• Immunodeficiencies can be either congenital or acquired.
• Immunodeficiencies often present as an increased susceptibility to infection as well as diarrhea, malabsorption, or failure to thrive; other manifestations can include unusual infections, including unexplained recurrent or chronic thrush.
• Consider immunodeficiencies if a child has two or more bacterial pneumonias per year, five or more episodes of otitis media per year or seven or more episodes in 2 years, recurrent or persistent sinusitis, or frequent, unusual, or unusually severe infections.

• Antibody immunodeficiencies (B-cell–associated immunodeficiencies)
  • X-linked agammaglobulinemia
  • IgG subclass deficiency
  • Common variable immunodeficiency
  • IgA deficiency
  • Transient hypogammaglobulinemia of infancy
• Cellular immunodeficiencies (T-cell–associated immunodeficiencies)
  • DiGeorge syndrome—thymic aplasia or hypoplasia
  • Chronic mucocutaneous candidiasis
• Combined cellular and antibody (B- and T-cell–associated immunodeficiencies)
  • Severe combined immunodeficiency
  • Adenosine deaminase (ADA) or nucleoside phosphorylase deficiency
  • Ataxia telangiectasia
  • Wiskott-Aldrich syndrome
• Natural-killer cell deficiency (abherent cell lysis)
• Phagocytic dysfunction
  • Chronic granulomatous disease
  • Hyper-IgE syndrome
• Complement deficiencies

• X-linked agammaglobulinemia—onset of symptoms after 6 months; infections by bacterial pathogens; respiratory system, skin, bone most commonly infected
• IgG subclass deficiency—infections with bacterial pathogens; IgG2 and IgG4 most common deficiencies in children; usually have normal or increased total IgG levels; may resolve spontaneously between 18 months and 6 years
• Common variable immunodeficiency—may appear in later childhood or adulthood; heterogeneous group of disorders with hypogammaglobulinemia
  • B cells fail to mature into plasma cells
  • Recurrent and sinopulmonary disease is common
• IgA deficiency—may be asymptomatic; pulmonary and gastrointestinal infections are the most common illnesses; difficult to establish prior to 2 years of age
• Transient hypogammaglobulinemia of infancy—occurs between 3 and 6 months of age; usually transient, although may last up to 8 years; repeated bacterial infections most common presentations
• Immunodeficiency with increased IgM—decreased IgG, IgE, IgA with increased IgM; symptoms begin in first or second year of life; recurrent bacterial infection
  • May be seen as associated neutropenia
• DiGeorge syndrome—aplasia of the thymus and hypoparathyroidism, hypothyroidism, congenital heart disease, and abnormal facial features; often present with hypocalcemia.
• Chronic mucocutaneous candidiasis—T-cell–deficient response to candida; 50% with endocrine abnormalities
  • NL T-cell response to other antigen
• Severe combined immunodeficiency—illness begins in the first months of life; illnesses include pneumonia, sepsis chronic diarrhea, FTT, thrust Pneumocystis carini pneumonia—common initial presentation and cause of pneumonia; at risk for viral and bacterial infection
• ADA deficiency—affects activity of both T- and B-cell function; associated chondro-osseus dysplasia
• Ataxia telangiectasia—progressive cerebellar ataxia; telangiectasis; sinopulmonary infections common; lymphopenia in some cases
• Wiscott-Aldrich syndrome—clinical picture of eczema, thrombocytopenia, and recurrent infections; poor antibody response to polysaccharide antigens and defective T-cell function; small platelets on peripheral blood smear; IgM low; IgG normal or slightly low; IgA and IgE elevated
• Natural-killer cell deficiency—recurrent infections, including severe herpesvirus infections; can be seen in Chédiak-Higashi syndrome, leukocyte adhesion molecule deficiency, and X-linked lymphoproliferative syndrome
• Chronic granulomatous disease—granulomas in skin, lungs, and lymph nodes; impaired bactericidal function of neutrophils; predisposes to infection with catalase-producing organisms; lymphadenopathy with purulent drainage and hepatosplenomegaly are common findings.
• Hyper-IgE syndrome—eczema with bacterial infections of the skin, lungs, middle ears, and sinuses; Staphylococcus aureus is a major cause of infection; absolute eosinophilia on peripheral smear is common.
• Complement deficiency—C2 is the most common deficiency; pyogenic infections are the most common problem; deficiency of the terminal components of the cascade C5-C9 are associated with Neisseria infections.

