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Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune deficiency in adults. At this time, the causes of these conditions are unknown. Patients with CVID experience immune system failure consequent to late onset antibody failure. They have increased susceptibility to infections and are also at risk of severe autoimmune and inflammatory disorders as a result of immune dysregulation. An increasing number of monogenic causes as well as a digenic disorder have been described in patients with a CVID phenotype. If a causative mutation is identified, patients are removed from the umbrella diagnosis of CVID and are reclassified as having a CVID-like disorder, resulting from a specific mutation. In non-consanguineous populations, next-generation sequencing (NGS) identifies a genetic cause in approximately 25% of patients with a CVID phenotype. It is six years since we published our diagnostic criteria for CVID. There is ongoing debate about diagnostic criteria, the role of vaccine responses and genetic analysis in the diagnosis of CVID. There have been several recent studies, which have addressed some of these uncertainties. Here we review this new evidence from the perspective of our CVID diagnostic criteria and speculate on future approaches, which may assist in identifying and assessing this group of enigmatic disorders.

Background Immunoglobulin therapy plays a critical role in the treatment of immunodeficiency disorders as well as autoimmune and inflammatory conditions. In immunodeficient patients, there has been controversy whether initial loading doses of intravenous (IVIG) should be based on actual body weight or a calculated parameter such as adjusted body weight in obese patients. Case presentation I describe a patient with Common Variable Immunodeficiency disorder (CVID) who underwent bariatric surgery for morbid obesity. Her weight decreased by 50% to below her calculated ideal body weight (IBW) while her immunoglobulin requirement fell by approximately 20%. Her steady state serum IgG increased from approximately 7 g/l to 11.7 g/l concomitant with weight loss. Conclusions I present this observation as support for the recommendation that initial loading doses of SCIG/IVIG in immunodeficiency should be based on adjusted body weight (AjBW) and not actual body weight in obese patients. This has important fiscal implications for treating obese patients with immunodeficiency disorders.

Rationale Transient myopericarditis has been recognised as an uncommon and usually mild adverse event predominantly linked to mRNA-based COVID-19 vaccines. These have mostly occurred in young males after the second dose of mRNA COVID-19 vaccines. Objectives Fulminant necrotising eosinophilic myocarditis triggered by a variety of drugs or vaccines is an extremely rare hypersensitivity reaction carrying a substantial mortality risk. Early recognition of this medical emergency may facilitate urgent hospital admission for investigation and treatment. Timely intervention can lead to complete cardiac recovery, but the non-specific clinical features and rarity make early diagnosis challenging. Findings The clinical and pathological observations from a case of fatal fulminant necrotising myocarditis in a 57-year-old woman, following the first dose of the Pfizer-BioNTech vaccine, are described. Other causes have been discounted with reasonable certainty. Conclusion These extremely rare vaccine-related adverse events are much less common than the risk of myocarditis and other lethal complications from COVID-19 infection. The benefits of vaccination far exceed the risks of COVID-19 infection.

Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune deficiencies in adults and children. In addition to recurrent and severe infections, patients with CVID are susceptible to autoimmune and inflammatory complications. The aetiologies of these uncommon conditions are, by definition, unknown. When the causes of complex disorders are uncertain, diagnostic criteria may offer valuable guidance to the management of patients. Over the last two decades, there have been four sets of diagnostic criteria for CVID in use. The original 1999 European Society for Immunodeficiencies and Pan-American Society for Immunodeficiency (ESID/PAGID) criteria are less commonly used than the three newer criteria: Ameratunga et al (Clin Exp Immunol 174:203–211, 2013), ESID (J Allergy Clin Immunol Pract, 2019) and ICON (J Allergy Clin Immunol Pract 4:38–59, 2016) criteria. The primary aim of the present study was to compare the utility of diagnostic criteria in a well-characterised cohort of CVID patients. The New Zealand CVID cohort study (NZCS) commenced in 2006 and currently comprises one hundred and thirteen patients, which represents approximately 70% of all known CVID patients in NZ. Many patients have been on subcutaneous or intravenous (SCIG/IVIG) immunoglobulin treatment for decades. Patients were given a clinical diagnosis of CVID as most were diagnosed before the advent of newer diagnostic criteria. Application of the three commonly used CVID diagnostic criteria to the NZCS showed relative sensitivities as follows: Ameratunga et al (Clin Exp Immunol 174:203–211, 2013), possible and probable CVID, 88.7%; ESID (J Allergy Clin Immunol Pract, 2019), 48.3%; and ICON (J Allergy Clin Immunol Pract 4:38–59, 2016), 47.1%. These differences were mostly due to the low rates of diagnostic vaccination challenges in patients prior to commencing SCIG/IVIG treatment and mirror similar findings in CVID cohorts from Denmark and Finland. Application of the Ameratunga et al (Clin Exp Immunol 174:203–211, 2013) CVID diagnostic criteria to patients on SCIG/IVIG may obviate the need to stop treatment for vaccine studies, to confirm the diagnosis.

