Approach to the child with recurrent infections

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Approach to the child with recurrent infections

Author: Manish J Butte, MD, PhD
Section Editors: Luigi D Notarangelo, MD, Sheldon L Kaplan, MD
Deputy Editor: Elizabeth TePas, MD, MS

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Apr 2025. | This topic last updated: Jun 30, 2022.

INTRODUCTION

A common reason for bringing an infant or child for a medical visit is recurrent infections.
This may refer to infections that are too great in number, too severe, too long lasting; that are
associated with unusual complications; or that fail to resolve with standard therapy. The
causes are multiple and can be grouped into four categories: the "normal" child, the child
with atopic disease, the child with another chronic condition, and the child with an
immunodeficiency.

The approach to the child with recurrent infections will be reviewed here. Laboratory studies
evaluating the function of the immune system and specific immunodeficiencies are discussed
briefly here and in more detail elsewhere. (See "Laboratory evaluation of the immune system"
and "Primary humoral immunodeficiencies: An overview" and "Selective IgA deficiency" and
"Severe combined immunodeficiency (SCID): An overview" and "Primary disorders of
phagocyte number and/or function: An overview" and "Clinical manifestations, epidemiology,
and diagnosis of common variable immunodeficiency in adults" and "Syndromic
immunodeficiencies" and "Inherited disorders of the complement system".)

OVERVIEW

The goal of this diagnostic approach is to differentiate the child with an inborn error of
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immunity (IEI; also called a primary immunodeficiency [PID]) from the "normal child" who has
more than the average number of infections or from the child who has an underlying disease
that mimics infection, predisposes the child to certain types of infections, and/or results in
secondary immune system dysfunction. Most often, these categories can be determined from
the history, physical examination, and screening investigations.

Recurrent infections are infections that are too great in number, too severe, or too long
lasting. Recurrent infections are defined as two or more severe infections in one year, three or
more respiratory infections (eg, sinusitis, otitis, bronchitis) in one year, or the need for
antibiotics for two months/year. Severe/serious infections include those with persistent
evidence of inflammation (eg, fever) or confinement to bed for a week or more (eg, missing
school or other activities); failure to respond to oral antibiotics and/or the need for
intravenous antibiotics or hospitalization; infections with an unusual pathogen; unusual
complications (eg mastoiditis, pleural effusion, abscesses); or persistent laboratory
abnormalities (eg, leukocytosis, elevated erythrocyte sedimentation rate [ESR]/C-reactive
protein [CRP], persistent imaging abnormalities).

Clinical features suggestive of a primary immunodeficiency — The following features

should lead to suspicion of an immunodeficiency and consideration of referral to an
immunology specialist for evaluation [1-7]. (The first 10 are modified from the 10 Warnings
Signs of PID created by the Jeffrey Modell Foundation [8]):
● Family history of immunodeficiency or unexplained early death (eg, before age 30 years)
● Failure to gain weight or grow normally (failure to thrive)
● Need for intravenous antibiotics and/or hospitalization to clear infections
● Six or more ear or respiratory tract infections within one year
● Two or more serious sinus infections or pneumonias within one year
● Four or more new ear infections within one year
● Two or more episodes of sepsis or meningitis in a lifetime
● Two or more months of antibiotics with little effect
● Recurrent or resistant oral or cutaneous candidiasis
● Recurrent deep skin or organ abscesses
● Infection caused by an unusual microbial organism and/or in an unusual location
● Complications from a live vaccine (eg, rotavirus, varicella, and Bacillus Calmette-Guérin

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[BCG] vaccines)
● Chronic diarrhea
● Nonhealing wounds
● Extensive skin lesions
● Persistent lymphopenia (a count of <1500 cells/microL in patients over five years and
<2500 cells/microL in younger children)
● Unexplained autoimmunity or fevers
● Granulomas
● Hemophagocytic lymphohistiocytosis (HLH)
● Lymphoma in childhood
● Features typical of syndromic PIDs (eg, cartilage-hair hypoplasia, Chediak-Higashi
syndrome, ataxia-telangiectasia) (see "Syndromic immunodeficiencies")

Family history of immunodeficiency was the most predictive factor of any PID in a
retrospective survey of 563 children who presented to two pediatric immunodeficiency
centers for evaluation of possible PID [9]. In addition, the use of intravenous antibiotics for
sepsis and failure to thrive were strong identifiers of neutrophil PID and T cell PID,
respectively.

In infants, additional features suggestive of a PID include hypocalcemia with or without

seizures, congenital heart defects (mainly conotruncal anomalies), absence of thymic shadow
on chest radiograph ( image 1), and delayed umbilical cord detachment (>30 days) [4].

Severe combined immunodeficiency (SCID) is considered a pediatric emergency, and special

precautions should be taken if this diagnosis is suspected. (See "Severe combined
immunodeficiency (SCID): An overview", section on 'Measures to prevent initial infections' and
'Management of the child with recurrent infection' below.)

MAJOR CAUSES

The majority of children who present with recurrent infections, especially localized to one
organ system, have increased exposure, allergy, or chronic disease, including anatomic
problems, rather than a defect in immune response. The percentages seen in each group
listed below are based upon the authors' clinical experience and may vary regionally
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depending upon the population and referral patterns.

The "normal" child — Approximately 50 percent of children with recurrent infections

referred for evaluation have no known significant cause for these infections.

Infants and children vary considerably as to the number of infections experienced. The
average child has four to eight respiratory infections per year [10-12]. Some infants and
young children have only one or two infections per year, especially if they have limited contact
with persons outside of their immediate family. Others may have 10 to 12 infections per year,
particularly if they have older siblings or if they attend daycare or preschool. Exposure to
passive smoking also increases the risk of upper respiratory infections [13].

The mean duration of viral respiratory symptoms is eight days [1]. However, the normal range
can extend beyond two weeks, which means that the "normal" child with over 10 viral
respiratory infections can have symptoms for nearly one-half of a year.

With regard to the number and types of infections seen, most of the respiratory infections are
viral. These children generally do not have more than one episode of pneumonia or more
than two episodes of uncomplicated otitis media in the first three years of life.

These children have normal growth and development, respond quickly to appropriate
treatment, recover completely, and appear healthy between infections. The physical
examination and laboratory tests are normal. (See 'Physical examination' below and
'Laboratory evaluation' below.)

An unusual cause of recurrent infection in a normal child is Munchausen syndrome by proxy,

a form of child abuse. These children have a history of repeated illnesses, based upon the
testimony of the caretaker, that often require repeated diagnostic procedures, treatment with
multiple medicines, and frequent school absenteeism and/or hospitalizations. Common
infectious complaints include fever, cough, recurrent skin infections, and/or diarrhea. These
illnesses are not validated by repeated medical examinations, and the child often gets better
in the hospital or in the absence of the caregiver.

Occasionally, the caregiver induces an infection by putting contaminated material (saliva,

urine, feces) in an intravenous line, on the skin, or in the ears. Bacterial cultures show
multiple organisms and mimic the profile present in the contaminating material.

