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Approach to the child with recurrent infections
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2012. | This topic last updated: Jan 31, 2012.

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, or 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 immune deficiencies: An overview" and "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis" and "Severe combined immunodeficiency (SCID): An overview" and "Primary disorders of phagocytic function: An overview" and "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency" and "Syndromic immunodeficiencies" and "Inherited disorders of the complement system".)

OVERVIEW — The goal of this diagnostic approach is to differentiate the child with a primary immunodeficiency from the normal child who had more than the average number of viral infections or 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 fever or confinement to bed for a week or more, 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 ESR/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]:

  • Family history of immunodeficiency or unexplained early death (eg, before age 30)
  • Failure to gain weight or grow normally (failure to thrive)
  • Need for intravenous antibiotics and/or hospitalization to clear infections
  • Six or more new 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 life time
  • Two or more months of antibiotics with little effect
  • Recurrent or resistant candidiasis
  • Recurrent tissue or organ abscesses
  • Infection with an opportunistic organism
  • Complications from a live vaccine (eg, rotavirus, varicella, and Bacillus Calmette-Guerin vaccines)
  • Chronic diarrhea
  • Nonhealing wounds
  • Extensive skin lesions
  • Persistent lymphopenia (a count of <1500 cells/uL in patients over five years and <2500 cells/uL in younger children)
  • Unexplained autoimmunity or fevers

Family history of immunodeficiency was the most predictive factor of any primary immunodeficiency (PID) in a retrospective survey of 563 children who presented to two pediatric immunodeficiency centers for evaluation of possible PID [8]. 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 primary immunodeficiency include hypocalcemia with or without seizures, congenital heart defects (mainly conotruncal anomalies), absence of thymic shadow on chest radiograph (picture 1), and delayed umbilical cord detachment (>30 days) [7].

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 'Treatment' 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 author's clinical experience and may vary regionally depending upon the population and referral patterns.

The "normal" child — About 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 [9-11]. Some infants and young children who are kept away from strangers have only one or two infections per year. 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 [12].

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.)

The child with atopic disease — About 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 "Diagnosis of allergic rhinitis (rhinosinusitis)" and "Virus-induced 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 [13]. This increased susceptibility to infection may be due to the enhanced adherence of pathogens to inflamed respiratory epithelium or alteration in mucosal permeability. The specific type of infection tends to recur in a given child. (See "Acute bacterial sinusitis in children: Clinical features and diagnosis", section on 'Predisposing factors' and "Acute otitis media in children: Epidemiology, microbiology, clinical manifestations, and complications", section on 'Risk 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 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 negative in an infant. An elevated IgE (eg, >100 IU/mL) is suggestive of allergy, but an elevated IgE alone is not diagnostic for atopic disease. (See 'Physical examination' below and 'General screening tests' below and "Overview of skin testing for allergic disease" and "Overview of in vitro allergy tests".)

It is important to note that primary immunodeficiencies and allergic disease can coexist. In a retrospective series of children evaluated for primary immunodeficiency, 31 percent (9/29) who had evidence of antigen-specific IgE by skin prick or blood testing were diagnosed with an immunodeficiency compared with 9 percent (6/68) of those who were negative on specific IgE testing [14]. Immunodeficiencies with associated atopy include selective IgA deficiency, common variable immunodeficiency, chronic granulomatous disease, and DiGeorge syndrome. Immunodeficiencies in which elevated levels of IgE are seen include hyper IgE syndrome, Wiskott-Aldrich syndrome, Omenn syndrome, and IPEX syndrome.

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 'Clinical features' and "Gastroesophageal reflux in infants" and "Clinical manifestations and diagnosis of gastroesophageal reflux disease in children and adolescents" and "Suspected heart disease in infants and children: Criteria for referral" and "Aspiration due to swallowing dysfunction in infants and children".)

Patients in this group are more susceptible to infection for various reasons, including the following [15]:

  • 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

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 [2]. 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 Toll-like receptor transduction factors, mannose binding protein, and respiratory tract cilia.

