URTICARIA AND ANGIOEDEMA

Urticaria is defined as a skin lesion consisting of awheal-and-flare reaction in

which localized intracutaneous edema (wheal) is surrounded by an area of redness
(erythema) that is typically pruritic. Individual hives can last as briefly as 30
minutes to as long as 36 hours. They can be as small as a millimeter or 68 inches
in diameter (giant urticaria). They blanch with pressure as the dilated blood
vessels are compressed, which also accounts for the central pallor of the wheal.
The dilated blood vessels and increased permeability that characterize urticaria are
present in the superficial dermis and involves the venular plexus in that location.
Angioedema can be caused by the same pathogenic mechanisms as urticaria but
he pathology is in the deep dermis and subcutaneous tissue and swelling is the
major manifestation. The overlying skin may be erythematous or normal. There is
less pruritus (fewer type C nerve endings at the deeper cutaneous levels) but there
may be pain or burning.
EPIDEMIOLOGY
Urticaria and angioedema are common. Age, race, sex, occupation, geographic
location, and season of the year may be implicated in urticaria and angioedema
only insofar as they may contribute to exposure to an eliciting agent. Of a group
of college students, 15%20% reported having experienced urticaria, while 1%
3% of the patients referred to hospital dermatology clinics in the United Kingdom
noted urticaria and angioedema. In the National Ambulatory Medical Care
Survey data from 1990 to 1997 in the United States, women accounted for 69% of
patient visits. There was a bimodal age distribution in patients aged birth to 9
years and 3040 years.1 Urticaria/angioedema is considered to be acute if it lasts
less than 6 weeks. Most acute episodes are due to adverse reactions to medications
or foods and in children, to viral illnesses. Episodes of urticaria/angioedema
persisting beyond 6 weeks are considered chronic and are divided into two major
subgroups: (1) chronic autoimmune urticaria (45%) and (2) chronic idiopathic
urticaria (55%) with a combined incidence in the general population of 0.5%.2

Physically induced urticaria/angioedema is not included in the definition. Various

types of physical urticaria/angioedema may last for years, but the individual
lesions last fewer than 2 hours (except delayed pressure urticaria) and are
intermittent. Whereas 85% of children experience urticaria in the absence of
angioedema, 40% of adult patients with urticaria also experience angioedema.
Approximately 50% of patients with chronic urticaria (with or without
angioedema) are free of lesions within 1 year, 65% within 3 years, and 85%
within 5 years; fewer than 5% have lesions that last for more than 10 years.
Angioedema alters the natural history, and only 25% of patients experience
resolution of lesions within 1 year. There are no data regarding the remission rate
in patients with only angioedema. The hereditary group is considered to be life
long once the diagnosis becomes clinically manifest.
PATHOGENESISMAST CELL AND HISTAMINE RELEASE
MAST CELL AND HISTAMINE RELEASEST CELL AND HISTAMINE R
The mast cell is the major effector cell in most forms of urticaria and
angioedema, although other cell types undoubtedly contribute. Cutaneous mast
cells adhere to fibronectin and laminin through the very late activation (VLA) 1
integrins VLA-3, VLA-4, and VLA-5 and to vitronectin through the v3
integrin. Cutaneous mast cells, but not those from other sites, release histamine in
response to compound 48/80, C5a, morphine, and codeine. The neuropeptides
substance P (SP), vasoactive intestinal peptide (VIP), and somatostatin, (but not
neurotensin, neurokinins A and B, bradykinin, or calcitonin gene-related peptide),
activate mast cells for histamine secretion. Dermal microdialysis studies of the
application of SP on skin indicate that it induces histamine release only at 106
M, which suggests that after physiologic nociceptor activation, SP does not
contribute significantly to histamine release.3 Yet it is a major contributor to the
flare reaction induced by histamine stimulation of afferent type C fibers
(mediating pruritus) with release of SP from adjacent nerve endings by antidrom
ic conduction. Histamine is found associated with the wheal.4 Recently, the spinal
cord afferent fibersmediating pruritis have, for the first time, been distinguished

from pain fibers in the lateral spinothalamic tracts.5

Not all potential biologic products are produced when cutaneous mast cells
are stimulated. For example, SP releases histamine from cutaneous mast cells
above 106 M but does not generate prostaglandin D2 (PGD2). Vascular
permeability in skin is produced predominantly by H1 histamine receptors (85%);
H2 histamine receptors account for the remaining 15%. The current hypothesis
regarding cellular infiltration that follows mast cell degranulation suggests that
the release of mast cell products (histamine, leucotrienes, cytokines, chemokines)
leads to alterations in vasopermeability, upregulation of adhesion molecules on
endothelial cells, and rolling and attachment of blood leukocytes, followed by
chemotaxis and transendothelial cell migration. Various forms of physical
urticaria/angioedema have provided experimental models for the study of
urticaria/angioedema by allowing the observation of the elicited clinical response,
examination of lesional and normal skin biopsy specimens, assay of chemical
mediators released into the blood or tissues, and characterization of peripheral
leukocyte responses.6,7 The intracutaneous injection of specific antigen in
sensitized individuals has provided an experimental model for analysis of the role
of immunoglobulin (Ig) E and its interaction with the mast cell. In many subjects,
the challenged cutaneous sites demonstrate a biphasic response, with a transient,
pruritic, erythematous wheal-and-flare reaction followed by a tender, deep,
erythematous, poorly demarcated area of swelling that persists for up to 24 hours.
This is the late-phase response with recruitment of variable numbers of eutrophils,
prominent eosinophils, monocytes, small numbers of basophils, and CD4 + Tlymphocytes of the TH2 subclass.8 Chemokines (chemotactic cytokines) strongly
associated with Th2 lymphocyte predominance include those reactive with
chemokine receptors CCR3, CCR4, and CCR8 on T lymphocytes. Characteristic
cytokines produced by Th2 lymphocytes include interleukins (ILs) 4, 5, 9, 13, 25,
31 and 33. The cellular infiltrate seen in biopsy specimens of delayed pressure
urticaria is a variant of a late-phase reaction while mast cell degranulation in most
other physical urticarias has no associated late phase. These include typical

acquired cold urticaria, cholinergic urticaria, dermatographism, and type I solar

urticaria.
AUTOIMMUNITY AND CHRONIC URTICARIA
The first suggestion that patients with chronic urticaria and angioedema
might have an autoimmune diathesis was the observation that there is an increased
incidence of antithyroid antibodies in such patients relative to the incidence in the
population at large.9 These include antimicrosomal (perioxidase) and
antithyroglobulin antibodies, as seen in patients with Hashimotos thyroiditis.10
Patients may have clinical hypothyroidism, but a small number might be
hyperthyroid if inflammation is at an early stage when thyroid hormone is
released into the circulation. This atypical presentation should be distinguished
from the occasional patient with graves disease. Nevertheless, most patients are
euthyroid. The incidence of antithyroid antibodies in chronic urticaria, as reported
in the literature, varies between 15% and 24%, but the most recent data are closer
to the latter figure12 and demonstrate segregation of antithyroid antibodies with
chronic autoimmune urticaria rather than chronic idiopathic urticaria. However,
the association is not absolute. The incidence in the autoimmune subgroup was
27%, in the chronic idiopathic urticaria subgroup 11%, while in the population at
large it is 7%8%. Gruber et al (1988) 13 considered the possibility that patients
might have circulating and anti-IgE antibodies that are functional and did indeed
find these in about 5%10% of patients. Gratten et al14,15 sought antibodies
reactive with skin mast cells by performing an autologous skin test and found a
30% incidence of positive reactions in patients with chronic urticaria. There were
only rare positive reactions in healthy control subjects or patients with other forms
of urticaria. Subsequently, this level of positivity was shown by Hide et al16 to be
due to an IgG antibody reactive with the subunit of the IgE receptor; in addition
a 5%10% incidence of functional anti-IgE antibodies was confirmed (eFig. 381.1 in online edition).17
CELLULAR INFILTRATE
Mast cell degranulation certainly initiates the inflammatory process in
autoimmune chronic urticaria and is assumed to also do so in idiopathic chronic

urticaria. Evidence for an increased number of mast cells in chronic urticaria has
been presented,36,37 but there are also publications indicating no significant
differences from normal;38 these studies did not discriminate the autoimmune from
the idiopathic groups. However, no alternative mechanisms for mast cell
degranulation in the idiopathic groups have been suggested to date. Yet the
histology of the two groups differs only in minor ways. Common to all biopsy
specimens is within the superficial and deep venular plexus, with a
prominence of CD4T lymphocytes and monocytes and virtually
no B cells.36,39 Granulocytes are quite variable but are plentiful if
the lesion undergoes biopsy early in its development. Neutrophils
and eosinophils are both present,40,41 although the degree of
eosinophils accumulation varies greatly.39 Even when eosinophils
are not evident, major basic protein can be identified within
lesions (in at least two-thirds of patients), which most likely
represents evidence of prior eosinophil degranulation.42 The
presence of basophils has also been recently demonstrated by
using an antibody (BB1) that is specific for this cell type.41 Thus,
the infiltrate resembles that of an allergic late-phase reaction, as
suggested previously,

