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Primary Immune Deficiency: Key Facts for Physicians and Patients

Date: September 1, 1995
Source: National Institutes of Health (NIH)
Author: National Institute of Allergy and Infectious Diseases (NIAID)

Selective IgA Deficiency

Selective IgA Deficiency occurs in one out of 400 to 2,000 individuals and is the most common primary immunodeficiency.

Signs: Many IgA-deficient patients are healthy, with no more than the usual number of infections. Symptomatic patients typically present with recurrent ear, sinus, or lung infections that may not respond to standard courses of antibiotics. These patients can have an increased frequency of allergies, asthma, chronic diarrhea (often due to giardiasis), and autoimmune diseases.

Diagnosis: The IgA levels are 5 mg/dl or less (normal range, 90-450 mg/dl). In contrast, the IgM and IgG readings usually fall within the normal range, as do the T-cell, phagocytic cell, and complement measures. Diagnostic tests should include:

  • Measurement of serum immunoglobulin concentrations
  • Assessment of IgG2
  • Assessment of antibody formation following immunization

Cause: The cause of IgA deficiency has not been determined. There is evidence of familial occurrences, and it is seen more frequently in relatives of individuals with common variable immunodeficiency.

Treatment: There is no specific treatment for selective IgA deficiency. The bacterial infections are treated with antibiotics, and patients with giardiasis are treated with metronidazole or quinacrine hydrochloride.

Common Variable Immunodeficiency

Common Variable Immunodeficiency (CVI) is also called hypogammaglobulinemia, adult-onset agammaglobulinemia, late-onset hypogammalobulin-emia, and acquired agammaglobulinemia. CVI is relatively common. It can present in infancy through the fifth decade of life.

Signs: Most patients with CVI present with recurrent bacterial infections of the ears, sinuses, bronchi, and lungs. Inflammatory symptoms may develop in the knee, ankle, elbow, or wrist joints. CVI patients frequently complain of gastrointestinal symptoms. Enlarged spleen and lymph nodes are also fairly common. Along with other autoimmune problems, some of the patients develop autoantibodies that attack blood cells. CVI patients have an increased risk of some cancers.

Cause: CVI has no clear pattern of inheritance and is associated with no outward physical abnormalities. The cause is unknown.

Diagnosis: Quantitative serum immunoglobulin levels of CVI patients show below normal levels of IgG and IgA. The IgG values range from 0 to slightly less than normal. The IgM levels are low to normal. Further evaluations should include:

  • Assessment of antibody formation to antigenic challenge
  • T-cell function
  • Evaluation for gastrointestinal infections

Treatment: Immunoglobulin (i.v., approximately 400 mg/kg every 3 weeks) is given to restore normal antibody levels. Infections are treated with appropriate antibiotics. Physical therapy and daily postural drainage may help clear lung secretions.

X-Linked Agammaglobulinemia

X-Linked Agammaglobulinemia (XLA) (sometimes called Bruton type, X-linked infantile, or congenital agammaglobulinemia) occurs in one out of 10,000 people.

Signs: Infants with XLA develop recurrent puss-producing infections of the inner ear, lungs, sinuses, and bones. Some infections go beyond the mucosal surface and into the bloodstream and internal organs. The patients tend to cope sufficiently well with most viral infections, but are very susceptible to hepatitis, polio, and ECHO viruses. They tend to have growth failure and an absence of tonsils and adenoids.

Diagnosis: In XLA, quantitative immunoglobulins show marked deficits or absence of all five immunoglobulin classes. Peripheral blood B-lymphocytes as measured by immunofluorescent techniques are usually absent.

Cause: XLA is caused by a defect in a gene found on the X chromosome. This gene encodes a protein called btk (B-cell tyrosine kinase), which is required for B-cell development.

Treatment: XLA requires lifelong antibody replacement through monthly injections of gamma globulin (i.v., ~400 mg/kg). The goal is to maintain serum IgG levels above 500 mg/dl, but some patients may require higher levels.