Immunodeficiency may be secondary or primary. Secondary immunodeficiencies usually occur well after infancy while most primary immunodeficiencies are inherited and present during the first years of life. Both primary and secondary immunodeficiency can lead to an increased susceptibility to malignancy and autoimmune disease. Primary immunodeficiencies most often affect B cell function, while secondary immunodeficiencies more often affect T cells (the cellular system).

Primary immunodeficiencies — The overall incidence of primary immunodeficiencies is 1 in 10,000. The prevalence of diagnosed primary immunodeficiency in the United States in 2005 was 1 in 2000 children [16]. More than 150 disorders have been characterized [2,3,17]. The type and pattern of recurring infections depend on which components of the immune system are affected (table 1) [2-4]. Infection severity also varies, ranging from mild respiratory infections to overwhelming systemic infections [2,3]. (See 'Clinical features suggestive of a primary immunodeficiency' above.)

Almost three-fourths of the primary immunodeficiencies are caused by an antibody (B cell) deficiency or a combined antibody plus cellular (T cell) abnormality (figure 1) [3]. Isolated T cell defects, as well as phagocytic cell, complement, and other innate immune defects, are much 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 immune deficiencies: An overview" and "Severe combined immunodeficiency (SCID): An overview" and "Combined immunodeficiencies" and "Primary disorders of phagocytic function: An overview" and "Inherited disorders of the complement system" and "Mendelian susceptibility to mycobacterial diseases (MSMD)" and "Toll-like receptors: Roles in disease and therapy", section on 'Primary immunodeficiency' and "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency".)

Secondary immunodeficiencies — Underlying disease states, medications, injury, previous surgical procedures, and prematurity can lead to immune system dysfunction. Secondary immunodeficiencies are more common than primary immunodeficiencies. Over 50 disorders leading to secondary immunodeficiency have been identified [3]. Common examples include HIV/AIDS, diabetes mellitus, malignancy, and immunosuppressive drugs. Secondary immune deficiencies are discussed in detail separately. (See "Secondary immune deficiency due to miscellaneous causes" and "Secondary immune deficiency induced by drugs and biologics".)

HISTORY AND PHYSICAL EXAMINATION

Birth history — Pregnancy history should be explored for maternal illness (eg, HIV, CMV), risky behaviors and exposure to toxins, prescription medications, illicit drugs, tobacco, and alcohol. 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.

Feeding history, including food intolerance and duration of breast feeding, 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 [18,19]. (See "Primary disorders of phagocytic function: An overview" and "Leukocyte adhesion deficiency".)

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 of age", section on 'Etiology' and "Etiology and evaluation of failure to thrive (undernutrition) in children younger than two years", section on 'Etiology'.)

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 certain primary immunodeficiencies, 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", section on 'Monitoring milestones'.)

Immunization history — Immunization history should be reviewed. Details of interest include any adverse effects from a vaccine, particularly live virus vaccines (eg, CNS complications from oral polio vaccination that is still used in some regions with a higher incidence of polio, or diarrhea following rotavirus vaccine [20]) as well as vaccine failure (eg, chicken pox in a varicella vaccinated child).

Live virus vaccines given in early infancy, including rotavirus or oral polio vaccine, are of special threat to patients with congenital immunodeficiencies (eg, agammaglobulinemia or combined immunodeficiency). 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 'Antibody titers' below and 'Vaccine challenge' below.)

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, such as glucocorticoids, should be noted. If immunoglobulin has been given, the route, brand, dose, frequency, use of premedication, and adverse effects should be noted. (See "Secondary immune deficiency induced by drugs and biologics".)

Other illnesses — The severity of childhood diseases, such as chickenpox, 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 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). 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, selective IgA deficiency, hyper IgE syndrome) [2].

Inquiring about consanguinity is important when considering autosomal recessive immunodeficiencies. Certain immunodeficiencies are more common in particular ethnic populations (eg, severe combined immunodeficiency [SCID] in Navajos and ataxia-telangiectasia in Amish).

