DESCRIPTION

Immunodeficiencies generally represent defects in host defenses. Other inborn errors of immunity represent immune dysregulation, with features of both autoimmunity and immunodeficiency. Some immunodeficiencies are associated with increased risk of atopy/allergy and malignancies. Currently, there are ~400 unique inborn errors of immunity described. Both congenital (primary) and acquired (secondary) forms of immune deficiency exist.

• Defects in antibody production: often characterized by frequent sinopulmonary infections with typical organisms
  • X-linked agammaglobulinemia: due to arrest in B-cell maturation, variants in Bruton tyrosine kinase (BTK)
    • Onset of symptoms after 6 months of age (time of waning maternal immunoglobulin [Ig] G); sinopulmonary infections with typical bacterial pathogens
    • Markedly decreased Ig and B cells; tonsils are absent.
  • Hyper-IgM syndromes: several forms, due to defects in CD40/CD40L
    • Usually present with recurrent bacterial infections in infancy; Pneumocystis jiroveci is seen; intermittent neutropenia is common.
    • Decreased/absent IgG, IgE, IgA with normal or increased levels of IgM
  • Common variable immunodeficiency (CVID)
    • Usually presents with recurrent bacterial infections; most commonly arises in the 2nd or 3rd decade (but seen at all ages); Ig levels and function gradually decline with poor response to vaccines.
    • Increased risk for autoimmunity, inflammatory bowel disease, bronchiectasis, and lymphoma
    • Heterogenous disorder; both polygenic and monogenic disorders result in CVID.
  • Selective IgA deficiency
    • Most common congenital immunodeficiency (1:600); most are asymptomatic.
    • Symptoms seen at any age; typically sinopulmonary infections; increased risk of allergy, autoimmune disease, and reactions to blood products on repeated exposure
  • Transient hypogammaglobulinemia of infancy: developmental delay of Ig production; function is intact; typically resolves between 1 and 2 years of age
• T-cell defects: most often characterized by persistent viral infections or opportunistic infections in addition to frequent typical infections
  • Severe combined immunodeficiency (SCID): severe life-threatening disease characterized by absence of T-cells number or function leading to impaired cellular and humoral immunity; all 50 states now have SCID newborn screening to identify patients before symptomatic.
    • Most common presentations are respiratory virus that fails to clear or chronic diarrhea. Failure to thrive, thrush, and P. jiroveci pneumonia are also common.
    • Hematopoietic stem cell transplant (HSCT): curative and definitive treatment
  • Other combined immune deficiencies
    • Children exhibit increased severity of a broad range of infections, opportunistic infections, and unusual autoimmunity/immune dysregulation.
  • Chromosome 22q11.2 deletion syndrome
    • See “22Q11.2 Deletion Syndrome” chapter
    • Immunodeficiency presentation varies from SCID-like phenotype to mild T-cell lymphopenia.
  • Chronic mucocutaneous candidiasis
    • Multiple forms of this disorder
    • Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) associated with polyendocrinopathies and ectodermal dysplasia
    • Other types more likely to have associated Th17-cell defects; infants have extensive or recurrent Candida infections; modest predisposition to other infections
  • Immunodeficiency, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome
    • Presents early in life with severe diarrhea associated with villous atrophy and T-cell infiltrate and progressive autoimmune destruction of endocrine organs
    • Infections can be severe, but autoimmune manifestations predominate.
• Neutrophil defects: characterized by infections with Staphylococcus, Pseudomonas, and/or unusual bacteria or fungi
  • Autoimmune neutropenia of infancy
