unit is considered to be of
clinical relevance. As shown in Figure 4, there was a consistent trend in the SB‐705498
treatment effect on the clinical endpoints with their dose ratios greater than unity.
It was estimated that a receptor occupancy at the TRPV-1 target of about 66% was
achieved based on the dose ratio of 2.8 computed for TSS endpoint using the equation
for competitive antagonism (fractional occupancy = dose ratio – 1/dose ratio) (35).
Although treatment with SB‐705498 reduced all individual symptoms assessed in the
study, the magnitude of the treatment effect on each of them was different. Burning
sensation was more profoundly affected (a 4‐fold shift in dose–response relative to
placebo) compared with the other rhinitis‐like symptoms suggesting this endpoint is
most directly coupled to TRPV-1 activity. Thus, the 4‐fold shift in dose–response for
the burning sensation endpoint would be associated with a high receptor occupancy
at the TRPV-1 target of 75% and is consistent with that predicted as discussed before.

Although the effect of treatment with intranasal SB‐705498 on capsaicin‐evoked

symptoms was marked, the results from the assessment of PNIF do not fully support
the same conclusion. After challenge with the lowest dose of capsaicin (2.5 μg),
patients treated with SB‐705498 presented an improvement in PNIF compared with 7
those who received placebo. However, this difference did not achieve statistical signif-
icance, while no significant effect was observed between SB‐705498 and placebo
after the challenges with higher doses of capsaicin. PNIF assessment is a simple
objective tool to evaluate changes in nasal patency by both inflammatory and obstruc-
tive causes (36). It is known that application of low doses of capsaicin in the nose
induces changes in the nasal mucosa that lead to vasodilation, increased vascular
permeability and glandular exudation that underlie the development of rhinitis‐like
symptoms (37). Capsaicin, is a potent and selective activator of the TRPV-1 receptor
at concentrations up to 1 μm, but may engage other targets at higher concentra-
tions (38). Capsaicin can exert direct effects on vascular tone (39, 40), smooth muscle
tension (41), ion fluxes (41), nitric oxide synthesis and COX2 gene expression (42).
In the context of the nasal mucosa it was recently shown, using ex vivo functional
experiments with human nasal tissue, that capsaicin induces TRPV-1‐independent
vasodilation of the nasal vascular bed (38). This vasodilatory effect was mediated
by modulation of COX‐2 enzymatic activity associated with reduced prostaglandin
E2 production and could be suppressed by sulprostone, an agonist of prostaglandin E
receptors (38). Therefore, we could speculate that antagonism of the TRPV-1 receptor
by the administration of intranasal SB‐705498 may lead to effective attenuation of the
direct TRPV-1‐mediated effects, as reflected by the marked reduction of the burning
sensation, but have a lesser effect on capsaicin‐induced responses via other signalling

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pathways that are engaged with high local concentrations of capsaicin. This may
explain why we observed variability in the degree of reduction on the PD parameters
assessed in this study.

The results of a topical, low dose of SB‐705498 on symptoms of allergic rhinitis in a 7

days repeat allergen challenge study were recently reported (5). In this study 15 ml of
a 30 μmsolution of SB‐705498 (equivalent to approximately 0.2 mg) was delivered via
nasal lavage to patients with seasonal allergic rhinitis 2 min prior to allergen challenge
and the effect on allergen challenge driven symptoms was measured following the
allergen challenge. The selected dose of SB‐705498, although it was found previ-
ously adequate to inhibit symptoms induced by a 5 μm capsaicin nasal spray, was
shown to be ineffective in attenuating symptoms induced by allergen. Whilst these
results may suggest that TRPV-1 is not a key driver of allergen evoked symptoms, it
is possible that the formulation used in this study did not have the necessary duration
of action to inhibit TRPV-1 beyond the 2 min explored for the capsaicin challenge
(allergen symptoms were recorded at 10 min post‐challenge). Hence, it is uncertain
as to whether the effect of this formulation was still sufficient to block TRPV-1 at the
point where allergen symptoms were recorded. Duration of action studies are required
to evaluate fully the effect of novel SB‐705498 formulations before conclusions can
be drawn about the role of TRPV-1 in rhinitis symptoms. Furthermore, it is expected
that TRPV-1 may play a more prominent role in nasal hyper‐responsiveness where the
primary defect is directly linked to sensory over‐sensitivity, as in many cases of NAR,
than in conditions with a major immunopathology involvement, as in allergy.

In conclusion, TRPV-1 antagonists offer a new mechanism of action for the potential
treatment of nasal hyper‐responsiveness. The results of these studies indicate that
intranasal SB‐705498, at a clinically safe and well‐tolerated dose, has target specific
PD activity in humans. The data provide the first clinical evidence that local application
of a TRPV-1 antagonist in the nose may alleviate symptoms triggered by stimulation
of capsaicin sensitive nasal nerves. This suggests that SB‐705498 could be further
developed as a novel form of treatment for rhinitis patients with difficult to treat nasal
hyper‐responsiveness.

Competing Interests

All authors have completed the Unified Competing Interest form at  http://www.
icmje.org/coi_disclosure.pdf and declare CH, CvD, CS, IT and WF are employees of
the Department of Otorhinolaryngology, Academic Medical Center, Amsterdam, the
Netherlands and this institution received funding from GSK for the conduct of the
study. CvD has received research grants from GSK, Allergopharma and ALK‐Abello
A/S. JD, KS, AN, MB and D are all employees of GSK and hold GSK shares.

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CHAPTER 8
General discussion and
future perspectives
CHAPTER 8

GENERAL DISCUSSION AND FUTURE PERSPECTIVES

Epidemiology
The prevalence rate of NAR is estimated to be around 200 million people worldwide
(1). This estimation is not very reliable as literature on the prevalence of NAR is limited
and mainly consists of patient groups visiting in first or mostly even second or third
line of health care. To reliably differentiate NAR from chronic rhinosinusitis (CRS) and
allergic rhinitis (AR) one needs accurate tests for allergen sensitization, nasal endos-
copy and/or CT-sinus. Not all these diagnostic tools are available in first line health
care. Thereby, within NAR one has to differentiate between the different phenotypes,
which can be difficult because of overlap and lack of strict definitions. All this makes
a reliable estimation of prevalence rate of NAR and its different phenotypes in first line
health care complicated. To assess the prevalence rate of NAR in the second or third
line of healthcare embarks the problem of population bias, as NAR patients who were
successfully treated with intranasal corticosteroids (INCS) and/or anti-histamines by
their general practitioner (GP) will likely not be referred to secondary care. Because of
these disadvantages related to patient selection, we did not perform a study on preva-
lence rate in NAR in our university setting. However, this question, preferably addressed
internationally on population level, does represent one of the most important future
needs. As we show in chapter 4, NAR patients have a significant impairment of quality
of life (QoL). Together with a risk to develop asthma later on in life and the estimated
high prevalence rate, NAR is likely to represent a disease with a significant burden of
disease with high socio-economic costs and consequences that needs awareness (2).

To improve the accuracy of an estimated prevalence rate of NAR, there is a need

for population-based (questionnaire) studies in Europe and worldwide, to assess the
prevalence rate of NAR and its phenotypes and endotypes, in both children and adults.
Also other demographic features, like distribution of gender and age and the preva-
lence rate/risk of (developing) associated conditions like asthma or chronic rhinosi-
nusitis in different phenotypes and endotypes of NAR, are unknown.

Diagnosis and pheno- and endotyping

For long, non-allergic rhinitis was seen as an undefined and ununderstood diagnosis,
wrongly interpreted as diagnosis per exclusionem. This resulted in a trial and error
approach of treatment, which is not only very frustrating for both doctor and patient
but also far from cost-effective. There is a need for a cost-effective diagnostic
flow-scheme in NAR like there is for patients with chronic rhinosinusitis with or without
nasal polyposis. The increasing knowledge on phenotypes and endotypes already
results in a more structured process of diagnosis and endotype-specific treatment
in NAR patients. However, optimal control of symptoms for all NAR patients -despite
the above described approach of phenotyping and endotype-specific treatment- is
far from an achieved goal, as QoL and treatment satisfaction questionnaire results

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 GENERAL DISCUSSION AND FUTURE PERSPECTIVES

show (chapter 4). Phenotyping can be complicated because of overlap and lack of
diagnostic tools. Besides from cold dry air provocation -mainly used for research
purposes-, the diagnostic tools in NAR are very limited.

There is a need for an international consensus on a flow-scheme for the diagnosis of

NAR, ranging from proper phenotyping, the use of questionnaires, allergen sensitiza-
tion testing, to performing nasal endoscopy and diagnostic tools like CT sinus.

Moreover, there is a need for more detailed and uniform definitions of some of
the phenotypes in NAR. For example, in smoke induced, occupational rhinitis and
hormonal rhinitis, the knowledge on the underlying endotype is based on scarce litera-
ture and definitions are copied from one paper to the other. Also, the different types of
medication-induced rhinitis -besides from the knowledge on xylometazoline or aspirin
and NSAIDS- deserve a better understanding and definition, also because this might
give us better insights in (sub)-endotyping of NAR in general.

Most of all the problem of better definition of phenotypes holds true for the idiopathic
phenotype that likely also consists of further subphenotypes. In mixed rhinitis patients,
with a perennial allergen sensitization, the clinical differentiation between allergic and
non-allergic symptoms can be very complicated. The idiopathic rhinitis phenotype is
often described with the symptom of nasal hyper-reactivity. It is not completely clear
whether all idiopathic rhinitis patients have nasal hyper-reactivity. And on the other
hand, a significant part of the patients with AR have nasal hyper-reactivity as well (3).
8
The phenotype of local allergic rhinitis (LAR) gained renewed attention during the last
few years. Prevalence studies in different countries have not been able to level the
prevalence rates in Malaga of 50-60% (4) (5). Explanations for this variation in preva-
lence rate range from demographic differences, different selection of patient groups
(patients in first- versus second- or third- line of healthcare), variation in diagnosis of
patient groups and differences in nasal-allergen provocation procedures. Multi-center
trials assessing prevalence rates of LAR with the same selection and definition of
patient groups and identical materials and methods to perform nasal allergen provo-
cation tests, will help us answer this question in the best way possible. Moreover, the
recently published EAACI guidelines on nasal provocation will limit methodological
differences (6).