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

Social history — The home, parents' work environment, and daycare or school should be explored for exposures, such as allergens, tobacco smoke, contaminated water supply, farm animals, solvents, and toxins, as well as location near industrial plants [21-23]. 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 [3,5,6].

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.

    Several primary immunodeficiencies are associated with early onset of severe infections, notably congenital neutropenia, leukocyte adhesion defects, severe combined immunodeficiencies, and complete DiGeorge syndrome. Defects in toll-like receptor 3 (TLR3) transduction are associated with herpes simplex encephalitis of the newborn [24-26].
  • 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 primary immunodeficiency. Congenital antibody deficiencies usually present at 7 to 12 months as maternal IgG disappears.
  • 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) also first present at this age. (See "Secondary immune deficiency due to miscellaneous causes".)
  • 6 to 18 years – It is unusual for recurrent infections to first present beyond six years of age. HIV infection and other sexually transmitted diseases should be considered in adolescents. Two or more episodes of bacterial meningitis or sepsis suggest a complement or other innate immune defect [2,3,25,27]. Early onset common variable immunodeficiency can present at this time. Infections associated with vasculitic lesions, arthritis, and recurrent fever suggests autoimmunity.

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 or cystic fibrosis 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.

    Nystatin-resistant or 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 [28]. Recurrent aphthous ulcers suggest autoimmune disease or a periodic fever syndrome. Recurrent pharyngitis or tonsillitis is not typically associated with immunodeficiency.
  • Lower respiratory tract – Recurrent pneumonia is rare in normal children or children with allergic disease, and suggests chronic cardiopulmonary disease or immunodeficiency. However, reactive airways disease/asthma is often misdiagnosed as pneumonia or bronchitis in young children. 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, bronchial 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, immotile cilia syndrome, 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 latter 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.
  • 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 "Pathogenesis, clinical features, and diagnosis of hidradenitis suppurativa".)

    Recurrent and/or chronic gastrointestinal infections occur in patients with IgA deficiency or common variable immunodeficiency [29].

    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 immune deficiency. (See 'Laboratory evaluation' below.)

As examples:

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.

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 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 "Clinical manifestations and epidemiology of allergic rhinitis (rhinosinusitis)" and "Clinical manifestations, pathophysiology, and diagnosis of chronic rhinosinusitis" and "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Sinus 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 long-standing lung or heart disease, inflammatory bowel disease, or chronic infection.

Atopic dermatitis (eczema), excoriations, and dermographism suggest allergic disease. However, several immunodeficiency syndromes are associated with eczema, including Wiskott-Aldrich, hyper IgE, IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked), Omenn syndrome, and severe combined immunodeficiency (SCID). Cutaneous granulomas, impetigo, or nonhealing sores suggest antibody or phagocytic immunodeficiency. Facial rashes, vitiligo, alopecia, and vasculitic lesions suggest autoimmunity [41]. (See "Wiskott-Aldrich syndrome" and "Hyperimmunoglobulin E syndrome" and "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked" and "T cell negative, B cell negative, NK cell positive severe combined immunodeficiency" and "Severe combined immunodeficiency (SCID): An overview".)

Immune deficiency disorders can be characterized by an over abundance (picture 2) or paucity (picture 3) of lymphoid tissue (eg, tonsils, lymph nodes, spleen) [42]. The absence of lymph tissue suggests X-linked agammaglobulinemia or severe combined immunodeficiency (SCID). However, adenopathy and hepatosplenomegaly can be seen in other B cell disorders (eg, common variable immunodeficiency [CVID], IgA deficiency) and HIV infection. Suppurative adenitis is common in chronic granulomatous disease (CGD).

Clinical patterns suggestive of immunodeficiency — Constellations of certain findings are characteristic of specific immunodeficiency syndromes. Examples include:

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 — Laboratory evaluation of children with recurrent infection depends upon history and physical examination findings [2]. Evaluation for primary immunodeficiency should focus on the component of the immune system that is most likely to be involved based upon the initial assessment. Laboratory studies for disorders that cause secondary immune deficiency (eg, sickle cell disease, diabetes mellitus) are discussed separately (see appropriate topic reviews). (See "Laboratory evaluation of the immune system" and "Laboratory evaluation of neutropenia and neutrophil dysfunction" and "Overview and clinical assessment of the complement system".)

