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 immunoglobulin A [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.

(Source: Primary Immunodeficiencies. J Allergy Clin Immunol 2010).

(Source: Cellular and Molecular Immunology, 9th edition. 2016 Philadelphia: Saunders/Elsevier.)

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

Recurrent infections are defined as:

• ≥2 severe infections in one year

• ≥3 respiratory infections (e.g., sinusitis, otitis, bronchitis) in one year or

• need for antibiotics for 2 months per year

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, uremia, diabetes, cystic fibrosis, and anatomic defects or abnormalities).

The following image lists the warning signs of PID that may warrant additional workup and evaluation:

(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.

The following table delineates clinical findings associated with 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 send. Labs may include:

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

• quantitative measurement of serum immunoglobulin levels (IgG, IgA, and IgM) to assess antibody concentrations (Of note, transient hypogammaglobulinemia of infancy is a diagnosis of exclusion that can be made retrospectively and is thought to be a prolongation of the physiologic nadir in immunoglobulins that is normally observed in the first 6 months of life as maternal antibody levels wane. Primary immunodeficiencies with permanent hypogammaglobulinemia must be excluded.)

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

For more-specific testing, an immunology consult or 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 [DHR] 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

Newborn Screening

All states now perform universal severe combined immunodeficiency (SCID) newborn screening using polymerase chain reaction(PCR) to amplify T-cell-receptor excision circles (TRECs). TRECs are formed when a T cell rearranges the variable region of its receptor and serves as a surrogate for newly synthesized naive T cells. This has allowed for early identification of some immunodeficiencies, which has allowed for earlier treatment and management before the development of life-threatening infections/complications.

For more information on newborn screening, see Pediatric Genetic/Metabolic Disorders, Pediatric Neonatal Care, and Preventive/Well Child Care.

Treatment

• Prompt treatment of immunodeficiencies and referral to an immunologist is necessary after the diagnosis is made.

• Severe combined immunodeficiency (SCID) is considered a pediatric emergency, and patients should be promptly evaluated for stem-cell transplantation. These patients should avoid live viral vaccines, and blood products must be irradiated, leukoreduced, and cytomegalovirus (CMV) negative.

• Other disorders treated with stem-cell transplantation include: X-linked hyper-IgM syndrome, Wiskott-Aldrich syndrome (WAS), and other severe immunodeficiencies. X-linked SCID, adenosine deaminase (ADA)-deficient SCID, and WAS can be treated with gene therapy. Patients with complete DiGeorge syndrome may benefit from thymic transplantation.

• In the cases of humoral deficiency, immunoglobulin replacement therapy is usually initiated. Several formulations are available for immunoglobulin replacement including intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG).

• There should be prompt recognition of infections, and they should be treated aggressively.

• For certain immunodeficiencies, prophylactic antibiotics may be considered.