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KEY FEATURES

Essentials of Diagnosis

  • Frequent sinopulmonary infections secondary to humoral immune deficiency

  • Two or more low serum immunoglobulin levels (IgG, IgA, or IgM) and deficient functional antibody responses to vaccination

  • Secondary causes for hypogammaglobulinemia and recurrent sinopulmonary infections have been ruled out

General Considerations

  • Most common symptomatic primary immunodeficiency disorder

  • Heterogeneous immunodeficiency disorder clinically characterized by an increased incidence of recurrent severe sinopulmonary infections with hypogammaglobulinemia

  • Approximately half of patients will also have autoimmune phenomena with or without neoplastic disease

Demographics

  • Onset is generally in adolescence or early adulthood but can occur at any age

  • The prevalence is about 1 in 25,000 in the United States

  • Most cases are sporadic; about 10–20% are familial

CLINICAL FINDINGS

  • Increased susceptibility to serious infections, especially with encapsulated organisms is the hallmark

  • Recurrent

    • Sinusitis

    • Bronchitis

    • Otitis

    • Pneumonia (as opposed to patients with severe atopy)

  • Infections may be prolonged or associated with unusual complications such as meningitis, empyema, or sepsis

  • Bronchiectasis occurs in > 25% of patients who are not treated with IgG-RT and is a leading cause of morbidity

  • Recurrent viral infections: not prototypic of common variable immunodeficiency, but varicella zoster reactivation, cytomegalovirus reactivation, and increased symptomatic disease from other herpes viruses and candida can occur

  • Gastrointestinal infections and dysfunction

    • Many patients develop an inflammatory sprue-like syndrome, with diarrhea, steatorrhea, malabsorption, protein-losing enteropathy, and hepatosplenomegaly

  • Norovirus and giardia can be problematic

  • Increased incidence of autoimmune disease (20%)

    • Patients often do not display the usual serologic markers as they are hypogammaglobulinemic

    • Autoimmune cytopenias are most common

    • Autoimmune endocrinopathies and seronegative rheumatic disease also common

  • Lymph nodes may be enlarged, yet biopsies show marked reduction in plasma cells

  • Noncaseating granulomas mimicking sarcoidosis can be found in the spleen, liver, lungs, or skin

DIAGNOSIS

  • Diagnosis is made when there are reduced serum immunoglobulins and poor antibody response to vaccines

    • Reduced serum immunoglobulins

      • Serum IgG reduced at least two standard deviations below normal

      • Either IgA or IgM also reduced at least two standard deviations below normal

      • IgA is commonly undetectable

  • Poor antibody response to vaccines

    • Check antibody response to polysaccharide (Pneumovax-23, H influenzae type b) and protein (tetanus, diphtheria) antigens

    • Demonstrates functional or quantitative defects in antibody production

  • Exclude secondary causes of hypogammaglobulinemia, such as

    • Proteinuria

    • Protein-losing enteropathy

    • Drug effects (eg, rituximab, antiepileptics)

    • Hematologic malignancies

  • Absolute B-cell count in peripheral blood can be normal; a subset of patients, however, have concomitant T-cell immunodeficiency with

    • Increased numbers of activated CD8 cells

    • Splenomegaly

    • Decreased delayed-type hypersensitivity

TREATMENT

  • Immune globulin replacement therapy (IgG-RT)

  • Should be treated aggressively with antibiotics at the first sign of infection; antibiotic therapy should cover encapsulated bacteria

  • Infections with ...

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