Initial tests — The screening evaluation should include both quantitative and qualitative tests. These tests are readily available, are recommended for all children with recurrent infections, and can be performed by the primary care clinician. Abnormalities of the following initial tests may suggest allergy, immunodeficiency, or a chronic illness and serve as a guide for subsequent investigations. Abnormal studies should prompt referral to the appropriate specialist, usually an immunologist. Further laboratory evaluation is probably futile if these tests are all normal. The patient's family can be reassured that infection or other serious disorder has been excluded, though further monitoring may be indicated.

General screening tests — General screening tests should include the following to exclude systemic disease:

  • Complete blood count with differential
  • Electrolytes, glucose, BUN, creatinine, and albumin
  • Urinalysis

Special attention should be paid to the total absolute lymphocyte count: lymphopenia is defined as a count of <1500 cells/uL in patients over five years and <2500 cells/uL in younger children. The presence of anemia, thrombocytopenia, or an abnormal differential count warrants further investigation. Eosinophilia suggests allergy. Thrombocytosis suggests chronic inflammation.

Immunoglobulin levels — Immunoglobulin levels, including IgG, IgM, IgA, and IgE, are included in the initial tests. Levels must be compared with age-matched controls, particularly in the first two years of life.

Antibody deficiency is suggested by an IgG less than 200 mg/dL and a total Ig (IgG plus IgM plus IgA) less than 400 mg/dL, or the complete absence of IgM or IgA (after infancy).

An elevated IgE (>100 IU/mL) suggests allergy, eczema, or chronic skin infections, or may occur in phagocytic disorders or hyper IgE syndrome (levels are generally >2000 IU/mL for this syndrome). Low or absent IgE levels suggest absence of IgE-mediated allergic disease.

Infection evaluation — Evaluation for infection may include:

  • Sedimentation rate (ESR) or C-reactive protein (CRP)
  • Appropriate cultures
  • Radiologic imaging of the site(s) of suspected infection

An elevated ESR or CRP suggests systemic or regional infection or an autoimmune process.

A nasal culture should be considered in the child with recurrent skin infection to determine if the child is a carrier of group A streptococcus or Staphylococcus aureus. If positive, family members may be cultured, particularly if they have chronic skin lesions.

A chest x-ray is indicated if the child has a chronic cough or other features suggesting lung problems. Thymic size should be noted in chest radiographs of newborns with recurrent infections (picture 1). Sinus and lateral neck films or sinus computed tomography (CT) scan with a lateral pharyngeal view for adenoidal size is indicated for the patient with suspected sinusitis or obstructive breathing (picture 3). Complete absence of adenoidal tissue suggests immunodeficiency. (See 'The child with atopic disease' above.)

Intermediate tests for immunodeficiency — These tests are indicated when the screening tests are abnormal or the clinical picture is highly suggestive for an immunodeficiency. Usually these are done by the specialist, but they can also be started by the generalist.

Antibody titers — The function of the antibody system is best assessed by checking antibody titers to previously administered vaccines. Response to protein antigens can be assessed by measurement of titers to tetanus, diphtheria, and Hemophilus influenzae type b (anti-PRP IgG). Response to polysaccharide antigens can be determined by measurement of titers to pneumococcus in adults and children over 24 months of age. We recommend a 23 valent panel, available in many commercial laboratories. (See "Assessing the immunologic response to vaccination".)

It is important to note whether or not the patient has received a conjugated (PCV7 or PCV13) or unconjugated (PPV23) pneumococcal vaccine. Positive titers to serotypes in the conjugated vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F in both Prevnar 7 and Prevnar 13 and 1, 3, 5, 6A, 7F, and 19A only in Prevnar 13) indicate an ability to respond to polysaccharides conjugated to protein antigens. To determine the ability to respond to pure polysaccharide antigens the response to pneumococcal polysaccharide vaccine must be determined. The 23 serotype antibody panel includes the serotypes present in the PPV23 and the PCV13 vaccines. Children two to five should respond to at least 50 percent of the polysaccharide antigens (1.3 ng/ml or greater) and older patients (6 to 60) should respond to at least 70 percent of the polysaccharide antigens.