The caregiver often resists stopping medications (such as antibiotics or immune globulin
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infusions) or discharging the child from the hospital. In addition, the caregiver often has a
history of abnormal behavior and may be seeking attention. A full description of the
syndrome is reviewed separately. (See "Medical child abuse (Munchausen syndrome by
proxy)".)

The child with atopic disease — Approximately 30 percent of children with recurrent
infections have atopic disease. Chronic allergic rhinitis may be mistaken for chronic or
recurrent upper respiratory infections. Children with atopic disease often develop coughing
and wheezing following viral respiratory infections. These symptoms are frequently
misdiagnosed as pneumonia or bronchitis rather than reactive airways disease/asthma.
These episodes respond poorly to antibiotics but well to allergy/asthma medications. (See
"Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis" and "Role of viruses in
wheezing and asthma: An overview".)

Children with atopic disease are more likely to develop recurrent and persistent upper
respiratory infections, such as sinusitis, rhinitis, and otitis media [14]. This increased
susceptibility to infection may be due to enhanced adherence of pathogens to inflamed
respiratory epithelium, increased mucosal permeability, or an altered immune response to
certain viral and bacterial pathogens [15,16]. The specific type of infection tends to recur in a
given child. (See "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis",
section on 'Predisposing factors' and "Acute otitis media in children: Epidemiology,
microbiology, and complications", section on 'Risk and protective factors'.)

Growth and development are usually normal. Children with atopy often have characteristic
physical findings, such as "allergic shiners" or a transverse nasal crease. A total
immunoglobulin E (IgE) is sometimes included in the laboratory screening for
immunodeficiency. A normal total IgE tends to exclude IgE-mediated allergy, although it may
be falsely low in an infant. An elevated IgE (eg, >100 int. units/mL) is suggestive of allergy, but
an elevated IgE alone is not diagnostic for atopic disease. (See 'Physical examination' below
and 'Laboratory evaluation' below and "Overview of skin testing for IgE-mediated allergic
disease" and "Overview of in vitro allergy tests".)

It is important to note that primary immunodeficiencies (PIDs) and allergic disease can
coexist. In a retrospective series of children evaluated for PID, 31 percent (9 of 29) who had
evidence of antigen-specific IgE by skin prick or blood testing were diagnosed with an
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immunodeficiency compared with 9 percent (6 of 68) of those who were negative on specific
IgE testing [17]. Immunodeficiencies with associated atopy include selective immunoglobulin
A (IgA) deficiency, common variable immunodeficiency (CVID), chronic granulomatous disease
(CGD), and DiGeorge syndrome. Immunodeficiencies in which elevated levels of IgE are seen
include hyperimmunoglobulin E syndrome due to signal transducer and activator of
transcription 3 (STAT3) mutations, interleukin (IL) 6 signal transducer (IL6ST) deficiency, zinc
finger protein 341 (ZNF341) deficiency, caspase recruitment domain family member 11
(CARD11) dominant negative defect, phosphoglucomutase 3 (PGM3) deficiency, IL-21 receptor
(IL21R) deficiency, erbb2-interacting protein (ERBIN) deficiency, actin-related protein 2/3
complex, subunit B (ARPC1b) defect, Wiskott-Aldrich syndrome, Omenn syndrome, IPEX
(immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, dedicator of
cytokinesis 8 (DOCK8) deficiency, and lipopolysaccharide-responsive-beige-like-anchor (LRBA)
deficiency. (See "Autosomal dominant hyperimmunoglobulin E syndrome" and "Wiskott-
Aldrich syndrome" and "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-
linked" and "Combined immunodeficiencies: Specific defects", section on 'CARD11 deficiency'
and "Syndromic immunodeficiencies" and "T-B-NK+ SCID: Pathogenesis, clinical
manifestations, and diagnosis", section on 'Omenn syndrome phenotype' and "Autoimmune
lymphoproliferative syndrome (ALPS): Clinical features and diagnosis", section on 'LRBA
deficiency disease'.)

The child with chronic disease — Ten percent of children with recurrent infections have an
underlying chronic disease other than atopy or immunodeficiency. The child with a
nonimmune chronic illness often presents with poor growth/failure to thrive, a sickly
appearance, and physical findings characteristic of the specific chronic disease. Diseases in
this category include cystic fibrosis, gastroesophageal reflux, congenital heart disease, and
chronic aspiration. Patients may also have an underlying anatomic defect. (See "Cystic
fibrosis: Clinical manifestations and diagnosis", section on 'Overview of clinical features' and
"Gastroesophageal reflux in infants" and "Gastroesophageal reflux disease in children and
adolescents: Clinical manifestations and diagnosis" and "Suspected heart disease in infants
and children: Criteria for referral" and "Aspiration due to swallowing dysfunction in children".)

Patients in this group are more susceptible to infection for various reasons, including the
following [18]:

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● Barrier failure – Skin or sinus tracts/fistulae or structural defects involving the cribriform
plate or other parts of the skull
● Inadequate clearance of secretions – Hypotonia or a central nervous system (CNS)
abnormality leading to aspiration, abnormal cilia structure or function, abnormal mucus
production
● Obstruction – Eustachian tube dysfunction, tonsillar and/or adenoidal hypertrophy,
ureteropelvic junction obstruction, chronic obstructive pulmonary disease
● Cardiovascular problems – Heart disease with increased pulmonary blood flow,
structurally abnormal cardiac valve
● Foreign body – Central venous line, ventriculoperitoneal shunt, artificial cardiac valve,
indwelling catheter, or noniatrogenic foreign body typically found in the nose, ear, or
airway
● Resistant organisms – Penicillin-resistant pneumococcus, Pseudomonas, vancomycin-
resistant Enterococcus, multidrug-resistant Mycobacterium tuberculosis (recurrent skin
infections caused by community-associated methicillin-resistant Staphylococcus aureus
[MRSA] are common both in children with chronic disease and in normal children
despite appropriate antibiotic therapy)
● Continuous reinfection – Contaminated water supply, chronically infected pet, deliberate
infection (Munchausen syndrome by proxy)

The child with an immunodeficiency — Ten percent of children with recurrent infections
have an immunodeficiency, with a defect in one or more components of the immune system
[5]. Components of the adaptive immune system include B cells (humoral or antibody system)
and T cells (cellular system). The innate immune system is made up of the phagocytic cell
system and the complement system. Other components of the innate immune system
include sensors of pathogen-associated molecular patterns (PAMPs), mannose-binding
protein, and respiratory tract cilia.

Immunodeficiency may be secondary or primary. Secondary immunodeficiencies usually

occur well after infancy, while many PIDs present during the first years of life. Both primary
and secondary immunodeficiency can lead to an increased susceptibility to malignancy and
autoimmune disease. PIDs most often affect B cell function, while secondary
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immunodeficiencies more often affect T cells (the cellular system).

Primary immunodeficiencies — The overall incidence of PIDs is 1 in 10,000. The prevalence

of diagnosed PID in the United States in 2005 was 1 in 2000 children [19]. In Sweden, the
prevalence in children ≤18 years of age was 1 in 10,000 [6]. More than 400 disorders, many
genetically defined, have been characterized [2,5,20]. The type and pattern of recurring
infections depend on which components of the immune system are affected ( table 1)
[2,5,7]. Infection severity also varies, ranging from mild respiratory infections to
overwhelming systemic infections [2,5]. In addition, the rate of infections drops remarkably
after early childhood. (See 'Clinical features suggestive of a primary immunodeficiency'
above.)

