Wiskott-Aldrich syndrome: a study of 577 patients defines the genotype as a biomarker for disease severity and survival.

ABSTRACT: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

A multicentre observational study to investigate feasibility of a direct oral penicillin challenge in de-labelling 'low risk' patients with penicillin allergy by non-allergy healthcare professionals (SPACE study): Implications for healthcare systems.

OBJECTIVE: The huge burden of inaccurate penicillin allergy labels (PALs) is an important driver of antimicrobial resistance. This is magnified by insufficient allergy specialists and lack of 'point-of-care' tests. We investigated the feasibility of non-allergy healthcare professionals (HCPs) delivering direct oral penicillin challenges (DPCs) for penicillin allergy de-labelling. METHODS: This prospective observational study was conducted in three hospitals in England across three settings (acute medical, pre-surgical and haematology-oncology). Patients with a PAL were screened and stratified as low risk/high risk. Low risk patients (non-immune mediated symptoms, benign rash, tolerated amoxicillin since and family history) underwent a DPC. RESULTS: N = 2257 PALs were screened, 1054 were eligible; 643 were approached, 373 declined, 270 consented and 259 risk stratified (low risk = 155; high risk = 104). One hundred and twenty-six low risk patients underwent DPC, 122 (96.8%) were de-labelled with no serious allergic reactions. Conversion rate from screening-to-consent was 12% [3.3% and 17.9% in acute and elective settings respectively; odds ratios for consent were 3.42 (p < 0.001) and 5.53 (p < 0.001) in haematology-oncology and pre-surgical setting respectively. Common reasons for failure to progress in the study included difficulty in reaching patients, clinical instability/medical reasons, lacking capacity to consent and psychological factors. INTERPRETATION: DPCs can be delivered by non-allergy HCPs. A high proportion of patients with PALs did not progress in the study pathway. Strategies to deliver DPC at optimal points of the care pathway are needed to enhance uptake. Elective settings offer greater opportunities than acute settings for DPC. The safety and simplicity of DPCs lends itself to adoption by healthcare systems beyond the UK, including in resource-limited settings.

Generalised urticaria and angioedema complicating switch back from subcutaneous to intravenous vedolizumab therapy.

We report a unique case of a 34-year-old man with ulcerative colitis, previously in complete remission with intravenous vedolizumab monotherapy, who developed an urticarial injection-site reaction on switching to a subcutaneous preparation and thereafter experienced a new hypersensitivity reaction on switch back to intravenous vedolizumab, necessitating complete discontinuation from this drug. This case highlights the need for vigilance on switching back to intravenous preparations of vedolizumab, in response to injection-site reactions with a subcutaneous preparation, even if the intravenous preparation had been previously well tolerated by the patient.

Treatment of CIDP.

Chronic inflammatory demyelinating polyneuropathy is a disabling but treatable disorder. However, misdiagnosis is common, and it can be difficult to optimise its treatment. Various agents are used both for first and second line. First-line options are intravenous immunoglobulin, corticosteroids and plasma exchange. Second-line therapies may be introduced as steroid-sparing agents or as more potent escalation therapy. It is also important to consider symptomatic treatment of neuropathic pain and non-pharmacological interventions. We discuss the evidence for the various treatments and explain the practicalities of the different approaches. We also outline strategies for monitoring response and assessing the ongoing need for therapy.

Outcomes following SARS-CoV-2 infection in patients with primary and secondary immunodeficiency in the UK.

In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to the hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir, and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count, and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.

Risk of Reactivation of Hepatitis B Virus (HBV) and Tuberculosis (TB) and Complications of Hepatitis C Virus (HCV) Following Tocilizumab Therapy: A Systematic Review to Inform Risk Assessment in the COVID-19 Era.