43

although the percentage of each cell

types differs, with neutrophils and monocytes

being relatively more prominent in urticaria. Endothelial cell
activation is suggested by the presence of intercellular adhesion
molecule 1 and E-selectin in biopsy specimens of urticarial
lesions.44 Sources of chemokines include the mast cell and the
activated endothelial cell; the latter cells are stimulated not only by cytokines or
monokines, such as IL-4, IL-1, and tumor necrosis factor-ke (TNF-), but also by
the vasoactive factors,for example, histamine and leukotrienes released from
activated mast cells.45 Complement activation and the release of C5a results not
only in augmented mast cell (and basophil) histamine release, but C5a is also
chemotactic for neutrophils, eosinophils, and monocytes. The presence of C5a is
one of the factors that would distinguish this lesion from a typical allergen5

induced cutaneous late-phase reaction. The particular chemokines released in

chronic urticaria have not been studied. The presence of increased plasma IL-4
levels 25 in patients with chronic urticaria provides indirect evidence
of lymphocyte activation, basophil activation, or both, and isolated CD4+
lymphocytes of patients were shown to secrete greater amounts of both IL-4and
IFN- compared with that seen in healthy control subjects on stimulation with
phorbol myristate acetate.
A direct comparison between cutaneous latephase reactions and the
histology of chronic urticaria evealed that infiltrating cells had characteristics of
both TH1 and TH2 cells, with production of IFN- by the former cells and IL-4
and IL-5 by the latter.46 Alternatively, this might represent activated TH0 cells
(i.e.,activated CD4+ lymphocytes that are not differentiated to TH1 or TH2 cells).
When the histology of atoimmune and idiopathic chronic urticarias was
compared,41 theautoimmune subgroup had greater prominence of granulocytes
within the infiltrate, whereas other infiltratingcells were quite similar, with a small
increment in cytokine levels in the autoimmune group and greater tryptase
positivity ( less degranulation) in the autoantibody-negative group. The patients
with autoimmune chronic urticaria generally had more severe symptoms than
those with idiopathic chronic urticaria.47
BASOPHIL RELEASIBILITY
(Figs. 38-1 and 38-2) The basophils of patients with chronic urticariahave been
own to be hyporesponsive to anti-IgE, an observation made by Kern and
Lichtenstein48 long before there were any clues to the pathogenesis of this
disorder. These findings were confirmed49 and appeared to be associated with
basopenia50 and to segregate with the autoimmune subgroup. One obvious
interpretation is that there is in vivo desensitization of basophils in the presence of
circulating anti-IgE receptor. Vonakis et al have demonstrated that patients
basophil hyporesponsiveness to anti-IgE is due to augmented levels of SHIP
phosphatase51 that limits phosphorylation reactions critical for histamine secretion.
Although manifest in about half the patients with chronic urticaria (and not
segregated with either the autoimmune or idiopathic subgroups), the abnormality

appears to reverse when patients remit. Thus, it may be a marker of disease

activity. We have found a paradoxical result when the isolated basophils of
patients with chronic urticaria were activated and compared with the basophils of
healthy control subjects. Although the basophils of the patients with urticaria
were clearly less responsive to anti-IgE, they demonstratedaugmented histamine
release when incubated with serum and it did not matter whether the serawere
taken from normal subjects, other patients with chronic urticaria, or was their
own.52 appeared to be associated with basopenia50 and to segregate with the
autoimmune subgroup. One obvious interpretation is that there is in vivo
desensitization of basophils in the presence of circulating anti-IgE receptor.
Vonakis et al have demonstrated that patients basophil hyporesponsiveness to
anti-IgE is due to augmented levels of SHIP phosphatase51 that limits
phosphorylation reactions critical for histamine secretion. Although manifest in
about half the patients with chronic urticaria (and not segregated with either the
autoimmune or idiopathic subgroups), the abnormality appears to reverse when
patients remit. Thus, it may be a marker of disease activity. We have found a
paradoxical result when the isolated basophils of patients with chronic urticaria
were activated and compared with the basophils of healthy control subjects.
Although the basophils of the patients with urticaria were clearly less responsive
to anti-IgE, they demonstrated augmented histamine release when incubatedwith
serum and it did not matter whether the serawere taken from normal subjects,
other patients with chronic urticaria, or was their own.52

ROLE OF THE EXTRINSIC COAGUATION CASCADE

Studies of the plasma of patient with chronic urticaria demonstrate the presence of
d-dimer and prothrombin 1 and 2 fragments indicating activation of prothrombin
to thrombin as well as digestion of fibrinogen by hrombin.53 The reaction is not
specific for chronic urticaria as similar observations have been noted in multiple
nonsteroidal hypersensitivity syndrome.54 Nevertheless, the data are of
considerable interest and activation of the coagulation cascade is dependent on
tissue factor rather than factor XII, i.e., the extrinsic coagulation cascade.
Although activated endothelial cells are a well-known source of the tissue factor,
histologic studies suggest that eosinophils are a prominent source.55 The
relationship of these observations to histamine release by basophils or mast cells
is not clear. Whereas thrombin activation of mast cells has been reported, the
amounts required are large and the observations thus far are confined to rodent
mast cells. One publication relating to eosinophil to histamine release found IgG
antibody to FceRII in the serum of patients with chronic urticaria which activates
eosinophils to release cationic proteins.56 They propose basophil activation by
these eosinophil cationic proteins but do not demonstrate it; however, they offer
an additional mechanism for basophil and possibly mast cell histamine release.

BRADYKININ: ROLE IN ANGIOEDEMA

Kinins are low-molecular-weight peptides that participate in inflammatory
processes by virtue of their ability to activate endothelial cells and, as a
consequence, lead to vasodilatation, increased vascular permeability, production
of nitric oxide, and mobilization of arachidonic acid. Kinins also stimulate
sensory nerve endings to cause a burning dysesthesia. Thus, the classical
parameters of inflammation (i.e., redness, heat, swelling, and pain) can all result
from kinin formation. Bradykinin is the best characterized of this group of
vasoactive substances.
There are two general pathways by which bradykinin is generated. The
simpler of the two has only two components: (1) an enzyme tissue kallikrein 57 and
(2) a plasma substrate, low-molecular-weight kininogen.58,59 Tissue kallikrein is
secreted by many cells throughout the body; however, certain tissues produce
particularly large quantities. These include glandular tissues (salivary and sweat
glands and pancreatic exocrine gland) and the lung, kidney, intestine, and brain.
The second pathway for bradykinin formation is far more complex and is
part of the initiating mechanism by which the intrinsic coagulation pathway is
activated (eFig. 38-1.2 in online edition).60 Factor XII is the initiating protein that
binds to certain negatively charged macromolecular surfaces and autoactivates
(autodigests) to form factor XIIa.61,62 This is synonymous with Hageman factor as
designated in the figure. There are two plasma substrates of factor XIIa, namely
(1) prekallikrein63 and (2) factor XI,64,65 and each of these circulates as a complex
with high-molecular-weight kininogen (HK).66,67 These complexes also attach to
initiating surfaces, and the major attachment sites are on two of the domains of
HK, which thereby places both prekallikrein and factor XI in optimal
conformation for cleavage to kallikrein (plasma kallikrein) and factor XIa,
respectively. It is important to note that plasma kallikrein and tissue kallikrein are
separate gene products and have little amino acid sequence homology, although
they have related functions (i.e., cleavage of kininogens). Tissue kallikrein prefers
low-molecular-weight kininogen but is capable of cleaving HK, whereas plasma
kallikrein cleaves HK exclusively. The two kininogens have an identical amino