As phenotyping is limited, the future of knowledge on NAR lies in gaining knowledge

on endotyping.

On an endotype-level, the increasing knowledge regarding neurogenic inflamma-

tion results in both development of new treatment options (TRPV-1-antagonist) and
better understanding of the working mechanisms of previously ‘found-to-be-effective’

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treatment options (capsaicin, azelastine) in NAR. However, there is still a lot unknown
when it comes to the neurogenic endotype, including the involved receptors, nerve
fibers, (action of) individual mediators and interaction between the autonomic nervous
system and local neurogenic inflammation. A lot of what is written on the neurogenic
endotype is not stated by firm evidence and is based on in vitro studies or hypotheses.
Further one, it is possible that the neurogenic inflammatory endotype needs to be
further differentiated into subendotypes.

The symptom of nasal hyper-reactivity seems to be a nonspecific symptom of chronic

rhinitis patients (chapter 2). However, TRPV-1 desensitization by means of capsa-
icin has not proven itself to be effective in all patients with nasal hyper-reactivity. It
seems to be not or less effective in AR or other NAR phenotypes like smoking rhinitis,
suggesting a different endotype of neurogenic inflammation, although the effective-
ness of capsaicin in different pheno- and endotypes of AR and NAR needs further
investigation (chapter 6). But also, within idiopathic rhinitis with nasal hyper-reactivity
not all patients are effectively treated with capsaicin suggesting different (sub-) pheno-
and endotypes that are not yet elucidated within this patient group. The goals of more
effective endotype-specific treatment options and more knowledge on phenotyping
and endotyping are therefore intertwined.

Thinking about endotypes, probably also should include thinking about (defective)
epithelial barrier function. In the lower airways and in chronic rhinosinusitis this
concept–and its interaction with known infectious and inflammatory processes–has
gained growing attention during the last years. Disruption of epithelial barrier function
–being part of the innate immune system–in AR is responsible for increased passage
of antigens and exposure of underlying tissue to these stimuli, thereby resulting in
progression of allergic disease. Allergen antigen proteolytic activity and breakdown of
tight junctions by inflammatory mediators like histamine and other cytokines in nasal
secretions of AR patients are responsible for epithelial disruption (7). It is very likely
that also in NAR there is a role for epithelial barrier dysfunction although no studies
on this topic are available until now.

Proteomic endotyping so far has not resulted in differentiating idiopathic rhinitis from
other forms of rhinitis like AR, mixed rhinitis and even healthy controls. However, also a
conclusion what idiopathic rhinitis is not about is of importance. Key-players in inflam-
mation like growth factors, eosinophils, neutrophils, several chemokines and mediators
of Th1/Th2-inflammation and mast cells of neurogenic inflammation do not seem to
be involved in idiopathic rhinitis (chapter 3). Limitations of this study are that we did
not assess neurogenic inflammatory mediators like CGRP or SP and that the quantity
of mediators was still limited which may have resulted in false negative outcomes.

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 GENERAL DISCUSSION AND FUTURE PERSPECTIVES

The novel transcriptomic approach of endotyping by means of micro-array analysis

assessing differences on a RNA-level is a promising new tool (8). This approach
has several advantages compared to a proteomic approach. Micro-array analysis
enables us to assess thousands of genes at once, unbiased and with a ‘helicopter
view’. Comparison of gene-expression profiles, not only with healthy controls but also
patients with allergic rhinitis and chronic rhinosinusitis with and without polyposis and
with or without asthma, will give us new insights in the underlying endotypes.

Finally, with optimal knowledge on phenotypes and endotypes, obtaining international

consensus on a phenotype to endotype and endotype-specific treatment flowchart
like in table 1 of the introduction, would be highly recommendable as it is very usable
in clinical practice.

Treatment
A meta-analysis of the randomized controlled trials that were performed on the effec-
tiveness of INCS in NAR gives no real recommendation for this treatment in NAR in
general (chapter 5). There is still a need for studies with INCS in distinct NAR pheno-
and endotypes. One can think of a higher effectiveness of INCS in NAR patients with
inflammatory endotypes like NARES, LAR, smoke induced rhinitis or pregnancy rhinitis.

Two, relatively old, randomized controlled trials showed effectiveness of azelastine in

NAR patients (9, 10). The effectiveness of antihistamine therapy in NAR remained an
intriguing and unanswered question for a long time, as one would not expect anti-his-
tamine therapy to be effective in a disease in which there is no (known) role for hista-
8
mine. A recent (in vitro) study suggested that azelastine could be effective in treating
symptoms of nasal hyper-reactivity in idiopathic rhinitis by inducing TRPV-1 desen-
sitization by means of influencing intraneuronal calcium flows (11). Future trials with
azelastine in better-defined pheno- and endotypes are recommended. Other questions
relate to the recommended dose and ways of delivery of azelastine (oral versus intra-
nasal) in NAR. The positive results of a novel treatment that combines INCS with
azelastine in AR raises the question of effectiveness of this combination treatment in
NAR (12). In clinical practice this combined therapy is sometimes already used in both
AR and NAR patients with positive results, however we are in need for more clinical
studies assessing this question. As mentioned above, INCS in NAR cannot be strongly
recommended based on the current literature (chapter 5). This raises the question
whether in (specific phenotypes of) NAR combined therapy of INCS and azelastine
will have a benefit above treatment with azelastine only.

Capsaicin is one of the few evidence-based treatment options in non-allergic rhinitis

with minor and limited side-effects (chapter 6). The effectiveness is under condition
of a high enough dose of capsaicin (120 ug) and the correct patient selection (likely
to be idiopathic rhinitis patients with nasal hyper-reactivity and gustatory rhinitis) (13).

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Different ways of delivery, when and how often treatment can be repeated, explana-
tion of effectiveness of capsaicin in different (sub-) phenotypes and in different types
and grade of severity of symptoms are all topics that need to be further investigated
(chapter 6).

As both capsaicin and azelastine seem to be effective in treating symptoms of

neurogenic inflammation, this raises the question whether either capsaicin or azelas-
tine (individual, successive or combined use) should be considered in an individual
idiopathic rhinitis patient with symptoms of nasal hyper-reactivity. Capsaicin has been
studied and proven to be effective in several clinical trials, while the effectiveness of
azelastine in NAR is limited to two trials and the suggestive working mechanism is only
reviewed in one in vitro study. On the other hand, treatment with capsaicin can induce
(although limited and very well treatable) symptoms of a burning sensation and mild
pain or discomfort that might discourage patients, while the use of a nasal spray like
azelastine might seem more comfortable to a patient. Azelastine has the disadvantage
that it (likely) has to be used chronically to remain its effectiveness, in contrast to the
longer-term effects of capsaicin after single or only limited repetitive use.

The TRPV-1 and TRPA-1 receptors are of interest when it comes to treating neurogenic
inflammation. A recently developed TRPV-1 antagonist has shown moderate results
(chapter 7). Other new treatment options could focus on different TRP-receptors,
sensory C-fibers and neuro-inflammatory mediators.

Novel treatment modalities like antibodies targeted at specific mediators or cells

(‘biologicals’) that have gained an important place in asthma and CRS might also
deserve a future role in NAR.

There also seems to be a role for either overactivity of the parasympathetic nervous
system or underactivity of the sympathetic nervous system, representing possible
goals for novel treatment options.

As both neurogenic inflammation and neurogenic dysbalance seem to interact, it

would be of interest to evaluate whether treatment like iptratroprium bromide acting
on the cholinergic receptor could be combined with azelastine acting on the TRPV-1
receptor.

Studies on the effectiveness of vidian neurectomy are mostly limited to case-control

studies. The results of these studies are promising and show limited side effects.
Unfortunately, most of these studies were (non-randomized) retrospective studies,
with both AR and NAR patients and in many there were no patient-reported outcomes
both pre- and post-operative. Therefore, the evidence for vidian neurectomy remains
controversial (14, 15). It would be of great interest to perform a cohort trial with a

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long follow-up period and uniform patient selection criteria for selection of NAR and
its phenotypes.

Finally, it is unknown whether there is role for inferior turbinate reduction in non-­allergic
rhinitis patients. When the underlying endotype is unknown and/or all available treat-
ments have failed, turbinate reduction is sometimes considered in both AR and NAR
patients with symptoms of nasal congestion. However, when inferior turbinate hyper-
trophy mainly consists of bone, the nowadays popular therapy of radio­frequency
coblation reduction will likely not be effective and surgical reduction (with higher post-­
operative risk of bleeding) is indicated. Thereby, in these cases of bony hypertrophy we
are rather talking about treating anatomy (in the same way as when we treat a septal
deviation) than about treating symptoms of mucosa, i.e. rhinitis. In case of mucosal
hypertrophy as result of rhinitis in either NAR or AR, reduction therapy will bear the
risk of only having temporary effectiveness, as the underlying disease mechanism
responsible for mucosal hypertrophy is not treated and regrowth of mucosa is to be
expected.

Therefore, to reliably assess effectiveness of turbinate reduction therapy, a pre-­

operative CT scan to assess either bony or mucosal hypertrophy could be indicated,
together with an accurate selection of distinct pheno- and endotypes and a long-term
follow-up.

