Clinical Reviews in Allergy & Immunology

, Volume 34, Issue 2, pp 129–140

Approach to the Patient With Recurrent Infections

Authors

    • Division of Allergy/Clinical Immunology, Department of Pediatrics, Women & Children’s Hospital of BuffaloSUNY Buffalo School of Medicine and Biomedical Sciences
Article

DOI: 10.1007/s12016-007-8041-2

Cite this article as:
Ballow, M. Clinic Rev Allerg Immunol (2008) 34: 129. doi:10.1007/s12016-007-8041-2

Abstract

Children with a history of recurrent or unusual infections present a diagnostic challenge. Differentiation between frequent infections caused by common risk factors, versus primary immune dysfunction should be based on a detailed history and physical examination and, if indicated, followed by appropriate laboratory studies. A high index of suspicion could lead to an early diagnosis and treatment of an underlying immune deficiency disease. This article presents to physicians an approach to the evaluation of children with recurrent infections. Important details from the history and physical examination, and an appropriate choice of screening laboratory test to be ordered in a given situation are discussed.

Keywords

Immunodeficiency diseaseRecurrent infectionsB-cell immune deficiencyT-cell immune deficiencyCarrier detectionInnate immune disorders

Abbreviations

SCID

Severe combined immunodeficiency disease

CVID

Common variable immunodeficiency

CGD

Chronic granulomatous disease

NEMO

NF-kB essential modulator

XLP

x-linked lymphoproliferative disease

NK

Natural killer

WHIMS

Warts, hypogammaglobulinemia, bacterial infections, and myelokathesis

HPV

Human papilloma virus

IPEX

Immune dysregulation, polyendocrinopathy, and enteropathy

FOXP3

Forkhead box protein 3

APECED

Autoimmune polyendocrinopathy candidiasis, ectodermal dystrophy syndrome

AIRE

Autoimmune regulator gene

LAD-1

Leukocyte adhesion deficiency type I

XLA

X-linked agammaglobulinemia

ICF

Immunodeficiency, centromeric region instability and facial anomalies

Introduction

The evaluation of a child with frequent infections requires a careful history and physical examination that could help identify the nature of the patient’s underlying immune defect. In this article, we will concentrate on presenting to the physician useful concepts in the evaluation of a child with recurrent infections. The deficiencies of the immune system that lead to frequent infections, and the important details of the history and physical examination, will be presented. A comprehensive guide for the diagnosis and management of primary immunodeficiency disorders has recently been published [1].

Primary immunodeficiencies are generally the result of genetic defects that interfere with a component of the immune system. These disorders are rare, with the exception of IgA deficiency that occurs with a frequency of approximately 1: 500––700 in Caucasians. The estimated range of prevalence for other primary immunodeficiencies is 1: 10,000–1:200,000, depending on the specific diagnosis [2]. Over the past decade, substantial knowledge has been gained regarding the genetic abnormalities involved in the pathogenesis of many of these disorders. More than 120 genetic defects have been identified that result in immune deficiency. Defects involving B-cell immunity are the most common immune abnormalities accounting for more than 50% of the recognized causes of primary immunodeficiency. Combined humoral and cellular deficiencies constitute 20–30% of all cases followed by phagocytic defects at about 18%, and complement deficiencies at 2% [2].

The Medical History in Immunodeficiency

Most often, frequent infections in children are because of common risk factors such as day care attendance or passive smoking (Table 1). To differentiate these factors from causing recurrent infections from immune deficiency should be based on a detailed history and physical examination, and, if indicated, followed by appropriate laboratory studies. Early diagnosis and treatment is important early in life to institute lifesaving treatments and genetic counseling.
Table 1

Common risk factors for frequent infections

Risk factors

Passive smoking

Day care

School aged siblings

Allergies

Anatomical defects of the upper or lower airways

Gastroesophageal reflux

Even with a normal immune system, young children can have up to four to six upper respiratory tract infections per year for the first 3–5 years of life. Children attending day care facilities or having school aged siblings at home can have even more frequent infections as a result of increased exposure to infectious agents. Typically, children with an intact immune system and no other predisposing factors handle these infections well with rapid resolution of bacterial infections using appropriate antibiotics. The risk factors contributing to the risk of recurrent infections in children is shown in Table 1. Passive tobacco smoke inhalation in the home is associated with an increased number of infections, and is a contributing factor to allergy and asthma symptoms [3]. Atopy affects 15–20% of children and causes chronic inflammation of the airways that can mimic recurrent or chronic upper respiratory infections. Atopy can also facilitate the adherence of pathogens to the respiratory epithelium and thus promote infections. Distinguishing between allergic rhinitis, allergy-related sinusitis, asthma-related cough, and possible immunodeficiency can present a difficult diagnostic challenge.