The author's approach is to assess baseline titers to pneumococcal serotypes. If titers are deficient and the child is over two years, the author gives unconjugated pneumococcal vaccine and rechecks titers in four to six weeks. If titers are still low, a conjugated vaccine is given and titers are retested again. This will determine if the patient can respond to protein and polysaccharide antigens.

Natural antibodies, such as isoagglutinins (isoantibodies to blood group antigens; anti-A, anti-B), anti-streptolysin titers, and E. coli antibodies are of less value, particularly in the young infant.

Complement activity — Complement activity should be assessed in patients with recurrent sepsis or Neisserial infection. The screening test is a total hemolytic complement determination (CH50). A normal CH50 level excludes nearly all hereditary complement deficiencies. Levels of individual complement components are measured if the CH50 is significantly reduced or zero. (See 'Complement component' below and "Laboratory evaluation of the immune system", section on 'Complement defects'.)

Diagnostic tests — Further testing is warranted when screening tests are abnormal or if there is a convincing history of immunodeficiency. These intermediate tests should provide some guidance as to which specific disorders must be considered and confirmed by additional studies. These tests should be undertaken in consultation with a pediatric immunologist. (See "Laboratory evaluation of the immune system".)

Lymphocyte subset analysis — Lymphocyte subset analysis by flow cytometry, including CD3 (total T cells), CD4 (T helper), CD8 (T cytotoxic), CD19 or CD20 (B cells), and CD16/56 (natural killer cells), is indicated when a B or T cell defect is suspected. Comparison with age-matched controls is necessary (infants and young children normally have lymphocytosis compared with adults) [2,3,43]. (See "Flow cytometry for the diagnosis of primary immunodeficiencies".)

The CD4 count is the most valuable reflection of the cellular immune system. An absolute CD4 count of <500 cells/uL in a person over five or <1000 cells/uL in younger children suggests a cellular immunodeficiency. An absolute B cell (CD19) count of <100 cells/uL suggests hereditary agammaglobulinemia. A low CD16/56 count (<2 percent) suggests a natural killer cell deficiency. Low levels of any lymphocyte subset should be repeated and, if confirmed, followed by functional analysis of the respective immune system component.

Vaccine challenge — Vaccine responsiveness is used to further assess the antibody system. A vaccine that has not been administered previously is given and titers are measured before and four to six weeks after vaccination. The unconjugated pneumococcal vaccine is typically used to assess response to polysaccharide antigens (see 'Antibody titers' above). Other inactivated vaccines that the child has not yet received can be used to measure antibody function, such as hepatitis A, hepatitis B, meningococcal, and polio vaccines. (See "Assessing the immunologic response to vaccination".)

IgG subset determinations — IgG subset determinations are sometimes of value, particularly in patients with a slightly low total IgG level and poor antibody response to vaccinations. A complete absence of IgG1, IgG2, or IgG3 suggests immune dysregulation, and may indicate the early onset of common variable immunodeficiency. A low level of one or more IgG subclasses does not, by itself, indicate an antibody deficiency; functional antibody studies must show a defect.

HIV testing — HIV testing, either by antibody titers or PCR, should be done in any patient suspected of a T cell deficiency. (See "Diagnostic assays for HIV infection" and "Diagnostic testing for HIV infection in infants and children younger than 18 months".)

Delayed cutaneous hypersensitivity — Delayed cutaneous hypersensitivity is a functional in vivo test of T cell function that may be performed in older children [2,3]. Children under age two often have negative tests despite intact cellular immunity. The usual skin tests employ candida antigen, tetanus or tetanus-diphtheria antigen, and/or tuberculin. A documented history of candida infection; a recent diphtheria, tetanus, or BCG vaccine; or previously positive tuberculin reaction are necessary to interpret a response to these antigens. (See "Laboratory evaluation of the immune system", section on 'Cutaneous delayed-type hypersensitivity'.)

