Approach to the child with recurrent infections

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: Clinical manifestations, pathophysiology, and diagnosis" 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 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 [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 'Protective measures' 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 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 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 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 "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis", section on 'LRBA deficiency disease' 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'.)

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 "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 children".)

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

●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 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 primary immunodeficiency' 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

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" 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'.)

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 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 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.

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: Clinical manifestations, pathophysiology, and diagnosis" 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. 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: Classification, 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. 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.

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: Classification, 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".)

●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 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" 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")

●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, 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 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" and "Diagnostic testing for HIV infection in infants and 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 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 'Protective measures'.)

●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.

●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 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".)