Common variable immunodeficiency disorders (CVIDs) are rare primary immunodeficiency diseases (PIDs) mostly associated with late onset antibody failure leading to immune system failure. Patients with CVID are predisposed to disabling complications such as bronchiectasis and systemic autoimmunity. In recent years a large number of genetic defects have become associated with these disorders. Patients with a causative mutation are deemed to have CVID-like disorders, while those with mutations predisposing to or modifying disease severity remain within the spectrum of CVID as defined by current diagnostic criteria. Next-generation sequencing (NGS) allows simultaneous analysis of multiple genes. Potential mutations identified from NGS are commonly evaluated with the American College of Medical Genetics (ACMG) variant interpretation criteria to determine their pathogenicity (causality). Patients with CVID and CVID-like disorders have marked genetic, allelic, and phenotypic heterogeneity. Although all patients with a CVID phenotype should undergo genetic testing, the complexity of the genetics associated with these disorders is challenging. Variants of unknown significance (VUS) remain a significant barrier to realising the full potential of NGS in CVID and CVID-like disorders. Here we explore the nuances of applying the ACMG criteria to patients with CVID and CVID-like disorders. Close collaboration between the clinician, bioinformatics, and genetics professionals will improve the diagnostic yield from genetic testing and reduce the frequency of VUS.

Adults with primary hypogammaglobulinemia are frequently encountered by clinicians. Where IgG levels are markedly decreased, most patients are treated with subcutaneous or intravenous immunoglobulin (SCIG/IVIG), because of the presumed risk of severe infections. The natural history of untreated severe asymptomatic hypogammaglobulinemia is thus unknown. Similarly, there are no long-term prospective studies examining the natural history of patients with moderate reductions in IgG. In 2006, we began a prospective cohort study of patients with symptomatic and asymptomatic reductions in IgG who were not immediately commenced on SCIG/IVIG. Over the course of 12 years, 120 patients were enrolled in the NZ hypogammaglobulinemia study (NZHS) including 59 who were asymptomatic. Five patients with profound primary hypogammaglobulinemia (IgG < 3 g/l), who were not on regular SCIG/IVIG have remained well for a mean duration of 139 months. This study has also shown most asymptomatic patients with moderate hypogammaglobulinemia (IgG 3.0-6.9 g/l) have been in good health for a mean observation period of 96 months. We have only identified one asymptomatic patient with moderate hypogammaglobulinemia who experienced progressive decline in IgG levels to <3 g/l and was accepted for IVIG replacement. Prospective monitoring has shown that none have suffered catastrophic infections or any of the severe autoimmune or inflammatory sequelae associated with Common Variable Immunodeficiency Disorders (CVID). Unexpectedly, 18.1% of asymptomatic and 41.6% of symptomatic hypogammaglobulinemic patients spontaneously increased their IgG into the normal range (≥7.0 g/l) on at least one occasion, which we have termed transient hypogammaglobulinemia of adulthood (THA). In this study, vaccine challenge responses have correlated poorly with symptomatic state and long-term prognosis including subsequent SCIG/IVIG treatment. In spite of our favorable experience, we recommend patients with severe asymptomatic hypogammaglobulinemia are treated with SCIG/IVIG because of the potential risk of severe infections. Patients with moderate asymptomatic hypogammaglobulinemia have a good prognosis. Patients with symptomatic hypogammaglobulinemia are a heterogeneous group where some progress to SCIG/IVIG replacement, while many others spontaneously recover. This study has implications for the diagnosis and treatment of CVID.

Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immune deficiency condition in adults. The genetic basis for the condition is not known and no single clinical feature or laboratory test can establish the diagnosis; it has been a diagnosis of exclusion. In areas of uncertainty, diagnostic criteria can provide valuable clinical information. Here, we compare the revised European society of immune deficiencies (ESID) registry (2014) criteria with the diagnostic criteria of Ameratunga et al. (2013) and the original ESID/pan American group for immune deficiency (ESID/PAGID 1999) criteria. The ESID/PAGID (1999) criteria either require absent isohemagglutinins or impaired vaccine responses to establish the diagnosis in patients with primary hypogammaglobulinemia. Although commonly encountered, infective and autoimmune sequelae of CVID were not part of the original ESID/PAGID (1999) criteria. Also excluded were a series of characteristic laboratory and histological abnormalities, which are useful when making the diagnosis. The diagnostic criteria of Ameratunga et al. (2013) for CVID are based on these markers. The revised ESID registry (2014) criteria for CVID require the presence of symptoms as well as laboratory abnormalities to establish the diagnosis. Once validated, criteria for CVID will improve diagnostic precision and will result in more equitable and judicious use of intravenous or subcutaneous immunoglobulin therapy.