Recurrent or chronic infections can be associated with anatomic defects that characteristically involve one organ system. Foreign bodies should be considered when the infections are chronic and localized to one anatomical site, e.g., one ear canal or one nostril. Recurrent otitis media is often associated with eustachian tube dysfunction secondary to atopy, and can be helped with PE tubes in the ear. Children with recurrent or chronic sinusitis with documented anatomic defects of the sinuses causing poor drainage frequently show favorable outcomes with corrective surgery. Gastroesophageal (GE) reflux is usually associated with asthma symptoms, but sometimes can be confused with bronchitis or lead to aspiration and recurrent pneumonia. Otolaryngologists believe that GE reflux can be a factor in recurrent otitis media and sinusitis. Finally, children with recurrent sinopulmonary infections, especially when accompanied by symptoms such as malabsorption or nasal polyps, should be evaluated for possible cystic fibrosis. The incidence of cystic fibrosis is up to 1:2,500 in some Caucasian populations, making this entity a much more common disease when compared to the incidence of primary immunodeficiencies. Recurrent sinopulmonary infections with situs inverus may indicate immotile cilia syndrome (primary ciliary dyskinesia; Kartagener syndrome).

The approach to the patient with recurrent infection begins with the medical history.

Age of Onset

A more severe presentation is generally associated with an earlier age of onset of infections. Patients with severe combined immunodeficiency disease (SCID) who lack function of both cell-mediated and B-cell immunity typically have onset of infection by 4–5 months of age. In contrast, patients with only B-cell deficiencies such as in x-linked agammaglobulinemia (Bruton’s disease) are usually infection-free until 7–9 months of age. The children with Bruton’s disease are protected by placentally derived maternal immunoglobulin G (IgG) until 7–9 months of age when the serum IgG decrease to below protective levels, resulting in increased susceptibility to infection [4].

Sites of Infection

The site, frequency, duration, severity, complications of infections, and the response to antimicrobial treatment are important to record (Table 2). Distinguishing an infectious process from a noninfectious condition such as allergy, and to document bacterial infection with appropriate cultures, are very helpful. The sites of infection may provide insight to the significance of the patient’s recurrent infections. Pneumonia complicated by multilobar involvement can ultimately lead to bronchiectasis, and recurrent otitis media could result in mastoiditis. Otitis media, sinusitis, pneumonia, gingivitis, meningitis, septicemia, skin infections, and abscesses are all sites of infection that may be associated with immune deficiency. On the other hand, recurrent pharyngitis is not typically a significant site of infection. The sites of infection in a patient may also provide insights into the type of immunologic abnormality. For example, patients with persistent or recurrent stomatitis or gingivitis may have a phagocytic defect or neutropenia. Skin infections also occur in patients with phagocytic abnormalities, and can be seen in patients with antibody immunodeficiency. Recurrent septicemia suggests an opsonic defect: either an inability to generate specific IgG antibody or a lack of the nonspecific opsonins of the classical, alternative, or late complement pathway components. Delayed separation of the umbilical cord beyond 6–8 weeks of age in neonates and poor wound healing can suggest a leukocyte adhesion deficiency [5].
Table 2

Important sites of infection

Sites

Skin

Otitis media

Sinusitis

Gingivitis/stomatitis

Pneumonia

Abscess—lymph node, subcutaneous tissues, muscle, organ tissue, etc.

Meningitis

Septicemia

Microbiology of the Infections

The type of pathogen responsible for the infection can yield important information about the nature of the immune deficiency (Table 3). The microorganisms that cause infection in patients with neutrophil defects, T-cell abnormalities, and antibody deficiency disorders are frequently quite distinct. For example, recurrent viral, fungal, mycobacterial, or protozoal infections suggest a T-cell defect. For example, patients with AIDS who have an acquired T-cell deficiency have recurrent or persistent candidiasis and frequently die of pneumonia as a result of cytomegalovirus or Pneumocystis jiroveci (carinii). Patients with cellular immune defects can also present with bacterial and viral infections as well as opportunistic infections. Mycobacterium avium intracellulare and Pneumocystis jiroveci (carinii) are typical opportunistic infections seen in patients with severe T-cell defects. CD40 ligand defects (and CD40 receptor) associated with elevated serum levels of IgM have infections with opportunistic pathogens such as Pneumocytis jiroveci (carinii), Cryptococcus, and Cryptosporidium [6] indicating that these patients have a T-cell deficiency [7].
Table 3

Immune deficiencies and associated pathogens

Deficiency

Pathogens

B-cell/immunoglobulin deficiency

Encapsulated bacteria, e.g., Streptococcus pneumoniae, Haemophilus influenzae type b;

Parasites, e.g., Giardia lamblia

Enteroviruses

 Echovirus or coxsackie virus—XLA

 Polio—IgA deficiency, CVID

Complement defects

 

 C3 complement

Encapsulated bacteria, neisserial infections

Late complement components (C5–C9)

Neisserial infections

T-cell immune deficiency

 Bacterial organisms—encapsulated bacteria; Gram-negative bacteria

 Fungal—Candida

 DNA viruses—cytomegalovirus

 Mycobacterial organisms—Mycobacterium avium intracellulare

Opportunistic infections, e.g., Pneumocystis jiroveci (carinii), Cryptosporidium

 Phagocytic abnormalities

Bacterial organisms

 Gram negative bacteria—E. coli, Burkholderia cepacia, Serratia

 Staphylococcus

Fungal infections, e.g., Aspergillus sp.