Many of the PIDs are caused by an antibody (B cell) deficiency or a combined antibody plus
cellular (T cell) abnormality ( figure 1) [2]. Isolated T cell defects, as well as phagocytic cell,
complement, and other innate immune defects, are less common. Thus, B cell (antibody) or
combined B and T cell diseases should be considered initially, unless clinical features suggest
otherwise. (See "Primary humoral immunodeficiencies: An overview" and "Severe combined
immunodeficiency (SCID): An overview" and "Combined immunodeficiencies: An overview"
and "Primary disorders of phagocyte number and/or function: An overview" and "Inherited
disorders of the complement system" and "Mendelian susceptibility to mycobacterial
diseases: Specific defects" and "Toll-like receptors: Roles in disease and therapy", section on
'TLR signaling defects in inborn errors of immunity' and "Clinical manifestations,
epidemiology, and diagnosis of common variable immunodeficiency in adults".)

Secondary immunodeficiencies — Underlying disease states, medications, injury, previous

surgical procedures, and prematurity can lead to immune system dysfunction. Secondary
immunodeficiencies are more common than PIDs. Over 50 disorders leading to secondary
immunodeficiency have been identified [2]. Common examples include human
immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), diabetes mellitus,
malignancy, and immunosuppressive drugs. (See "Secondary immunodeficiency induced by
biologic therapies".)

HISTORY AND PHYSICAL EXAMINATION

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Birth history — Pregnancy history should be explored for maternal illness (eg, human
immunodeficiency virus [HIV], cytomegalovirus [CMV]), risky behaviors and exposure to
toxins, prescription medications, illicit drugs, tobacco, and alcohol. These factors can increase
the risk of secondary immunodeficiency in the newborn. Birth history should include length
of gestation, birth weight, and neonatal problems, such as jaundice, respiratory distress, or
need for intensive care. Transfusions in the neonatal period should be recorded. (See
"Recognition of immunodeficiency in the first three months of life", section on 'Risk factors for
immunodeficiency and infection'.)

Feeding history, including food intolerance, duration of breastfeeding, and a possible history
of gastroesophageal reflux (which may predispose to aspiration pneumonia), should be
reviewed. Delayed detachment of the umbilical cord should be noted since persistent
attachment beyond 30 days is suggestive of a leukocyte-adhesion defect [21,22]. Newborn
screening for primary immunodeficiencies (PIDs), if available, should be reviewed. Seemingly
normal infants will be identified by newborn screening for severe combined
immunodeficiency (SCID) [23]. Other clinical features that suggest an immunodeficiency in
newborns and infants in the first months of life are reviewed in detail separately. (See
"Primary disorders of phagocyte number and/or function: An overview" and "Leukocyte-
adhesion deficiency disorders" and "Recognition of immunodeficiency in the first three
months of life", section on 'Clinical features suggestive of immunodeficiency' and "Newborn
screening for inborn errors of immunity".)

Growth and development — Weight, height, and head circumference should be plotted and
followed over time. Children with chronic disease or immunodeficiency often have poor
weight gain or even weight loss. This is particularly true in the presence of oral ulcers,
candidiasis, or chronic diarrhea. Children with chronic lung, heart, or gastrointestinal disease
are often small because of anorexia, high energy expenditure, or malabsorption caused by
infection or bacterial overgrowth. (See "Poor weight gain in children older than two years in
resource-abundant settings", section on 'Etiology' and "Poor weight gain in children younger
than two years in resource-abundant settings: Etiology and evaluation", section on 'Causes
and risk factors'.)

Functional assessment of a child's development should be made in the following five areas:
motor (gross and fine), language, cognitive, social, and emotional. Chronic disease and

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certain PIDs, most notably the syndromic immunodeficiencies, such as ataxia-telangiectasia

and DiGeorge syndrome, can lead to delay in attaining developmental milestones.
Progressive neurologic dysfunction is seen in young adults with Chediak-Higashi syndrome.
Delayed speech can occur with recurrent and chronic otitis media. (See "Syndromic
immunodeficiencies" and "Developmental-behavioral surveillance and screening in primary
care".)

Immunization history — Immunization history should be reviewed. Details of interest

include any adverse effects from a vaccine, particularly live-virus vaccines (eg, central nervous
system [CNS] complications from oral polio vaccination that is still used in some regions with
a higher incidence of polio or diarrhea following rotavirus vaccine [24]) as well as vaccine
failure or vaccine-strain-related infection (eg, chicken pox in a varicella-vaccinated child).

Live attenuated vaccines given in early infancy, including Bacillus Calmette-Guérin (BCG),
rotavirus, and oral polio vaccine, are of special threat to patients with PIDs (eg,
agammaglobulinemia, combined immunodeficiency, or those with Mendelian susceptibility to
mycobacterial infection). Patients with T cell deficiencies or who are on immunosuppressive
drugs including glucocorticoids may develop progressive infections following live-virus
vaccines. A person who develops infections despite immunization may be immunodeficient
and should be evaluated, including measuring the antibody response to the vaccine.

The immunization record is also valuable when examination of vaccine titers is planned to
evaluate antibody function. (See 'Laboratory evaluation' below and "Assessing antibody
function as part of an immunologic evaluation".)

Medications — Current and past medications (including over-the-counter medicines and

supplements) should be recorded, including duration, effectiveness, and adverse reactions.
Use of any immunosuppressive medications, including glucocorticoids, should be noted. If
immunoglobulin has been given, the route, brand, dose, frequency, use of premedication,
and adverse effects should be noted. Maternal exposure to immunosuppressive medications
such as azathioprine or its metabolites is a well-known cause of lymphopenia in the newborn.
(See "Secondary immunodeficiency induced by biologic therapies".)

Other illnesses — The severity of childhood diseases, such as chicken pox, roseola, and
febrile illnesses, should be noted. An inquiry about past hospitalizations, injuries or accidents,
surgeries, or prolonged school absences may provide clues to the present illness. System
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review should include other immune problems, such as allergies, anaphylaxis, arthritis, or
autoimmunity.

Family history — The presence of family members with similar diseases, recurrent infections,
unexplained death, or autoimmune disease suggests the possibility of a genetic illness.
Inheritance patterns are variable. Many immunodeficiencies have X-linked transmission (eg,
some forms of agammaglobulinemia and chronic granulomatous disease [CGD]). An
autosomal-recessive pattern is seen in conditions such as some complement defects and
ataxia-telangiectasia. An inconstant familial tendency may also be seen (eg, common variable
immunodeficiency [CVID], selective IgA deficiency, hyperimmunoglobulin E syndrome) [5].

Inquiring about consanguinity is important when considering autosomal-recessive

immunodeficiencies. Certain immunodeficiencies are more common in particular ethnic
populations (eg, Artemis-deficiency SCID in Navajos and ataxia-telangiectasia in the
Amish/Mennonites).

Inquiry should also be made about infections in family members, including such illnesses as
tuberculosis, mononucleosis, hepatitis B, herpes simplex, and HIV.