Severe Combined Immunodeficiency

Severe Combined Immunodeficiency (SCID) is a group of inherited disorders that together have an incidence of approximately one in 1,000,000. SCID represents a severe defect in both antibody- and cell-mediated immunity.

Signs: The typical case involves an infant less than one year of age, who has excessive, serious or life-threatening, treatment-resistant infections (especially pneumonia, meningitis, and sepsis). Infections with varicella zoster virus, cytomegalovirus, or Pneumocystis carinii can overwhelm the patient's immune system. Also common are chronic skin infections, Candida infections of the mouth and diaper area, chronic hepatitis, diarrhea, and hematologic disorders. Eosinophilia or monocytosis may be a signal of one of the unusual infections these patients develop.

Diagnosis: The following tests may have to be repeated several times to avoid skewing by intercurrent infections:

  • Lymphocyte count from blood smear (are significantly below normal in SCID)
  • Lymphocyte population analysis (levels of B- and T-lymphocytes are absent or below normal)
  • Lymphocyte response to mitogen (is absent or below normal in SCID)
  • Quantitative measurements of IgG, IgA, and IgM (show marked deficits)

Cause: A number of genetic defects can cause SCID. The two most common forms result from:

  • a deficiency of the enzyme called adenosine deaminase
  • a defect in the gene that encodes a receptor on T-lymphocytes called the IL-2 receptor gamma chain

Treatment: Bone marrow transplantation from an HLA-matched normal sibling is the most effective treatment. If a matched sibling is not available, a donor as closely matched as possible is used. Until the transplantation takes effect (in one to three years), gamma globulin is given to normalize antibody levels.

Chronic Granulomatous Disease

Chronic Granulomatous Disease (CGD) occurs in only one in 1,000,000 people and is four times more likely to affect males than females. The CGD patient's defense system is not effective against certain bacteria and fungi, including Escherichia coli along with species of Staphylococcus, Pseudomonas, Serratia, and Aspergillus.

Signs: CGD may be suspected in male infants between 3 months and 2 years of age who present with a history of fever, skin infections, pneumonia, chronic lung abscesses, lymphadenitis, and hepatospleno-megaly. Cases may present as late as adolescence. The infections lead to the formation of granulomas. These localized, swollen collections of infected tissue are usually found in the skin, lungs, lymph nodes, liver, or bones, but they can also cause obstruction of the intestine or urinary tract. The lesions tend to drain for a long time after treatment. Lymph node and liver enlargement are also evident.

Diagnosis: The lab findings will typically include leukocytosis, anemia, elevated sedimentation rate, abnormal chest x-rays, and hypergammaglobulinemia. Antibody titers are in the normal range. Skin tests will show delayed hypersensitivity. To confirm a CGD diagnosis, specialized laboratories are needed to perform the following tests of phagocyte function and killing:

  • Nitroblue tetrazolium reduction
  • Chemiluminescence
  • Superoxide production
  • Biochemical analysis of neutrophil components

Cause: CGD is caused by defects in genes that make proteins required for the production of oxygen metabolites such as hydrogen peroxide and superoxide, which kill bacteria and fungi.

Treatment: Early diagnosis and aggressive treatment with prolonged high doses of antibiotics are the mainstay of treatment. There is not yet a specific therapy to correct the defect in CGD. To prolong infection-free periods, physicians often prescribe continuous prophylactic oral antibiotics, such as trimethoprim combined with sulfamethoxazole. Abscesses often require surgical drainage. The granulomas ultimately resolve in response to the long-term antibiotic therapy. Steroids reduce the gastrointestinal and genitourinary tract obstructions. Anemia may require whole blood transfusions.

Researchers at the National Institute of Allergy and Infectious Diseases developed a now-approved CGD treatment regimen with gamma interferon that reduces the number of serious infections by up to 72%. The treatment can be given at home by subcutaneous injections three times a week.