Lower and upper airways

Non-allergic rhinitis seems to be a risk to develop non-allergic asthma later on in life
8
(2) The risk of developing asthma is independent on IgE-sensitization as rhinitis and
asthma were found to be comorbidities independent of the atopic state (16). Ipratro-
prium bromide known as treatment in both the upper airways as the lower airways
both act on the muscarinic cholinergic receptor. In the lower airways there seems to
be an interaction between the muscarinic cholinergic receptor and the TRP-receptor,
indicating an interaction between neurogenic dysbalance and neurogenic inflamma-
tion. Neurogenic inflammation and overexpression over TRPV-1 receptors as part
of lower airway hyper-reactivity seem to play an important role in the development
of non-atopic asthma (17). However, the exact mechanism of the development of
non-allergic rhinitis to non-atopic asthma remains unknown and further research on
this topic will reveal more knowledge on the underlying endotypes and possible treat-
ment options.

A question that needs to be answered is whether desensitization of TRPV-1 receptors

in non-allergic rhinitis will also desensitize these TRP receptors in the lower airways,
resulting in inhibition of development to non-allergic asthma. Can ipratroprium bromide
nasal spray also be used to modulate TRP-receptors in the upper airways, as it seems
to be able to do in the lower airways? Can a combination of intranasal steroid with

379
CHAPTER 8

ipratroprium bromide -as in asthma- have a beneficial effect in non-allergic rhinitis

patients as well?

NAR versus AR and CRS

Nasal hyper-reactivity is a common symptom (prevalence 63-65%) in both allergic
rhinitis and non-allergic rhinitis patients (chapter 2). Does that mean that neuro-
genic inflammation is part of allergic rhinitis patients as it is in non-allergic rhinitis?
Capsaicin as TRPV-1 agonist does not seem to be effective in treating hyper-reactivity
in allergic rhinitis, however fluticasone combined with azelastine does seem to have
a beneficial effect on nasal hyper-reactivity in AR (3). Sensory C fibers seem to be
also present in the nasal mucosa of AR patients and are thought to be able to release
similar neurotransmitters in both AR and NAR patients after provocation/stimulation
(18). In AR patients treating the IgE-mediated inflammation seems to down-regulate
the neurogenic inflammation (3). In other words, the sequence of events resulting in
neurogenic inflammation is likely to be different in AR compared to NAR. Assessment
of these differences is of interest as it can give us insights in the differences between
neurogenic inflammation in different patients and better treatment options.

Preliminary results of micro-array analysis of epithelial cells in different diseases of

the upper airways show that there might also be a role for neurogenic inflammation
in chronic rhinosinusitis (CRS). As hyper-responsiveness of the lower airways is a
nonspecific symptom not related to a specific disease or phenotype, it is very likely
that nasal hyper-reactivity is a nonspecific symptom of diseased upper airway mucosa
in CRS with or without nasal polyposis. This raises the question for a possible role of
treatment options of neurogenic inflammation like azelastine in CRS.

CONCLUDING REMARKS

Non-allergic rhinitis has been ignored and put aside as a diagnosis per exclusionem
with different names and explanations for too long, frustrating both doctor and patient.

The diagnosis of NAR deserves at least the same -and preferably more- attention
the coming years as allergic rhinitis. In allergic rhinitis the detailed understanding of
the underlying disease mechanism has resulted in public attention, awareness and
understanding, resulting in elegant treatment options ranging from commercially avail-
able tablets or nasal sprays to immunotherapy. The socio-economic burden of NAR
is comparable -and likely even higher- compared to AR, as prevalence rate of both
diseases are competitive and their rhinitis symptoms very comparable. In contrast to
the proportion of AR patients with seasonal symptoms only, most NAR patients suffer
from their symptoms whole year round. However, in NAR patients the amount of avail-
able and effective treatment options are limited when compared to AR. Thereby NAR

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 GENERAL DISCUSSION AND FUTURE PERSPECTIVES

patients often lack compassion from doctors and their surroundings, as their diagnosis
is unknown and ununderstood. At home or in the work-environment of these patients, a
sniffing nose without explanation is often put aside as minor or even existing only in the
mind of the patient. It was not even long ago, that non­­-­allergic rhinitis was considered
more to be a psychogenic than a physical disorder. The now known significant quality
of life impairment of these patients and the growing knowledge on the underlying
disease mechanisms should make doctors humble and aware on how much these
patients are suffering. When it comes to rhinitis symptoms and irritability or tiredness
this suffering seems to be significantly more than patients with allergic rhinitis.

As in CRS and in the lower airways, international studies like GA2LEN with consensus
on definition and diagnostic criteria are desperately needed, addressing demographic
and social features of NAR and increasing public awareness and future research
investments.

Spreading the today available knowledge on NAR phenotypes and endotype-specific

treatments will help change the attitude of doctors and change NAR from an unknown
and unpopular diagnosis per excusionem with a trial and error approach of treatment,
to a more structured diagnosis and treatment strategy, improving satisfaction of both
doctor and patient.

The latest promising developments in the field of understanding nasal hyper-reactivity

and neurogenic inflammation resulting in development of novel effective treatment
options, encourages us to continue our studies on the neurogenic endotype and its
8
subendotypes, in different phenotypes of NAR and AR patients. A helicopter view
-enabling us to compare not only different diseases of the upper airways but also
to learn from the lower airways- will gain the fastest results. Micro-array analysis
is a promising new tool for endotyping and deserves a prominent position in novel
research. Neurogenic inflammation and the role of neurogenic dysbalance, is not
limited to the upper airways or lower airways only. Also, in other diseases like migraine
there is a growing attention for this disease mechanism, encouraging the development
of novel treatment options.

NAR has been left in the cold for too long. It deserves a position as hot topic in the
exciting research field of neurogenic inflammation and endotyping. This will improve
not only its status but also -most importantly- the quality of life of these patients that
deserve a better understanding and treatment after all these years.

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CHAPTER 8

REFERENCES
1. Bousquet, J. et al. Important research questions in allergy and related diseases:
non-­allergic rhinitis: a GA2LEN paper. Allergy, 2008. 63(7): p. 842-53.
2. Shaaban, R. et al. Rhinitis and onset of asthma: a longitudinal population-based study.
Lancet, 2008. 372(9643): p. 1049-57.
3. Kortekaas Krohn, I. et al. MP29-02 reduces nasal hyper-reactivity and nasal mediators in
patients with house dust mite-allergic rhinitis. Allergy, 2018. 73(5): p. 1084-1093.
4. Rondon, C. G. Canto, and M. Blanca, Local allergic rhinitis: a new entity, characterization
and further studies. Curr Opin Allergy Clin Immunol, 2010. 10(1): p. 1-7.
5. Rondon, C. et al. Prevalence and clinical relevance of local allergic rhinitis. Allergy, 2012.
67(10): p. 1282-8.
6. Auge, J. et al. EAACI Position paper on the standardization of nasal allergen challenges.
Allergy, 2018. 73(8): p. 1597-1608.
7. Toppila-Salmi, S. et al. Molecular mechanisms of nasal epithelium in rhinitis and rhinosi-
nusitis. Curr Allergy Asthma Rep, 2015. 15(2): p. 495.
8. van Drunen, C.M. et al. Considerations on the application of microarray analysis in
rhinology. Rhinology, 2008. 46(4): p. 259-66.
9. Banov, C.H. P. Lieberman, and G. Vasomotor Rhinitis Study, Efficacy of azelastine nasal
spray in the treatment of vasomotor (perennial non-allergic) rhinitis. Ann Allergy Asthma
Immunol, 2001. 86(1): p. 28-35.
10. Gehanno, P. et al. Vasomotor rhinitis: clinical efficacy of azelastine nasal spray in compar-
ison with placebo. ORL J Otorhinolaryngol Relat Spec, 2001. 63(2): p. 76-81.
11. Singh, U. et al. Azelastine desensitization of transient receptor potential vanilloid 1: a
potential mechanism explaining its therapeutic effect in non-allergic rhinitis. Am J Rhinol
Allergy, 2014. 28(3): p. 215-24.
12. Guo, L. et al. Clinical study of the combination therapy with intranasal antihistamine and
nasal corticosteroids in the treatment of nasal obstruction of persistent non-allergic rhinitis.
Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi, 2015. 29(3): p. 243-5, 251.
13. Blom, H.M. et al. Intranasal capsaicin is efficacious in non-allergic, non-infectious peren-
nial rhinitis. A placebo-controlled study. Clin Exp Allergy, 1997. 27(7): p. 796-801.
14. Harvey, R. From legacy to novel: vidian neurectomy and eustachian tube balloon dilatation
in modern ENT practice. J Laryngol Otol, 2016. 130 Suppl 4: p. S1.
15. Robinson, S.R. and P.J. Wormald, Endoscopic vidian neurectomy. Am J Rhinol, 2006.
20(2): p. 197-202.
16. Leynaert, B. et al. Epidemiologic evidence for asthma and rhinitis comorbidity. J Allergy
Clin Immunol, 2000. 106(5 Suppl): p. S201-5.
17. Bernstein, J.A. and U. Singh, Neural Abnormalities in Non-allergic Rhinitis. Curr Allergy
Asthma Rep, 2015. 15(4): p. 18.

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 GENERAL DISCUSSION AND FUTURE PERSPECTIVES

18. Baraniuk, J.N. and S.J. Merck, Neuroregulation of human nasal mucosa. Ann N Y Acad
Sci, 2009. 1170: p. 604-9.

383
APPENDICES

APPENDICES
Summary
Samenvatting
Authors and affiliations
Portfolio
List of publications
About the author
Dankwoord
384
VERKORTE TITEL

385
APPENDICES

SUMMARY

Non-allergic rhinitis (NAR) is a chronic disease with a high prevalence rate and a signif-
icant burden of disease. For long it was considered a diagnosis per exclusionem and
was characterized by several changing names and definitions and a lack of knowledge
regarding the underlying disease mechanism(s). As a result, treatment of patients
with non-allergic rhinitis was often characterized by an unsuccessful trial and error
approach without evidence-based treatment strategies.