acid sequence starting at the N-terminus and continuing to 12 amino acids beyond
the bradykinin moiety59 but differ in C-terminal domains because of alternative
splicing at the transcription level.68,69 Both factor XII and HK bind to endothelial
cells (which may function as the natural surface in the presence of physiologic
zinc ion), thus activation may occur at the cell surface.70,71
A scheme for both production and degradation of kinins is shown in eFig.
38-1.2 in online edition. The enzymes that destroy bradykinin consist of kininases
I and II. Kininase I is also known as plasma carboxypeptidase N,72 which removes
the C-terminal arg from bradykinin or kallidin to yield des-arg73 bradykinin or
des-arg74 kallidin, respectively.75 It is the same enzyme that cleaves the C-terminal
arg from the complement anaphylatoxins C3a and C5a. Kininase II is identical to
angiotensin-converting enzyme (ACE).76 Kininase II is a dipeptidase that cleaves
the C-terminal phearg from bradykinin to yield a heptapeptide, which is cleaved
once again to remove ser-pro and to leave the pentapeptide arg-pro-pro-gly-phe.75
If the C-terminal arg of bradykinin is first removed with kininase I, then ACE
functions as a tripeptidase to remove ser-pro-phe and to leave the above
pentapeptide.77 Bradykinin and kallidin stimulate constitutively produced B2
receptors, 78 whereas des-arg73-BK or des-arg74 lys-BK both stimulate B1
receptors,79 which are induced as a result of inflammation. Stimuli for B1 receptor
transcription include IL-1 and TNF-.80,81
CLINICAL FINDINGS
Circumscribed, raised, erythematous, usually pruritic, evanescent areas of edema
that involve the superficial portion of the dermis are known as urticaria (Fig. 383); when the edematous process extends into the deep dermis and/or subcutaneous
and submucosal layers, it is known as angioedema. Urticaria and angioedema
may occur in any location together or individually. Angioedema commonly affects
the face or a portion of an extremity, may be painful but not pruritic, and may last
several days. Involvement of the lips, cheeks, and periorbital areas is common, but
angioedema also may affect the tongue, pharynx, or larynx. The individual lesions

10

of urticaria arise suddenly, rarely persist longer than 2436 hours, and may
continue to recur for indefinite periods. They are highly pruritic.
IMMUNOLOGIC: IMMUNOGLOBULIN E- AND IMMUNOGLOBULIN E
RECEPTOR-DEPENDENT URTICARIA/ANGIOEDEMA
Atopic Diathesis. Episodes of acute urticaria/angioedema that occur in
individuals with a personal or family history of asthma, rhinitis, or eczema are
presumed to be IgE dependent. However, in clinical practice,
urticaria/angioedema infrequently accompanies an exacerbation of asthma,
rhinitis, or eczema. The prevalence of chronic urticaria/angioedema is not
increased in atopic individuals.

Figure 38-3 Urticaria and angioedema. This patient has urticaria

occurring on the face, neck, and upper trunk with angioedema about
the eyes.
Specific Antigen Sensitivity. Common examples of specific antigens that
provoke urticaria/angioedema include foods such as shellfish, nuts, and chocolate;
drugs and therapeutic agents notably penicillin; aeroallergens; and Hymenoptera
venom (see Fig. 38-3). Urticaria in patients with helminthic infestations has been

11

attributed to IgE-dependent processes; however, proof of this relationship is often

lacking. Specific allergens and nonspecific stimuli may activate local reactions
termed recall urticaria at sites previously injected with allergen immunotherapy.
PHYSICAL URTICARIA/ANGIOEDEMA5,6
Dermographism. Dermographism is the most common form of physical urticaria
and is the one most likely to be confused with chronic urticaria. A lesion appears
as a linear wheal with a flare at a site in which the skin is briskly stroked with a
firm object (Fig. 38-4). A transient wheal appears rapidly and usually fades within
30 minutes; however, the patients normal skin is typically pruritic so that an itch
scratch sequence may appear. The prevalence of dermographism in the general
population was reported as 1.5% and 4.2%, respectively, in two studies,
and its prevalence in patients with chronic urticaria is 22%. It is not associated
with atopy. The peak prevalence occurs in the second and third decades. In one
study, the duration of dermographism was greater than 5 years in 22% of
individuals and greater than 10 years in 10%.

Figure 38-4 Topical dermatographic response to scratching the

skin.
Elevations in blood histamine levels have been documented in some patients
after experimental scratching, and increased levels of histamine,82 tryptase, SP,
12

and VIP, but not calcitonin gene-related peptide, have been detected in
experimental suction-blister aspirates. The dermographic response has been
passively transferred to the skin of normal subjects with serum or IgE.83
In delayed dermographism, lesions develop 36 hours after stimulation,
either with or without an immediate reaction, and last 2448 hours. The eruption
is composed of linear red indurated wheals. This condition may be associated with
delayed pressure urticaria and these two may, in fact, represent the same entity.
Cold-dependent dermographism is a condition characterized by marked
augmentation of the dermatographic response when the skin is chilled.84
Pressure Urticaria. Delayed pressure urticaria appears as erythematous, deep,
local swellings, often painful, that arise from 3 to 6 hours after sustained pressure
has been applied to the skin.85,86 Spontaneous episodes are elicited on areas of
contact after sitting on a hard chair, under shoulder straps and belts, on the feet
after running, and on the hands after manual labor. The peak prevalence occurs in
the third decade. Delayed pressure urticaria may occasionally be associated with
fever, chills, arthralgias, and myalgias, as well as with an elevated erythrocyte
sedimentation rate and leukocytosis. In one study, it accompanied chronic
urticaria in 37% of patients. This is far more commonly seen than patients with
pressure urticaria and no spontaneously occurring hives. An IgE-mediated
mechanism has not been demonstrated; however, histamine and IL-6 have been
detected in lesional experimental suction-blister aspirates and in fluid from skin
chambers, respectively. 8789
Vibratory Angioedema. Vibratory angioedema may occur as an acquired
idiopathic disorder, in association with cholinergic urticaria, or after several years
of occupational exposure to vibration.90 It has been described in families with an
autosomal dominant pattern of inheritance.91 The heritable form
often is accompanied by facial flushing. An increase in the level of plasma
histamine was detected during an experimental attack in patients with the
hereditary form and in patients with acquired disease.91,92 A typical symptom is
hives across the back when toweling off after a shower (in the absence of
dermatographism).

13

Cold Urticaria. There are both acquired and inherited forms of cold
urticaria/angioedema; however, the familial form is rare. Idiopathic or primary
acquired cold urticaria may be associated with headache, hypotension, syncope,
wheezing, shortness of breath, palpitations, nausea, vomiting, and diarrhea.
Attacks occur within minutes after exposures that include changes in ambient
temperature and direct contact with cold objects. The elicitation of a wheal after
the application of ice has been called a diagnostic cold contact test (Fig. 38-5).
This can be performed with thermoelectric elements with graded temperatures so
that the temperature threshold for producing a wheal can be determined and a
dose-response (sensitivity) in terms of stimulus duration can be readily obtained.92
If the entire body is cooled (as in swimming), hypotension and syncope, which are
potentially lethal events (by drowning), may occur. In rare instances, acquired
cold urticaria has been associated with circulating cryoglobulins, cryofibrinogens,
cold agglutinins, and cold hemolysins, especially in children with infectious
mononucleosis.9395 Passive transfer of cold urticaria by intracutaneous injection of
serum or IgE to the skin of normal recipients has been documented.96,97 Histamine,
chemotactic factors for eosinophils and neutrophils, PGD2, cysteinyl
leukotrienes, platelet-activating factor, and TNF- have been released into the
circulation after experimentalchallenge.98104 Histamine, SP, and VIP, but not
calcitonin gene-related peptide, have been detected in experimental suction-blister
aspirates. Histamine has been released in vitro from chilled skin biopsy specimens
that have been rewarmed.105 Neutrophils harvested from the blood of an
experimentally coldchallenged arm manifested an impaired chemotactic response
suggesting in vivo desensitization. Whereas complement has no role in primary
acquired cold urticaria, cold challenge of patients with cold urticaria who have
circulating immune complexes (such as cryoglobulins) can provoke a cutaneous
necrotizing venulitis with complement activation.106109