• HIV infection
• Malignancy
• Viral suppression
• Nephrotic syndrome

• B-cell dysfunction—leads to antibody deficiency; poor opsonization of bacterial pathogens to allow for phagocytosis.
• T-cell dysfunction—poor response to fungal and viral pathogens
• Complement deficiency—pyogenic infections due to poor opsonization and immune adherence of circulating white blood cells
• Granulocytopenia—poor phagocytosis of bacterial pathogens

• X-linked agammaglobulinemia—X-linked
• IgG subclass deficiency—autosomal recessive?
• Common variable immunodeficiency—autosomal recessive or dominant
• IgA deficiency—autosomal recessive or dominant
• Transient hypogammaglobulinemia of infancy—unknown
• Immunodeficiency with increased IgM—X-linked or autosomal recessive
• DiGeorge syndrome—?
• Chronic mucocutaneous candidiasis—autosomal recessive
• Severe combined immunodeficiency—autosomal recessive or X-linked
• ADA or nucleoside phosphorylase deficiency—autosomal recessive
• Immunodeficiency with ataxia telangiectasia—autosomal recessive
• Wiskott-Aldrich syndrome—X-linked
• Natural-killer cell deficiency—unknown
• Chronic granulomatous disease—X-linked or autosomal recessive
• Hyper-IgE syndrome—autosomal dominant or unknown
• Complement deficiencies—autosomal recessive or dominant

• Severe invasive bacterial disease
• Recurrent respiratory tract infections
• Failure to thrive
• Unusual infection with unusual organism
• Chronic diarrhea
• Bronchiectasis, chronic or recurrent pneumonia, recurrent bronchitis
• Recurrent or resistant thrush
• Skin lesions—pyoderma or necrotic abscesses

• Familial history
• Number and duration of infections
• Recurrent pneumonias
• Chronic diarrhea
• Association of rashes, diarrhea, failure to thrive
• Neurological problems
• HIV risk factors
• Endocrine disorders B hypothyroidism and hypoparathyroidism seen in DiGeorge syndrome

Finding: Skin—telangectasia
Significance: Ataxia telangectasia

Finding: Thrush (candidiasis)
Significance: T-cell deficiencies

Finding: Eczema
Significance: Wiskott-Aldrich syndrome, hyper-IgE syndrome

Finding: Pulmonary—chronic lung disease
Significance: IgA deficiency, chronic granulomatous disease, hyper-IgE syndrome, X-linked hypogammaglobulinemia

Finding: Short stature
Significance: Common presentation of immune deficiency

• Complete blood count with differential
• Quantitative immunoglobulins
• Antibody responses to immunizations (must be certain that the child has been immunized)
• Anergy panel plus PPD—can include trichophyton, Candida, tetanus, mumps
• T-cells—total and subsets
• Nitroblue tetrazolium test
• Phagocytic function
• CH50—total hemolytic complement
• Complement levels—C2-C6
• HIV ELISA and Western blot. If positive in children under 15 months of age, HIV infection should be confirmed with HIV PCR and HIV co-culture

• DiGeorge syndrome
• Severe combined immunodeficiency (SCID)
• SCID with ADA deficiency
• Wiskott-Aldrich syndrome
• Chronic granulomatous disease

• DiGeorge syndrome
• Gamma globulin replacement therapy
• X-linked agammaglobulinemia
• Immunodeficiency with elevated IgM
• Common variable immunodeficiency
• IgG subclass deficiency
• Prophylactic antibiotics/antifungals
• IgG subclass deficiency
• Chronic mucocutaneous candidiasis
• Ataxia telangiectasia
• Hyper-IgE syndrome
• Complement deficiencies

Q: Do I have to worry about a previously well child who on routine CBC has neutropenia?
A: It is unlikely that a child who was previously well would have a significant immunodeficiency. The most likely diagnosis is viral suppression of the bone marrow. CBC should be repeated in approximately 2 weeks to confirm a normal neutrophil count.

Q: Does every child who has an episode of varicella-zoster need an immunologic workup?
A: No. One isolated course of non-complicated zoster does not require an immunologic evaluation. However, if more than one dermatome is involved or if the episodes are repeated, an immunologic evaluation is warranted.

Q: Should I be concerned about an immunodeficiency disorder in a 4-year-old child with thrush? How should such a child be evaluated?
A: There is no absolute age at which oral thrush is indicative of an underlying immunodeficiency. Obviously, one should look for predisposing factors such as antibiotic therapy or inhaled steroids as predisposing factors for oral thrush. Many authorities use 2 years as an age beyond which thrush should be evaluated. This evaluation should first include a culture from the plaque lesions to be certain that the condition is truly oral candidiasis. Immunologic workup should include an HIV ELISA confirmed with a Western blot study when positive, T-cell subsets to include CD4 and CD8, and T-cell mitogen studies. Evaluation of these tests may require the assistance of a pediatric immunologist.

• X-linked agammaglobulinemia—survive to second or third decade
• IgG subclasss deficiency—50% with IgG2 or IgG4 resolve by 18 months to early childhood
• Common variable immunodeficiency—good prognosis; survive to adulthood
• IgA deficiency—the earlier the onset of symptoms: guarded prognosis
• Transient hypogammaglobulinemia of infancy—self-limited with excellent prognosis
• DiGeorge syndrome—good prognosis
• Chronic mucocutaneous candidiasis—severe form: survive to third decade; mild form survive normal life span
• Severe combined immunodeficiency—die by age 1 or 2 years without bone marrow transplantation
• ADA or nucleoside phosphorylase deficiency—die without bone marrow transplantation
• Ataxia telangiectasia—variable
• Wiskott-Aldrich syndrome—variable; may die from massive bleeding at a young age
• Chronic granulomatous disease—survival up to the second decade
• Hyper-IgE syndrome—may survive into adulthood
• Complement deficiencies—usually survive into adulthood

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