Of all the upper respiratory tract diseases, perhaps NAR is most in need of a phenotype
and endotype-driven diagnostic approach and endotype-specific treatment strategies.

This thesis focused on optimizing the diagnostic process and phenotyping in NAR
and improving evidence-based treatment strategies.

In chapter 2 we describe a prospectively collected database study to assess patient-­

reported symptoms of hyper-reactivity in non-allergic (NAR) and allergic rhinitis (AR)
patients. In the second part, cold dry air provocation (CDA) was performed as an
objective hyper-reactivity measure in NAR and AR patients and healthy controls.
Symptoms scores, nasal secretions and peak nasal inspiratory flow (PNIF) were
measured. Comparisons were made between NAR and AR patients in both studies.

For long, nasal hyper-reactivity was considered a defining symptom of NAR patients
only and triggered by either physical or chemical stimuli.

This study demonstrated a similar hyper-reactivity prevalence rate in AR of 63.4%

and in NAR of 66.9%. There were no differences between AR and NAR in terms of the
number or type of hyper-reactivity stimuli. Hyper-reactivity to physical stimuli did not
exclude a response to chemical stimuli, or vice versa.

In chapter 3 we assessed a wide panel of inflammatory mediators in nasal secretions

of NAR, AR en mixed patients and healthy controls. Until now it has been proven
difficult to endotype NAR patients, in contrast to AR patients. Whether NAR patients
have an inflammatory endotype is a relevant question as this will predict therapeutic
effectiveness of intranasal corticosteroids in this patient group. After performing a
multiplex ELISA with 29 inflammatory mediators no Th1/Th2-inflammatory endotype
in NAR or mixed rhinitis patients could be found. This confirms that in most NAR
patients there is a non-inflammatory endotype that is in need of other treatments than
the conventional treatments like intranasal corticosteroids.

In chapter 4 we present the results of an observational cohort study in 287 AR and

160 NAR patients assessing quality of life (QoL) and use of medication and treatment

386
 SUMMARY

satisfaction. Until now, no validated QoL questionnaire was available for NAR
patients. After performing a validation for the mini-Rhinoconjunctivitis Quality of Life
(mini-RQLQ) in NAR patients, a significantly impaired QoL in NAR patients was shown.
Impairment of QoL in NAR patients was comparable to AR patients, with an exception
for the mini-RQLQ subdomains ‘nasal complaints’ and ‘other complaints’ (i.e. tiredness
etc.) for which NAR scored significantly higher (lower quality of life) compared to AR.
More than half of NAR and AR patients were unsatisfied with their current treatment.

In chapter 5 the results of a Cochrane Review on intranasal steroids in 4452 NAR

patients are presented. The overall quality of the evidence in this review is low to
very low. Intranasal corticosteroids are compared to placebo (2045 patients) but
also to other treatment modalities. It is unclear whether intranasal corticosteroids
reduce patient-reported disease severity in non-allergic rhinitis patients compared
with placebo when measured at up to three months follow-up.

In chapter 6 the results of a Cochrane Review on intranasal capsaicin in 302 idiopathic

NAR patients are presented. There is low to moderate quality level of evidence of the
effectiveness of capsaicin in NAR. Capsaicin seems to work better than intranasal
steroids in NAR patients. The recommended treatment strategy is to give 5 treat-
ments in one day with at least 4 ug capsaicin per puff. Given that many other options
do not work well in non-allergic rhinitis, capsaicin is a reasonable option to try under
physician supervision.

In chapter 7 the results of two randomized controlled trials (RCT’s) are presented,
showing that a TRPV-antagonist has an appropiate safety profile and is capable of
achieving a clinically relevant attenuation of capsaicin-provoked rhinitis symptoms in
patients with NAR.

Chapter 8 comprises the general discussion, overall conclusions and future perspec-
tives of this research.

387
APPENDICES

SAMENVATTING

Niet-allergische rhinitis (NAR) is een chronische ziekte met een hoog prevalentiecijfer
en een significant hoge ziektelast. Voorheen werd NAR beschouwd als een diagnosis
per exclusionem en had verschillende benamingen en definities door een tekort aan
kennis omtrent het onderliggende ziektemechanisme. Het gevolg hiervan was dat NAR
patiënten vaak onsuccesvol werden behandeld op een ‘trial en error’ wijze. Er was een
gebrek aan evidence-based behandelstrategieën.

Van alle ziektebeelden van de bovenste luchtweg heeft NAR misschien wel het meest
behoefte aan een fenotype- en endotype-gerichte diagnostische benadering en aan
endotype-specifieke behandelingen.

Dit proefschrift is erop gericht de diagnostiek en fenotypering van NAR te optimali-

seren en evidence-based behandelstrategieën voor NAR patiënten te definiëren.

In hoofdstuk 2 beschrijven we in het eerste deel een prospectieve database studie

naar symptomen van nasale hyper-reactiviteit gerapporteerd door niet-allergische
rhinitis (NAR) en allergische rhinitis (AR) patiënten.

In het tweede deel werd een koude droge lucht provocatie uitgevoerd als objectieve
maat voor het bepalen van nasale hyper-reactiviteit in NAR patiënten, AR patiënten
en gezonde controles. Nasale symptomen, nasaal secreet en nasale passage (peak
nasal inspiratory flow (PNIF)) werden na deze provocatie in kaart gebracht. In zowel
het eerste als in het tweede deel van de studie werden NAR en AR patiënten met
elkaar vergeleken.

Voor een lange periode was het een algemene aanname dat nasale hyper-­reactiviteit
alleen toebehoort aan NAR patiënten en dat deze patiëntengroep zich met dit
symptoom onderscheidt van andere chronische rhinitis patiëntengroepen. Tevens
werd gedacht dat nasale hyper-reactiviteit kon worden onderscheiden in twee groepen;
nasale hyper-reactiviteit uitgelokt door fysische stimuli en nasale hyper-reactiviteit
uitgelokt door chemische stimuli.

Deze studie liet echter een vergelijkbaar prevalentiecijfer van nasale hyper-reactiviteit
zien in zowel AR (63.4%) als NAR (66.9%) patiënten. Er was niet alleen geen significant
verschil in het prevalentiecijfer, er konden ook geen verschillen worden aangetoond
tussen AR en NAR wat betreft het aantal of type stimuli die hyper-reactiviteit kunnen
uitlokken. Hyper-reactiviteit voor fysische stimuli sloot een hyper-reactiviteit voor
chemische stimuli niet uit en vice versa.

388
 SAMENVATTING

In hoofdstuk 3 onderzochten we een breed aantal inflammatoire mediatoren in het

nasaal secreet van NAR, AR en mixed rhinitis (mengvorm van NAR en AR) patiënten
en gezonde controles. Het is tot nu toe altijd moeilijk gebleken om het endotype van
NAR patiënten te bepalen in tegenstelling tot dat van AR patiënten. Het is van belang
om te bepalen of NAR patiënten een inflammatoir endotype hebben aangezien dit kan
voorspellen of intranasale corticosteroïden effectief zullen zijn in deze patiëntengroep.
Na het uitvoeren van een multiplex ELISA (Enzyme-Linked Immuno Sorbent Assay)
met 29 inflammatoire mediatoren kon er in deze studie noch een Th1 noch een Th2
inflammatoir endotype worden aangetoond in de NAR en mixed rhinitis patiënten.
Dit bevestigt dat er bij de meeste NAR patienten sprake is van een niet-inflammatoir
endotype en dat een andere behandeling dan de gebruikelijke behandeling (intranasale
corticosteroïden) voor deze patiëntengroep in veel gevallen noodzakelijk is.

In hoofdstuk 4 worden de resultaten getoond van een observationele cohort studie in

287 AR en 160 NAR patiënten naar de kwaliteit van leven, het gebruik van medicatie
en tevredenheid met de huidige behandeling. Tot nu toe was er geen gevalideerde
‘kwaliteit van leven’ vragenlijst beschikbaar voor NAR patiënten. Na het uitvoeren van
een validatie van de mini-Rhinoconjunctivitis Quality of Life Questionnaire (mini-RQLQ)
voor het gebruik bij NAR patiënten, kon na het gebruik van deze vragenlijst in de
NAR patiëntenpopulatie, een significante beperking in kwaliteit van leven van NAR
patiënten worden aangetoond. Deze beperking in kwaliteit van leven van NAR patiënten
was vergelijkbaar met AR patiënten, met de uitzondering dat voor de subdomeinen
‘neussymptomen’ en ‘andere klachten’ (bv. vermoeidheid) NAR patiënten zelfs signifi-
cant slechter (i.e. een lagere kwaliteit van leven) scoorden dan AR patiënten. Meer dan
de helft van de NAR en AR patiënten waren ontevreden met hun huidige behandeling.

In hoofdstuk 5 worden de resultaten getoond van een Cochrane Review naar het
effect van intranasale corticosteroïden in 4452 NAR patiënten. De kwaliteit van de
evidence is in het algemeen laag tot zeer laag. Intranasale corticosteroïden werden
vergeleken met placebo (2045 patiënten) maar ook met andere behandelopties. Het
is onduidelijk of bij een follow-up duur tot 3 maanden, intranasale corticosteroïden de
door NAR patiënten gerapporteerde ziekte-ernst verlaagt.