14

Figure 38-6 Lesions of cholinergic urticaria observed in a

patient after 15 minutes of exercise in a warm room.
Rare forms of acquired cold urticaria have been described mainly in case
reports include systemic cold urticaria,84 localized cold urticaria,110 cold-induced
cholinergic urticaria, cold-dependent dermographism, 84 and localized cold reflex
urticaria.111,112 Three forms of dominantly inherited cold urticaria have been
described. Familial cold urticaria which has been termed familial cold
autoinflammatory syndrome and is considered a type of periodic fever.113 It is a
disorder showing an autosomal dominant pattern of inheritance with a genetic
linkage to chromosomes 1q44. The responsible gene has been identified as CIASI,
which codes for a protein involved in regulation of inflammation and
apoptosis.114 The eruption occurs as erythematous macules and infrequent wheals
and is associated with burning or pruritus. Fever, headaches, conjunctivitis,
arthralgias, and a neutrophilic leukocytosis are features of attacks. The delay
between cold exposure and onset of symptoms is 2.5 hours, and the
average duration of an episode is 12 hours. Renal disease with amyloidosis occurs
infrequently. Skin biopsy specimens show mast cell degranulation and an infiltrate
of neutrophils. Results of the cold contact test and passive transfer with serum
have been negative. Serum levels of IL-6 and granulocyte colony stimulating
factor were elevated in one patient. Other studies suggest a pathogenic role for IL1. Delayed cold urticaria occurs as erythematous, edematous, deep

15

swellings that appear 918 hours after cold challenge. Lesional biopsy specimens
show edema with minimal numbers of mononuclear cells; mast cells are not
degranulated; and neither complement proteins nor immunoglobulins are
detected. Cold immersion does not release histamine, and the condition cannot be
passively transferred. Recently, a new form of familial cold urticaria with
dominant inheritance has been reported with pruritus, erythema, and urticaria with
cold exposure that can progress to syncope. The ice cube test is negative and it
lacks the fever, and flu-like symptoms associated with familial cold
autoinflammatory syndrome.115
Cholinergic Urticaria. Cholinergic urticaria develops after an increase in core
body temperature, such as during a warm bath, prolonged exercise, or episodes of
fever.116 The highest prevalence is observed in individuals aged 2328 years. The
eruption appears as distinctive, pruritic, small, 1- to 2-mm wheals that are
surrounded by large areas of erythema (Fig. 38-6). Occasionally, the lesions may
become confluent, or angioedema may develop. Systemic features include
dizziness, headache, syncope, flushing, wheezing, shortness of breath, nausea,
vomiting, and diarrhea. An increased prevalence of atopy has been reported. The
intracutaneous injection of cholinergic agents, such as methacholine chloride,
produces a wheal with satellite lesions in approximately one-third of patients.117,118
Alterations in pulmonary function have been documented during experimental
exercise challenge119 or after the inhalation of acetylcholine, but
most are asymptomatic.
A major subpopulation of patients with cholinergic urticaria have a positive
skin test result and in vitro histamine release in response to autologous sweat.120 It
is not clear whether this is IgE mediated and any antigen present in sweat is
unidentified. This is the same subpopulation with a positive methacholine skin test
with satellite lesions and a nonfollicular distribution of the wheals. The remaining
patients had negative results on autologous sweat skin tests or in vitro histamine
release. Results of the methacholine skin test are negative for satellite lesions and
the hives tend to be follicular in distribution.

16

Familial cases have been reported only in men in four families.121 This
observation suggests an autosomal dominant pattern of inheritance. One of these
individuals had coexisting dermographism and aquagenic urticaria.
After exercise challenge, histamine and factors chemotactic for eosinophils
and neutrophils have been released into the circulation.99,119 Tryptase has been
detected in lesional suction-blister aspirates. The urticarial response has been
passively transferred on one occasion; however, most other attempts to do so have
been unsuccessful.
Cold urticaria and cholinergic urticaria are not uncommonly seen
together122,123 and cold-induced cholinergic urticaria represents an unusual variant
in which typical cholinergic appearing lesions occur with exercise, but only if
the person is chilled, for example, with exercise outside on a winters day. The ice
cube test and methacholine skin test are both negative.124
Local Heat Urticaria. Local heat urticaria is a rare form of urticaria in which
wheals develop within minutes after exposure to locally applied heat. An
increased incidence of atopy has been reported. Passive transfer has been
negative. Histamine, neutrophil chemotactic activity, and PGD2 have been
detected in the circulation after experimental challenge.125 A familial delayed form
of local heat urticaria in which the urticaria occurred in 12 hours after challenge
and lasted up to 10 hours has been described.
Solar Urticaria. Solar urticaria occurs as pruritus, erythema, wheals, and
occasionally angioedema that develop within minutes after exposure to sun or
artificial light sources. Headache, syncope, dizziness, wheezing, and nausea are
systemic features. Most commonly, solar urticaria appears during the third
decade.126 In one study, 48% of patients had a history of atopy. Although solar
urticaria may be associated with systemic lupus erythematosus and polymorphous
light eruption, it is usually idiopathic. The development of skin lesions under
experimental conditions in response to specific wavelengths has allowed
classification into six subtypes; however, individuals may respond to more than
one portion of the light spectrum. In type I, elicited by wavelengths of 285320
nm, and in type IV, elicited by wavelengths of 400500 nm, the responses have

17

been passively transferred with serum, suggesting a role for IgE antibody. In type
I, the wavelengths are blocked by window glass.127,128 Type VI, which is identical
to erythropoietic protoporphyria, is due to ferrochelatase (hemesynthetase)
deficiency (see Chapter 132).74 There is evidence that an antigen on skin may
become evident once irradiated with the appropriate wave length of light followed
by complement activation and release of C5a.129131
Histamine and chemotactic factors for eosinophils and neutrophils have
been identified in blood after exposure of the individuals to ultraviolet A,
ultraviolet B, and visible light.132,133 In some individuals, uncharacterized serum
factors with molecular weights ranging from 25 to 1,000 kDa, which elicit
cutaneous wheal-and-erythema reactions after intracutaneous injection, have been
implicated in the development of lesions.
Exercise-Induced Anaphylaxis. Exercise-induced anaphylaxis is a clinical
symptom complex consisting of pruritus, urticaria, angioedema respiratory
distress, and syncope that is distinct from cholinergic urticaria.134137 In most
patients, the wheals are not punctate and resemble the hives seen in acute or
chronic urticaria. The symptom complex is not readily reproduced by exercise
challenges as is cholinergic urticaria. There is a high prevalence of an atopic
diathesis. Some cases are food dependent, i.e., exercise will lead to an
anaphylaxis-like episode only if food was ingested within 5 hours of the exercise.
The food dependency is subdivided into two groups: in the first the nature of the
food eaten is not relevant, whereas in the second a specific food to which there is
IgE-mediated hypersensitivity must be eaten for hives to appear.138141 Yet in these
cases, eating the food without exercise does not result in urticaria. The fooddependent group is easier to treat because avoidance of food (or a specific food)
for 56 hours before exercise prevents episodes. Cases not related to food require
therapy for acute episodes and attempts to prevent episodes with high-dose
antihistaminics or avoidance of exercise. Results of a questionnaire study of
individuals who had had exercise-induced anaphylaxis for more than a decade142
disclosed that the frequency of attacks had decreased in 47% and had stabilized in
46%. Forty-one percent had been free of attacks for 1 year. Rare familial forms

