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Laboratory Diagnosis of Primary Immunodeficiencies.Pdf Clinic Rev Allerg Immunol (2014) 46:154–168 DOI 10.1007/s12016-014-8412-4 Laboratory Diagnosis of Primary Immunodeficiencies Bradley A. Locke & Tr i v i k r a m D a s u & James W.Verbsky Published online: 26 February 2014 # Springer Science+Business Media New York 2014 Abstract Primary immune deficiency disorders represent a complex assays in clinical care, one must have a firm under- highly heterogeneous group of disorders with an increased standing of the immunologic assay, how the results are propensity to infections and other immune complications. A interpreted, pitfalls in the assays, and how the test affects careful history to delineate the pattern of infectious organisms treatment decisions. This article will provide a systematic and other complications is important to guide the workup of approach of the evaluation of a suspected primary immuno- these patients, but a focused laboratory evaluation is essential deficiency, as well as provide a comprehensive list of testing to the diagnosis of an underlying primary immunodeficiency. options and their results in the context of various disease Initial workup of suspected immune deficiencies should in- processes. clude complete blood counts and serologic tests of immuno- globulin levels, vaccine titers, and complement levels, but Keywords Primary immunodeficiency . Diagnosis . these tests are often insufficient to make a diagnosis. Recent Laboratory assessment . Flow cytometry advancements in the understanding of the immune system have led to the development of novel immunologic assays to aid in the diagnosis of these disorders. Classically utilized to Introduction enumerate lymphocyte subsets, flow cytometric-based assays are increasingly utilized to test immune cell function (e.g., Over the past 25 years, extensive research and technological neutrophil oxidative burst, NK cytotoxicity), intracellular cy- advancements have furthered the scientific understandings of tokine production (e.g., TH17 production), cellular signaling the immune system. Clinical immunologists have been able to pathways (e.g., phosphor-STATanalysis), and protein expres- capitalize on these scientific advancements by translating sion (e.g., BTK, Foxp3). Genetic testing has similarly expand- basic science findings to patients, thus providing improve- ed greatly as more primary immune deficiencies are defined, ments in the diagnosis and treatment of primary immunodefi- and the use of mass sequencing technologies is leading to the ciencies. The classification of primary immunodeficiencies identification of novel disorders. In order to utilize these has expanded as a result of this increased knowledge, and there are currently greater than 180 known primary immuno- deficiencies [1]. Physicians are now able to diagnose immune B. A. Locke disorders much earlier, provide more effective and targeted Department of Pediatrics, Division of Allergy and Clinical Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, treatment, reduce patient morbidity/mortality, and enhance USA their patient’s quality of life. This chapter will focus on the : laboratory tests and interpretations that should ideally be T. Dasu J. W. Verbsky considered in various primary immunodeficiencies. Clinical Immunodiagnostic and Research Laboratory, Medical College of Wisconsin, Milwaukee, WI 53226, USA Disorders of Humoral Immunity J. W. Verbsky (*) Department of Pediatrics, Division of Rheumatology, Medical Approximately 50–60 % of all identified primary immunode- College of Wisconsin, Suite C465 9000 W. Wisconsin Avenue, PO Box 1997, Milwaukee, WI 53201-1997, USA ficiencies are caused by defects in antibody production [2]. e-mail: [email protected] Individuals with these disorders typically develop recurrent Clinic Rev Allerg Immunol (2014) 46:154–168 155 sinopulmonary infections related to encapsulated bacteria, common vaccinations, such as the tetanus, diphtheria, pneu- such as Streptococcus pneumoniae and Haemophilus mococcus, and Haemophilus influenzae type b (Hib). Tetanus influenzae. These patients also are known to have an increased and diphtheria are protein-based vaccines which generate risk of developing infectious diarrhea, typically due to strong, long lasting immunity. On the other hand, Giardia, rotavirus, enterovirus, Campylobacter, Salmonella, polysaccharide-based vaccines (i.e., pneumococcus) generate or Shigella [3]. Humoral defects have also been associated a weaker immunologic memory response [6]. If any serum with an increased incidence of developing autoimmunity, vaccination titers are below normal, revaccination and assess- enteropathy, granulomatous disease, and lymphocytic infil- ment of titers 4–6 weeks later is warranted. There is contro- trate of the lung [4, 5]. versy