Social history — The home, parents' work environment, and daycare or school should be
explored for exposures, such as ill classmates, allergens, tobacco smoke, contaminated water
supply, pets, farm animals, solvents, and toxins, as well as location near industrial plants [25-
27]. Prior residences and travel history may be important in exposure to infectious agents or
allergens. Daycare and school attendance increases the risk of exposure to respiratory
pathogens.

Infection history — The infection history should include the age of onset, duration,
frequency, sites, organisms, treatment, and response to therapy [2,3,5,6]. Any severe infection
in an otherwise immunocompetent host is sufficient impetus for an immunodeficiency
workup.

Age of onset
● Birth to six months – Infections presenting shortly after birth may be secondary to
prolonged rupture of membranes, congenital infection, infection exposure during the
birth process, or aspiration. Premature infants, especially those needing respirators or
intravenous catheters, are at high risk for infection.
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Several PIDs are associated with early onset of severe infections, notably congenital
neutropenias, leukocyte-adhesion defects, Toll-like receptor (TLR) defects (eg, NEMO),
complement deficiencies, and complete DiGeorge syndrome. Defects in TLR3 signaling
are associated with herpes-simplex encephalitis of the newborn [28-30].
● Six months to two years – Infants and children presenting with infection from six
months to two years of age may fall into any of the four categories listed above (see
'Major causes' above). Normal infants exposed to other children or to tobacco smoke are
more prone to recurrent respiratory infections. Wheezing, eczema/atopic dermatitis,
and food intolerance suggest allergy. Persistent diarrhea, chronic cough, or failure to
thrive suggests cystic fibrosis or a PID. Congenital antibody deficiencies and many
combined immunodeficiencies (eg, zeta-chain associated protein 70 [ZAP-70] deficiency,
CD25 deficiency, immunologic causes of very-early-onset inflammatory bowel disease
[IBD]) usually present at 7 to 12 months, as maternal immunoglobulin G (IgG)
disappears. (See "Primary humoral immunodeficiencies: An overview" and
"Agammaglobulinemia" and "Combined immunodeficiencies: An overview".)
● Two to six years – Children developing infection in the two- to six-year age range may
also fit into any of the four categories outlined above. Secondary immunodeficiencies
resulting from malignancy, nephrotic syndrome, or gastrointestinal problems often
begin at this age. Gastrointestinal disorders can cause loss of protein or specific vitamin
or mineral deficiencies due to malabsorption. Daycare or school entry often results in
frequent respiratory and gastrointestinal infections. Less serious antibody deficiencies
(eg, IgA deficiency and selective antibody deficiency) and combined immunodeficiencies
also first present at this age. As examples, persistent candidiasis suggests chronic
mucocutaneous candidiasis (CMCC), ataxia with infections suggests ataxia-
telangiectasia, and growth retardation with infections suggests combined
immunodeficiencies or cartilage-hair hypoplasia. (See "Syndromic immunodeficiencies"
and "Combined immunodeficiencies: An overview" and "Selective IgA deficiency" and
"Specific antibody deficiency".)
● 6 to 18 years – It is unusual for recurrent infections to first present beyond six years of
age, although defects of adaptive memory may present in young adulthood. HIV
infection and other sexually transmitted diseases should be considered in adolescents.

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Two or more episodes of bacterial meningitis or sepsis suggest a complement or other

innate immune defect [2,5,29,31]. Candidiasis suggests CMCC. Early-onset CVID can
present at this time. Infections associated with vasculitic lesions, arthritis, or recurrent
fever suggest autoimmunity or autoinflammatory disease. The association of
autoimmune cytopenias (especially autoimmune thrombocytopenia and autoimmune
hemolytic anemia) with recurrent infections is a common sign at onset of CVID. (See
"Pediatric HIV infection: Epidemiology, clinical manifestations, and outcome" and
"Inherited disorders of the complement system" and "Chronic mucocutaneous
candidiasis" and "Common variable immunodeficiency in children".)

Sites of infection
● Upper respiratory tract – The upper respiratory tract (nose, throat, ears, sinuses) is the
most common site of infection. Most upper respiratory infections are viral.

Chronic purulent nasal discharge and cough secondary to postnasal drainage suggest
chronic sinusitis. Refractory asthma is sometimes associated with chronic sinusitis.
Gastroesophageal reflux can also cause chronic cough and recurrent otitis media and
sinusitis. Persistently opacified sinuses, particularly cases refractory to antibiotics, may
be due to an antibody deficiency, cystic fibrosis, or primary ciliary dyskinesia in a small
subset of patients. Unilateral purulent nasal discharge suggests a foreign body.

Allergic disease is associated with chronic or seasonal clear nasal discharge, congestion,
itchy eyes, nocturnal cough, and a poor response to antibiotics. Allergic rhinitis can be
misdiagnosed as recurrent upper respiratory infections.

Recurrent candidiasis (after three months of age), stomatitis, gingivitis, and oral
ulcerations occur in T cell and phagocytic cell disorders. Other oral manifestations of
immunodeficiencies are reported [32]. Recurrent aphthous ulcers suggest autoimmune
disease or a periodic fever syndrome. Recurrent pharyngitis or tonsillitis is associated
with defective responses to group A Streptococcus [33].
● Lower respiratory tract – Recurrent pneumonia is rare in immunocompetent children
or children with allergic disease and suggests chronic cardiopulmonary disease, cystic
fibrosis, primary ciliary disease, or immunodeficiency. However, reactive airways
disease/asthma is often misdiagnosed as pneumonia or bronchitis in young children.

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Recurrent pneumonia limited to a particular anatomic region (eg, right middle lobe) is
typically caused by a local anatomic abnormality (eg, foreign body, bronchial
compression by mediastinal adenopathy or vascular anomaly, pulmonary sequestration
or cyst). By contrast, patients with sequential lower respiratory tract infections involving
different regions of the lung often have an underlying systemic disorder (eg, cystic
fibrosis, primary ciliary dyskinesia, recurrent aspiration).
● Blood and brain – Bacterial meningitis and sepsis suggest an antibody deficiency or
complement defect. Chronic enteroviral encephalomyelitis occurs in patients with
profound antibody deficiency and commonly follows oral polio vaccine.

Recurrent meningitis or meningitis with an unusual organism may occur with structural
defects of the cribriform plate, inner ear (Mondini defect), or sinuses. The last is
sometimes a complication of sinus surgery. A cerebrospinal fluid leak through the nose,
ear, or sinuses may occur with structural defect.

Brain abscesses usually result from parameningeal foci of infection, such as sinusitis or
mastoiditis. Remote infections that seed the systemic arterial supply, such as lung
abscesses and infective endocarditis, can also result in brain abscesses. These brain
infections should be distinguished from brain tumors and from lymphocytic infiltrates in
the brain, which are often responsive to immunosuppressive agents (glucocorticoids,
abatacept). The latter have been reported in several patients with cytotoxic T
lymphocyte antigen 4 (CTLA4) deficiency and may also be seen in patients with
lipopolysaccharide-responsive-beige-like-anchor (LRBA) deficiency.
● Other – Abscesses of the skin, lymph nodes, or internal organs suggest a phagocytic or
antibody deficiency. Recurrent abscesses at the same site may indicate an underlying
anatomic defect, such as a congenital branchial cleft cyst, pilonidal cyst, hidradenitis
suppurativa, or a retained foreign body. (See "Hidradenitis suppurativa: Pathogenesis,
clinical features, and diagnosis".)