In hoofdstuk 6 worden de resultaten getoond van een Cochrane Review naar het
effect van intranasaal capsaïcine in 302 idiopatische NAR patiënten. De kwaliteit van
de evidence is laag tot matig. Capsaicine lijkt beter te werken dan intranasale corti-
costeroïden in NAR patiënten. De aanbevolen behandelstrategie is om intranasaal
capsaïcine 5 maal op een dag te geven in een dosis van minimaal 4 ug capsaïcine
per spray. Aangezien veel andere behandelopties in niet-allergische rhinitis niet goed

389
APPENDICES

werken, kan redelijkerwijs een behandeling met intranasaal capsaïcine onder super-
visie van een arts worden overwogen.

In hoofdstuk 7 worden de resultaten van twee randomized controlled trials (RCT’s)

gepresenteerd die laten zien dat een TRVP-antagonist een geschikt veiligheidsprofiel
heeft en daarnaast in staat is om een klinisch relevante afname te bewerkstelligen van
door capsaïcine uitgelokte rhinitis symptomen in NAR patiënten.

In hoofdstuk 8 worden de conclusies van het onderzoek besproken, gevolgd door een
algemene discussie en perspectieven voor de toekomst.

390
SAMENVATTING

391
APPENDICES

AUTHORS AND AFFILIATIONS

C.T. Holland, MD. Department of Otorhinolaryngology, Flevoziekenhuis, Almere, The

Netherlands.

S.M. Reinartz, PhD. Department of Otorhinolaryngology, Ter Gooi Ziekenhuis, The

Netherlands.

I. Terreehorst, PhD. Department of Otorhinolaryngology, Academic Medical Center,

Amsterdam, The Netherlands.

A. Gevorgyan, PhD. Department of Otorhinolaryngology, University of Toronto, Canada.

P.W. Hellings, PhD. Department of Otorhinolaryngology, Academic Medical Center,

Amsterdam, The Netherlands and Department of Otorhinolaryngology; Catholic
University of Leuven, Belgium.

C.M. van Drunen, PhD. Department of Otorhinolaryngology, Academic Medical Center,

Amsterdam, The Netherlands.

W.J. Fokkens, PhD. Department of Otorhinolaryngology, Academic Medical Center,

Amsterdam, The Netherlands.

R. Gorissen, MD.

K. Avdeeva, PhD. Department of Otorhinolaryngology, Academic Medical Center,

Amsterdam, The Netherlands.

S. Chusakul, MD. Department of Otorhinolaryngology, Bumrungrand International

Hospital, Thailand.

J. Kanjanaumporn, MD. Department of Otorhinolaryngology, Samitivej Hospital,

Thailand.

S. Aeumjaturapat, MD. Department of Otorhinolaryngology, Chulalongkorn University

Hospital, Thailand.

L.F. Reeskamp, MD. Department of Vascular Medicine, Academic Medical Center,

Amsterdam, The Netherlands.

K. Snidvongs, PhD. Bumrungrand International Hospital, Thailand.

392
 AUTHORS AND AFFILIATIONS

J.C. Denyer, MsC. Pharmacology.

K. Smart, PhD. Pharmacology.

A. Newlands, MsC. Statistics.

M. Beerahee, MsC. Pharmacology.

D. Tsitoura, PhD. Immunology.

393
APPENDICES

PORTFOLIO

PhD student: C.L. Segboer

PhD supervisor: Prof. dr. W.J. Fokkens
PhD cosupervisors: Dr. C.M. van Drunen
Dr. I. Terreehorst

Courses

• 2011: Good Clinical Practice (GlaxoSmithKline) (ECTS 1.00)

• 2011: Advanced Immunology (ECTS 1.00)
• 2011: Clinical Data Management (ECTS 0.30)
• 2012: Pubmed (ECTS 0.10)
• 2012: Reference Manager Basic (ECTS 0.50)
• 2012: Practical Biostatistics (ECTS 1.00)
• 2012: Evidence Based Medicine (ECTS 1.00)
• 2012: Basiscursus Regelgeving en Organisatie voor (ETCS 0.50)
Klinisch onderzoek
• 2012: Mini-Endoscopie course, UMCG, Groningen (ECTS 0.50)
• 2013: Mini-FESS course, LUMC, Leiden (ECTS 0.50)
• 2014: Teach the Teacher course, AMC, Amsterdam (ECTS 0.25)
• 2014: KNO-Radiologie ‘KNOR’ course, Zaandam (ECTS 0.50)
• 2014: Mini-OSAS, OLVG, Amsterdam (ECTS 0.50)
• 2015: Mini-Oren course, Radboud UMC, Nijmegen (ECTS 0.50)
• 2015: Mini-around the nose, Radboud UMC, Nijmegen (ECTS 0.50)
• 2016: Mondpathologie course, Breukelen (ECTS 0.25)
• 2017: Nascholingscursus Kliniek van Duizeligheid en (ECTS 0.50)
Evenwichtsstoornissen
• 2018: European Rhinoplasty Course, Leuven (ECTS 0.50)

394
 PORTFOLIO

Presentations

• 2019 ‘Lokale allergische rhinitis: feit of fabel.’ Oral (ECTS 0.50)

presentation, Symposium Kinderallergologie. April 2019,
Maarssen (The Netherlands)
• 2019: ‘Liefde voor de Neus’, oral symposium at several (ECTS 0.50)
locations in the Netherlands during 2019’. February-
November 2019, The Netherlands
• 2018 ‘Innovatieve Behandelingsstrategieën binnen (ECTS 0.50)
KNO-luchtwegpathologie’. Oral presentation, regionale
refereeravond Zeeland en Brabant (ZEEBRA). September
2018, Bergen op Zoom (The Netherlands)
• 2018 ‘Rhinitis en rhinosinusitis’. Oral presentation, Amster- (ECTS 0.50)
dams Geneeskundig Genootschap (AGG). October 2018,
Amsterdam (The Netherlands)
• 2017 ‘Biologicals in rhinosinusitis’. Oral presentation, (ECTS 0.50)
European Academy of Allergy and Clinical Immunology
(EAACI). May 2018, München (Germany)
• 2017 ‘Neurogenic inflammation in NAR and AR’. Oral (ECTS 0.50)
presentation, ORL-HNS congress. October 2017, Barcelona
(Spain)
• 2017 ‘Oral presentation, refereeravond Academic Medical (ECTS 0.50)
Center Amsterdam (AMC). September 2017, Amsterdam
(The Netherlands)
• 2017 ‘Niet-allergische rhinitis: diagnostiek en nieuwe (ECTS 0.50)
behandelopties’. Oral presentation, regionale refereeravond
AMC. June 2017, Amsterdam (The Netherlands)
• 2017 ‘Innovatieve behandelstrategieën binnen KNO-­lucht­ (ECTS 0.50)
wegpathologie’. Oral presentation, VinK (Vrouwen in de
KNO). May 2017, Vlieland (The Netherlands)
• 2016 ‘Quality of life in allergic and non-allergic rhinitis (ECTS 0.50)
patients. Poster presentation, European Forum for
Research and Education in Allergy and Airway Disease
(EUFOREA). November 2016, Brussels (Belgium)
• 2016 ‘Local nasal allergy – clinical relevance?’ Oral (ECTS 0.50)
presentation, European Rhinologic Society (ERS) congress.
July 2016, Stockholm (Sweden)
• 2016 ‘Uncontrolled upper-airway disease. Non-allergic (ECTS 0.50)
rhinitis’. Oral presentation, EAACI congress. June 2016,
Vienna (Austria)

395
APPENDICES

• 2016 ‘Lokale allergische rhinitis: fact or fiction‘. Oral (ECTS 0.50)

presentation, symposium van Nederlandse Vereniging
voor Allergologie (NVvA). September 2016, Breukelen (The
Netherlands)
• 2015 ‘Lokale allergische rhinitis: feit of fictie’. Oral (ECTS 0.50)
presentation, regionale allergie refereermiddag AMC.
September 2015, Zaandam (The Netherlands)
• 2015 ‘Molecular cellular pathogenesis of non-allergic and (ECTS 0.50)
allergic rhinitis’. Oral presentation, EAACI congress. June
2015, Barcelona (Spain)
• ‘New Insights into The Pathogenesis Of Non-allergic (ECTS 0.50)
Rhinitis’. Poster presentation (poster award), Symposium
on Experimental Rhinology and Immunology of the Nose
(SERIN) congress. March 2015, Stockholm (Sweden)
• 2015 ‘Breek me de bek niet open’. Oral presentation, KNO (ECTS 0.50)
Vergadering. April 2015, Nieuwegein (The Netherlands)
• 2014 ‘Differentiating groups of rhinitis patients based on (ECTS 0.50)
molecular markers in nasal secretions’. (oral presenta-
tion award), ERS congress. June 2014, Amsterdam (The
Netherlands)
• 2014 ‘Nasal hyper-reactivity in non-allergic and allergic (ECTS 0.50)
rhinitis patients’. Symposium, ERS congress. June 2014,
Amsterdam (The Netherlands)
• 2014 ‘Nasal hyper-reactivitity in non-allergic and allergic (ECTS 0.50)
rhinitis patients’. Oral presentation, EAACI congress. June
2014, Copenhagen (Denmark)
• 2014 ‘Nasale hyper-reactiviteit in niet-allergische en aller- (ECTS 0.50)
gische rhinitis patiënten’. Oral presentation, KNO Vergade-
ring. April 2014, Nieuwegein (The Netherlands)
• 2013 ‘Kwaliteit van leven in niet-allergische rhinitis (ECTS 0.50)
patienten’. Oral presentation, KNO Vergadering. November
2013, Nieuwegein (The Netherlands)
• 2013 ‘Quality of life in allergic and non-allergic rhinitis (ECTS 0.50)
patients’. Oral presentation, SERIN. March 2013, Leuven
(Belgium)
• 2011 ‘Nasal hyper-reactivity in allergic and non-allergic (ECTS 0.50)
rhinitis patients’. Poster presentation, EAACI congress.
June 2011, Istanbul (Turkey)
• 2010 ‘Nasal hyper-reactivity in allergic and non-allergic (ECTS 0.50)
rhinitis patients’. Oral presentation, SERIN congress.
November 2010, Brussels (Belgium)

