Immunodeficiency Disorders
Immunodeficiency Disorders: INTRODUCTION.
Primary Immunodeficiency Disorders:| Selective Immunoglobulin A Deficiency Selective IgA deficiency is the most common primary immunodeficiency disorder and is characterized by the absence of serum IgA with normal levels of IgG and IgM; its prevalence is about 1:500 individuals. Most persons are asymptomatic because of compensatory increases in secreted IgG and IgM. Some affected patients have frequent and recurrent infections such as sinusitis, otitis, and bronchitis. Some cases of IgA deficiency may spontaneously remit. When IgG2 subclass deficiency occurs in combination with IgA deficiency, affected patients are more susceptible to encapsulated bacteria and the degree of immune impairment can be more severe. Patients with a combined IgA and IgG subclass deficiency should be assessed for functional antibody responses to glycoprotein antigen immunization. Atopic disease and autoimmune disorders can be associated with IgA deficiency. Occasionally, a sprue-like syndrome with steatorrhea has been associated with an isolated IgA deficit. Treatment with commercial immune globulin is ineffective, since IgA and IgM are present only in trace quantities in these preparations. Frequent infusions of plasma (containing IgA) or unwashed blood transfusions are hazardous, since anti-IgA antibodies may develop, resulting in systemic anaphylaxis or serum sickness.
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| Common Variable Immunodeficiency Essentials of Diagnosis
General Considerations The most common cause of panhypogammaglobulinemia in adults is common variable immunodeficiency, a heterogeneous immunodeficiency disorder clinically characterized by an increased incidence of recurrent infections, autoimmune phenomena, and neoplastic diseases. The onset generally is during adolescence or early adulthood but can occur at any age. The prevalence of common variable immunodeficiency is about 1:80,000 in the United States. Clinical Findings Symptoms and Signs The pattern of immunoglobulin isotype deficiency is variable. Most patients present with significantly depressed IgG levels, but over time all antibody classes (IgG, IgA, and IgM) may be affected. Increased susceptibility to pyogenic infections is the hallmark of the disease. Virtually all patients suffer from recurrent sinusitis, with bronchitis, otitis, pharyngitis, and pneumonia also being common infections. Infections may be prolonged or associated with unusual complications such as meningitis or sepsis. Gastrointestinal disorders 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 increase risk of lymphoma), gastric carcinomas, and skin cancers. Laboratory Findings Diagnosis is confirmed in patients with recurrent infections by demonstration of functional or quantitative defects in antibody production. Serum IgG levels are usually less than 250 mg/dL; serum IgA and IgM levels are also subnormal. Decreased to absent functional antibody responses to protein antigen immunizations establish the diagnosis. The cause of the panhypogammaglobulinemia in the majority of common variable immunodeficiency patients is an intrinsic B cell defect preventing terminal maturation into antibody-secreting plasma cells. In a small number, excessive suppressor T cell activity that inhibits B cells—or helper T cell activity inadequate to assist B cells to make antibody—has been identified. The absolute B cell count in the peripheral blood in most patients, despite the underlying cellular defect, is normal. A subset of these patients have concomitant T cell immunodeficiency with increased numbers of activated CD8 cells, splenomegaly, and decreased delayed-type hypersensitivity. Treatment Patients may 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. Only after the development of bronchiectasis or after sinus surgery do patients become significantly affected by more virulent organisms such as Staphylococcus aureus or Pseudomonas aeruginosa. Maintenance intravenous immune globulin (IGIV) therapy is indicated, with infusions of 300–500 mg/kg of IGIV given at about monthly intervals. Adjustment of dosage or of the infusion interval is made on the basis of clinical responses and steady-state trough serum IgG levels. Such therapy is effective in decreasing the incidence of potentially life-threatening infections and increasing quality of life. The yearly cost of monthly infusions can be in excess of $20,000–$30,000.
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| Diseases of Immunoglobulin Overproduction (Gammopathies) The monoclonal gammopathies include those diseases in which there is a proliferation of a single clone of immunoglobulin-forming cells that produce a homogeneous heavy chain, light chain, or complete molecule. The amino acid sequence of the variable (V) regions is fixed, and only one type (  or  ) of light chain is produced. Polyclonal gammopathies result from proliferation of many B cell clones, resulting in a diffuse increase of immunoglobulins.Monoclonal Gammopathy of Uncertain Significance Essentials of Diagnosis
General Considerations The incidence of monoclonal gammopathy of uncertain significance (MGUS) increases with age, and the prevalence may approach 5% in persons 70 years of age or older. Lymphoid malignancies, amyloidosis, macroglobulinemia, or multiple myeloma will develop in as many as one-third of patients with apparently benign monoclonal gammopathies (1% per year). No specific therapy is necessary, but close observation is required. Patients with MGUS should be periodically monitored for changes in serum M proteins, urinary Bence Jones proteins, evidence of renal failure, anemia, hypercalcemia, lytic bone lesions, or bone marrow plasmacytoses. Parameters that suggest a favorable prognosis include (1) concentrations of homogeneous immunoglobulin less than 2 g/dL, (2) no increase in concentration of the immunoglobulin from the time of diagnosis, (3) no decrease in the concentration of normal immunoglobulins, (4) absence of a homogeneous light chain in the urine, and (5) normal hematocrit and serum albumin. Clinical Findings Symptoms and Signs No clinical symptoms are associated with MGUS. In patients with MGUS, the quantity of M protein is stable, and the lymphadenopathy, splenomegaly, or bony lesions seen with multiple myeloma are absent. Laboratory Findings The diagnosis of MGUS is made upon finding of a monoclonal spike on serum protein electrophoresis, confirmed by immunoelectrophoresis to be a homogeneous immunoglobulin with either or  light chains.
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