Interferon/ IL-12 cytokine pathway

Mycobacterial organisms—Mycobacterium avium intracellulare

Nontyphi salmonella

XLA—x-linked a gammaglobulinemia

CVID—common variable immunodeficiency

Infections with encapsulated invasive bacteria, such as Streptococcus pneumoniae and Haemophilus influenzae type b, suggest an antibody deficiency disorder. Patients with IgA deficiency or common variable immunodeficiency (CVID) frequently have protracted gastrointestinal symptoms as a result of Giardia lamblia. Patients with X-linked hypogammaglobulinemia (Bruton’s disease) have an increased susceptibility to infections with enteroviruses (echovirus and coxsackievirus), which can lead to meningoencephalitis. Arthritis of the large joints can be caused by Ureaplasma urealyticum.

A child presenting with lymphadenitis or recurrent abscesses caused by low-virulence Gram-negative organisms such as Escherichia coli, Burkholderia cepacia, Serratia, or Klebsiella, may have an abnormality in phagocytic function such as in chronic granulomatous disease (CGD) [8]. Another characteristic presentation of patients with a phagocytic defect is a history of recurrent skin infections with Staphylococcus aureus, and recurrent gingivitis. Aspergillus or other fungal organisms can also cause infection in patients with phagocytic abnormalities. Infections with Neisseria organisms is a hallmark presentation for the congenital complement deficiencies affecting the late complement components (C5, C6, C7, and C8) [9]. A defect in IFN-γ/IL-12 cytokine pathway, either in the form of cytokine production defects, or receptor defects often presents with atypical mycobacterial infection, nontyphi Salmonella or severe herpes virus infection [1012]. Infection with atypical mycobacteria can also be seen in patients with ectodermal dysplasia who have defects in the NF-κB pathway (NF-κB essential modulator or NEMO). Patients with x-linked lymphoproliferative disease (XLP) develop a fulminant infectious mononucleosis after infection with Epstein-Barr virus. Deficiencies of natural killer (NK) cell function result in recurrent infections with herpes virus. Patients with warts, hypogammaglobulinemia, bacterial infections, and myelokathesis (WHIMS) have human papilloma virus (HPV)-related diseases, which typically manifest as treatment refractory cutaneous warts, and HPV involving the genital tract [13]. The myelokathesis results in moderate to severe neutropenia. The hypogammaglobulinemia is variable as is the T-cell function. WHIMS is an autosomal dominant disorder, with mutations in the gene encoding for the chemokine receptor CXCR4 [14].

Gastrointestinal Disturbances

Children with SCID often present initially with chronic diarrhea and failure to thrive. Many patients with primary immune-deficiency disease have symptoms and clinical findings of the gastrointestinal tract. Bacterial overgrowth of the small bowel, including infections with Yersinia and Campylobacter, parasitic infestations with such organisms as Giardia lamblia, and chronic viral enteritis caused by enteroviruses and cytomegalovirus (CMV) are relatively common in patients with B- or T-cell immune defects. The incidence of lactose intolerance is higher in patients with immune deficiency than in the normal population [15]. Patients with the x-linked syndrome of immune dysregulation, polyendocrinopathy, and enteropathy (IPEX) often present with watery diarrhea that can lead to failure to thrive [16, 17]. This immune dysfunction is caused by mutations in the FOXP3 gene [18].

Autoimmune disease

An autoimmune disease can be associated with a primary immune deficiency. Patients lacking one of the early complement components often present with a lupus-like illness [9]. Patients can have the typical features of systemic lupus erythematosus (SLE) presenting with serology-negative disease, e.g., anti-deoxyribonucleic acid (DNA) antibodies are absent, and the ANA is present in low titer. Homozygous factor H deficiency may present as hemolytic-uremic syndrome [19]. Likewise, deficiencies of late complement components may occasionally be associated with vasculitis or other lupus-like illnesses. Less frequently, patients with late component deficiencies have developed Raynaud disease, scleroderma, or dermatomyositis. Deficiencies of the third component of complement are associated with both recurrent infections and an increased incidence of lupus-like illness, including glomerulonephritis [20].

Approximately 20% of patients with CVID have rheumatic diseases or autoimmune endocrinopathies [2123]. Organ-specific autoimmunity of the endocrine glands (parathyroid, adrenal, gonads, pancreas, and thyroid), and chronic mucocutaneous candidiasis is seen in patients with autoimmune polyendocrinopathy candidiasis, ectodermal dystrophy (APECED) syndrome [24]. This disorder is associated with mutations of the autoimmune regulator gene (AIRE) [25]. The most common autoimmune disease in IPEX syndrome is early-onset insulin-dependent diabetes, but other autoimmune endocrinopathies or hematological autoimmune disease can occur [16]. Patients with autoimmune lymphoproliferative disease (ALPS) have Coombs’ positive autoimmune hemolytic anemia and immune thrombocytopenia [26]. Massive splenomegaly and lymphadenopathy can be associated with the neutropenia. ALPS is caused by a defect in lymphocyte apoptosis, most frequently from mutations in the TNF receptor gene (TNFRSF6) encoding Fas (CD95) [27]. Gene mutations encoding Fas ligand and caspase 8 and 10 have also been described [27, 28]. Autoimmune disease has been reported in 40% of patients with the Wiskott–Aldrich syndrome [29].