396
 PORTFOLIO

National and international conferences

• 2019 European Academy of Allergy and Clinical (ECTS 0.50)

Immunology, Istanbul, Portugal
• 2018 European Rhinoplasty Course, Brussels, Belgium (ECTS 0.50)
• 2018 European Academy of Allergy and Clinical (ECTS 0.75)
Immunology, München, Germany
• 2017 Otorhinolaryngology Head and Surgery (ORL-HNS (ECTS 0.50)
congress), Barcelona, Spain
• 2017 Rhinology World Congress, Hong Kong (ECTS 0.75)
• 2016 European Rhinology Research Forum (EUFOREA),
Brussels, Belgium (ECTS 0.50)
• 2016 European Academy of Allergy and Clinical (ECTS 0.75)
Immunology, Vienna, Austria
• 2016 Congress of the European Rhinologic Society, (ECTS 0.75)
Stockholm, Sweden
• 2015 Symposium on Experimental Rhinology and (ECTS 0.50)
Immunology of the Nose, Stockholm, Sweden
• 2014 Congress of the European Rhinologic Society, (ECTS 0.75)
Amsterdam, The Netherlands
• 2014 European Academy of Allergy and Clinical (ECTS 0.75)
Immunology, Copenhagen, Denmark
• 2013 Symposium on Experimental Rhinology and (ECTS 0.50)
Immunology of the Nose, Leuven, Belgium
• 2011 European Academy of Allergy and Clinical (ECTS 0.50)
Immunology, Istanbul, Turkey
• 2010 Symposium on Experimental Rhinology and (ECTS 0.50)
Immunology of the nose, Brussels, Belgium

Others
• 2014-until now Member of Junior European Rhinologic Society

Awards
• 2014 ERS, Oral Presentation Prize
• 2015 SERIN, Poster Prize

397
APPENDICES

LIST OF PUBLICATIONS

• Segboer C, Gevorgyan A, Avdeeva K, Chusakul S, Kanjanaumporn J, Aeumjaturapat,

S, Reeskamp LF, Snidvongs K, Wytske F. Intranasal corticosteroids in non-
allergic rhinitis. Cochrane Database Syst Rev: 2019; 2(11)
• Seys S, Bousquet J, Bachert C, Fokkens W, Agache I, Bernal-Sprekelsen M,
Callebaut I, Cardel L, Carrie S, Castelnuovo P, Cathcart R, Constantinidis J, Cools
L, Cornet M, Clement G, de Sousa JC, Cox T, Doulaptsi M, Gevaert P, Hopkins C,
Hox V, Hummel T, Hosemann W, Jacobs R, Jorissen M, Landis B, Leunig A, Lund
VJ, Mullol J, Onerci M, Palkonen S, Proano I, Prokopakis E, Ryan D, Riechelmann H,
Saevels J, Segboer C, Speleman K, Steinsvik EA, Surda P, Tomazic PV, Vanderveken
O, Van Gerven L, Van Zele T, Verhaeghe B, Vierstraete K, Vlaminck S, Wilkinson
J, Williams S, Pugin B, Hellings P. mySinusitisCoach: patient empowerment in
chronic rhinosinusitis using mobile technology. Rhinology 2018; 56(3):209-215
• Segboer C, Terreehorst I, Gevorgyan A, Hellings P, van Drunen CM, Fokkens W.
Quality of life is significantly impaired in non-allergic rhinitis patients. Allergy
2018; 73(5):1094-1100
• Segboer C, Fokkens W, Terreehorst I, van Drunen C. Endotyping of non-allergic,
allergic and mixed rhinitis patients using a broad panel of biomarkers in nasal
secretions. PLoS One. 2018; 26;13(7)
• Hellings P, Akdis CA, Bachert C, Bousquet J, Pugin B, Adriaensen G, Advani
R, Agache I, Anjo C, Anmolsingh R, Annoni E, Bieber T, Bizaki A, Braverman I,
Callebaut I, Castillo Vizuete J, Chalermwatanachai T, Chmielewski R, Cingi C, Cools
L, Coppije C, Cornet M, De Boeck I, De Corso E, De Greve G, Doulaptsi M, Edmiston
R, Erskine S, Gevaert E, Gevaert P, Golebski K, Hopkins C, Hox V, Jaeggi C, Joos G,
Khwaja S, Kjeldsen A, Klimek L, Koennecke M, Kortekaas Krohn I, Krysko O, Kumar
BN, Langdon C, Lange B, Lekakis G, Levie P, Lourijsen E, Lund VJ, Martens K, Mő
Sges R, Mullol J, Nyembue T, Palkonen S, Philpott C, Pimentel J, Poirrier A, Pratas
A, Prokopakis E, Pujols L, Rombaux P, Schmidt-Weber C, Segboer C, Spacova I,
Staikuniene J, Steelant B, Steinsvik E, Teufelberger A, Van Gerven L, Van Gool K,
Verbrugge R, Verhaeghe B, Virkkula P, Vlaminck S, Vries-Uss E, Wagenmann M,
Zuberbier T, Seys S, Fokkens WJ. EUFOREA Rhinology Research Forum 2016:
report of the brainstorming sessions on needs and priorities in rhinitis and
rhinosinusitis. Rhinology 2017; 55(3):202-210
• Fokkens W, Hellings P, Segboer C. Capsaicin for Rhinitis. Curr Allergy Asthma
Rep 2016; 16(8):60
• Gevorgyan A1, Segboer C1 (1:shared first authorship), Gorissen R, van Drunen
CM, Fokkens W. Capsaicin for non-allergic rhinitis. Cochrane Database Syst
Rev 2015; 14(7)
• Segboer C, Holland C, Reinartz S, Terreehorst I, Gevorgyan A, Hellings P, van
Drunen C, Fokkens W. Nasal hyper-reactivity is a common feature in both
allergic and non-allergic rhinitis. Allergy 2013; 68(11): 1427-34

398
 LIST OF PUBLICATIONS

• Holland C, van Drunen C, Denyer J, Smart K, Segboer C, Terreehorst I, Newlands

A, Beerahee M, Fokkens W, Tsitoura D. Inhibition of capsaicin-driven nasal
hyper-reactivity by SB-705498, a TRPV-1 antagonist. Br J Clin Pharmacol 2014;
77(5):777-88
• Dietz de Loos D, Segboer C, Gevorgyan A, Fokkens W. Disease-specific quality-
of-life questionnaires in rhinitis and rhinosinusitis: review and evaluation. Curr
Allergy Asthma Rep. 2013; 13(2):162-70
• van Drunen C, Mjösberg J, Segboer C, Cornet M, Fokkens W. Role of innate
immunity in the pathogenesis of chronic rhinosinusitis: progress and new
avenues. Curr Allergy Asthma Rep. 2012; 12(2):120-6
• Segboer C, Rijntjes E. ‘Schizispatiënt geboren met tanden’. Nederlands Tijdschrift
voor Keel-Neus-Oorheelkunde (NTvKNO); 2009

399
APPENDICES

ABOUT THE AUTHOR

Christine Louise Segboer was born on the 25th of May in 1985 in The Hague, The
Netherlands. After graduation at the Maerlant Lyceum in The Hague (2003, summa
cum laude), she started her medical training at the University of Leiden. During her
study she participated in several scientific research projects, including at the Otorhi-
nolaryngology department of the Leids Universitair Medisch Centrum (LUMC), Leiden.
In 2009 she completed her medicine studies (cum laude) with a scientific research
project at the Otorhinolaryngology department of the Academic Medical Center in
Amsterdam (prof. dr. W.J. Fokkens).

As of 2010 she started her PhD project (prof. dr. W.J. Fokkens, Dr. C.M. van Drunen)
combined with clinical work at the department of Otorhinolaryngology. In 2012 she
continued her fulltime specialist training in Otorhinolaryngology at the Academic
Medical Center in Amsterdam (prof. dr. W J. Fokkens, prof. dr. S. van der Baan, dr.
S.M. Reinartz, dr. A.M. König). After finishing her specialist training in 2017 she worked
for one year as an ENT surgeon both at the Academic Medical Center in Amsterdam
as at the Alrijne Hospital in Leiden/Leiderdorp.

From the beginning of 2018 she obtained a position as an ENT surgeon at the
Dijklander Hospital in Hoorn, subspecialized in Rhinology.

400
ABOUT THE AUTHOR

401
APPENDICES

DANKWOORD

Dankzij de hulp, steun en vriendschap van vele mensen heb ik dit boekje kunnen
voltooien. Daar ben ik ongelooflijk dankbaar voor.

Een aantal mensen wil ik in het bijzonder noemen:

Mijn promotor, prof. dr. W.J. Fokkens. Lieve Wytske, je bent voor mij veel meer
geweest dan alleen een promotor en opleider. Dankzij jou ben ik gekomen waar ik nu
ben. Je hebt mij altijd gesteund, ook waar het soms moeilijk was. Voor mij ben je een
promotor en opleider met vlag en wimpel.

Jouw liefde voor de wetenschap heb je met jouw onaflaatbare enthousiasme op mij
overgedragen. Ik heb een immense bewondering voor jouw wetenschappelijk inzicht,
jouw kritische en eerlijke blik, jouw kennis en kunde als dokter maar bovenal jouw
inzicht en vermogen om breder en vooruitstrevender te denken dan velen. Ik hoop dat
we elkaar in de toekomst veel mogen blijven zien, niet alleen voor een rhinologisch
overleg maar bovenal om gezellig bij te praten. Dank je wel voor je vriendschap.