18

have been described. In exercise-induced anaphylaxis, baseline pulmonary

function tests are normal. Biopsy specimens show mast cell degranulation, and
histamine and tryptase are released into the circulation when symptoms appear.
Adrenergic Urticaria. Adrenergic urticaria occurs as wheals surrounded by a
white halo that develop during emotional stress. The lesions can be elicited by the
intracutaneous injection of norepinephrine.
Aquagenic Urticaria And Aquagenic Pruritis. Contact of the skin with water of
any temperature may result in pruritus alone or, more rarely, urticaria. The
eruption consists of small wheals that are reminiscent of cholinergic urticaria.
Aquagenic urticaria has been reported in more than one member in five
families.143 Aquagenic pruritus without urticaria is usually idiopathic but also
occurs in elderly persons with dry skin and in patients with polycythemia vera,
Hodgkins disease, the myelodysplastic syndrome, and the hypereosinophilic
syndrome. Patients with aquagenic pruritus should be evaluated for the emergence
of a hematologic disorder. After experimental challenge, blood histamine levels
were elevated in subjects with aquagenic pruritus and with aquagenic urticaria.
Mast cell degranulation was present in lesional tissues. Passive transfer was
negative.
CONTACT URTICARIA
Urticaria may occur after direct contact with a variety of substances. It may be IgE
mediated or nonimmunologic. The transient eruption appears within minutes, and
when it is IgE mediated, it may be associated with systemic manifestations.
Passive transfer has been documented in some instances. Proteins from latex
products are a prominent cause of IgE-mediated contact urticaria.144 Latex proteins
also may become airborne allergens, as demonstrated by allergen-loaded airborne
glove powder used in inhalation challenge tests. These patients may manifest
cross-reactivity to fruits, such as bananas, avocado, and kiwi.145 Associated
manifestations include rhinitis, conjunctivitis, dyspnea, and shock. The risk group
is dominated by biomedical workers and individuals with frequent contact with
latex, such as children with spina bifida. Agents such as stinging nettles, arthropod
hairs, and chemicals may release histamine directly from mast cells.

19

PAPULAR URTICARIA
Papular urticari occurs as episodic, symmetrically distributed, pruritic, 3- to 10mm urticarial papules that result from a hypersensitivity reaction to the bites of
insects such as mosquitoes, fleas, and bedbugs. This condition appears mainly in
children. The lesions tend to appear in groups on exposed areas such as the
extensor aspects of the extremities.146
URTICARIA/ANGIOEDEMA MEDIATED BY BRADYKININ, THE
COMPLEMENT SYSTEM OR OTHER EFFECTOR MECHANISMS
Kinins And C1 Inhibitor Deficiency. C1 inhibitor (C1 INH) is the sole plasma
inhibitor of factor XIIa and factor XIIf,147,148 and it is one of the major inhibitors of
kallikrein149 as well as factor XIa.150 Thus, in the absence of C1 INH, stimuli that
activate the kinin-forming pathway will do so in a markedly augmented fashion;
the amount of active enzyme and the duration of action of the enzymes are
prolonged. C1 INH deficiency can be familial, in which there is a mutant C1 INH
gene, or it can be acquired. Both the hereditary and acquired disorders have two
subtypes. For the hereditary disorder, type I hereditary angioedema (HAE) (85%)
is an autosomal dominant disorder with a mutant gene (often with duplication,
deletions, or frame shifts) leading to markedly suppressed
C1 INH protein levels as a result of abnormal secretion or intracellular
degradation.151 Type 2 HAE (15%) is also a dominantly inherited disorder,
typically with a point (missense) mutation leading to synthesis of a dysfunctional
protein.152 The C1 INH protein level may be normal or even elevated, and a
functional assay is needed to assess activity. The acquired disorder has been
portrayed as having two forms, but they clearly overlap and have in common B
cell activation that is often clonal. One group is associated with B-cell
lymphoma153155 or connective tissue disease,156 in which there is consumption of
C1 INH. Examples are systemic lupus erythematosus and cryoglobulinemia, in
which complement activation is prominent, and B-cell lymphomas, in which
immune complexes are formed by anti-idiotypic antibodies to monoclonal
immunoglobulin expressed by the transformed B lymphocytes.157 A second group
has a prominence of a circulating IgG antibody to INH itself,158160 but this may be

20

seen with lymphoma or systemic lupus erythematosus as well. Acquired types

have depressed C1q levels, whereas hereditary types do not, and depressed C4
levels characterize all forms of C1 INH deficiency. The acquired autoimmune
subgroup has a circulating 95-kDa cleavage product of C1 INH because the
antibody depresses C1 INH function yet allows cleavage by enzymes with which
it usually interacts.159162
It is now clear that depletion of C4 and C2 during episodes of
swelling163,164 is a marker of complement activation but does not lead to release
of a vasoactive peptide responsible for the swelling. Bradykinin is, in fact, the
mediator of the swelling165167and the evidence in support of this conclusion is
summarized below. Patients with HAE are hyperresponsive to cutaneous injection
of kallikrein.168 They have elevated bradykinin levels, and low prekallikrein and
HK levels during attacks of swelling.169171 The augmentation in complement
activation seen at those times may be due to activation of C1r and C1s by factor
XIIf.172 The presence of kallikreinlike activity in induced blisters of patients with
HAE also supports this notion,173 as does the progressive generation of bradykinin
on incubation of HAE plasma in plastic (noncontact-activated) tubes165,166 as well
as the presence of activated factor XII and cleaved HK levels seen during
attacks.174 One unique family has been described in which there is a point
mutation in the C1 INH (A1a 443 Val) leading to an inability to inhibit
complement but normal inhibition of factor XIIa and kallikrein.175,176 No family
member of this type 2 mutation has had angioedema,175 although complement
activation is present. In recent studies plasma bradykinin levels have been shown
to be elevated during attacks of swelling in both hereditary and acquired C1
inhibitor deficiency,169 and local bradykinin generation has been documented at
the sites of swelling.177 It is not known whether bradykinin generation is
predominantly seen in the fluid phase, occurs along cell (endothelial) surfaces, or
both. A rodent model of HAE demonstrated that angioedema can be prevented by
knockout of the B-2 receptor.178 Figure 38-7 depicts a patient with facial
swelling due to HAE. Figure 38-8 is a diagram depicting the steps in the
bradykinin-forming cascade that are inhibitable by C1 INH.

21

An estrogen-dependent form of hereditary angioedema has been recognized

that is now designated type 3 HAE. One of the first reports involved a single
family with seven affected individuals in three generations, which suggests a
hereditary (autosomal dominant) pattern. 73 Clinical features include angioedema
without urticaria, laryngeal edema, and abdominal pain with vomiting. Attacks
occur during pregnancy and with the administration of exogenous estrogen.
Numerous subsequent reports support these observations.179 In one subgroup,
there is a mutation in factor XII such that the activated form (factor XIIa) is more
potent than normal. 180 These patients all have normal C4 and normal C1 INH
protein and function. Bradykinin is the likely mediator; for those with a factor XII
mutation, the active enzyme may be less readily inhibited. Although uncommon,
a male with the disorder has been described181 and a bradykinin receptor
antagonist (Icatibanit) has provided effective therapy for acute episodes.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS.
Angioedema has been associated with the administration of ACE inhibitors.182
The frequency of

Figure 38-7 Hereditary angioedema. Extensive involvement (A) is to be

contrasted with the patients normal facies (B).
angioedema occurring after ACE inhibitor therapy is 0.1%0.7%. There is a
predilection to ACE inhibitor reactions in the African-American population that
may relate to polymorphisms in the genes encoding other enzymes that
22

catabolize bradykinin such as aminopeptidase P or neutral endopeptidase. Low

levels of these would predispose to bradykinin accumulation. Angioedema
develops during the first week of

Figure 38-8 Pathways for formation of bradykinin, indicating all steps inhibitable
by C1 inhibitor as well as complement activation by means of factor XIIf.
therapy in up to 72% of affected individuals and usually involves the head and
neck, including the mouth, tongue, pharynx, and larynx. Urticaria occurs only
rarely. Cough and angioedema of the gastrointestinal tract are associated
features. It has been suggested that therapy with ACE inhibitors is
contraindicated in patients with a prior history of idiopathic angioedema,
HAE, and acquired C1 INH deficiency. It appears that this swelling is also
a consequence of elevated levels of bradykinin; 169 however, the
accumulation of bradykinin is due to a defect in degradation rather than an
excessive production. ACE, being dentical to kininase II, is the major enzyme
responsible for bradykinin degradation (See eFig. 38-1.2in online edition) and
although it is present in plasma, the vascular endothelium of the lung appears
to be its major site of action. 184 The action of ACE always leads to the formation

