The clinical screening of antibody-mediated immune function can be accomplished by measuring the levels of the major immunoglobulin classes, IgG, IgA, IgM, and IgE. The results must be compared with age-matched reference intervals (normal ranges) as these levels change significantly during childhood; the results are typically expressed as 95% confidence intervals. The serum immunoglobulin levels are the net of protein production, utilization, catabolism, and loss.

There are no rigid standards regarding the diagnosis of immunoglobulin deficiency, although an IgG value below 4 g/L (400 mg/dL) in an adult or adolescent generally suggests an increased risk for infection. Hypogammaglobulinemia associated with significant recurrent bacterial infection is a definitive indication for intravenous or subcutaneous immunoglobulin replacement therapy after completing the immunologic evaluation and establishing a diagnosis.

Measurement of a functional antibody response is often required before immunoglobulin replacement therapy is approved and is particularly useful when the total immunoglobulin levels are only modestly depressed or normal in the face of a strong history of recurrent infection. The simplest means to accomplish this is evaluation for spontaneous antibodies (e.g., anti-blood group antibodies [isohemagglutinins] and antibodies to documented prior immunizations). The definitive method is immunizing and assessing preimmunization versus 3- to 4-week post-immunization antibody levels using both protein antigens (e.g., tetanus toxoid) and polysaccharide antigens (e.g., Pneumovax®). Guidelines for normal responses, which are usually provided by the testing laboratory, typically consist of at least a 4-fold increase in antibody and/or protective levels of antibody following immunization.

An additional and readily available test is quantitation of IgG subclass levels; these are most useful in evaluating the IgA-deficient patient with significant recurrent bacterial infections. However, in many settings detection of an IgG subclass deficiency still requires the demonstration of an abnormality in specific antibody production before immunoglobulin replacement therapy is indicated.

Despite the preponderance of recurrent opportunistic infections resulting from HIV infection, appropriate testing to rule this out should be considered even in the face of recurrent bacterial infection. This type of clinical presentation may be seen more often in children infected with HIV. Testing focused on viral load may be needed to rule out HIV infection in the face of absent or diminished antibody production, because the screening tests depend on detecting anti-HIV antibodies (enzyme-linked immunosorbent assay [ELISA] and Western blot assays).

Additional tests focused on humoral immune function are generally performed in specialized centers and fall into two general categories: evaluation of the number and characteristics of B cells and testing the function of B cells in vitro. The former determines the number of B cells as well as specific surface characteristics of B cells and is generally performed by flow cytometry (immunophenotyping). This is evolving as a useful approach to subcategorize patients with common variable immunodeficiency. The latter involves studies that test in vitro B-cell signaling and immunoglobulin biosynthesis and these are generally confined to research centers.

Evaluating T-cell function

A clinical history of recurrent opportunistic infections strongly suggests an abnormality in T-cell function. Immunodeficiency involving T cells has the highest prevalence as a secondary defect associated with HIV infection. Thus, initial screening assays should always include testing for HIV infection. In addition, the absolute lymphocyte count (generated from the white blood cell count and differential) and cutaneous delayed-type hypersensitivity (DTH) response to recall antigens have served as standard T-cell function screening tests. The significance of the former relates to the fact that T cells constitute approximately three-fourths of circulating lymphocytes such that conditions that inhibit T-cell development or increase T-cell destruction will typically cause lymphopenia. The DTH response provides an in vivo window of T-cell function in response to a previously encountered antigen. However, failure to respond may either reflect T-cell dysfunction (T-cell anergy) or indicate that the host has not been exposed (sensitized) to the antigen. Consequently, it is prudent to use more than one antigen for testing and increasing issues with availability of recall antigens has resulted in decreasing use of DTH testing. Clinical correlates in the medical history of a DTH response include the cutaneous response to poison ivy and/or other contact hypersensitivity reactions (Table 84.2).

The screening tests for T-cell function are often followed by additional testing to complete the assessment of cellular immunity. This parallels that of B cells with quantitation and characterization (immunophenotyping) of T cells and T-cell subsets by flow cytometry together with in vitro functional testing (e.g., proliferation assays [mitogens, recall antigens, alloantigens], cytokine production, cytotoxicity testing). Both of these approaches are generally available in large medical centers as well as via commercial laboratories.

Evaluating defects in the IL-12/23 and interferon-Ɣ pathways

Recent data have identified abnormalities in specific components of a cytokine-linked pathway involving T cells and monocytes/macrophages associated with recurrent infections to a limited range of opportunistic organisms, particularly NTM. The infections are typically invasive and fail to respond to long-term multiple-agent antimicrobial therapy. These findings led to a study demonstrating that interferon-γ is an effective adjunct to antimicrobials in treating some of these patients. Specific defects involving various components of this pathway have been identified in approximately one-half of these patients with the current research focus being clarification of the molecular basis of the remaining patients. Additional defects continue to be identified that are associated with the clinical phenotype of recurrent infections involving this more limited range of microorganisms. The laboratory evaluation of patients with persistent NTM is generally performed in specialized centers and is focused on evaluating for defects in the cellular signaling pathways involving IL-12/23 and interferon-γ. Most recently, a secondary defect associated with high titer autoantibodies to interferon-γ

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