Mijn copromotor, dr. C.M. van Drunen. Lieve Kees, als de dag van gisteren herinner
ik mij de eerste dagen op het laboratorium bij jou. Waar ik zo groen was als gras
heb jij mij de beginselen van het basaal wetenschappelijke onderzoek bijgebracht
en mijn enthousiasme geprikkeld, keer op keer. Ik denk met veel dankbaarheid terug
aan de ontelbare gesprekken die wij in jouw kamer voerden omtrent de resultaten
van ons onderzoek. Ik heb veel bewondering voor jouw kennis en intelligentie en de
rust waarmee je telkens weer tot de kern weet te komen. Daarnaast heb je heel veel
gevoel voor humor en verliet ik altijd met een lach en opgeruimd gevoel jouw kamer.
Dank je wel.

Mijn copromotor, dr. I. Terreehorst. Lieve Ingrid, met veel dankbaarheid denk ik terug
aan mijn laatste jaar in het AMC waarbij wij vele middagen gezamenlijk achter de
computer zaten en kritisch mijn artikelen doornamen, vaak met een goede kop koffie
‘van beneden’. Jouw optimisme, gevoel voor humor, helder inzicht en praktische instel-
ling hebben ervoor gezorgd dat de artikelen in een stroomversnelling kwamen. Ik ben
heel erg dankbaar voor de vele keren dat ik baat heb gehad bij jouw grote kennis als
het gaat om de wetenschap maar ook wat betreft de allergologie. Je stond altijd voor
mij klaar. Daarnaast hebben we ongelooflijk veel gelachen en gezellig buiten het werk
afgesproken. Ik hoop dat we dit in de toekomst vaak zullen blijven doen.

402
 DANKWOORD

Leden van de promotiecommissie: Prof. Dr. E.H.D. Bel, Prof. dr. P.P.G. van Benthem,
Prof. dr. F.G. Dikkers, Prof. dr. P.W. Hellings, Prof. dr. L. Klimek en Prof. dr. B.
Kremer, hartelijk dank voor de tijd die u hebt vrijgemaakt om mijn proefschrift te
beoordelen en om plaats te nemen in mijn promotiecommissie.

Prof. dr. P.W. Hellings. Beste Peter, dank je wel voor de vele gelegenheden die je
me hebt geboden om te spreken tijdens internationale congressen en de goede
gesprekken die we hebben gevoerd omtrent niet-allergische rhinitis. Ik kan mij nog
goed de dag herinneren dat ik mocht meelopen in jullie ziekenhuis in Leuven en jullie
‘koude droge lucht apparaat’ mocht bekijken.

Prof. dr. F.G. Dikkers. Beste Freek, dank je wel voor het vertrouwen dat je mij bood als
staflid in het AMC met als aandachtsgebied de kinderluchtwegpathologie. Ik kijk met
een positief gevoel terug op deze periode waarin je mij veel hebt geleerd. Het was een
geweldig jaar. Dank je wel voor je positieve instelling en enthousiasme.

Alle patiënten die hebben deelgenomen aan de onderzoeken van dit proefschrift.
Zonder jullie was vrijwel niets van dit boekje tot stand gekomen. Dank jullie wel voor
jullie vertrouwen en jullie tijdsinvestering.

Collega’s van het lab. Beste Daniëlle en Esther, zonder jullie was ik nergens geweest.
Jullie hebben mij niet alleen de beginselen van het pipeteren bijgebracht maar hebben
ook heel veel tijd gestoken in diverse analyses. Daarnaast hebben we veel gezellige
uren doorgebracht in de kamer naast Kees. Dank jullie wel. Beste Silvia, ook al werk
je niet meer in het AMC, ik heb veel van je mogen leren tijdens het eerste jaar van mijn
onderzoek. Dank je wel voor je humor en eerlijkheid.

Beste Ottoline, als zusje van mijn paranimf Dirk, heb je heel veel werk verzet met het
bellen van diverse patiënten en het bijwerken van de database. Dank je wel.

Beste Allard, via Jan Sander heb ik jou benaderd of je me wilde helpen met het bellen
van patiënten voor vragenlijstonderzoek. Dit heb je geweldig gedaan. Dank je wel.

De KNO-research afdeling, dank voor al jullie hulp en inzet. Met bijzondere dank aan
Judith Kosman en Marieke Bakker.

Alle medeauteurs, dank jullie wel voor jullie fijne samenwerking.

Dear Artur, thank you so much for all your hard work on the two Cochrane Reviews.
You are very accurate, committed and hard working. I admire you a lot.

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APPENDICES

Lieve Carlijn, van jou heb ik ‘het stokje’ over mogen nemen in het onderzoek naar
niet-allergische rhinitis. Je had al veel werk verzet waarvan ik heb mogen profiteren.
Ik herinner mij nog goed de begindagen op de KNO-research waarop we gezamenlijk
door de studiemappen liepen en je mij alle protocollen liet zien. Dank je wel dat je alles
met enthousiasme helpt gevolgd en geholpen hebt waar je kon. Daarnaast ben je een
heel fijne collega die altijd voor me klaar stond. Dank je wel.

AIOS KNO in het AMC sinds 2009. Dankzij jullie was de opleidingstijd een onver-
getelijke en misschien wel niet te overtreffen periode. We hebben heel veel mooie
momenten met elkaar meegemaakt en lief en leed met elkaar gedeeld. Wat zijn er
veel feestjes, skivakanties, KNO-uitjes, KNO-vergaderingen (met name de avonden) en
cursussen die ik nooit meer zal vergeten. Jullie waren er altijd. Heel veel dank daarvoor.
Ik hoop op een toekomst van fijne en gezellige samenwerking waarbij we regelmatig
terugdenken aan deze mooie periode. En dat de feestjes mogen voortbestaan.

Stafleden KNO AMC. Dank jullie wel voor jullie steun, inzet en vertrouwen, zowel als
AIOS als staflid. Ik heb veel van jullie mogen leren en van een erg goede samenwerking
mogen genieten.

Beste Erik, dank je wel voor de vele gesprekken die we hebben gevoerd. Je was er
altijd. Onder je grappen en grollen schuilt een heel klein hart. Er is nu nóg een gelegen-
heid om die fles wijn samen op te drinken. Dank je wel.

Gwijde Adriaensen en Sietze Reitsma. Als rhinologen heb ik heel veel van jullie mogen
leren, zowel in de kliniek als op de OK. Dank jullie wel, ook voor jullie vertrouwen en
de vele gezellige uren.

Lieve Marijke en GertJan, toen Mamma overleed zijn jullie mijn vervangend thuis
geweest in Zuthpen. Dit thuis betrof niet alleen een kamer waar ik met veel plezier
heen ging tijdens de weekenden, maar ook een luisterend oor en een onvoorwaar-
delijke steun op al die ontelbare momenten. Jullie hebben mij door de moeilijkste jaren
gebracht. Daar zijn geen woorden voor. Zonder jullie was dit boekje er nooit gekomen
en was ik niet gekomen waar ik nu ben. Mede dankzij mijn ouders, dank jullie wel.

Lieve Guido, je bent voor mij altijd meer als een broer dan een neef geweest. Als
geen ander begrijp je mij en sta je altijd voor me klaar. Wat hebben we veel gezellige
avonden doorgebracht in een van jouw vele mooie woonplekken in Amsterdam, met
wijn en goede muziek. Dankzij deze gezelligheid heb ik de motivatie gehouden om
door te gaan. Jouw oprechte blijdschap omdat ik er dan nu eindelijk gekomen ben, is
voor mij hartverwarmend.

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 DANKWOORD

Lieve Jesse en Marie-Elise, dank jullie wel voor die vele momenten dat ik bij jullie
aan de tafel zat met een lekkere cappuccino of glas wijn en de vele perikelen van de
opleidings­tijd en promotie met jullie besprak. Door jullie adviezen en luisterend oor
heen sprak altijd de oprechte warme belangstelling en familieband waar geen woorden
voor zijn.

Lieve Vera en Louk, als ik bij jullie binnenstap is het alsof ik weer terug ga naar mijn
eerste kinderjaren, daar verandert niets aan. Lieve Vera, als zus van Mamma voelt het
bij jullie enorm vertrouwd, dat is mij enorm dierbaar. Dank jullie wel dat jullie er altijd
en overal voor me zijn geweest, en nog. Jullie blijdschap en trots vullen het gemis op.
Jullie kennen mij door en door en dankzij jullie luisterend oor, steun en gezelligheid,
ben ik waar ik nu ben. Dank jullie wel.

Lieve Marjoleine en Ewout, jullie toveren altijd een lach op mijn gezicht. Er is geen moment
dat ik niet met een blij gevoel bij jullie vandaan ga vanuit jullie gezellige huis in Den Haag.
Jullie vervullen een enorm belangrijke rol in mijn leven met jullie warmte en gezelligheid.
Marjoleine, enorm bedankt voor de vele patiënten die je voor mij hebt gebeld. Je staat
altijd -samen met Ewout- echt voor mij klaar. Dank jullie wel.

Lieve Jan en Henriëtte, jullie zijn voor mij als familie. Ik denk met een enorm positief
en dankbaar gevoel terug aan de vele weekenden die ik bij jullie o.a. in Den Haag heb
mogen doorbrengen. Na een gezamenlijke gezellige dag en een goed gesprek, heb ik
mede dankzij jullie de motivatie gehouden om door te gaan, ook als het soms moeilijk
was. Ik kon met alles bij jullie terecht, juist op die momenten waar het nodig was. Jullie
optimistische levensinstelling waarbij jullie altijd klaar staan voor anderen, is voor mij
een groot voorbeeld. Dank jullie wel. Op naar nog veel mooie momenten samen.