Objectives: Tocilizumab (TCZ), an IL-6 receptor antagonist, is used in the treatment of severe COVID-19 caused by infection with SARS-CoV-2. However, unintended consequences of TCZ therapy include reactivation of tuberculosis (TB) or hepatitis B virus (HBV), and worsening of hepatitis C virus (HCV). We set out to assimilate existing data for these complications, in order to help inform evidence-based risk assessments for the use of TCZ, and thus to reduce the risk of serious but preventable complications. Methods: We searched the global WHO database of Individual Case Safety Reports (ICSRs) and adverse drug reactions (ADRs) ("VigiBase") and undertook a systematic literature review, in accordance with PRISMA guidelines. We generated mean cumulative incidence estimates for infection complications. Results: Mean cumulative incidence of HBV and TB were 3.3 and 4.3%, respectively, in patients receiving TCZ. Insufficient data were available to generate estimates for HCV. These estimates derive from heterogeneous studies pre-dating SARS-CoV-2, with differing epidemiology and varied approaches to screening and prophylaxis, so formal meta-analysis was not possible. Conclusions: We underline the need for careful individual risk assessment prior to TCZ prescription, and present an algorithm to guide clinical stratification. There is an urgent need for ongoing collation of safety data as TCZ therapy is used in COVID.

Lessons of the month 2: Meningococcal epiglottitis and connective tissue disease associated with C2 deficiency.

CASE PRESENTATION: A 68-year-old woman was referred for immunological investigation following an episode of meningococcal epiglottitis with associated septicaemia. Several years previously, she had been diagnosed with undifferentiated connective tissue disease. On investigation, alternative pathway complement function was normal; however, classical pathway complement activation was reduced. C1q, C3 and C4 levels were all measured and found to be within their respective normal ranges, but C2 levels were low. Sequencing of the C2 gene was subsequently performed, confirming a diagnosis of type 1 C2 deficiency (C2D). DISCUSSION: C2D is usually hereditary and inherited in an autosomal recessive manner. C2D is often asymptomatic, however, some patients suffer from infections with encapsulated bacteria and/or autoimmune diseases, particularly systemic lupus erythematosus. Recognition of complement pathway deficiency is important due to the predisposition to severe and/or recurrent infections by encapsulated bacteria. Immunisations have the potential to reduce both mortality and morbidity not only for the patient but also for any affected relatives.

Pharmacogenomics in the UK National Health Service: opportunities and challenges.

Despite increasing interest in pharmacogenomics, and the potential benefits to improve patient care, implementation into clinical practice has not been widespread. Recently, there has been a drive to implement genomic medicine into the UK National Health Service (NHS), largely spurred on by the success of the 100,000 Genomes Project. The UK Pharmacogenetics and Stratified Medicine Network, NHS England and Genomics England invited experts from academia, the healthcare sector, industry and patient representatives to come together to discuss the opportunities and challenges of implementing pharmacogenomics into the NHS. This report highlights the discussions of the workshop to provide an overview of the issues that need to be considered to enable pharmacogenomic medicine to become mainstream within the NHS.

Is direct oral amoxicillin challenge a viable approach for 'low-risk' patients labelled with penicillin allergy?

Spurious penicillin allergy (PenA) is a major public health problem. Up to 10% of the population and 20% of inpatients are labelled with PenA, but only <5%-10% have a proven allergy following comprehensive investigations. PenA tests are labour intensive and require specialist input, which may not be readily available due to limited allergy services. Therefore, patients with PenA receive alternative antibiotics that are associated with higher rates of iatrogenic infections, antimicrobial resistance and a longer hospital stay with consequent increased costs. Recent evidence suggests that a supervised 'direct' oral amoxicillin challenge (without performing allergy tests) is a safe option in low-risk patients (those least likely to be allergic based on history). Patient selection for this procedure is based on a careful guideline-based risk stratification process. Further research is needed to validate this intervention in routine clinical practice and explore potential facilitators and barriers to implementation in different healthcare settings.

Peri-Operative Anaphylaxis-An Investigational Challenge.