Family History

Many of the immune deficiency diseases are inherited either as an autosomal recessive or an X-linked disorder. Therefore, a careful family history is very important. For example, chronic granulomatous disease is inherited as an X-linked disorder in approximately two thirds of patients. Wiskott–Aldrich syndrome, infantile X-linked agammaglobulinemia or Bruton’s disease, and CD40 ligand deficiency are other examples of X-linked disorders. Consanguinity raises the possibility of an autosomal recessive disorder. CVID and IgA deficiency are familial and are often seen in a setting of other family members with autoimmune disorders, such as pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, or autoimmune hematologic diseases. In a family in which the mother’s brother died of recurrent infection in early childhood, the first serious bacterial infection in her son should cause the astute clinician to suspect the possibility of an X-linked immune deficiency in the boy.

Adverse Reactions to Vaccines or Transfusions

An adverse vaccine or transfusion reaction may indicate an underlying immune deficiency. For example, paralytic polio occurs in patients with B-cell deficiency and severe combined immunodeficiency who received live attenuated oral polio vaccine [30]. Polio in children with IgA deficiency has been reported in families after exposure to normal children who have just received the oral vaccine and are still actively shedding the poliovirus in their stools. Disseminated mycobacterial disease after BCG immunization can be seen in interferon-gamma and interleukin-12-related immune deficiencies [11, 31]. Anaphylactic transfusion reactions can occur in patients with IgA deficiency because of the presence of IgE antibodies to IgA [32].

Physical Examination

The physical examination is an important component in assessing a patient for an underlying immune deficiency (Table 4). Significant findings can direct the physician to further evaluation. However, a normal physical examination does not exclude an underlying immunodeficiency. For example, children with X-linked lymphoproliferative disease typically do not develop any symptoms or signs of disease before developing an Epstein-Barr virus (EBV) infection. Some of the children with underlying immunodeficiency may appear chronically ill and underweight. If the initial onset of the disease occurs early in life, growth and development may be delayed, leading to failure to thrive. Repeated pyogenic infections may leave permanent scars. Digital clubbing or a loud pulmonic heart sound with a right ventricular heave indicates pulmonary hypertension, which implies that serious pulmonary damage has occurred. Not only can the examination reveal physical signs that reflect the patient’s previous infectious history, but there are a number of immunodeficiency syndromes that are associated with certain physical abnormalities and/or dysmorphisms. The physical examination of the child with suspected immunodeficiency is discussed in a system-by-system fashion. Table 4 outlines areas of the physical examination deserving special attention.
Table 4

Important considerations on physical exam

Considerations

Failure to thrive—T-cell defects

Skin/oral mucosa

 Infection

  Candidiasis—T-cell defect

 Eczema—Hyper IgE syndrome, Wiskott–Aldrich syndrome

 Petechiae—Wiskott–Aldrich syndrome

Conjunctivae

 Infection—B-cell defects

 Telangiectasia—ataxia telangiectasia

Scarring of the tympanic membrane of the ear/chronic otitis media—B-cell defects

Dysmorphic features

 Face—DiGeorge anomaly

 Extremities—Cartilage-hair hypoplasia

 Ectodermal dysplasia—NEMO

Congenital heart disease—DiGeorge anomaly

Lymphoid tissues

 Absent—x-linked agammaglobulinemia (XLA)

 Hypertrophy—Common variable Immunodeficiency; autoimmune lymphoproliferative syndrome (ALPS)

Chest exam

 Rales/rhonchi/digital clubbing (bronchiectasis)—B-cell defects

Musculoskeletal

 Lupus-like disease—complement defect

 Infectious arthritis—XLA

 Spondyloepiphyseal dysplasia—cartilage hair syndrome

Table 5

Tests for T-cell immunity

Tests

Screening tests

 Absolute lymphocyte count

 Chest x-ray for thymus shadow in newborns

 Delayed skin hypersensitivity to recall antigens

  Candida

  Tetanus

  Other fungal antigens

 Quantification of T-cell subsets by flow cytometry

  CD4

  CD8

Advanced testing

 Lymphocyte proliferative responses to mitogens, antigens, and allogeneic cells (MLC)

 Lymphocyte-mediated cytotoxicity—NK and ADCC activity

 Production of cytokines

 Functional response to cytokines

 Signal transduction studies

 Molecular analysis for specific defects

Failure to Thrive and Embryologic Abnormalities

Early onset of recurrent infections in the first 6 months of life is frequently accompanied by growth failure and delayed maturation. Children with significant T-cell impairment such as in SCID grow poorly and often suffer from failure to thrive during their first years of life. Developmental embryologic abnormalities of the thymus result in atresia or dysplasia, and consequently a T-cell immunodeficiency. Embryologic abnormalities of the third and fourth branchial pouches give rise to abnormalities of the thymus and parathyroid glands, the mandible, and related structures, as well as the great blood vessels and the heart resulting in the syndrome known as DiGeorge anomaly. Neonatal tetany, congenital heart disease, and facial abnormalities, including hypoplastic mandible, high-arched palate, shortened philtrum, small mouth, and low-set, posteriorly rotated ears, are frequently recognized before the immunodeficiency. DiGeorge anomaly is part of the spectrum of velocardiofacial syndrome [33]. Conotruncal abnormalities of the heart, e.g., tetralogy of Fallot, ventricular septal defect (VSD)/atrial septal defect (ASD), or pulmonic artery atresia/stenosis are often seen. The disease is variable in its expression, however, and patients with profound T-cell immunodeficiency without significant hypoparathyroidism or cardiac anomaly can occur, usually presenting with severe, persistent candidiasis, and growth failure [34]. Approximately 80–90% of the DiGeorge anomaly patients have a deletion at 22q11.2, whereas other patients (1–2%) have deletions at chromosome 10p14 [35]. Some patients have been found to have mutations in the TBX1 gene [36].