Lieve Pauline, wat hebben we veel mooie momenten samen meegemaakt en lief en
leed gedeeld. Je had altijd een luisterend oor voor mij en gaf advies waar nodig. Dank
je wel voor je frisse en objectieve blik waarmee ik zo veel dingen weer in perspectief
kon plaatsen. Mede dankzij jouw vriendschap heb ik dit boekje kunnen afmaken.

Lieve Marrit en Douwe, ik denk met een warm gevoel aan de vele gezellige avonden
die we samen hebben doorgebracht, met een onvergetelijk begin aan de Kanaalweg
in Den Haag. Jullie zijn altijd oprecht betrokken op al die ontelbare momenten. Mede
dankzij jullie vriendschap heb ik dit boekje kunnen afmaken.

Lieve Chris en Kees, dank jullie wel voor jullie oprechte belangstelling aan de zijlijn.
Er ging geen etentje voorbij of jij Chris, vroeg altijd wel hoe het ervoor stond met de
promotie. Dit is een positieve stimulans geweest. Chris, we missen allebei Pappa op
de belangrijke momenten in ons leven. Hij zou blij zijn ons zo samen te zien.

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APPENDICES

Lieve collega’s van de gehele KNO-afdeling Hoorn, met jullie heb ik de beste werkplek
en de fijnste collega’s die ik me kan wensen. Dank jullie wel voor jullie betrokkenheid,
flexibiliteit en oprechte belangstelling als het ging om mijn promotieonderzoek.

Daarnaast ben ik erg blij met de vele gezellige en persoonlijke momenten die ik met
jullie buiten het werk doorbreng. Ik hoop dat dit tot in de lengte der jaren zal voortduren.

Loet, jij vroeg telkens met veel belangstelling naar de vorderingen binnen mijn promotie­
traject. Dank je wel dat je gedurende een half jaar meer bent gaan werken zodat ik
(onder andere) dit proefschrift kon afmaken. Bij het corrigeren van dit proefschrift
gonst jouw citaat van de Utrechtse hoogleraar door mijn hoofd: “Ik heb hem!” (de
eerste gevonden spelfout in een proefschrift). Ik weet zeker dat we deze spelfout
samen zullen vinden en er hartelijk om kunnen lachen. Dank je wel voor wat ik van je
mag leren.

Milène, jij hebt enorm meegeleefd in de laatste fase van mijn proefschrift en wist
telkens precies hoe het ervoor stond met de beruchte ‘Cochrane-review’ en alle
vervolgstappen richting het aanvragen van de promotiedatum. In jullie heerlijke
huis - samen met Teun - heb ik veel kunnen schrijven. Je bent enorm meelevend en
betrokken. Daarnaast kan ik erg met jou lachen en bof ik met alle door jou gehaalde
cappuccino’s die altijd alles weer goedmaken. Je staat werkelijk altijd voor me klaar.
Dank je wel voor alles.

Marein, jij weet heel goed hoe heerlijk het voelt als een promotietraject tot een einde
komt en hebt dan ook erg met mij meegeleefd. Met Jip, al springend voor mijn laptop-
scherm, was het soms een uitdaging om te schrijven, maar nu is het eindelijk af. Dank
je wel voor je betrokkenheid, toegankelijkheid en alles wat je aan regelzaken op je
neemt. Dit heeft ook bijgedragen aan het kunnen afronden van mijn proefschrift. Je
bent een heel fijne collega en ik kan altijd bij je terecht.

Jiska, als ‘maatje’ is het superfijn om met jou alles te kunnen bespreken en zo veel
van elkaar te begrijpen. Samen kunnen we het allemaal weer wat relativeren - zelfs
de diesel - en met elkaar lachen. Ik ben benieuwd of we nu gezellig naast elkaar naar
Hoorn zullen rijden nu ik je niet meer kan inhalen straks met een maximumsnelheid
van 100 km per uur. Ik bof met jou als collega.

Lieve Paranimfen, lieve Marjolein en Dirk. Het lag met onze appgroep ‘Paranimfen’ al
vele jaren vast dat jullie mijn paranimfen zouden zijn en met jullie heb ik dan ook de
beste paranimfen die ik me kan wensen.

Lieve Marjolein, na onze vele gemeenschappelijke jaren ‘in hetzelfde schuitje’ is een
mooie vriendschap ontstaan. Ik zie nog levendig jouw eerst dagen voor me in het AMC

406
 DANKWOORD

en de eerste persoonlijke gesprekken die we voerden. Ik heb veel te danken aan jouw
altijd luisterend oor, je vrolijkheid en heldere en eerlijke blik. Met niemand kan ik zo goed
lachen als met jou. We hebben elkaar er op meerdere momenten doorheen gesleept
en met resultaat. Nu is het eindelijk af. Maar gelukkig komt daarbij geen einde aan de
vele momenten van koffie drinken, etentjes en congressen in het buitenland. Want ik
ken niemand die zo van het leven kan genieten als jij. Ik kan me er nu al op verheugen
dat er in dit opzicht nog vele jaren voor ons liggen.

Lieve Dirk, met jouw komst was ons drietal compleet en we hebben een lange periode
als laatste ‘AGIKO’s’ onze stempel gedrukt op de KNO-research. Onze gemeenschap-
pelijke ‘Leidsche’ tongval waarmee we het niveau van de ochtendoverdracht hoog
hebben gehouden, schiep natuurlijk meteen een band. Als geen ander ben jij altijd
gelijkmatig, nauwkeurig, behulpzaam en collegiaal. Waar zal ik ooit een collega vinden
die zoveel deuren voor mij opendoet en op zoveel momenten mijn ski’s draagt als
jij, Dirk? Gelukkig kennen we ook een andere kant van jou. Maar die hoort niet in dit
boekje thuis. Nu jij nog Dirk, we veranderen de naam van onze appgroep pas als jij
ook klaar bent met je promotie. Gelukkig heeft Marjolein zich al opgeworpen als jouw
copromotor. Zo is ze.

Lieve schoonfamilie, lieve Harry en Carola, lieve Sophie, Alexander en Pieter,

Jullie zijn de liefste en meest betrokken schoonfamilie die ik mij ooit had kunnen
wensen. Met het missen van mijn eigen ouders, had dit gemis niet beter kunnen
worden opgevuld.

Lieve Sophie, je bent een lieve en betrokken schoonzus die altijd oprechte belangstelling
heeft. Je hebt heel erg meegeleefd met mijn promotieonderzoek en was als geen
ander blij voor mij dat het nu eindelijk af is. Nu heb ik eindelijk tijd om op de donderdag
koffie te komen drinken in Eemnes. Dank je wel voor je steun en vriendschap.
Lieve Alexander, als de twee ‘dokters’ hebben we onze gemeenschappelijke last van
vele uren zwoegen in het ziekenhuis en zitten achter onze laptop, en begrijpen we dit
ook van elkaar als geen ander. Welke zwager stimuleert nu zijn zus om brood te smeren
voor mij omdat ik het al zo druk heb? Blijven zeggen hoor, wie weet op een dag...
Je bent er altijd en helemaal, of het nou gaat om klussen in ons nieuwe huis of om
gezellige gelegenheden. Dank je wel daarvoor en voor je steun en vriendschap.
Lieve Pieter, altijd vroeg je hoe het ging met de promotie en luisterde je belangstellend
naar de vorderingen of hobbels op de weg. Je bent een gezellige zwager en we delen
veel interesses waardoor we over allerlei onderwerpen kunnen kletsen onder het genot
van een speciaal biertje. Laten we dit altijd blijven doen. Dank je wel voor je steun en
vriendschap.

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APPENDICES

Lieve Harry en Carola, ik weet nog goed de middag dat ik jullie voor het eerst
ontmoette in café Lazy Louis in Amersfoort. Daar vertelde ik dat ik bezig was met
mijn promotieonderzoek, en in de afrondende fase was. Die afrondende fase heeft
nog wat jaren voortgeduurd maar nu kunnen jullie dan eindelijk het resultaat met mij
vieren. Jullie warmte, gezelligheid en jullie aanwezigheid en steun op alle momenten
in de breedste zin van het woord, zijn in geen woorden uit te drukken. Waar tref je
schoonouders die precies weten wanneer je dienst hebt, een belangrijke vergadering
of wanneer er extra brood of yoghurt moet worden meegegeven? Ik bof enorm met
jullie, jullie zijn heel waardevol voor mij en het is dan ook een feit dat dit boekje er niet
was geweest zonder jullie. Dank jullie wel.

Lieve Charlotte, als belangrijkste en liefste persoon in mijn leven, gaat mijn grootste
dank uit naar jou. Jij hebt mijn leven in alle opzichten veranderd en mij gelukkig
gemaakt. Dat is de beste basis en vanuit die basis is dit boekje nu eindelijk af. Je bent
mijn allerliefste en ik hou van jou.

Lieve Pappa en Mamma, de warme en liefdevolle jeugd die ik heb gehad heeft ervoor
gezorgd dat ik hier nu ben aangekomen. Jullie hebben mij werkelijk alle tijd, kansen
en gelegenheden geboden om mij te ontwikkelen en mij op mijn studie te richten.
Bovenal hebben jullie mij levenswijsheid meegegeven. Lievere ouders en een warmer
gezin had ik mij niet kunnen wensen. Mamma, wat was je trots toen ik eindexamen
deed en een jaar later mijn propedeuse Geneeskunde behaalde. Ik zie je nog zitten in
de zaal. In mijn hart zijn jullie er bij al die andere mijlpalen die volgden ook bij geweest,
misschien nog wel meer dan ooit. Ik draag dit boekje aan jullie op.

408
DANKWOORD

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