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This Current perspectives article will review and highlight the importance of accurate diagnosis of patients who have failed to produce specific antibodies to naturally encountered foreign proteins or polysaccharides or after vaccination and the appropriate institution of immunoglobulin replacement therapy. The field of primary immunodeficiency disease (PIDD) has expanded remarkably since the early descriptions 6 decades ago. With greater recognition and advanced cellular and molecular diagnostic technology, new entities and single-gene defects in patients with PIDD are rapidly being defined. This, combined with treatment advances and newborn screening for severe combined immunodeficiency, has resulted in improved outcomes and survival and even permanent cures. Awareness of PIDD has also increased, but the guidelines for recognition remain to be validated. The zeal for registering and enrolling patients has potentially created a large body of “patients” treated with immunoglobulin replacement unnecessarily. The complexity, diversity, and availability of laboratory testing have brought awareness of PIDD to the forefront, but because of an absence of standardization of certain assays, concerns about the correct diagnosis and appropriate treatment have increased. We hope to refocus the discussion on identifying clear laboratory and clinical guidelines for the establishment of an accurate diagnosis of antibody deficiency, its rationale, and, where indicated, institution of safe treatment. [Copyright &y& Elsevier]

Background A subgroup of patients with common variable immunodeficiencies (CVIDs) responds to vaccination. The aim of this study was to try to identify predictive markers for those with a humoral immune response after influenza vaccination. Methods Forty-eight patients with CVID (29 female and 19 male patients; mean age, 57.7 years) were vaccinated with the A(H1N1) influenza vaccine Pandemrix (GlaxoSmithKline, Wavre, Belgium) and boosted after 1 month. Blood samples were collected before each vaccination and 2 months later. Patients with a 4-fold titer increase in results on the hemagglutinin inhibition test (≥1:40) were considered responders and compared with nonresponders for clinical, immunologic, and genetic markers. Results Eight (16.7%) patients responded to the vaccination. A significantly higher proportion of the responders, who showed a EUROclass SmB−Trnorm21norm profile (P =.03) with a post–germinal center B-cell pattern (P =.04) in blood, experienced enteropathies (P =.04) compared with nonresponders. On the other hand, bronchiectasis was found exclusively among nonresponders (n = 7), as was autoimmune cytopenia (n = 5). Nonresponders with a EUROclass SmB−Trnorm21low profile (P =.02) had a significantly greater prevalence of progressive antibody deficiency (P =.048) and, at diagnosis, a higher mean serum IgM level (P =.03), lower mean serum IgG 1 level (P =.007), expansion of absolute counts of cytotoxic CD8+ T cells (P =.033), and increased proportion of memory CD8+ T cells (P =.044) in blood. CVID-associated HLA markers were not detected in responders (P =.03). Conclusion About one fifth of the patients with CVIDs achieved protective antibody levels after A(H1N1) vaccination and selected clinical, and immunologic markers were identified that might predict a positive outcome of influenza vaccination. Patients with CVID should be offered vaccination also against seasonal influenza because of the potential severity of the infection and risk for bacterial complications. [ABSTRACT FROM AUTHOR]

Background: The 1858T allele of protein tyrosine phosphatase nonreceptor type 22 (PTPN22; R620W) exhibits one of the strongest and most consistent associations with sporadic autoimmune disease. Although autoimmunity is common in patients with primary antibody deficiency (PAD), it remains unknown whether its pathogenesis is similar when it arises in this context compared with in immunocompetent patients. Objective: We set out to determine whether the 1858T allele of PTPN22 was associated with PAD or with autoimmunity in the context of PAD. Methods: We genotyped rs2476601 (g.1858C>T), a single nucleotide polymorphism encoding substitution of arginine for tryptophan in PTPN22 (R620W), in 193 patients with PAD and 148 control subjects from an Australian cohort. We also performed a subgroup analysis according to the presence of autoimmunity and B-cell phenotypes. Results: C/T and T/T PTPN22 genotypes were more common in patients with PAD than in the matched control subjects (C/T, 18.1% vs 9.5%; T/T, 1.04% vs 0.6%). The T allele was associated with an increased risk of PAD relative to control subjects (odds ratio, 2.10; 95% CI, 1.11-4.00). The distribution of genotypes in control subjects was similar to those reported previously and did not deviate significantly from Hardy-Weinberg equilibrium. We found a strong association between the 1858T allele and PAD with coexistent autoimmune diseases. In patients with PAD and autoimmunity, 16 (43.2%) of 37 had at least one T allele of PTPN22 compared with 27 (17.3%) of 156 with the C/C genotype (P = .0014; odds ratio, 3.64; 95% CI, 1.68-7.88). We found no evidence that this effect was mediated by enrichment of CD21low B cells. Conclusion: The 1858T PTPN22 allele is strongly associated with autoimmunity in patients with PAD. [Copyright &y& Elsevier]

A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research. [Copyright &y& Elsevier]