Certain anatomical or dysmorphic features are typical of some primary immunodeficiencies. Defects in bone formation and the immune abnormalities are seen in the syndrome of cartilage-hair hypoplasia [37]. Because of the physical findings of short-limbed dwarfism and abnormal hair, these children can be identified early in infancy on the basis of their appearance, before the clinical manifestation of their immune defects. Defects in NF-κB regulation (NEMO) are associated with ectodermal dysplasia characterized by conical teeth, fine sparse hair, and frontal bossing [38]. About 70% of patients with ICF syndrome have hypertelorism, epicanthal folds, and a flat nasal bridge [39]. Growth retardation occurs in about half of these patients, along with developmental delays. These patients also have chromosomal abnormalities that are diagnostic of ICF syndrome [40].

Skin and Mucous Membranes

Infections of the skin and mucus membranes may indicate an immune defect of the phagocytic system. For example, the congenital neutropenic disorders are characterized by a reduction in the absolute neutrophil count that enhances the susceptibility of patients to bacterial skin infections, deep tissue infections, sepsis, and fever (reviewed in reference [41]). Patients with CD40 ligand and CD40 deficiency may also have neutropenia. In contrast, patients with leukocyte adhesion defects have a leukocytosis associated with poor wound healing, skin infections, and frequently severe periodontal disease [5].

The skin and oral mucosa can reflect an underlying disease process. Patients with Wiskott–Aldrich syndrome present with recurrent infections, intractable eczema, and petechiae. Candidiasis of the skin or mucus membranes, as mentioned previously, may be an important indication of T-cell deficiency. Patients with ataxia-telangiectasia have recurrent infections, cerebellar ataxia, and telangiectasia of the skin. These small vessel abnormalities over the bulbar conjunctivae, bridge of the nose, the ears, and antecubital fossa tend to occur in late childhood, usually several years after the onset of ataxia and infection problems [42]. A form of skin disease resembling severe atopic dermatitis is common in the Hyper IgE syndrome [43]. Additional clinical findings include craniosynostosis, course facies, and skeletal and dental abnormalities [44]. Erythroderma and severe seborrheic dermatitis may be seen in children with severe T-cell and combined immunodeficiency diseases. In many cases, these skin manifestations lead to the diagnosis of immune deficiency.

Rashes can offer a clue to the type of underlying immune deficiency. Boys with X-linked agammaglobulinemia can develop a dermatomyositis-like rash, with livedo reticularis, muscle weakness, neurologic symptoms, and developmental failure or regression resulting from chronic infection with an enterovirus [45]. A lupus-like malar rash with negative or low-titer antinuclear antibodies (ANA) may occur in deficiencies of the early components of the classical complement pathway [46]. Discoid lupus erythematosus or, less commonly, systemic lupus erythematosus, has been seen in mothers of boys with CGD. Erythroderma in a patient with failure to thrive, eosinophilia, hepatosplenomegaly, and recurrent infections may suggest Omenn syndrome [47]. Silvery hair, pale skin, and photophobia are seen in children with Chédiak–Higashi syndrome [37, 48]. Griscelli syndrome patients have characteristic clinical findings of the skin and hair, including large melanin clumps in the hair shaft, and abnormal skin melanocytes [49, 50]. In a related disease, Hermansky–Pudlak syndrome is characterized by oculocutaneous albinism, severe thrombasthenia, and immune deficiency [51, 52]. An important indication of T-cell deficiency, e.g., patients with SCID or chronic mucocutaneous candidiasis [53] is candidiasis of the skin or mucus membranes. Patients with APECED [24, 54] and IPEX [55] have mucocutaneous candidiasis as part of their complicated clinical picture. Children with defects of NF-κB regulation have not only facial dysmorphisms, but abnormal thermal regulation caused by decreased eccrine sweat glands [38]. Most patients have a mutation in the IKBKG gene on the X-chromosome that encodes the IKKγ chain (NF-kB essential modulator or NEMO). Patients with NEMO have severe bacterial infections and increased susceptibility to atypical mycobacterial infections.

Ear, Nose, Mouth, and Throat Evaluation

Recurrent otitis media is a very common problem in pediatrics, and is also common in persons with antibody deficiency. In studies of children with recurrent otitis media, however, this type of infection does not prove to be a reliable indicator of immune deficiency. Increased exposure to viral and bacterial pathogens because the child is in a day care facility or lives in a home with other school-age children or with parents who smoke may contribute to the risk of recurrent otitis media (Table 2).