Lymphoproliferative assays — Lymphoproliferative assays are in vitro assays used to further assess the cellular immune system. The ability of lymphocytes to proliferate to mitogens (phytohemagglutinin, concanavalin, pokeweed), stimulatory monoclonal antibodies (anti-CD3), or allogeneic cells (in a mixed leukocyte reaction) indicates intact lymphocyte activation to nonspecific stimuli. Diminished or absent proliferation to mitogens signals a serious derangement of T cell function such as severe combined immunodeficiency. (See "Laboratory evaluation of the immune system", section on 'In vitro studies of T cell function'.)

Lack of a lymphoproliferative response to a specific antigen to which the patient has been exposed by infection or immunization (eg, candida, tuberculin, tetanus) indicates anergy and a probable T cell defect. Responses to specific antigens are diminished or even absent while mitogen responses remain intact in many cases of combined immune deficiency.

Phagocytic oxidative responses — Phagocytic oxidative responses are correlated with the ability of leukocytes to kill bacteria. This is best assessed using a fluorescent dye (dihydrorhodamine) and flow cytometry. A negative response is seen in chronic granulomatous disease. This procedure is faster and more informative than nitroblue tetrazolium dye reduction assays used previously. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Dihydrorhodamine 123 (DHR) test'.)

Leukocyte adhesion defect testing — Suspected cases of leukocyte adhesion deficiency (LAD) can be evaluated by examination of cell surface marker expression by flow cytometry. CD11 and CD18 are absent in LAD I and CD15a is absent in LAD II. Patients with LAD III have normal integrin expression. Diagnosis requires demonstration of impaired integrin activation. (See "Flow cytometry for the diagnosis of primary immunodeficiencies", section on 'Leukocyte adhesion deficiencies (LAD)' and "Leukocyte adhesion deficiency".)

Complement component — Complement component assays are indicated if there is very low or absent CH50 activity on repeat testing. These assays are available through many commercial laboratories. (See "Laboratory evaluation of the immune system", section on 'Complement defects'.)

Confirmatory diagnostic studies — A definite diagnosis by advanced tests will direct treatment options, prognostic information, and genetic counseling. These advanced tests are discussed elsewhere and in the sections on the individual diseases. (See "Laboratory evaluation of the immune system".)

Many of these tests are available in specialized reference or research laboratories. A genetic diagnosis is available for over 100 different immunodeficiency syndromes [44]. (See "Primary humoral immune deficiencies: An overview" and "Severe combined immunodeficiency (SCID): An overview" and "Primary disorders of phagocytic function: An overview" and "Inherited disorders of the complement system".)

MANAGEMENT OF THE CHILD WITH RECURRENT INFECTION — Children undergoing evaluation for recurrent infection need special care during the evaluation process. This includes:

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 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 evidence of immunodeficiency, in the uncommon event that this antibiotic regimen fails.

RESOURCES — Helpful material is available for clinicians and parents from:

  • The Immune Deficiency Foundation (www.primaryimmune.org). This includes Diagnostic and Clinical Care Guidelines [45] and a Patient and Family Handbook. A free physician-to-physician consulting immunologist program is also available.
  • The Jeffrey Modell Foundation (www.info4pi.org) (accessed on January 31, 2012).

SUMMARY AND RECOMMENDATIONS

  • 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 'Major causes' above.)
  • Primary disorders of immune function should be considered in 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. (See 'Major causes' above.)
  • A careful history and physical examination can usually isolate the disorder to one of the four components of the immune system in children in whom a primary immunodeficiency is suspected. B cell and combined B and T cell abnormalities account for nearly three-fourths of the primary immunodeficiencies and should be considered initially. Isolated T cell, phagocytic, and complement defects are rare. (See 'History and physical examination' above.)
  • The screening evaluation should include both quantitative and qualitative tests. Screening tests may include a complete blood count with differential, chemistry studies, urinalysis, sedimentation rate or 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".)

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