    • Most common neutrophil defect of childhood; usually detected at ~6 to 12 months of age
    • Often resolves by 2 years of age
  • Congenital neutropenia
    • Infections may be skin infections or sinopulmonary. Patients have either persistently absent or markedly low neutrophil counts.
    • Cyclic neutropenia: 21-day cycles of neutropenia; fevers and oral ulcers may also accompany drops in neutrophil count.
  • Leukocyte adhesion deficiency: defect in neutrophil chemotaxis
    • ~10% have delayed separation of the umbilical cord.
    • Most common presentations are recurrent skin ulcers and periodontitis; spontaneous peritonitis can occur.
  • Chronic granulomatous disease (CGD): impaired phagocytic clearance of pathogens due to defective respiratory oxidative burst
    • Recurrent skin abscesses common, deep hepatic abscesses, and pulmonary infections
    • Typical organisms are catalase-positive (Staphylococcus aureus, Burkholderia, Serratia, Nocardia, mycobacteria, Aspergillus, and Candida).
• Innate immunity defects: typically present with severe bacterial or viral infections in early infancy
  • IRAK4 and MyD88 deficiencies
    • Associated with staphylococcal, streptococcal, or pseudomonal sepsis/meningitis
    • Clostridial infections are also seen; fever can be mild or absent despite significant infection.
  • Recurrent herpes simplex encephalitis is associated with several gene defects (including TLR3 and IRF3).
• Macrophage activation defects
  • Associated with disseminated atypical mycobacteria and Salmonella infections
  • Biopsies may reveal poorly formed granulomas.
• Complement deficiency
  • Deficiencies of terminal complement (C5–C9) are associated with Neisseria infections.
  • Deficiencies of C1, C2, and C4 are associated with lupus and recurrent bacterial infections.
  • C3 deficiency associated with glomerulonephritis and severe recurrent infections
  • Defects in complement regulatory proteins are associated with atypical hemolytic uremic syndrome (HUS) or hereditary angioedema.
• Other immunodeficiency syndromes
  • Ataxia telangiectasia
    • Progressive cerebellar ataxia during infancy; ocular telangiectasias at about 5 to 15 years of age
    • Recurrent sinopulmonary infections; α-fetoprotein is elevated; IgA and IgG2 are diminished.
  • Wiskott-Aldrich syndrome
    • Clinical triad of eczema, thrombocytopenia, and recurrent infections
    • Ig levels are variable but responses to vaccines often poor; small platelets and thrombocytopenia
  • Hyper-IgE syndrome
    • Recurrent infections of the skin and lungs; S. aureus is a major cause of infection.
    • Pulmonary infections typically heal with pneumatoceles.
  • X-linked lymphoproliferative syndrome
    • Four main types of presentation and two genetic types: acute Epstein-Barr virus (EBV) infection with hemophagocytosis, lymphoma, hypogammaglobulinemia, and aplastic anemia
    • Family history is the key to diagnosis.
  • Chédiak-Higashi syndrome
    • Pigmentary dilution, progressive neuropathy, and frequent infections; associated with hemophagocytic process
    • Neutrophil counts are low, and neutrophils have giant inclusions.
  • Familial hemophagocytic lymphohistiocytosis (familial HLH)
    • Multiple defects in cytotoxic function
    • Presents with episodes of HLH with fever, pancytopenia, and hepatosplenomegaly; usually <5 years of age
  • Ectodermal dysplasia with immune deficiency
    • Two forms: variable ectodermal dysplasia and variable immune deficiency; Ig levels are variable as are responses to vaccines.
    • Susceptibility to mycobacteria, Pneumocystis, and common bacterial pathogens
• Secondary immunodeficiencies include the following: HIV infection, malignancy, viral suppression, nephrotic syndrome, malnutrition, medications, splenectomy, complex cardiac anomalies, and/or thymic disruption.

