Immunodeficiency

Primary immunodeficiencies (PIDs) are inherited defects of the innate or adaptive arms of the immune system that lead to an increased incidence, frequency, or severity of infections. PIDs are rare, with an estimated prevalence of 1:10,000 live births (excluding asymptomatic IgA deficiency). More than 200 PID disorders have been characterized. PIDs may be caused by defects in the adaptive immune response, including combined immunodeficiencies and antibody deficiency syndromes, or by defects in the innate immune response, including phagocytic disorders, complement pathway defects, or disorders of toll-like receptor (TLR) signaling.

Presentation

Medical history: The diagnosis of PID should be considered when a patient has a family history of PID or severe, unusual, frequent, or difficult-to-treat infections. A detailed history should include:

• types of infection

• sites involved

• frequency of infections

• organisms

Secondary causes of immunodeficiency should always be ruled out (e.g., HIV, immunosuppressant drugs, cancer, autoimmune disease, protein-wasting conditions [e.g., enteropathy], malnutrition, cirrhosis, or uremia).

The following image lists the warning signs of PID.

(Source: Jeffrey Modell Foundation 2016.)

Type of infection may help to identify the defect in the immune system:

• Recurrent sinopulmonary infections with encapsulated bacteria (e.g., Haemophilus influenzae type B or Streptococcus pneumoniae) may suggest an antibody deficiency, whereas frequent viral, fungal, or protozoal infections suggest T-cell dysfunction.

• Infections such as pneumonia, solid-organ abscesses, and skin infections with catalase-positive organisms are suggestive of disorders of phagocyte number or function.

• Recurrent neisserial infections are characteristic of late complement component (C5-9) defects.

• Recurrent viral or pyogenic bacterial infections without the presence of significant inflammatory response suggest a defect in TLR signaling.

• Mycobacterial infections are characteristic of defects in interleukin-12, interferon-gamma, or their receptors.

• In adult patients, the most common defects include humoral antibody deficiencies such as common variable immunodeficiency (CVID) and IgA deficiency.

The following table describes clinical findings for the major PID subgroups:

(Source: Primary Immunodeficiencies, Am Fam Physician 2003.)

Physical exam: Failure to thrive can be one of the first presenting signs of PID. Specific findings on physical exam are associated with certain immunodeficiencies, such as absent lymph nodes in X-linked agammaglobulinemia. Other findings may include partial albinism, ataxia, telangiectasia, eczema, or generalized erythroderma. A more extensive list of clinical findings suggestive of different primary immunodeficiencies can be found here.

Laboratory Testing

Laboratory testing should be ordered based on clinical suspicion. Results should be interpreted in the context of age and can be affected by ongoing infection, medications, or autoimmune disease. Often, an allergy-immunology specialist can help to determine the appropriate tests to order. Labs may include:

• complete blood count with differential, complete metabolic panel, urinalysis, and inflammatory markers (e.g., erythrocyte sedimentation rate [ESR] and C-reactive protein[CRP])

• quantitative measurement of serum immunoglobulin levels (IgG, IgA, and IgM) to assess antibody concentrations

• serum antibody concentrations to common vaccines (including pneumococcal, tetanus, and H. influenzae type B) to help functionally evaluate the humoral response

For more-specific testing, an immunology referral is recommended, and testing may include:

• flow cytometry to enumerate lymphocyte counts (B cells, T cells, and natural killer [NK] cells) as well as the percentages of memory B cells and naive/memory T cells

• T-cell proliferation assays to mitogen and antigen to assess the functional competence of T cells

• flow cytometry to assess phagocyte function (e.g., dihydrorhodamine flow for chronic granulomatous disease)

• evaluation of the complement components by measuring total complement (often ordered as CH50) for the classical complement pathway and AP50 for the alternate pathway; if these are low, individual complement levels can be evaluated

• genetic testing may also be warranted depending on the clinical presentation, with either a targeted panel or whole exome sequencing, usually performed in consultation with a clinical immunologist, geneticist or both.

Treatment

• prompt referral to an immunologist

• in cases of humoral deficiency (e.g., CVID), immunoglobulin replacement therapy

• prompt recognition and aggressive treatment of infections

• prophylactic antibiotics for certain immunodeficiencies