23

of degradation products with no activity, whereas kininase I alone yields the

desarg products, which are capable of stimulating B1 receptors.
The excessive accumulation of bradykinin implies that production is
ongoing, with activation of the plasma cascade or release of tissue
kallikrein faulty inactivation of bradykinin then leads to swelling.
Continuous turnover of the plasma cascade is implied by data demonstrating
activation along the surface of cells and cellular expression or secretion of a
prekallikrein activator other than factor XIIa .185,186
URTICARIAL VENULITIS
Chronic urticaria and angioedema may be manifestations of cutaneous
necrotizing venulitis, which is known as urticarial venulitis (See Chapter
163).187,188 Associated features include fever, malaise, arthralgia, abdominal pain
and less commonly conjunctivitis, uveitis, diffuse glomerulonephritis, obstructive
and restrictive pulmonary disease, and benign intracranial hypertension. The
term hypocomplementemic urticarial vasculitis syndrome is used in patients with
more severe clinical manifestations of urticarial venulitis with
hypocomplementemia and a low-molecularweight C1q-precipitin that has been
identified as an IgG autoantibody directed against the collagen-like region of
C1q.
SERUM SICKNESS
Serum sickness, which was defined originally as an adverse reaction
that resulted from the administration of heterologous serum to humans, but may
similarly occur after the administration of drugs. Serum sickness occurs 721
days after the administration of the offending agent and is manifested by fever,
urticaria, lymphadenopathy, myalgia, arthralgia, and arthritis. Symptoms are
usually self-limited and last 45 days. More than 70% of patients with serum
sickness experience urticaria that may be pruritic or painful. The initial
manifestation of urticaria may appear at the site of injection. .189197
REACTIONS TO THE ADMINISTRATION OF BLOOD PRODUCTS

24

Urticaria/angioedema may develop after the administration of blood

products. It usually is the result of immune complex formation and complement
activation that leads to direct vascular and smooth muscle alterations and
indirectly, via anaphylatoxins, to mast cell mediator release. Aggregated IgG may
also be responsible for human reactions to immunoglobulins as evidenced by the
fact that the administration of IgG from which aggregates have been removed is
not associated with urticaria or anaphylaxis.An uncommon mechanism for the
development of urticaria after the administration of blood products is the
transfusion of IgE of donor origin directed toward an antigen to which the
recipient is subsequently exposed. Another mechanism may be the transfusion of
a soluble antigen present in the donor preparation into a previously sensitized
recipient.
INFECTIONS
Episodes of acute urticaria can be associated with upper respiratory
tract viral infections, most commonly in children.198 The acute urticaria
resolves within 3 weeks. Hepatitis B virus infection has been associated with
episodes of urticaria lasting up to 1 week that are accompanied by fever and
arthralgias as part of the prodrome. The mechanism is analogous to that seen in
serum sickness-like reactions with virusantibody immune complexes. The
mechanism for urticaria occasionally associated with infectious monomucleosis
may be analogous.
URTICARIA/ANGIOEDEMA AFTER DIRECT MAST CELL
DEGRANULATION
Various therapeutic and diagnostic agents have been associated with
urticaria/angioedema. Up to 8% of patients receiving radiographic contrast media
experience such reactions, which occur most commonly after intravenous
administration. Decreased serum alternative pathway complement protein levels
and increased serum histamine levels have been detected in patients receiving
radiocontrast media. Opiate analgesics, polymyxin B, curare, and d-tubocurarine
induce release of histamine from mast cells and basophils.

25

URTICARIA/ANGIOEDEMA RELATING TO ABNORMALITIES OF

ARACHIDONIC ACID METABOLISM
Intolerance to aspirin manifested as urticaria/angioedema occurs in
otherwise normal individuals or in patients with allergic rhinitis and/or bronchial
asthma. Urticaria/angioedema in response to aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) occurred in approximately 10%20% of
individuals referred to a hospital dermatology clinic in the United Kingdom.
Patients intolerant of aspirin also may react to indomethacin and to other
NSAIDs.
Reactions to aspirin are shared with other NSAIDs because they reflect
inhibition of prostaglandin endoperoxide synthase 1 (PGHS-1, cyclooxygenase I)
199

as well as inhibition of the inducible PGHS-2 (cyclooxygenase 2). Sodium

salicylate and choline salicylate generally are well tolerated because of their
weak activity against PGHS-1. PGHS-2 inhibitors are generally well tolerated in
those with NSAID-induced urticaria. 200,201 Reactions to NSAIDs increase the
levels of cysteinyl leukotrienes, 202 which may relate to the appearance of
urticaria, although their role in NSAID-induced asthma is better characterized.
Prick skin tests are of no diagnostic value, passive transfer reactions are negative,
and neither IgG nor IgE antibodies have been associated with clinical disease. The
clinical manifestations elicited by aspirin challenge of aspirin-intolerant
patients are blocked when such patients are protected with a cysteinyl
leucotriene receptor blocker or biosynthetic inhibitor; this finding confirms a
pathobiologic role for the cysteinyl leukotrienes.
CHRONIC IDIOPATHIC URTICARIA AND IDIOPATHIC ANGIOEDEMA
Because the clinical entities of chronic idiopathic urticaria (with or without
angioedema) and idiopathic angioedema are frequently encountered, have a
capricious course, and are recognized easily, they are frequently associated with
concomitant events. Such attributions must be interpreted with caution. Although
infections, food allergies, adverse reactions to food additives, metabolic and
hormonal abnormalities, malignant conditions, and emotional factors have been
claimed as causes, proof of their etiologic relationship often is lacking. Among

26

the recent considerations is chronic urticaria as a consequence of infection

with Helicobacter pylori. Articles both supporting 203205 and denying 206209 a
relationship are numerous and a definite answer is not available. However, the
H. pyloriinfection rate in the population at large is far greater than the incidence of
chronic urticaria and in the opinion of this author, the association is spurious. The
controversy has been put in perspective by M. Greaves. 210 Idiopathic angioedema
is diagnosed when angioedema is recurrent, when urticaria is absent, and when no
exogenous agent or underlying abnormality is identifiable. An extensive review of
angioedema has been recently published.184
Cyclic episodic angioedema has been associated with fever, weight gain,
absence of internal organ damage, a benign course, and peripheral blood
eosinophilia.211 Biopsy specimens of tissues show eosinophils, eosinophil granule
proteins, and CD4 lymphocytes exhibiting HLA-OR. Blood levels of IL-1,
soluble IL-2 receptor, and IL-5 are elevated.
Idiopathic angioedema is characterized by recurrent episodes of
angioedema in the absence of any urticaria, which may include the face (lips,
tongue, periorbital region, pharynx), extremities, and genitalia, but is not
associated with laryngeal edema or massive tongue/pharyngeal swelling that yield
airway obstruction. It may not be a continuum with chronic urticaria with or
without concomitant angioedema, as is often considered, because the incidence in
men and women is about the same and the presence of antithyroid antibodies or
anti-IgE receptor antibodies is far less. Extreme cases, particularly if associated
with laryngeal edema, could represent type 3 HAE in a patient with a new
mutation (i.e., no family history) or a variant of idiopathic anaphylaxis.
MISCELLANEOUS
MuckleWells syndrome consists of urticaria, amyloidosis, and nerve
deafness and is due to the same gene defect as is seen in familial cold urticaria.114
Schnitzler syndrome is a chronic urticaria with histology resembling an urticarial
vasculitis associated with fever, joint pain, an IgM monoclonal protein, and
osteosclerosis. An antibody to IL-1has been shown to be present. 212
APPROACH TO THE PATIENT