Recurrent and/or chronic gastrointestinal infections occur in patients with IgA deficiency
or CVID [34]. Persistent norovirus infection leading to protracted, watery diarrhea and
weight loss is common in patients with typical and atypical SCID and in patients with
agammaglobulinemia or severe hypogammaglobulinemia and may occur at any age.

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Recurrent urinary tract infections are uncommon in immunodeficiency and usually

reflect a structural abnormality, such as obstruction, reflux, or bladder dysmotility.

Organisms — Isolation of the same organism repeatedly from a single site suggests a
structural defect, while isolation of an organism from a normally sterile site suggests an
underlying defect in immunity.

Certain immunodeficiencies commonly present with infections caused by "signature"

organisms. Children who present with such infections should undergo laboratory evaluation
for immunodeficiency. (See 'Laboratory evaluation' below.)

As examples:
● Recurrent sinopulmonary infections with encapsulated organisms (eg, pneumococcus,
Haemophilus influenzae type b) suggest B cell abnormalities. (See "Primary humoral
immunodeficiencies: An overview".)
● Recurrent pneumococcal disease suggests a PID, such as agammaglobulinemia or
complement defect. Secondary immunodeficiency due to sickle cell disease, asplenia
(congenital or secondary), HIV/AIDS, or nephrotic syndrome also results in recurrent
pneumococcal disease [35]. (See "Primary humoral immunodeficiencies: An overview"
and "Inherited disorders of the complement system".)
● Pneumocystis jirovecii (carinii) pneumonia is a hallmark of CD40 ligand deficiency and
other primary or secondary T cell immunodeficiencies, including SCID and the T cell
defects associated with HIV or immunosuppressive therapy [36]. (See "Severe combined
immunodeficiency (SCID): An overview" and "Pediatric HIV infection: Epidemiology,
clinical manifestations, and outcome", section on 'Other'.)
● Pseudomonas sepsis may occur in phagocytic disorders or in profound antibody or T cell
immunodeficiency. Pseudomonas infection also occurs in patients with cystic fibrosis,
burns or soft tissue injury, or neutropenia. (See "Cystic fibrosis: Clinical manifestations
and diagnosis", section on 'Overview of clinical features'.)
● Enteroviral meningoencephalitis can be the presenting infection in children with X-linked
agammaglobulinemia (XLA) [37-39]. It is rare in children receiving regular doses of
immune globulin replacement (subcutaneous immune globulin [SCIG] or intravenous
immune globulin [IVIG]). (See "Agammaglobulinemia".)
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Approach to the child with recurrent infections
● Aspergillus, Staphylococcus aureus, coagulase-negative staphylococci, Serratia
marcescens, and Chromobacterium violaceum are common organisms found in
abscesses or soft-tissue infections in patients with CGD [39]. (See "Chronic
granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis".)
● Recurrent staphylococcal skin infections, abscesses, lung cysts, or pneumonia are
characteristic of hyperimmunoglobulin E syndrome. (See "Autosomal dominant
hyperimmunoglobulin E syndrome".)
● Prolonged and severe candidiasis involving the buccal mucosa, tongue, and palate may
be the earliest sign of abnormal T cell immunity [40,41]. (See "Severe combined
immunodeficiency (SCID): An overview" and "Combined immunodeficiencies: An
overview" and "Chronic mucocutaneous candidiasis".)
● Invasive infection with Neisseria species (N. meningitidis, N. gonorrhoeae) occurs in
patients with deficiencies of the late components of complement (C5 to C9) [42-45]. (See
"Inherited disorders of the complement system".)
● Infection with vaccine strains following live vaccines, including oral rotavirus, oral polio,
measles, varicella, or BCG, suggest PID. Vaccine failure (eg, recurrent chicken pox or
shingles in the vaccinated child) also suggests a cellular immunodeficiency. (See
'Immunization history' above.)
● Deep or systemic infections with nontuberculous mycobacteria suggest a deficiency in
type 1 immunity, including the pathways of interferon-gamma or interleukin (IL) 12. (See
"Mendelian susceptibility to mycobacterial diseases: Specific defects".)

Physical examination — The physical examination in children with recurrent infections

provides information as to their general health and may suggest the presence of allergy,
chronic disease, or immunodeficiency.

The child's overall appearance, demeanor, and activity are the first clues to the general state
of health. Vital signs (including oxygen saturation if cardiac or pulmonary disease is
suspected) should be recorded. Unusual dysmorphic appearance may signify a genetic
syndrome. Head circumference should be measured in young infants.

Growth and development is documented by growth charts and maturational milestones.

Weight loss or failure to thrive is suggested by muscle wasting or atrophy of the buttock fat
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Approach to the child with recurrent infections

deposits. Profound growth failure (eg, dwarfism) is noted in some syndromic

immunodeficiencies. (See "Syndromic immunodeficiencies".)

The presence of acute or chronic otitis media should be determined since upper respiratory
infections are the most common recurrent infection. Hearing should be evaluated in children
with recurrent otitis. Draining ears and perforated tympanic membranes suggest
immunodeficiency.

Pallor without anemia, dark circles under the eyes, conjunctivitis, a transverse nasal crease,
congested turbinates, and clear nasal discharge suggest allergy. Purulent nasal discharge,
postnasal drip, and diminished gag reflex are consistent with chronic sinusitis. Pharyngeal
cobblestoning may be seen with either allergic rhinitis or chronic sinusitis. Mouth ulcers,
gingivitis, mucosal candidiasis, and poor dentition suggest immunodeficiency. Diminished or
absent tonsils and cervical nodes in the presence of recurrent respiratory infections suggest
an antibody deficiency. Nasal polyps suggest cystic fibrosis. (See "Chronic rhinosinusitis:
Clinical manifestations, pathophysiology, and diagnosis" and "Cystic fibrosis: Clinical
manifestations and diagnosis", section on 'Sinus and nasopharyngeal disease'.)

All older patients should be asked to cough. A productive or wheezy cough suggests
bronchitis, pneumonia, or asthma. Chest asymmetry, an increased posterior-anterior chest
diameter, and pectus excavatum are associated with asthma and chronic lung disease.
Crackles, wheezes, and abnormal breath sounds should be noted. Digital clubbing suggests
longstanding lung or heart disease, IBD, or chronic infection.

Atopic dermatitis (eczema), excoriations, and dermographism suggest allergic disease.

