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.
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 (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.
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.
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.
COVID-19 has had a calamitous effect on the global community. Despite intense study, the immunologic response to the infection is only partially understood. In addition to older age and ethnicity, ...patients with comorbidities including obesity, diabetes, hypertension, coronary artery disease, malignancy, renal, and pulmonary disease may experience severe outcomes. Some patients with primary immunodeficiency (PID) and secondary immunodeficiency also appear to be at increased risk from COVID-19. In addition to vulnerability to SARS-CoV-2, patients with PIDs often have chronic pulmonary disease and may not respond to vaccines, which exacerbates their long-term risk. Patients with common variable immunodeficiency disorders, the most frequent symptomatic PID in adults and children, have a spectrum of B- and T-cell defects. It may be possible to stratify their risk for severe COVID-19 based on age, ethnicity, the severity of the T-cell defect, and the presence of other comorbidities. Patients with common variable immunodeficiency disorders and other immunodeficiencies are at risk for Chronic COVID-19, a dangerous stalemate between a suboptimal immune response and SARS-CoV-2. Intra-host viral evolution could result in the rapid emergence of vaccine-resistant mutants and variants of high consequence; it is a public health emergency. Vaccination and prevention of Chronic COVID-19 in immunodeficient patients is therefore of the utmost priority. Having a reliable diagnostic assay for T-cell immunity to SARS-CoV-2 is critical for evaluating responses to vaccines in these patients. New treatments for SARS-CoV-2 such as NZACE2-Pātari are likely to be particularly beneficial for immunodeficient patients, especially those who fail to mount a robust T-cell response to COVID-19 vaccines.
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.
Objectives
Dominant‐activating (DA) lesions in RAC2 have been reported in 18 individuals to date. Some have required haematopoietic stem cell transplantation (HSCT) for their (severe) combined ...immunodeficiency syndrome phenotype. We aimed to investigate clinical and cellular features of a kindred harbouring a novel variant in RAC2 p.Ile21Ser (I21S) to better understand DA lesions' phenotypic spectrum.
Methods
Clinical and immunological information was collated for seven living individuals from the same kindred with RAC2 p.I21S. We evaluated neutrophil morphology, RAC2 protein expression and superoxide production using freshly isolated neutrophils stimulated with phorbol‐12‐myristate‐13‐acetate (PMA) and N‐formyl‐MetLeuPhe (fMLP).
Results
Patient 1 (P1, aged 11, male) has a history of bacterial suppurative otitis media, viral and bacterial cutaneous infections. P1's siblings (P2, P3), mother (P4), maternal aunt (P5) and uncle (P6) have similar infection histories. P1's maternal cousin (P7) presented with Burkitt's lymphoma at age 9. All affected individuals are alive and none has required HSCT to date. They have chronic lymphopenia affecting the CD4+T and B‐cell compartments. P1–3 have isolated reduction in IgM levels whereas the adults universally have normal immunoglobulins. Specific antibody responses are preserved. Affected individuals have neutrophil vacuolation, and their neutrophils have enhanced superoxide production compared to healthy controls.
Conclusion
RAC2 p.I21S is an activating variant causing notable morphological and functional abnormalities similar to other reported DA mutations. This novel variant expands the broad clinical phenotypic spectrum of RAC2 DA lesions, emphasising the need to tailor clinical management according to patients' disease phenotype and severity.
We report the clinical and immune features of 7 individuals from the same kindred with a novel genetic variant in RAC2 (c.62T > G, p.I21S). We provide evidence that this is a dominant activating (DA) variant causing notable morphological and functional abnormalities similar to other reported DA mutations. This novel variant expands the phenotypic spectrum of RAC2 DA lesions, emphasising the need to tailor clinical management according to patients' disease phenotype and severity.
Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five ...unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-β). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses.
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