Patients with suspected peri-operative anaphylaxis (POP) require thorough investigation to identify underlying trigger(s) and enable safe anesthesia for subsequent surgery. The changing epidemiology of POP has been striking. Previous estimates of the incidence of POP have ranged between 1:6,000 and1:20,000 anesthetics, but more recent data from France and the United Kingdom suggest an estimated incidence of 1:10,000. Other important changes include a change in the hierarchy of well-recognized triggers, with antibiotics (beta-lactams) supplanting neuromuscular blockers (NMB) as the leading cause of POP. The emergence of chlorhexidine, patent blue dye, and teicoplanin as important triggers have also been noteworthy findings. The mainstay of investigation revolves around critical analysis of the time-line of events leading up to anaphylaxis coupled with judicious skin testing. Skin tests have limitations with respect to unknown predictive values for most drugs/agents and therefore, knowledge of background positivity in healthy controls, test characteristics of individual drugs and the use of non-irritant concentrations is essential to avoid both false-positive and false-negative results. Specific IgE assays for individual drugs are available only for a limited number of agents and are not a substitute for skin testing. Acute serum total tryptase has a high specificity and positive predictive value in IgE-mediated POP anaphylaxis but is limited by its moderate sensitivity and negative predictive value. Planning for safe anesthesia in this group of patients is particularly challenging and consequently anesthetists need to be alert to the possibility of repeat episodes of anaphylaxis. Because of the limitations of current investigations for POP, collecting systematic data on the outcome of repeat anesthesia is valuable in validating current investigatory approaches. This paper reviews the changing epidemiology of POP with reference to the main triggers, and the investigation and outcome of subsequent anesthesia.

Treatment stratification of respiratory syncytial virus infection in allogeneic stem cell transplantation.

BACKGROUND: Due to paucity of evidence to guide management of allogeneic haematopoietic stem cell transplantation (allo-HSCT) patients with respiratory syncytial virus (RSV) infections national and international guidelines make disparate recommendations. METHODS: The outcomes of allo-HSCT recipients with RSV infection between 2015 and 2017 were assessed using the following treatment stratification; upper respiratory tract infections (URTI) being actively monitored and lower respiratory tract infections (LRTI) treated with short courses of oral ribavirin combined with intravenous immunoglobulin (IVIG, 2 g/kg). RESULTS: During the study period 49 RSV episodes were diagnosed (47% URTI and 53% LRTI). All patients with URTI recovered without pharmacological intervention. Progression from URTI to LRTI occurred in 15%. Treatment with oral ribavirin given until significant symptomatic improvement (median 7 days [3-12]) and IVIG for LRTI was generally well tolerated. RSV-attributable mortality was low (2%). CONCLUSIONS: In this cohort study, we demonstrate that active monitoring of allo-HSCT patients with RSV in the absence of LRTI was only associated with progression to LRTI in 15% of our patients and therefore appears to be a safe approach. Short course oral ribavirin in combination with IVIG was effective and well-tolerated for LRTI making it a practical alternative to aerosolised ribavirin. This approach was beneficial in reducing hospitalisation, saving nursing times and by using oral as opposed to nebulised ribavirin.

Immunoglobulin replacement for secondary immunodeficiency after B-cell targeted therapies in autoimmune rheumatic disease: Systematic literature review.