However, several immunodeficiency syndromes are associated with eczema, including
Wiskott-Aldrich, the hyperimmunoglobulin E syndromes, IPEX, Omenn syndrome,
phosphoglucomutase 3 (PGM3) deficiency, caspase recruitment domain family member 11
(CARD11) disease, and atypical forms of SCID. Cutaneous granulomas, impetigo, or
nonhealing sores suggest antibody or phagocytic immunodeficiency or combined
immunodeficiency (such as milder forms of recombination-activating gene [RAG] deficiency).
Facial rashes, vitiligo, alopecia, and vasculitic lesions suggest autoimmunity [46]. These
autoimmune manifestations may also be observed in patients with atypical forms of SCID.
(See "Wiskott-Aldrich syndrome" and "Autosomal dominant hyperimmunoglobulin E
syndrome" and "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked"
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Approach to the child with recurrent infections

and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis" and "Severe
combined immunodeficiency (SCID): An overview".)

Immunodeficiency disorders can be characterized by an overabundance ( picture 1) or

paucity ( image 2) of lymphoid tissue (eg, tonsils, lymph nodes, spleen) [47]. The absence of
lymph tissue suggests XLA or SCID. Adenopathy and hepatosplenomegaly are frequently seen
in phosphatidylinositol 3-kinase (PI3K) gain of function, B cell disorders (eg, CVID, IgA
deficiency), or HIV infection. Suppurative adenitis is common in CGD.

Clinical patterns suggestive of immunodeficiency — Constellations of certain findings are

characteristic of specific immunodeficiency syndromes [5]. Examples include:
● Ataxia, telangiectasia, and developmental delay in ataxia-telangiectasia (see "Ataxia-
telangiectasia")
● Petechiae, easy bleeding, eczema, and chronic draining ears in Wiskott-Aldrich
syndrome (see "Wiskott-Aldrich syndrome")
● Coarse features with facial asymmetry, chronic-infected eczema, deep-seated abscesses,
and scoliosis in hyperimmunoglobulin E syndrome due to signal transducer and
activator of transcription 3 (STAT3) mutations (see "Autosomal dominant
hyperimmunoglobulin E syndrome")
● Short stature with metaphyseal dystrophy and fine hair in cartilage-hair hypoplasia (see
"Cartilage-hair hypoplasia")
● Congenital heart disease, developmental delay, and dysmorphic facies with low-set ears,
hypertelorism, down-turning eyes, and micrognathia in DiGeorge syndrome (see
"DiGeorge (22q11.2 deletion) syndrome: Management and prognosis" and "DiGeorge
(22q11.2 deletion) syndrome: Epidemiology and pathogenesis")
● Early onset of seborrheic dermatitis and alopecia in some forms of SCID (see "Severe
combined immunodeficiency (SCID): An overview")
● Oral ulcers, gingivitis, and impetigo in CGD or leukocyte-adhesion defects (see "Chronic
granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis" and
"Chronic granulomatous disease: Treatment and prognosis" and "Leukocyte-adhesion
deficiency disorders")

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Approach to the child with recurrent infections
● Oculocutaneous albinism in Chediak-Higashi disease (see "Chediak-Higashi syndrome")
● Abnormal dentition, decreased sweating, and sparse hair associated with frequent
infection suggest ectodermal dysplasia (see "Combined immunodeficiencies: An
overview", section on 'Presentation')
● Dermatomyositis-like rash in XLA (see "Agammaglobulinemia")
● Lupus-like rash in early complement component defects (see "Inherited disorders of the
complement system")
● Extensive warts or molluscum contagiosum in T cell disorders, innate immune defects,
or the warts hypogammaglobulinemia infections myelokathexis (WHIM) syndrome (see
"Molluscum contagiosum" and "Congenital neutropenia" and "Epidermodysplasia
verruciformis", section on 'WHIM syndrome')

Many patients with genetic syndromes have recurrent infection. Syndromic

immunodeficiency is the term given to a variety of conditions in which the immune system is
only one of several organ systems involved. These disorders are covered elsewhere. (See
"Syndromic immunodeficiencies".)

LABORATORY EVALUATION

Initial laboratory evaluation of children with recurrent infection depends upon the history of
past illnesses and the physical examination [5]. Evaluation for primary immunodeficiency
(PID) should focus on the component of the immune system that is most likely to be involved
based upon the initial assessment. The initial laboratory evaluation is reviewed briefly here
and discussed in greater detail separately. Laboratory studies for disorders that cause
secondary immunodeficiency (eg, sickle cell disease, diabetes mellitus) are also discussed
separately (see appropriate topic reviews on the specific disorders). (See "Laboratory
evaluation of the immune system" and "Laboratory evaluation of neutrophil disorders" and
"Overview and clinical assessment of the complement system".)

At a minimum, the following initial panel is suggested:

● Complete blood count (CBC) with differential
● Chemistry panel, including electrolytes, glucose, blood urea nitrogen (BUN), creatinine,
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Approach to the child with recurrent infections

and albumin
● Urinalysis
● Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP)
● IgG, IgM, IgA and IgE levels

On the CBC, particular attention should be paid to the total absolute lymphocyte count.
Lymphopenia, suggestive of a T cell deficiency, is defined as a count of <1500 cells/microL for
patients over five years and <2500 cells/microL for younger children. The presence of anemia,
thrombocytopenia, leukocytosis, or leukopenia should be investigated. An elevated platelet
count suggests chronic inflammation.

The chemistry panel may point to liver disease, hemolysis, diabetes, renal disease,
hypoalbuminemia suggesting protein loss, or malnutrition. Urinalysis for proteinuria, casts,
or cells may suggest nephritis. Excessive protein losses in the urine can also explain
hypogammaglobulinemia in the circulation.

An elevated ESR and/or CRP suggests chronic infection or an autoimmune disease. This
should be followed by appropriate cultures, additional laboratory studies, and/or imaging
based upon the history and physical examination. The lungs and the sinuses are the most
common site of chronic infection. Review of the chest radiograph of a young child should
include examination for the absence of a thymic shadow, a finding common in severe T cell
deficiencies. All children with pneumonitis should have a sweat test for cystic fibrosis. Patients
with bona fide systemic infections but who lack fever and/or elevated CRP should be
evaluated for innate immune diseases.

Immunoglobulin levels should be compared with age-matched controls since

immunoglobulin levels change throughout infancy, childhood, and into adulthood. Low
immunoglobulin levels will suggest antibody or combined immunodeficiencies. An IgG <300
mg/dL, a total Ig (IgG + IgM + IgA) less than 500 mg/dL, or the complete absence of IgA
and/or IgM in a child older than six months suggests an antibody deficiency. IgG subclasses
are not measured as part of a screening evaluation. An elevated IgE level (>100 int. units/mL)
suggests allergy, eczema, or chronic skin infections. A very elevated IgE level (>2000 int.
units/mL) is not uncommon in patients with active eczema but begins to suggest a
monogenic disorder of atopy or one of the hyper-IgE immunodeficiency syndromes. IgD is
also not measured as part of a screening evaluation. Defects in generating functional
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Approach to the child with recurrent infections

antibodies can occur despite normal IgG levels. Thus, normal immunoglobulin levels are not
fully reassuring. (See "Assessing antibody function as part of an immunologic evaluation".)