27

The evaluation of patients with urticaria/angioedema (Fig. 38-9) begins

with a comprehensive history, with particular emphasis on the recognized
causes, and a physical examination. Some varieties of urticaria may be
identified by their characteristic appearance, such as the small wheals with a
large erythematous flare of cholinergic urticaria, the linear wheals in
dermographism, and the localization of lesions to exposed areas in light- or
cold-induced urticaria. If suggested by the history, the physical examination
in all patients with urticaria should include tests for physical urticaria, such
as a brisk stroke to elicit dermographism, the use of a weight to elicit delayed
pressure urticaria, and application of a cold or warm stimulus for cold-induced
urticaria and localized heat urticaria, respectively. Exercise, such as running
in place, may elicit cholinergic urticaria and, in some instances, exerciseinduced anaphylaxis. Phototests to elicit solar urticaria usually are performed
in referral centers, as are challenges for exercise-induced anaphylaxis.
When urticaria has been present for days or weeks at a time (but less than
6 weeks) or occurs recurrently for similar intervals, the main considerations are
allergic reactions (IgE mediated) to food or drugs. A careful history regarding
possibilities is essential. Skin testing can corroborate IgE-mediated
hypersensitivity to foods or can provide suspects when the history is unrevealing.
Double-blind placebo-controlled food challenge can demonstrate clinical
relevance in cases in which the role of a food is uncertain. Non-IgEmediated
causes of urticaria include adverse reactions to NSAIDs and opiates. Any of these
can be associated with concomitant angioedema or, less commonly, present as
angioedema in the absence of urticaria. Children may have acute urticaria in
association with viral illnesses; it is unclear whether infection with bacteria such
as Streptococcuscan induce urticaria as well, but neither form occurs in adults
with the exception of urticaria in association with infectious mononucleosis
(EpsteinBarr virus) or as a prodrome to hepatitis B

28

Figure 38-9 Approach to the patient with urticaria/angioedema. ACE =

angiotensin-converting enzyme; IgE, immunoglobulin E; INH = inhibitor; =
decreased.
infection. In each of these circumstances, individual lesions last anywhere from
4 hours to 24 hours and fade without associated purpura. If hives last less
than 2 hours, the cause is usually physical urticaria, the most common being
dermatographism, cholinergic urticaria, and cold urticaria. The main exception is
delayed pressure urticaria, in which lesions typically last 1236 hours and first
appear 36 hours after the initiating stimuli. Once urticaria continues for longer
than 6 weeks (particularly if present for many months or years) chronic urticaria is
present. The term chronic spontaneous urticaria has been employed recently to
eliminate confusion with physical urticarias. Chronic urticaria is now divided into

29

chronic idiopathic urticaria for which a cause has not yet been found and chronic
autoimmune urticaria. Angioedema accompanies chronic urticaria in 40% of cases
and is more problematic in the autoimmune subgroup. Swelling in association
with chronic urticaria can affect hands, feet, eyes, cheeks, lips, tongue, and
pharynx, but not the larynx. When angioedema is present in the absence of an
identifiable antigen or exogenous stimulus, the main entities to consider are
C1 INH deficiency (hereditary or acquired) and idiopathic angioedema.
Approximately 0.5% of patients have an urticarial vasculitis with palpable
purpura or other stigmata of a possible vasculitis, such as fever, elevated
sedimentation rate, petechiae or purpura, elevated white blood cell count, or
lesions of unusual duration (3672 hours). The differential diagnosis of acute,
chronic, and physical urticaria/angioedema is summarized in Box 38-1.
LABORATORY FINDINGS
In most patients with chronic urticaria/angioedema, no underlying disorders or
causes can be discerned.

Diagnostic studies should be based on findings elicited by the history and

physical examination. Evaluation of chronic urticaria/angioedema should include

30

thyroid function tests, assays for antimicrosomal and antithyroglobulin antibodies,

and the autologous skin test can be done, even in an office setting.213 Routine
screening laboratory tests are of little value. The histamine release assay for antiIgE receptor or anti-IgE antibodies are now available in specialized
laboratories. Serum hypocomplementemia is not present in chronic idiopathic
urticaria or chronic autoimmune urticaria and mean levels of serum IgE in
these patients are not different from the general population in which the incidence
of atopy is 20%.
Cryoprotei should be sought in patients with acquired cold urticaria. An
antinuclear antibody test should be obtained in patients with solar urticaria.
Assessment of serum complement proteins may be helpful in identifying patients
with urticarial venulitis or serum sickness (C4-, C3-, C1q-binding assay for
circulatory immune complexes), as well as those with hereditary and acquired
forms of C1 INH deficiency (C4, C1 INH by protein and function, C1q level).
Skin biopsy of chronic urticarial lesions should be undertaken to identify
urticarial venulitis or to assess rashes where the urticarial nature is not clear.
There is little role for routine prick skin testing or the
radioallergosorbent test in the diagnosis of specific IgE-mediated antigen
sensitivity in chronic urticaria/angioedema. Inhalant materials are uncommon
causes of urticaria/angioedema, and food skin tests may be difficult to interpret.
The tests for drugs are limited to penicillin but cannot be performed in patients
with dermographism. The radioallergosorbent test should be reserved for those
in whom skin testing is contraindicated, unavailable, or unrevealing despite a
highly suspected history.
A finding of the release of histamine from peripheral basophilic leukocytes
has supported the diagnosis of anaphylactic sensitivity to a variety of antigens,
which include pollens and insect venom.
HISTOPATHOLOGY
Edema involving the superficial portion of the dermis is characteristic
of urticaria, whereas angioedema involves the deeper dermis and subcutaneous
tissue. Both disorders are associated with dilatation of the venules.

31

In chronic urticaria, the dermal infiltrating inflammatory cells may be

sparse or dense and include more CD4 than CD8 T lymphocytes, neutrophils,
eosinophils, and basophils 46,214 without B lymphocytes or natural killer (NK)
cells. NKT cells have not been assessed. Increased expression of TNF-and IL3 on endothelial cells and perivascular cells was detected in the upper dermis of
patients with acute urticaria, chronic idiopathic urticaria, and delayed -pressure
urticaria and in one patient with cold urticaria. 215 TNF- also was detected on
epidermal keratinocytes in lesional and nonlesional biopsy specimens. In
chronic idiopathic urticaria, CD11b and CD18 cells were detected about the
blood vessels in the superficial and deep dermis. Direct immunofluorescence
tests for immunoglobulins and complement proteins were negative.
Major basic protein and eosinophil cationic protein, which are derived
from the eosinophils granule, are present around blood vessels and are dispersed
in the dermis in lesions of acute urticaria, chronic idiopathic urticaria,
delayed-pressure urticaria, cholinergic urticaria, and solar urticaria. In chronic
idiopathic urticaria, free eosinophil granules in the dermis were increased in
wheals of greater than 24 hours duration as compared with wheals lasting
fewer than 24 hours. The secreted form of eosinophil cationic protein and
eosinophil-derived neurotoxin were detected on cells in greater amounts in
biopsy specimens from patients with chronic urticaria without autoantibodies
than in those with autoantibodies. P-selectin, E-selectin, intercellular
adhesion molecules 1, and vascular cellular adhesion molecule 1 have been
demonstrated on the vascular endothelium of patients with chronic idiopathic
urticaria and dermographism. Major histocompatability complex class II antigen
also is upregulated on the endothelial cells of patients with chronic urticaria,
and the peripheral blood lymphocytes have increased CD40 ligand expression
and higher Bcl-2 expression; these observations suggest an augmentation of
autoimmune phenomena.216
In papular urticaria, the epidermis is thick with intercellular edema and
lymphocytes. In the dermis, there is edema with an infiltrate containing T

32

lymphocytes, macrophages, eosinophils and neutrophils without B lymphocytes

or the deposition of immunoglobulins, fibrin and C3.
TREATMENT
Therapy of acute urticaria uses antihistamines as described in Fig. 3810; however, the rash can be severe and generalized, and angioedema may be
present as well. Thus, if relief provided by nonsedating antihistamines
appears insufficient, one can try hydroxyzine or diphenhydramine at 2550 mg
qid.217 Alternatively nonsedating antihistamines can be tried employing up to 46
tablets/day as has been reported for treatment of cold urticaria. 92 A course of
corticosteroid can be used, for example, 4060 mg/day for 3 days and taper
by 510 mg/day. Epinephrine can relieve severe symptoms of urticaria or
angioedema (generalized urticaria, severe pruritus, accelerating angioedema) and
is indicated if laryngeal edema is present. Edema of the posterior tongue and/or
pharyngeal edema can be confused with it.
The ideal treatment for urticaria/angioedema is identification and
removal of its cause. Many patients with acute urticaria and angioedema probably
are not treated by physicians because the cause is identified by the individual or
the course is limited. Treatment of chronic urticaria focuses on measures that
provide symptomatic relief. The physician should provide not only medications
but also support and reassurance. In a questionnaire study, patients with chronic
idiopathic urticaria considered the worst aspects to be pruritus and the
unpredictable nature of the attacks. The presence of facial angioedema can be
particularly disconcerting and tongue and/or pharyngeal edema is often
considered life threatening. This is not the case and is confused with the
potential for laryngeal edema seen with anaphylaxis, or anaphylactic-like
reactions, C1 INH deficiency, or reactivity to ACE inhibitors. Affected
individuals reported sleep disturbances, diminished energy, social isolation,
and altered emotional reactions as well as difficulties in relation to work, home
activities, social life, and sex life. 218,219 Another study showed a correlation
between the severity of chronic idiopathic urticaria and depression. In a
questionnaire study, individuals with delayed pressure urticaria and