BACKGROUND: Consensus guidelines are not available for the use of immunoglobulin replacement therapy (IGRT) in patients developing iatrogenic secondary antibody deficiency following B-cell targeted therapy (BCTT) in autoimmune rheumatic disease. OBJECTIVES: To evaluate the role of IGRT to manage hypogammaglobulinemia following BCTT in autoimmune rheumatic disease (AIRD). METHODS: Using an agreed search string we performed a systematic literature search on Medline with Pubmed as vendor. We limited the search to English language papers with abstracts published over the last 10 years. Abstracts were screened for original data regarding hypogammaglobulinemia following BCTT and the use of IGRT for hypogammaglobulinemia following BCTT. We also searched current recommendations from national/international organisations including British Society for Rheumatology, UK Department of Health, American College of Rheumatology, and American Academy of Asthma, Allergy and Immunology. RESULTS: 222 abstracts were identified. Eight papers had original relevant data that met our search criteria. These studies were largely retrospective cohort studies with small patient numbers receiving IGRT. The literature highlights the induction of a sustained antibody deficiency, risk factors for hypogammaglobulinemia after BCTT including low baseline serum IgG levels, how to monitor patients for the development of hypogammaglobulinemia and the limited evidence available on intervention thresholds for commencing IGRT. CONCLUSION: The benefit of BCTT needs to be balanced against the risk of inducing a sustained secondary antibody deficiency. Consensus guidelines would be useful to enable appropriate assessment prior to and following BCTT in preventing and diagnosing hypogammaglobulinemia. Definitions for symptomatic hypogammaglobulinemia, intervention thresholds and treatment targets for IGRT, and its cost-effectiveness are required.

Opinion: redefining the role of the physician in laboratory medicine in the context of emerging technologies, personalised medicine and patient autonomy ('4P medicine').

The role of clinical pathologists or laboratory-based physicians is being challenged on several fronts-exponential advances in technology, increasing patient autonomy exercised in the right to directly request tests and the use of non-medical specialists as substitutes. In response, clinical pathologists have focused their energies on the pre-analytical and postanalytical phases of Laboratory Medicine thus emphasising their essential role in individualised medical interpretation of complex laboratory results. Across the European Union, the role of medical doctors is enshrined in the Medical Act. This paper highlights the relevance of this act to patient welfare and the need to strengthen training programmes to prevent an erosion in the quality of Laboratory Medicine provided to patients and their physicians.

Recommendations for the management of secondary hypogammaglobulinaemia due to B cell targeted therapies in autoimmune rheumatic diseases.

OBJECTIVES: The association of B cell targeted therapies with development of hypogammaglobulinaemia and infection is increasingly recognized. Our aim was to develop consensus recommendations for immunoglobulin replacement therapy for management of hypogammaglobulinaemia following B cell targeted therapies in autoimmune rheumatic diseases. METHODS: A modified Delphi exercise involved a 17-member Taskforce committee, consisting of immunologists, rheumatologists, nephrologists, haematologists, a gastroenterologist, an immunology specialist nurse and a patient representative. The first round identified the most pertinent topics to address in the recommendations. A search string was agreed upon for the identification of publications in PubMed focusing on these areas, for a systematic literature review. Original data was presented from this review to the Taskforce committee. Recommendations from the British Society for Rheumatology, the UK Department of Health, EULAR, the ACR, and the American Academy of Allergy, Asthma, and Immunology were also reviewed. The evidence was discussed in a face-to-face meeting to formulate recommendation statements. The levels of evidence and statements were graded according to Scottish Intercollegiate Guidelines Network methodology. RESULTS: Three overarching principles, eight recommendation statements and a research agenda were formulated. The Taskforce committee voted on these statements, achieving 82-100% agreement for each recommendation. The strength of the recommendations was restricted by the low quality of the available evidence, with no randomized controlled trial data. The recommendations cover risk factors, monitoring, referral for hypogammaglobulinaemia; indications, dosage and discontinuation of immunoglobulin replacement therapy. CONCLUSION: These are the first recommendations specifically formulated for B cell targeted therapies related to hypogammaglobulinaemia in autoimmune rheumatic diseases. The recommendations are to aid health-care professionals with clinical decision making for patients with hypogammaglobulinaemia.

Correction to: Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials.

The article Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials, written by Mark Ballow, Richard L. Wasserman, Stephen Jolles, Helen Chapel, Mel Berger, Siraj A. Misbah, was originally published Online First without open access.