Children with antibody deficiency frequently suffer from recurrent infection of the paranasal sinuses. In children, the clinical diagnosis of sinusitis is frequently overlooked. As already noted, however, pharyngitis is not a marker for immune deficiency. Examination of the oropharynx for the presence of tonsillar tissue in the child with recurrent upper respiratory infection could lead to a diagnosis of Burton’s X-linked agammaglobulinemia if absent [45]. Chronic periodontitis is commonly seen in patients with neutrophil abnormalities. Severe gingivostomatitis often with dental erosions occurs in patients with leukocyte adhesion defects, for example, leukocyte adhesion deficiency type I (LAD-1).[56, 57]

Pulmonary Examination

The examination of the chest is important in the evaluation of the patient with recurrent infections and should include careful auscultation for rales or rhonchi. Not all children who wheeze have simple asthma. Other conditions that also cause wheezing, including cystic fibrosis and chronic bronchitis or bronchiectasis related to underlying immune deficiency. The presence of rales and rhonchi may indicate bronchiectasis or pneumonia pointing to a diagnosis of possible immune deficiency. The presence of digital clubbing is an important indicator of significant lung disease necessitating a careful workup. In patients with chronic lung disease, especially in patients with a B-cell immune deficiency, a baseline high-resolution chest computed tomography (CT) is recommended.

Cardiovascular Examination

Conotruncal cardiac defects such as tetralogy of Fallot, micrognathia, and ear anomalies may be associated with congenital absence of the thymus and hypoparathyroidism. Physical findings of pulmonary hypertension may be noted in patients with chronic lung disease resulting from repeated infections in the immune deficient host.

Evaluation of the Lymphoreticular System

The examination of the lymphatic system for hepatosplenomegaly and for the presence or absence of lymphoid tissue is an important aspect of the physical examination in a patient suspected of immune deficiency. Patients with severe combined immunodeficiency disease or infantile X-linked agammaglobulinemia (XLA) do not have palpable lymphoid tissue or visible tonsils. However, the presence of lymphoid tissue can be misleading in which patients with CVID may have enlarged lymphoid tissue and even hepatosplenomegaly [58]. This occurs because the reticuloendothelial system undergoes hyperplasia in the absence of opsonic antibody. Draining abscesses of the lymph nodes suggests a phagocyte defect such as in CGD.

Patients with ALPS usually present before age 5 with a chronic, nonmalignant lymphadenopathy, and massive splenomegaly, and have increased circulating double negative (CD4-/CD8-) α/β+ receptor T cells. These patients have a significantly higher risk for developing lymphoma [59]. X-linked lymphoproliferative (XLP) disease is a disease that manifests as an unusual susceptibility to Epstein Barr viral (EBV) infections. Clinical manifestations include a fulminant and often fatal infectious mononucleosis, a lymphoproliferative disease resulting in lymphoma, and the development of a dysgammaglobulinemia.

Neurologic Examination

The first indicator of ataxia-telangiectasia may be abnormalities of the neuromuscular system. Affected patients with this disorder usually present with broad-based gait and stumbling in the first or second year of life, and the cerebellar ataxia progresses with age [60]. The serum alpha fetoprotein is elevated in these children [61]. The onset of immune deficiency usually occurs after the onset of neurologic disease but occasionally preceding it [62]. Flaccid paralysis after live poliomyelitis vaccination suggests combined immunodeficiency or antibody defects [30]. Neurologic symptoms are also seen in Chediak–Higashi syndrome. Patients may have cognitive impairment, nystagmus and cerebellar, spinal and peripheral neuropathies [37, 48]. Patients with Griscelli syndrome have neurologic clinical manifestations that include seizures, ataxia, and oculomotor and reflex abnormalities.

Musculoskeletal Evaluation

Patients with immune deficiency may have arthritis or joint infections. Children with antibody deficiency and occasionally those with deficiencies of the complement system are subject to an increased incidence of septic arthritis with pyogenic bacteria. Children with deficiencies of the early classical complement pathway often present with arthritis, frequently in conjunction with dermal vasculitis resulting in a lupus-like syndrome. Children with antibody deficiency diseases often have arthralgia until placed on adequate immunoglobulin therapy. Patients with XLA have an increased incidence of arthritis (25% to 35%) from infection with a mycoplasma organism (Ureaplasma urealyticum). Patients with XLA and other B-cell abnormalities may also present with dermatomyositis, arthralgia, or overt arthritis [45]. Patients with cartilage hair syndrome (short-limbed dwarfism with metaphyseal or spondyloepiphyseal dysplasia) and adenosine deaminase deficiency (rib end cupping and flaring) also have skeletal abnormalities. Craniosynostosis is seen in patients with hyper-IgE syndrome. Other clinical features include hyperextensible joints, bone fragility, and scoliosis [43].

Screening Laboratory Tests for the Evaluation of Patients with Recurrent Infections

Elements of the history and physical examination will lead the physician evaluating a patient with recurrent infection into an appropriate direction for further evaluation. The task then is to identify which of the recognized abnormalities in immune function that best fits the patient and to confirm this with pertinent laboratory studies. A number of groups have developed diagnostic criteria for the primary immunodeficiency disorders [1, 63, 64]. These criteria were established to help physicians formulate a diagnosis using simple, objective guidelines and definitions. In addition, several lay organization including the Jeffrey Modell Foundation (http://www.info4pi.org) and the Immune Deficiency Foundation (http://www.primaryimmune.org) have initiated educational and public awareness programs for primary immune deficiencies. As outlined above, the history and physical exam are extremely critical in the initial assessment of a patient with recurrent infections. The application of basic screening tests will permit the clinician to determine the need for further, more detailed laboratory testing and referral to a clinical immunologist.