regarding “normal” response to vaccination, particularly The most important initial screening tests when a humoral to polysaccharide vaccine. However, some groups define the immunodeficiency is suspected are evaluations of quantitative following criteria as an adequate vaccination response: (1) a immunoglobulins (IgG, IgA, IgM, and IgE) (Table 1). It is measured protective titer per lab normals; (2) a fourfold in- critically important that the results of these tests be compared crease in post-vaccination titer level compared to pre- to age-adjusted normal values, particularly in children. In vaccination titer; and (3) a measured response to >50 % of general, hypogammaglobulinemia is defined when the value polysaccharide serotypes tested from ages 2–5yearsoldora is less than two standard deviations below the age-adjusted response of >70 % in patients greater than 5 years of age [7]. normal. Additionally, agammaglobulinemia is defined by an These criteria have not been validated among all immunode- IgG of less than 100 mg/dL. If either of these findings is ficiencies, but they did demonstrate validity with 73 % sensi- found, then further immunologic workup should be pursued. tivity and 57 % specificity in a cohort of children infected with Since antibody specificity is as important as immunoglob- the human immunodeficiency virus [8]. ulin levels, assessment of specific antibody titers is also crit- A significant dilemma when attempting to evaluate the ical in the evaluation of a suspected humoral immunodeficien- humoral immune system occurs in individuals receiving im- cy. This assessment can be done by evaluating serum titers to munoglobulin replacement therapy since immunoglobulin preparations contain detectable titers to common vaccines. Currently, the options for evaluation in these patients are Ta b l e 1 Algorithm to evaluate of a suspected humoral immune defect limited. However, in select medical centers, patients are able Screening evaluation • CBC with differential to be vaccinated with a neoantigen, bacteriophage Phi X174, • Quantitative immunoglobulins and antibody responses evaluated [9]. Research is also being o (IgG, IgA, IgM, IgE) done regarding the use of the rabies vaccine and the • Baseline and post-immunization titers Salmonella typhi Vi vaccine for this purpose [10]. o Protein and polysaccharide antigens If initial screening of quantitative antibody levels or spe- (i.e., Pneumococcal, Diphtheria) cific antibody production yields concerning results, additional • CH50/AH50 testing can be done such as flow cytometry to evaluate lym- • Chemistry panel phocyte numbers and maturation, or genetic testing for muta- • Urinalysis tions to cause humoral defects. Finally, there are other testing Advanced testing • B-cell maturation assessment by flow modalities available in select medical centers which are able to cytometry evaluate for B cell signaling defects and problems with im- • Assessment of other immunizations munoglobulin biosynthesis [11]. • B-cell signaling assays • TREC/KREC analysis Common Variable Immunodeficiency • Advanced flow cytometry studies o i.e., BTK presence, pH2AX One of the most common diseases that results in a significant immunofluorescence humoral deficit is common variable immunodeficiency • Genetic mutational analysis (CVID). The diagnosis of CVID requires a low IgG with a o i.e., BTK, TACI, ATM mutations low IgA and/or IgM, as well as defective antibody response to (Known disease causing mutations) vaccination [12]. Significant sources of morbidity in addition to infection in these patients include the development of CBC complete blood count; IgG immunoglobulin G; IgA immunoglob- ulin A; IgM immunoglobulin M; IgE immunoglobulin E; CH50 total bronchiectasis, enteropathy, polyclonal lymphocytic infiltra- hemolytic complement activity; AH50 alternative pathway hemolytic tion, granulomatous disease, and autoimmunity [5]. Flow activity; TREC T-cell receptor excision circles; KREC kappa rear- cytometry can be used to evaluate the maturational state of ’ rangement excision circles; BTK Bruton s tyrosine kinase; pH2AX B lymphocytes based upon the expression of IgM, IgD, phosphorylated H2A histone family, member X; TA C I transmembrane activator and calcium modulator and cyclophilin ligand interactor; ATM CD27, and CD38. Mature, naïve B lymphocytes express ataxia-telangiectasia mutated IgM and IgD, but do not express CD27 and CD38. Upon 156 Clinic Rev Allerg Immunol (2014) 46:154–168 antigen activation, B lymphocytes upregulate the activation/ (ICOS), CD19, and tumor necrosis factor receptor superfam- memory marker CD27 and become memory B cells. The ily member 13C (TNFRSF13C, also known as BAFFR) defi- memory B-cell compartment can be further divided between ciency are autosomal recessive disorders and
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