ESSENTIALS OF DIAGNOSIS
Frequent sinopulmonary infections secondary to humoral immune deficiency.
Low serum immunoglobulin levels and deficient functional antibody responses.
Primary defect may be with B cells or T cells.
The most common symptomatic primary immunodeficiency disorder is common variable immunodeficiency, a heterogeneous immunodeficiency disorder clinically characterized by an increased incidence of recurrent infections, autoimmune phenomena, and neoplastic diseases. The onset is generally in early adulthood but it can occur at any age. The prevalence of common variable immunodeficiency is about 1 in 25,000 in the United States. Most cases are sporadic; about 10–20% are familial.
Increased susceptibility to infections, especially with encapsulated organisms, is the hallmark of the disease. Chronic lung disease is one of the most frequent complications of common variable immunodeficiency. Virtually all patients suffer from recurrent sinusitis; bronchitis, otitis, pharyngitis, and pneumonia are common infections. Infections may be prolonged or associated with unusual complications such as meningitis, empyema, or sepsis. Bronchiectasis occurs in at least 25% of patients with common variable immunodeficiency and is a leading cause of morbidity.
Gastrointestinal infections and dysfunction are commonly associated with common variable immunodeficiency, and a sprue-like syndrome, with diarrhea, steatorrhea, malabsorption, protein-losing enteropathy, and hepatosplenomegaly, may develop in patients. Paradoxically, there is an increased incidence of autoimmune disease (20%), although patients may not display the usual serologic markers. Autoimmune cytopenias are most common, but autoimmune endocrinopathies, seronegative rheumatic disease, and gastrointestinal disorders are also commonly seen. Lymph nodes may be enlarged in these patients, yet biopsies show marked reduction in plasma cells. Noncaseating granulomas are frequently found in the spleen, liver, lungs, or skin. There is an increased propensity for the development of B-cell neoplasms (50- to 400-fold increased risk of lymphoma) and gastric carcinomas.
Assess serum quantitative immunoglobulin levels. All patients with common variable immunodeficiency have a reduced serum IgG level, and either serum IgM or IgA or both are reduced as well. Demonstration of functional or quantitative defects in antibody production is essential and is typically performed by checking antibody response to polysaccharide (Pneumovax-23) and protein antigens (such as tetanus and diphtheria). The diagnosis is made in patients who have reduced serum immunoglobulins and poor antibody response to vaccines, after exclusion of secondary causes (eg, proteinuria, protein-losing enteropathy, drug effects such as rituximab and other immunosuppressants, antiepileptics, and hematologic malignancies).
The causes of hypogammaglobulinemia in patients with common variable immunodeficiency include intrinsic B-cell defects that prevent terminal maturation into antibody-secreting plasma cells. The absolute B-cell count in the peripheral blood, however, can be normal. A subset of these has concomitant T-cell immunodeficiency with increased numbers of activated CD8 cells, splenomegaly, and decreased delayed-type hypersensitivity.
Patients with common variable immunodeficiency should be treated aggressively with antibiotics at the first sign of infection. Since antibody deficiency predisposes patients to high-risk pyogenic infections, antibiotic coverage should be sure to cover encapsulated bacteria. Infections with other microorganisms also can develop, including viruses, parasites, and extracellular gram-positive or gram-negative bacteria (such as S aureus or P aeruginosa). Mainstay of preventive therapy is with subcutaneous or intravenous immunoglobulin replacement therapy, with a typical monthly dose of 300–600 mg/kg. Subcutaneous injections of IgG offer the convenience of self-administration at home and lower incidence of adverse effects and can be administered every 1–4 weeks. Adjustment of the dosage or infusion interval is made primarily on the basis of clinical responses in addition to serum IgG levels. Such therapy is essential for decreasing the incidence of potentially life-threatening infections, increasing quality of life, and reducing the progression of lung disease.
Refer patients with low serum immunoglobulins and history of recurrent or unusual infections, autoimmune disease, or family history of immunodeficiency to an allergist or immunologist.
The presence of bronchiectasis without a known underlying cause such as cystic fibrosis should raise the suspicion of a primary immunodeficiency; even when total serum immunoglobulins levels are normal, the patient can have a specific antibody deficiency that would warrant further evaluation.