Additional tests that are often done by the primary clinician prior to referral to a specialist,
include:
● A total complement measurement (CH50) for patients with history of sepsis or neisserial
infection. Measurement of individual, specific complement levels is not a useful
screening step. (See "Overview and clinical assessment of the complement system".)
● Human immunodeficiency virus (HIV) tests for children with delayed onset of severe
infection or with unexplained lymphopenia. HIV testing should be polymerase chain
reaction (PCR) based and not antibody based in patients evaluated for primary
immunodeficiency. (See "Screening and diagnostic testing for HIV infection in adults"
and "Pediatric HIV infection: Diagnostic testing in children younger than 18 months".)
● Lymphocyte analysis by flow cytometry to assess T, B, and natural killer (NK) cells. (See
"Flow cytometry for the diagnosis of inborn errors of immunity".)
● Antibody titers to vaccine antigens including tetanus, diphtheria, and pneumococcus. In
infants under one year of age, isohemagglutinins (IgM and IgG antibodies against the
blood group antigens) may be useful as well. (See "Assessing antibody function as part
of an immunologic evaluation".)

Genetic testing is not included as an initial test by primary care clinicians, as it should be
reserved for immunology and genetics specialists.

MANAGEMENT OF THE CHILD WITH RECURRENT INFECTION

Children undergoing evaluation for recurrent infection need special care during the
evaluation process [5]. This includes:
● Infections must be promptly recognized and aggressively treated. Empiric antibiotic
therapy should be instituted pending culture results.
● Prophylactic antibiotics may be administered depending upon the type of disorder
suspected. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of

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Approach to the child with recurrent infections

management".)
● Live-virus vaccines (eg, oral polio, oral rotavirus, varicella, measle-mumps-rubella [MMR],
smallpox [vaccinia], yellow fever, intranasal influenza) and the live Bacillus Calmette-
Guerin (BCG) vaccine must not be administered to the child ( table 2). Family members
may receive varicella, MMR, and shingles vaccines but not oral polio or smallpox
vaccines. Inactive influenza vaccine may be preferred for household contacts of some
immunocompromised individuals.
● Postexposure infectious prophylaxis may be necessary following exposure to varicella.
● Only irradiated, leukocyte-filtered, virus-inactivated products should be used if blood or
platelet transfusions are necessary. (See "Severe combined immunodeficiency (SCID): An
overview", section on 'Measures to prevent initial infections'.)
● Intravenous immune globulin (IVIG) or subcutaneous immune globulin (SCIG) should
not be given until there has been a thorough evaluation of the patient's immune system.
IVIG and SCIG are expensive, will negate an antibody investigation for several months,
and have potential adverse effects. Their use for antibody replacement should be
restricted to immunologists.

The author will often treat the child with recurrent or chronic bacterial infections (eg, otitis
media, sinusitis, bronchitis, pneumonia) with a six-week course of antibiotic therapy (eg,
cefdinir), followed by prophylactic antibiotics (eg, azithromycin 5 mg/kg orally twice or three
times a week, maximum dose 250 mg/day) while the immune evaluation is ongoing. A three-
to six-month trial of IVIG or SCIG may be indicated for documented severe chronic sinusitis,
mastoiditis, pneumonia, or bronchitis, even if there is no overt evidence of immunodeficiency,
in the uncommon event that this antibiotic regimen fails.

RESOURCES

Helpful material is available for clinicians and parents from [5]:

● The Immune Deficiency Foundation. This includes Diagnostic and Clinical Care
Guidelines [48] and a Patient and Family Handbook [49]. A free physician-to-physician
consulting immunologist program is also available.
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Approach to the child with recurrent infections
● The Jeffrey Modell Foundation.
● American Academy of Allergy, Asthma, and Immunology.
● European Society for Immunodeficiencies.
● International Patient Organization for Primary Immunodeficiencies.
● Resource for Asian Primary Immunodeficiency Diseases (RAPID).
● Primary Immunodeficiency Database in Japan (PIDJ).
● US Immunodeficiency Network (USIDNET).

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Inborn errors of
immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

● Most common causes of recurrent infections in children – The majority of children

who present with recurrent infections, especially localized to one organ system, have
increased exposure, allergy, or an anatomic problem rather than a defect in immune
response. (See 'The "normal" child' above and 'The child with atopic disease' above and
'The child with chronic disease' above.)
● Primary disorders of immune function – Inborn errors of immunity (IEI or primary
immunodeficiencies [PID]) should be considered in infants and children who have
recurrent and/or complicated bacterial infections (eg, sinopulmonary infection,
recurrent soft tissue or organ abscesses, two or more episodes of bacterial sepsis or
meningitis); persistent oral candidiasis; infection with opportunistic, unusual, or
"signature" organisms; failure to thrive; or a family history of immunodeficiency or
unexplained early deaths ( table 1). (See 'Major causes' above.)
● History and physical examination – A careful history and physical examination can
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Approach to the child with recurrent infections

usually isolate the disorder to one of the four components of the immune system in
children in whom a primary immunodeficiency (PID) is suspected. B cell and combined B
and T cell abnormalities account for nearly three-fourths of the PIDs and should be
considered initially. Isolated T cell, phagocytic, and complement defects are rare. (See
'History and physical examination' above.)
● Initial testing – The initial evaluation should include both quantitative and qualitative
tests. Initial tests may include a complete blood count with differential, chemistry
studies, urinalysis, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP),
appropriate cultures, radiologic imaging of the infection site, immunoglobulin levels,
antibody titers to vaccine antigens, and complement activity. Definitive diagnostic
testing should be performed if the initial screening evaluation is abnormal. Definitive
testing should be undertaken in consultation with a pediatric immunologist. (See
'Laboratory evaluation' above and "Laboratory evaluation of the immune system".)

ACKNOWLEDGMENT

The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed to earlier
versions of this topic review.

REFERENCES

1. Bush A. Recurrent respiratory infections. Pediatr Clin North Am 2009; 56:67.

2. Stiehm ER, Ochs HD, Winkelstein JA. Immunodeficiency disorders: general consideration
s. In: Immunologic disorders in infants and children, 5th ed, Stiehm ER, Ochs HD, Winkels
tein JA (Eds), Saunders/Elsevier, 2004. p.289.

3. Ballow M. Approach to the patient with recurrent infections. Clin Rev Allergy Immunol
2008; 34:129.

4. Carneiro-Sampaio M, Jacob CM, Leone CR. A proposal of warning signs for primary
immunodeficiencies in the first year of life. Pediatr Allergy Immunol 2011; 22:345.

5. Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and
management of primary immunodeficiency. J Allergy Clin Immunol 2015; 136:1186.

- Page 24 of 28 -
Approach to the child with recurrent infections

6. Brodszki N, Jönsson G, Skattum L, Truedsson L. Primary immunodeficiency in infection-

prone children in southern Sweden: occurrence, clinical characteristics and
immunological findings. BMC Immunol 2014; 15:31.
7. Hernandez-Trujillo VP. Approach to Children with Recurrent Infections. Immunol Allergy
Clin North Am 2015; 35:625.

8. http://www.info4pi.org/library/educational-materials/10-warning-signs.
9. Subbarayan A, Colarusso G, Hughes SM, et al. Clinical features that identify children with
primary immunodeficiency diseases. Pediatrics 2011; 127:810.

10. Monto AS. Viral respiratory infections in the community: epidemiology, agents, and
interventions. Am J Med 1995; 99:24S.