Evaluation of Innate Immune Disorders

The white blood cell count and differential are used to calculate the absolute neutrophil count to exclude neutropenia, and the peripheral blood smear is used to evaluate the leukocyte morphology. Evaluation of the complement system is most easily accomplished by obtaining a CH50, or total hemolytic complement assay [9]. In patients with congenital complement deficiency, the CH50 will be immeasurable. If a deficiency of one of the early components of the alternative pathway is suspected, an alternative pathway CH50 using rabbit erythrocytes will be required. A C3 or C4 is most useful for evaluating patients with vasculitis or complement consumption caused by immune complex diseases such as SLE. An NBT or dihydrorhodamine assay by flow cytometry is useful as a screening test for defects of neutrophil oxidative metabolism such as CGD. Assays for chemotactic defects, or opsonic or phagocytic disorders require specialized laboratories. In the patient with delayed separation of the umbilical cord, infections with poor localization of leukocytes at infected foci, or poor wound healing, flow cytometry using monoclonal antibodies to CD11/CD18 and sLex expression (CD15a), the absence of these leukocyte adhesion glycoproteins on the cell surface of leukocytes is diagnostic.

The Evaluation of T-cell Immunity

The evaluation of patients suspected of T-cell immune deficiency is outlined in Table 5. The finding of a total lymphocyte count below 1,500/mm3 in the adult or below 2,500/mm3 in the child should be considered significant, and raise the suspicion of T-cell immunodeficiency. Delayed-type hypersensitivity (DTH) skin testing remains the major screening test of cellular immunity, but must be interpreted with caution, especially in the young child where exposure to antigens may be limited, or in a patient with an underlying acquired immune deficiency, e.g., uremia, malnourished patient. In the majority of patients suspected of cellular immunodeficiency, in vitro analysis of lymphocyte subsets using flow cytometry testing will be helpful. A FISH assay for chromosomal abnormalities such as deletions at 22q11.2 will be helpful in those patients with possible DiGeorge anomaly. Chromosome analysis will be extremely helpful in the diagnosis of ICF syndrome. The α-fetoprotein levels will be raised in patients with ataxia-telangiectasia. Patients with Wiskott–Aldrich syndrome have thrombocytopenia and small platelets. More advanced testing of T-cell function, including in vitro lymphocyte proliferation assays to mitogens, e.g., PHA and concanavalin-A (Con-A), and antigens such as tetanus or Candida proteins, or to allogeneic cells in mixed lymphocyte culture (MLC), or more advanced testing such as NK cell function, analysis of cytokine production or signaling pathways, may be required. With the identification of gene mutations for many of the SCID syndromes and other T-cell deficiencies, molecular studies can be extremely helpful in making a diagnosis.

Evaluation for B-cell Immune Deficiency

Table 6 outlines an approach to the evaluation of patients with suspected B-cell deficiency. Serum immunoglobulin concentrations should be measured by quantitative techniques (nephelometry). Values in children must be compared with laboratory normals for age. Immunoelectrophoresis (IEP) is semiquantitative and should not be used to evaluate the patient with suspected antibody deficiency. IEP should only be used to examine serum for paraproteins such as those found in Waldenstrom’s macroglobulinemia or multiple myeloma. IgG subclass quantitation may be helpful, although there is continuing debate over the utility of these measurements [65]. A careful history and physical examination are important to determine the clinical significance of an IgG subclass deficiency. In addition, the measurement of functional or specific antibodies is most important to determine the clinical relevance of an IgG subclass deficiency [66].
Table 6

Laboratory tests for the evaluation of B-cell immune function

Tests

Screening

 Quantitative serum immunoglobulins

  IgG, IgM, IgA

 

 Specific antibody production to vaccine responses

   Tetanus/diphtheria (IgG1)

   Pneumococcal and meningococcal polysaccharides (IgG2)

   Common viral respiratory pathogens (IgG1 and IgG3)

    Influenza A & B

    Respiratory syncytial virus

    Parainfluenza

   Other vaccines—hepatitis B, influenza, MMR, polio (killed vaccine)

 Isohemagglutinins (IgM antibodies to A and B blood group antigens)

 B-cell quantitation by flow cytometry

Advanced Testing-

 In vitro B-cell immunoglobulin production

 Regulation of immunoglobulin synthesis

 CD40 ligand-CD40 interactions

 Molecular analysis for gene deletions or mutations

Patients may have normal total serum immunoglobulins and normal IgG subclasses yet fail to make specific antibodies to bacterial or common viral pathogens. Therefore, the assessment of specific antibody formation after vaccine administration is an important part of the laboratory evaluation in patients with suspected B-cell deficiency. Isohemagglutinins are naturally occurring IgM antibodies to the ABO blood group substances. By 1 year of age, 70% of infants have positive isohemagglutinin titers depending, of course, on their blood type [2]. Responses to protein antigens generally fall in the IgG1 subclass, whereas the immune response to the polysaccharide antigens resides within the IgG2 subclass. With the conjugated vaccines for Haemophilus influenzae type b and pneumococcal polysaccharides, antibody responses occur primarily in the IgG1 rather than IgG2 subclass [67]. Therefore, these conjugate vaccines may not be as helpful in the functional evaluation of a IgG2 subclass deficiency or a selective polysaccharide antibody deficiency. Fortunately, the vaccine for pneumococcal polysaccharide antigens is still available for evaluating patients for a selective or antigen-specific antibody deficiency [68].

