Challenges for gene editing in common variable immunodeficiency disorders: Current and future prospects.

The original CRISPR Cas9 gene editing system and subsequent innovations offers unprecedented opportunities to correct severe genetic defects including those causing Primary Immunodeficiencies (PIDs). Common Variable Immunodeficiency Disorders (CVID) are the most frequent symptomatic PID in adults and children. Unlike many other PIDs, patients meeting CVID criteria do not have a definable genetic defect and cannot be considered to have an inborn error of immunity (IEI). Patients with a CVID phenotype carrying a causative mutation are deemed to have a CVID-like disorder consequent to an IEI. Patients from consanguineous families often have highly penetrant early-onset autosomal recessive forms of CVID-like disorders. Individuals from non-consanguineous families may have autosomal dominant CVID-like disorders with variable penetrance and expressivity. This essay explores the potential clinical utility as well as the current limitations and risks of gene editing including collateral genotoxicity. In the immediate future the main application of this technology is likely to be the in vitro investigation of epigenetic and polygenic mechanisms, which are likely to underlie many cases of CVID and CVID-like disorders. In the longer-term, the CRISPR Cas9 system and other gene-based therapies could be utilized to treat CVID-like disorders, where the underlying IEI is known.

The Rapidly Expanding Genetic Spectrum of Common Variable Immunodeficiency-Like Disorders.

The understanding of common variable immunodeficiency disorders (CVID) is in evolution. CVID was previously a diagnosis of exclusion. New diagnostic criteria have allowed the disorder to be identified with greater precision. With the advent of next-generation sequencing (NGS), it has become apparent that an increasing number of patients with a CVID phenotype have a causative genetic variant. If a pathogenic variant is identified, these patients are removed from the overarching diagnosis of CVID and are deemed to have a CVID-like disorder. In populations where consanguinity is more prevalent, the majority of patients with severe primary hypogammaglobulinemia will have an underlying inborn error of immunity, usually an early-onset autosomal recessive disorder. In nonconsanguineous societies, pathogenic variants are identified in approximately 20% to 30% of patients. These are often autosomal dominant mutations with variable penetrance and expressivity. To add to the complexity of CVID and CVID-like disorders, some genetic variants such as those in TNFSF13B (transmembrane activator calcium modulator cyclophilin ligand interactor) predispose to, or enhance, disease severity. These variants are not causative but can have epistatic (synergistic) interactions with more deleterious mutations to worsen disease severity. This review is a description of the current understanding of genes associated with CVID and CVID-like disorders. This information will assist clinicians in interpreting NGS reports when investigating the genetic basis of disease in patients with a CVID phenotype.

Selective IgA Deficiency May Be an Underrecognized Risk Factor for Severe COVID-19.

SARS-CoV-2, the agent responsible for COVID-19, has wreaked havoc around the globe. Hundreds of millions of individuals have been infected and well over six million have died from COVID-19. Many COVID-19 survivors have ongoing physical and psychiatric morbidity, which will remain for the rest of their lives. Early in the pandemic, it became apparent that older individuals and those with comorbidities including obesity, diabetes mellitus, coronary artery disease, hypertension, and renal and pulmonary disease were at increased risk of adverse outcomes. It is also clear that some immunodeficient patients, such as those with innate or T cell-immune defects, are at greater risk from COVID-19. Selective IgA deficiency (sIgAD) is generally regarded as a mild disorder in which most patients are asymptomatic because of redundancy in protective immune mechanisms. Recent data indicate that patients with sIgAD may be at high risk of severe COVID-19. SARS-CoV-2 gains entry primarily through the upper respiratory tract mucosa, where IgA has a critical protective role. This may underlie the vulnerability of sIgAD patients to adverse outcomes from COVID-19. This perspective highlights the need for ongoing research into mucosal immunity to improve COVID-19 treatments for patients with sIgAD.

Clinical outcomes and the impact of prior oral anticoagulant use in patients with coronavirus disease 2019 admitted to hospitals in the UK - a multicentre observational study.

Coagulation dysfunction and thrombosis are major complications in patients with coronavirus disease 2019 (COVID-19). Patients on oral anticoagulants (OAC) prior to diagnosis of COVID-19 may therefore have better outcomes. In this multicentre observational study of 5 883 patients (≥18 years) admitted to 26 UK hospitals between 1 April 2020 and 31 July 2020, overall mortality was 29·2%. Incidences of thrombosis, major bleeding (MB) and multiorgan failure (MOF) were 5·4%, 1·7% and 3·3% respectively. The presence of thrombosis, MB, or MOF was associated with a 1·8, 4·5 or 5·9-fold increased risk of dying, respectively. Of the 5 883 patients studied, 83·6% (n = 4 920) were not on OAC and 16·4% (n = 963) were taking OAC at the time of admission. There was no difference in mortality between patients on OAC vs no OAC prior to admission when compared in an adjusted multivariate analysis [hazard ratio (HR) 1·05, 95% confidence interval (CI) 0·93-1·19; P = 0·15] or in an adjusted propensity score analysis (HR 0·92 95% CI 0·58-1·450; P = 0·18). In multivariate and adjusted propensity score analyses, the only significant association of no anticoagulation prior to diagnosis of COVID-19 was admission to the Intensive-Care Unit (ICU) (HR 1·98, 95% CI 1·37-2·85). Thrombosis, MB, and MOF were associated with higher mortality. Our results indicate that patients may have benefit from prior OAC use, especially reduced admission to ICU, without any increase in bleeding.

Perspective: Application of the American College of Medical Genetics Variant Interpretation Criteria to Common Variable Immunodeficiency Disorders.

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.

Defining Common Variable Immunodeficiency Disorders in 2020.

Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune deficiency in adults. Because there is no known cause for these conditions, there is no single clinical feature or laboratory test that can confirm the diagnosis with certainty. If a causative mutation is identified, patients are deemed to have a CVID-like disorder caused by a specific primary immunodeficiency/inborn error of immunity. In the remaining patients, the explanation for these disorders remains unclear. The understanding of CVID continues to evolve and the authors review recent studies, which have addressed some of these uncertainties.

Paying the price for an incentive: an exploratory study of smokers' reasons for failing to complete an incentive based smoking cessation scheme.

OBJECTIVES: In 2009, one Scottish region launched a smoking cessation programme offering a weekly financial incentive of £12.50 over a 12-week period. However, a significant proportion of registered participants dropped out of the programme, some even failing to collect the financial reward they were owed. We explore reasons for disengagement and failure to re-engage within this group. METHOD: Individuals (n = 14) were interviewed in depth. Transcripts from recorded interviews formed the dataset and were analysed using the "Framework" method. RESULTS: Incentives appeared to introduce a potential change/reversal in the felt contractual relationship between service provider and client: the client was now the provider and being paid to quit. This led to an increased sense of obligation towards the service, and enhanced feelings of failure, guilt and shame post-relapse, and reluctance to continue engagement or re-engagement. Other service factors promoting disengagement included issues of practical delivery through location, timing, administrative burden and incentive preference. CONCLUSION: The future design of incentive-based schemes should be cognisant of the potential impact on the client-professional relationship. Increasing the value of the incentive may overcome clients' antipathy towards bureaucracy and monitoring, but may simultaneously exacerbate the sense of failure and resultant stigma associated with relapse. It may be more cost-effective to reduce barriers/costs such as inconvenience, lack of privacy, timing and embarrassment of association of attendance at the pharmacy with methadone use. Alternatively, risks may be managed by reframing weekly rewards as three separate month-long stages, increasing a sense of achievement that a particular stage has been achieved before any relapse.