11. Campbell H. Acute respiratory infection: a global challenge. Arch Dis Child 1995; 73:281.

12. Grüber C, Keil T, Kulig M, et al. History of respiratory infections in the first 12 yr among
children from a birth cohort. Pediatr Allergy Immunol 2008; 19:505.

13. Environmental tobacco smoke: a hazard to children. American Academy of Pediatrics

Committee on Environmental Health. Pediatrics 1997; 99:639.

14. Daly KA, Hoffman HJ, Kvaerner KJ, et al. Epidemiology, natural history, and risk factors:
panel report from the Ninth International Research Conference on Otitis Media. Int J
Pediatr Otorhinolaryngol 2010; 74:231.

15. James KM, Peebles RS Jr, Hartert TV. Response to infections in patients with asthma and
atopic disease: an epiphenomenon or reflection of host susceptibility? J Allergy Clin
Immunol 2012; 130:343.

16. Larsen JM, Brix S, Thysen AH, et al. Children with asthma by school age display aberrant
immune responses to pathogenic airway bacteria as infants. J Allergy Clin Immunol 2014;
133:1008.

17. MacGinnitie A, Aloi F, Mishra S. Clinical characteristics of pediatric patients evaluated for
primary immunodeficiency. Pediatr Allergy Immunol 2011; 22:671.
18. Skoda-Smith S, Barrett DJ. When earaches and sore throats become more than a pain in
the neck. Contemp Pediatr 2000; 17:156.

19. Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency
- Page 25 of 28 -
Approach to the child with recurrent infections

diseases in the United States. J Clin Immunol 2007; 27:497.

20. Picard C, Al-Herz W, Bousfiha A, et al. Primary Immunodeficiency Diseases: an Update on
the Classification from the International Union of Immunological Societies Expert
Committee for Primary Immunodeficiency 2015. J Clin Immunol 2015; 35:696.

21. Woroniecka M, Ballow M. Office evaluation of children with recurrent infection. Pediatr
Clin North Am 2000; 47:1211.

22. Etzioni A. Adhesion molecules--their role in health and disease. Pediatr Res 1996; 39:191.
23. Jyonouchi S, Jongco AM, Puck J, Sullivan KE. Immunodeficiencies Associated with
Abnormal Newborn Screening for T Cell and B Cell Lymphopenia. J Clin Immunol 2017;
37:363.

24. Patel NC, Hertel PM, Estes MK, et al. Vaccine-acquired rotavirus in infants with severe
combined immunodeficiency. N Engl J Med 2010; 362:314.

25. Owen MJ, Baldwin CD, Swank PR, et al. Relation of infant feeding practices, cigarette
smoke exposure, and group child care to the onset and duration of otitis media with
effusion in the first two years of life. J Pediatr 1993; 123:702.

26. Paradise JL, Rockette HE, Colborn DK, et al. Otitis media in 2253 Pittsburgh-area infants:
prevalence and risk factors during the first two years of life. Pediatrics 1997; 99:318.

27. DiFranza JR, Lew RA. Morbidity and mortality in children associated with the use of
tobacco products by other people. Pediatrics 1996; 97:560.

28. Bustamante J, Zhang SY, von Bernuth H, et al. From infectious diseases to primary
immunodeficiencies. Immunol Allergy Clin North Am 2008; 28:235.

29. Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex
encephalitis. Science 2007; 317:1522.

30. von Bernuth H, Ku CL, Rodriguez-Gallego C, et al. A fast procedure for the detection of
defects in Toll-like receptor signaling. Pediatrics 2006; 118:2498.

31. Cunningham-Rundles C. Autoimmune manifestations in common variable

immunodeficiency. J Clin Immunol 2008; 28 Suppl 1:S42.

32. Szczawinska-Poplonyk A, Gerreth K, Breborowicz A, Borysewicz-Lewicka M. Oral

manifestations of primary immune deficiencies in children. Oral Surg Oral Med Oral

- Page 26 of 28 -
Approach to the child with recurrent infections

Pathol Oral Radiol Endod 2009; 108:e9.

33. Dan JM, Havenar-Daughton C, Kendric K, et al. Recurrent group A Streptococcus tonsillitis
is an immunosusceptibility disease involving antibody deficiency and aberrant TFH cells.
Sci Transl Med 2019; 11.

34. Hausser C, Virelizier JL, Buriot D, Griscelli C. Common variable hypogammaglobulinemia

in children. Clinical and immunologic observations in 30 patients. Am J Dis Child 1983;
137:833.

35. Mason EO Jr, Wald ER, Tan TQ, et al. Recurrent systemic pneumococcal disease in
children. Pediatr Infect Dis J 2007; 26:480.

36. Buckley RH. The multiple causes of human SCID. J Clin Invest 2004; 114:1409.

37. McKinney RE Jr, Katz SL, Wilfert CM. Chronic enteroviral meningoencephalitis in
agammaglobulinemic patients. Rev Infect Dis 1987; 9:334.

38. Wilfert CM, Buckley RH, Mohanakumar T, et al. Persistent and fatal central-nervous-
system ECHOvirus infections in patients with agammaglobulinemia. N Engl J Med 1977;
296:1485.

39. Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report
on a national registry of 368 patients. Medicine (Baltimore) 2000; 79:155.

40. Fischer A. Primary T-lymphocyte immunodeficiencies. Clin Rev Allergy Immunol 2001;
20:3.

41. Fischer A. Severe combined immunodeficiencies (SCID). Clin Exp Immunol 2000; 122:143.

42. Ellison RT 3rd, Kohler PF, Curd JG, et al. Prevalence of congenital or acquired complement
deficiency in patients with sporadic meningococcal disease. N Engl J Med 1983; 308:913.

43. Lim D, Gewurz A, Lint TF, et al. Absence of the sixth component of complement in a
patient with repeated episodes of meningococcal meningitis. J Pediatr 1976; 89:42.
44. Zoppi M, Weiss M, Nydegger UE, et al. Recurrent meningitis in a patient with congenital
deficiency of the C9 component of complement. First case of C9 deficiency in Europe.
Arch Intern Med 1990; 150:2395.

45. Potter PC, Frasch CE, van der Sande WJ, et al. Prophylaxis against Neisseria meningitidis
infections and antibody responses in patients with deficiency of the sixth component of

- Page 27 of 28 -
Approach to the child with recurrent infections

complement. J Infect Dis 1990; 161:932.

46. Lehman HK, Ballow M. Immune deficiency disorders with autoimmunity and
abnormalities in immune regulation-monogenic autoimmune diseases. Clin Rev Allergy
Immunol 2008; 34:141.

47. Paul ME, Shearer WT. The child who has recurrent infection. Immunol Allergy Clin North
Am 1999; 19:423.

48. Buckley RH (Ed). Diagnostic and clinical care guidelines for primary immunodeficiency dis
eases: Immune Deficiency Foundation 2006. www.primaryimmune.org (Accessed on Aug
ust 28, 2009).

49. Patient and Family Handbook for Primary Immunodeficiency Diseases, 5th ed, Blase RM,
Stiehm ER, Bonilla FA, Younger ME (Eds), Immune Deficiency Foundation, 2013.

Topic 5949 Version 43.0

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