33

cholinergic urticaria had the most quality-of-life impairment.220 Those with

cholinergic urticaria suffered in relation to their sporting activities and sexual
relationships. Although urticaria/angioedema may be a source of frustration to
both physicians and patients, most individuals can achieve acceptable
symptomatic control of their disease without identification of the cause. In some
individuals, it is important to avoid aspirin and other NSAIDs. Antipruritic
lotions, cool compresses, and ice packs may provide temporary relief. H1-type
antihistaminic drugs are the mainstays in the management of
urticaria/angioedema. The older H1-type antihistaminics are known as classic,
traditional, or first generationH1-type antihistamines. Newer, low-sedating, or
second- and third generation H1-type antihistamines with reduced sedative and
anticholinergic side effects have become the initial therapeutic agents of
choice. The drug should be taken on a regular basis and not as needed. If the
initial drug chosen is ineffective, an agent from a different pharmacological
class should be used and nonsedating antihistaminics can be combined or the dose
of any one of them increased. When this is ineffective, doses of hydroxyzine or
diphenhydramine in the 2550 mg qid may be tried. The same is true for the
treatment of dermatographism when it is particularly severe. It should be noted
that if the molar release of histamine in the skin exceeds that of the delivered
antihistamine (as can be seen with dermatographism), the histamine will keep
the receptors to which it is bound in the active conformation, and therapeutic
efficacy with the antihistamine will be achieved only when its molar
concentration is much greater than that of histamine. Diphenhydramine is an
alternative to hydroxyzine or cetirizine for dermatographism but not for
cholinergic urticaria.221,22 Cold urticaria can be treated with most antihistaminics
but cyproheptadine at 48 mg tid or qid seems to be particularly
effective.223226 Excellent results have been recently reported with
desloratadine at four times/day.92Local heat urticaria is treated with
antihistaminics; no regimen is particularly favored. Although anecdotal
reports suggest that delayed pressure urticaria will respond to NSAIDs,
dapsone, cetirizine, or sulfasalazine, most require corticosteroids (used as in

34

chronic urticaria) to control symptoms and cyclosporine can be a particularly

effective alternative. Familial cold autoinflammatory syndrome (urticaria)
responds to parenteral IL-1 receptor antagonist (anakinra) as does some cases of
Schnitzler syndrome.
Treatment choices for chronic urticaria (idiopathic or autoimmune)
have been reviewed 227 and are

Figure 38-10 Treatment of chronic idiopathic or autoimmune

urticaria/angioedema. Note that the following agents are expected to be effective
rarely, if ever: hydroxychloroquine, colchicine, dapsone, sulfasalazine,
mycophenolate mofetil. Hydroxychloroquine is, however, the drug of choice for
the hypocomplementemic urticarial vasculitis syndrome. Urticarial vasculitis may
respond to dapsone or colchicine. Omalizumab (IgG anti IgE monoclonal
antibody), not yet approved for treatment of chronic spontaneously occurring

35

urticaria and angioedema is as effective as cyclosporine with far less toxicity and
when available, will be a major therapeutic advance.
summarized in Fig. 38-10. It is important to use first-generation
antihistamines at a maximal dose if nonsedating antihistamines have not been
helpful before resorting to corticosteroids or cyclosporine. H2-receptor
antagonists may yield some additional histamine receptor blockade, although
their contribution is usually modest. The efficacy of leucotriene antagonists is
controversial, with equal numbers of pro and con articles. If steroids are used, this
author recommends not exceeding 25 mg q.o.d. or 10 mg daily. With either
approach, attempts to slowly taper the dose should be made every 23 weeks. One
mg prednisone tablets can be very helpful when the daily dose is less than 10
mg. Double-blind placebocontrolled studies of cyclosporine indicate that it is
a good alternative to corticosteroid,228,229 and can be safer when used appropriately.
Measurement of blood pres sure, blood urea nitrogen level, and creatinine level,
and a urinalysis should be done every 68 weeks. The starting adult dose is 100
mg bid; it can be slowly advanced to 100 mg tid, but not higher. The response rate
is 75% in the autoimmune groups and 50% in the idiopathic group. No
comparable studies (or clinical effects) have been obtained with dapsone,
hydroxychloroquine, colchicine, sulfasalazine, or methotrexate and only small
numbers cases have been treated successfully with intravenous globulin or
plasmapheresis.230,231 Successful treatment of chronic autoimmune urticaria has
been reported with Omalizumab 232 with results comparable to that seen with
cyclosporine. The rate of response can be very striking, for example, remission
with a single dose. Additional articles have appeared, 233,234 although
uncontrolled.
Urticarial vasculitis is treated with antihistamines and if severe, with lowdose corticosteroid. Here dapsone or hydroxychloroquine may be steroid
sparing. When urticarial vasculitis is part of a systemic disease, the treatment
will focus on what is needed for the underlying disorders. The drug of choice
for the hypocomplementemic urticarial vasculitis syndrome (with circulating
immune complexes due to IgG anti-C1q)195 is hydroxychloroquine. 235

36

Angioedema caused by ACE inhibitor can be an acute emergency with

laryngeal edema or tongue or pharyngeal edema that is so extensive the
patient cannot manage secretions and intubation is necessary. Supportive
therapy, epinephrine, and time are needed; there is no response to
antihistamines or corticosteroids. Other antihypertensive agents can be
substituted, including those that block angiotensin II receptors.
Acute attacks of HAE are unresponsive to antihistaminics or
corticosteroid. Epinephrine may be given but a positive response is actually
uncommon. Intubation or tracheostomy may be needed when severe laryngeal
edema is encountered. Recently, a preparation of C1 INH (Berinert) has been
approved in the United States for intravenous infusion to treat acute attacks of
HAE. It is effective and has been available and employed in Europe and Brazil for
over two decades. Icatibant, 236 a bradykinin B-2 receptor antagonist, has been
approved for acute treatment in Europe but not in the United States. It is
given by subcutaneous injection. Kalbitor, a plasma kallikrein inhibitor
(ecallantide), has been approved for the treatment of acute attacks of HAE in the
United States. It too is administered by subcutaneous injection. 237 In the past,
fresh frozen plasma was an option. It has been used with excellent success for
years, but occasional dramatic worsening of symptoms has been reported
because all the plasma factors needed for bradykinin generation are also being
infused.
A second C1 INH nanofiltered preparation (Cinryze) has been approved in
the United States for prophylactic treatment of AHE types I and II. It is
administered by intravenous injection up to twice weekly. Prophylaxis with
androgens such as Danazol (200 mg tablets) or Stanazolol (2 mg tablets) 238,239
or antifibrinolytics such as E-aminocaprioc acid or tranexamic acid 240 have been
employed (used) successfully for many years. 241,242 The androgens are more
commonly usedone watches for hirsutisum, irregular menses, and abnormal
liver chemistries, as potential side effects. In the long term, hepatic adenomas may
appear. Increased dosages may be used when a patient undergoes elective

37

surgical procedures (e.g., 3 tablets/day for 23 days before the procedure, the day
of the procedure, and 1 day after)
Fresh frozen plasma is a safe alternative given a few hours prior to the
procedure and clearly C1 INH concentrate can be used. Acquired C1 INH
deficiency can be treated with low-dose androgens in addition to therapy for
the underlying condition. C1 INH concentrate may be helpful but the presence of
anti-C1 INH will limit responsiveness to reasonable doses. Plasmapheresis and/or
cytotoxic agents may be used.
ACKNOWLEDGMENT
I wish to thank Dr Nicholas Soter who reviewed this manuscript, made many
helpful suggestions, and contributed two of the photos.

38

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