EPIDEMIOLOGY

Primary immune deficiencies range from the common (1:600) to the very rare (1:1,000,000).

• 1:600 for IgA deficiency
• 1:3,000 for chromosome 22q11.2 deletion syndrome
• 1:50,000 for SCID
• 1:200,000 for CGD

RISK FACTORS

HISTORY

• Question: Is there a family history of similar presentation? Consanguinity?
• Significance: Autosomal recessive and X-linked disorders are common.
• Question: How many infections and how long do they last?
• Significance: Determine whether the problem is one of clearance or increased frequency or susceptibility.
• Question: What types of infections?
• Significance: Infections of skin are frequently due to neutrophil problems, whereas recurrent infections of a single site imply an anatomic problem. Opportunistic infections are associated with both neutrophil defects (unusual bacteria and fungi) and T-cell defects (opportunistic viruses).
• Question: Social and sexual/drug history?
• Significance: HIV risk factors

PHYSICAL EXAM

Examination should be directed at defining organ damage as a result of infection, the presence of any current infections, syndromic features including dysmorphic facies, signs of autoimmune disease, and characterization of accessible lymphoid organs, including the liver and spleen.

DIAGNOSTIC TESTS & INTERPRETATION

• Newborn screening/T-cell receptor excision circles (TRECs): biomarker of naïve T-cell production indicative of newborn’s intrinsic T-cell production; severely depressed in patients with SCID and other severe forms of T-cell lymphopenia
• Complete blood count (CBC) with differential; IgG, IgA, and IgM levels; and diphtheria and tetanus titers: In certain patients, it may be difficult to differentiate between viral processes and bacterial processes. In these cases, a CBC with differential; IgG, IgA, and IgM levels; and diphtheria and tetanus titers are a useful screen to evaluate for the most common immunodeficiencies.
• IgG, IgA, IgM, and IgE levels and responses to vaccines such as pneumococcal vaccine polyvalent (Pneumovax 23^®) and tetanus: Recurrent sinopulmonary infections with typical organisms are associated with defects in antibody production.
• Evaluation of T-cell production and function—T-cell enumeration and lymphocyte proliferation studies: T-cell defects will often have low T-cell numbers and/or decreased function.
• Evaluation of neutrophil numbers and function—CBC with differential, morphologic exam of neutrophils, and a measure of respiratory burst: Neutropenia is the most common type of neutrophil defect followed by CGD.
• Special studies designed to test the function of the toll-like receptor signaling complex: Innate defects, such as IRAK4, MyD88, and NEMO deficiencies, can be detected.
• CH50 tests for the function of the complement system and will detect most of the structural component deficiencies; special studies are needed for defects of the alternative pathway (AH50) and regulatory proteins.

GENERAL MEASURES

• Prophylactic antimicrobials for opportunistic infections (i.e., antifungals, P. jiroveci pneumonia prophylaxis)
  • Chronic mucocutaneous candidiasis
  • SCID
  • Hyper-IgE syndrome
  • CGD
• Suspected SCID requires isolation, cytomegalovirus-negative/irradiated blood products, live vaccine avoidance, and a prompt evaluation for HSCT.
• Ig replacement (either IV or SC)
  • X-linked agammaglobulinemia
  • Hyper-IgM
  • CVID
  • Selective IgA–deficient individuals may be at increased risk for severe anaphylaxis to blood/blood products, including Ig, containing trace amounts of IgA.
• Specific strains of probiotic supplements may be useful for antibiotic-associated diarrhea.
• Hand washing to prevent infections

SURGERY/OTHER PROCEDURES

• HSCT
  • SCID
  • Wiskott-Aldrich syndrome
  • X-linked lymphoproliferative syndrome
  • Chédiak-Higashi syndrome
  • Familial HLH
  • Selected cases of hyper-IgM, CGD, macrophage activation defects
• Thymus transplantation
  • Severe chromosome 22q11.2 deletion syndrome (DiGeorge syndrome)
  • Immunodeficiency in CHARGE syndrome (coloboma, heart defects, atretic choanae, growth issues, genital, and ear abnormalities) is due to impairment in thymic development
  • Complete thymic aplasia

PROGNOSIS

• Patients with SCID who received transplant before 3.5 months of age and prior to onset of infections have >90% 5-year survival rate. Most antibody deficiencies have an excellent prognosis with appropriate initiation of IgG replacement. Transient or developmental deficiencies of IgG or IgG subclasses typically resolve by 2 years of age.
• Some patients with CVID can develop malignancy or autoimmune disease which defines the prognosis.
• The treatment of neutrophil disorders remains problematic; most children with CGD will not have full life expectancy. HSCT can be curative.
• Patients with T-cell disorders for whom bone marrow transplantation is not performed can do well if the defect is mild and if they do not suffer from autoimmune disease, malignancy, or recurrent infections.

COMPLICATIONS

• Bronchiectasis
• Deafness
• Autoimmune disease
• Lymphoreticular malignancies occur in patients with T-cell disorders.
• Live viral vaccines administered to patients with significant T-cell dysfunction can result in disease.
• Oral polio vaccine administered to patients with agammaglobulinemia can cause meningoencephalitis.

ICD 10

• D84.9 Immunodeficiency, unspecified
• D80.9 Immunodeficiency with predominantly antibody defects, unspecified
• D83.9 Common variable immunodeficiency, unspecified
• D80.0 Hereditary hypogammaglobulinemia
• D80.8 Other immunodeficiencies with predominantly antibody defects
• D84.8 Other specified immunodeficiencies