Because a common complaint of many of these patients is recurrent upper respiratory tract infections, one can test the serum for the presence of antibodies to common respiratory viral agents such as influenza A and B, mycoplasma, respiratory syncytial virus, adenovirus, and the parainfluenza viruses [69]. These antibodies fall into both the IgG1 and IgG3 subclasses [70]. Molecular analysis for genetic abnormalities, especially those that involve the early stages of B-cell maturation in those patients who present with absent B cells, e.g., XLA, can be very helpful in diagnostic evaluations.

Recent advances in the chromosomal mapping of the various immunodeficiency diseases have made carrier detection and prenatal diagnosis possible in some immune deficiency disorders. Genetic counseling is important not only for the child’s parents, but also for siblings and the extended family. Advances in molecular biology over the past decade have enabled identification of the genes responsible for many of the immune deficiency disorders. Once a diagnosis has been made, it is often possible to counsel the parents on the inheritance patterns and the potential for carrier detection. In families with x-linked disorders, it is particularly important to address issues of carrier detection and prenatal diagnosis.

Prenatal diagnosis can be established by performing analyzes on fetal blood samples, amniotic fluid cells, or chorionic villus biopsy specimens. Diseases such as ADA deficiency, leukocyte adhesion deficiency, and bare lymphocyte syndrome, among others, can be diagnosed prenatally.

Carrier Detection and Genetic Counseling

Recent advances in the chromosomal mapping of the various immunodeficiency diseases have made carrier detection and prenatal diagnosis possible in some immune deficiency disorders. Genetic counseling is important not only for the child’s parents, but also for siblings and the extended family. Advances in molecular biology over the past decade have enabled identification of the genes responsible for many of the immune deficiency disorders. Once a diagnosis has been made, it is often possible to counsel the parents on the inheritance patterns and the potential for carrier detection [71]. In families with x-linked disorders, it is particularly important to address issues of carrier detection and prenatal diagnosis. Prenatal diagnosis can be established by performing analyses on fetal blood samples, amniotic fluid cells, or chorionic villus biopsy specimens. Diseases such as ADA deficiency, leukocyte adhesion deficiency, and bare lymphocyte syndrome, among others, can be diagnosed prenatally.

Carrier detection can be accomplished in several ways. If the exact location of the involved gene is known, carriers can be identified with reasonable certainty with the use of genetic markers. For a known gene mutation in a given immune deficiency, polymerase chain reaction (PCR) analysis can be performed, or a technique called single-strand conformation polymorphism. Another approach is linkage analysis using specific DNA probes that identify polymorphisms near the gene of interest, if the mutation is not known. If the nature of the disease involves a deficiency of enzymatic activity or complement components than heterozygote carriers can be established by documenting reduced levels of enzyme or complement component in parents or siblings. In some X-linked recessive conditions, a phenomenon of preferential X-inactivation has been observed in female carriers in which assays can detect the selective use of the nonmutant X chromosome as the active X chromosome. Examples of these immune deficiencies include x-linked agammaglobulinemia, x-linked SCID, and Wiskott–Aldrich syndrome. Skewing of the X chromosome occurs because of the deleterious effects of the defective gene on cell growth and differentiation.

Management Issues for the Pediatrician

Once the diagnosis of primary immunodeficiency has been established, important issues for the pediatrician still exist. Early empirical coverage for suspected pathogens may be indicated after obtaining appropriate cultures. Prophylactic antibiotics for Pneumocystis jiroveci (PCP) may be indicated for children with significant T-cells defects, but evaluation for bone marrow or stem cell transplantation is crucial for prognosis. Children with B-cell immunodeficiencies are candidates for replacement therapy with intravenous immunoglobulin (IgIV). Live-attenuated vaccines like oral polio, varicella, and Bacillus of Calmette and Guérin (BCG) should not be given to patients or family members with suspected or diagnosed antibody or T-cell immune deficiency as vaccine-induced infection is a risk in these patients. If there is a need for blood transfusion, only irradiated, leukocyte-poor, and virus-free (CMV) products should be used in patients with T-cell defects to avoid graft-vs-host disease and CMV infection. In patients with T-cell deficiency, varicella-zoster immunoglobulin may be indicated after varicella exposure. Significant advances within the past decade in our understanding of the molecular and genetic mechanisms responsible for some of the primary immunodeficiencies have greatly expanded our options for treatment. Currently available treatment techniques include bone marrow transplantation, immunoglobulin replacement, and enzyme (adenosine deaminase conjugated to polyethylene glycol) therapies. Gene therapy for immune deficiency disorders have been initiated in clinical trials, and hopefully will become a standard for therapy in the future.

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© Humana Press Inc. 2007