Immunologic Screening Tests

Initial laboratory tests that may indicate that a patient has an immune deficiency can be done in most regional laboratories and community hospitals, and the results should be available in a few days. These should include measurement of the major immunoglobulins and IgG subclasses. In adults, serum protein electrophoresis should also be included because patients with monoclonal gammopathy, multiple myeloma, or chronic lymphocytic leukemia (CLL) may have antibody deficiency with a normal total level of any given class of immunoglobulin if the paraprotein is a member of that class. Interpretation of the results of measurement of the serum of concentrations of IgG and its subclasses is often less than straightforward ( 3.7,42). First of all, age-specific norms must be used, because of the marked changes in values during the first 2 years of life. Although some laboratories may report IgG concentrations as low as 200 mg/dL as normal in 3- to 6-month-old infants, concentrations of less than 400 mg/dL frequently fail to provide sufficient protective antibody levels. Second, even within a given age group, most laboratories report a normal range whose upper limit may be twofold or more higher than its lower limit. This probably reflects the fact that the total serum IgG concentration represents the sum of hundreds of separately regulated responses rather than a single variable whose physiology requires reasonably tight control, like that of an electrolyte or the blood glucose. Concentrations of IgG, and particularly its subclasses, vary not only among individuals of the same age who have different exposure histories but also in a single individual at different times. Thus, before any conclusions are reached about the diagnosis of IgG subclass deficiency, the tests should be repeated several weeks apart, and analysis of specific antibody titers should also be considered (see later).

In judging the adequacy of any given IgG concentration in a given individual, the history of exposure and the frequency of documented infections must be considered. Thus, normal individuals with frequent exposure to pathogens and those whose host defenses are compromised by conditions that do not affect lymphocyte responses, such as cystic fibrosis and chronic granulomatous disease, often have elevated total serum IgG concentrations. This may be thought of as reflecting a physiologic adaptation or as a response to increased or persistent antigen exposure by the normal immune system. IgG concentrations within the normal range, but toward its lower limit, in patients with comparably increased frequency of infection or morbidity due to infection (but without such underlying defects) may thus actually indicate relative deficiency in specific antibodies and should be evaluated further, as explained later.

In addition to those conditions in which paraproteins may conceal true antibody deficiencies within normal total IgG levels, several diseases may be associated with nonspecific polyclonal B-cell activation that may cause the total IgG or IgM level to be within the normal range or even elevated, whereas specific antibodies may actually be deficient. This occurs most often in systemic lupus erythematosus, Epstein-Barr virus infection, and HIV infection ( 43,44). Finding low or absent serum IgA together with low-normal or borderline levels of one or more IgG subclasses, particularly subclass 2, should also raise suspicion of more severe defects in specific antibody production than would be suggested by the total IgG concentration itself, and such patients should also be investigated further ( 45). Elevated serum IgE and IgA concentrations may be found coexisting with deficiency of antibodies to polysaccharides in Wiskott-Aldrich syndrome, and extremely high IgE levels may suggest, but are not by themselves diagnostic of, hyper-IgE or Job syndrome.

Analysis of lymphocyte surface antigens by flow cytometry is now widely available and should be included as a screening test in all patients in whom immune deficiency is suspected (46). A CBC with differential should always accompany lymphocyte surface marker analysis so that the absolute number of any given type of cell per cubic millimeter of blood can be calculated, in addition to ratios such as CD4/CD8 ( 47). As with immunoglobulin determinations, age-specific norms should be used (47). The physician should be careful about what specific test is ordered because, in the era of widespread treatment of HIV, many laboratories offer a standard lymphocyte surface marker panel, an analysis that includes only the total number of T cells (CD3 +) and the two major subsets of T cells (CD4+ and CD8+). Because antibody deficiency due to decreased B-cell number or function is the most common type of immune deficiency overall, a complete analysis, including enumeration of natural killer (NK) and B cells, should be performed. Analysis of these lymphocyte subsets frequently provides important clues to the actual molecular defect in many cases of SCID (see later). In addition, because patients with chronic CLL may present with antibody deficiency, the ratio of lymphocytes positive for k as opposed to l light chains should also be determined. Flow cytometry to determine the presence of leukocyte integrins of the CD11/CD18 family can easily confirm or exclude the diagnosis of leukocyte adhesion deficiency type I (48). Similarly, flow cytometry may be used to test neutrophils for the sialyl-Lewis X antigen, whose absence establishes the diagnosis of the more rare leukocyte adhesion deficiency type II ( 49).

More rare deficiencies involving other arms of the immune system can also be identified and characterized at this level of testing. In patients suspected of defects in T-cell-mediated immunity, the overall functional activity of T cells is best assessed by determining the patient's ability to mount cutaneous delayed hypersensitivity reactions to recall antigens such as candida, mumps, or tetanus toxoid (3.7.,5.C). Obviously, delayed hypersensitivity skin tests have little meaning in children younger than 2 years of age, who may not be adequately immunized with the antigens in question. Patients who have infections suggestive of defects in T-cell-mediated immunity should also undergo HIV screening.

The CBC will give an indication of the number of phagocytes, but assessing their function requires more specialized laboratory capabilities. Complement screening should include measurement of the serum C3 concentration and the total hemolytic activity (CH 5C) because the former may be seriously reduced without affecting the latter. Although the CH5C is the best overall screening test for complement defects and is zero in cases of late component defects, such as those that predispose to recurrent or disseminated neisserial infections (22), the serum for this test must be handled carefully or artifactually low values will be measured. In patients with a history of bacteremia, sepsis, or hematogenously spread infection, a careful review of the peripheral blood smear, looking for Howell-Jolly bodies in the erythrocytes, may suggest anatomic or functional asplenia or severely impaired reticuloendothelial system function.

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