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Increasing detections of vaccine-derived poliovirus (VDPV) globally, including in countries previously declared polio free, is a public health emergency of international concern. Individuals with primary immunodeficiency (PID) can excrete polioviruses for prolonged periods, which could act as a source of cryptic transmission of viruses with potential to cause neurological disease. Here, we report on the detection of immunodeficiency-associated VDPVs (iVDPV) from two asymptomatic male PID children in the UK in 2019. The first child cleared poliovirus with increased doses of intravenous immunoglobulin, the second child following haematopoetic stem cell transplantation. We perform genetic and phenotypic characterisation of the infecting strains, demonstrating intra-host evolution and a neurovirulent phenotype in transgenic mice. Our findings highlight a pressing need to strengthen polio surveillance. Systematic collection of stool from asymptomatic PID patients who are at high risk for poliovirus excretion could improve the ability to detect and contain iVDPVs. There is increasing incidence of vaccine-derived poliovirus (VDPV) in countries thought to be polio free. Here, the authors report detection of VDPV in 2 UK children with primary immunodeficiency. The children did not develop paralysis, but isolated viruses showed intra-host evolution and neurovirulent potential.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency, characterised by life-threatening bacterial and fungal infections and inflammatory complications. 1 Cognitive difficulties are also described. 2 Chronic ill health and cognitive difficulties potentially expose patients to psychological difficulties. In the general population, boys are more likely to present with conduct or hyperactivity disorders; 4 however, boys with chronic illness often exhibit increased emotional difficulties as demonstrated in this study. 5 The response rate in this study was high, with nearly all UK CGD patients recruited.

Rituximab (a monoclonal antibody against CD20-expressing B lymphocytes) is increasingly used for antibody-mediated autoimmunity and lymphoproliferative disorders. While safety data for children are limited, recent reports have highlighted neutropenia and persistent hypogammaglobulinaemia1 2 as potential consequences of rituximab therapy. Rarely, rituximab may unveil inborn errors of immunity presenting with autoimmunity.1

Receptor Interacting Serine/Threonine Kinase 1 (RIPK1) is widely expressed and integral to inflammatory and cell death responses. Autosomal recessive RIPK1-deficiency, due to biallelic loss of function mutations in RIPK1 , is a rare inborn error of immunity (IEI) resulting in uncontrolled necroptosis, apoptosis and inflammation. Although hematopoietic stem cell transplantation (HSCT) has been suggested as a potential curative therapy, the extent to which disease may be driven by extra-hematopoietic effects of RIPK1-deficiency, which are non-amenable to HSCT, is not clear. We present a multi-centre, international review of an additional 5 RIPK1-deficient children who underwent HSCT. All patients presented with very early onset inflammatory bowel disease, 2 also suffered from inflammatory arthritis. Median age at transplant was 3 years (range 1—5 years); 1 received matched sibling marrow, 1 matched unrelated peripheral blood stem cells (PBSC), 2 TCRαβ/CD19-depleted PBSC from maternal-haploidentical donors, and 1 had TCRαβ/CD19-depleted PBSC from a mismatched unrelated donor. All received reduced-toxicity conditioning, based on treosulfan ( n  = 4) or busulfan ( n  = 1); 1 patient underwent a successful second transplant following autologous reconstitution. Four of five patients (80%) survived; 1 child died due to multi-drug resistant pseudomonas infection and multi-organ failure. With a median duration of 14 months follow-up, 2 survivors were disease-free, and 2 had substantially improving enteropathy. These findings demonstrated that HSCT is a potential curative therapy for RIPK1-deficiency.

Background X-linked agammaglobulinaemia (XLA), caused by mutations in BTK , is characterised by low or absent peripheral CD19 + B lymphocytes and agammaglobulinaemia. The mainstay of treatment consists of immunoglobulin replacement therapy (IgRT). As this cannot fully compensate for the immune defects in XLA, patients may therefore continue to be at risk of complications. Objectives To describe the clinical outcomes of XLA patients in the United Kingdom and Hong Kong and evaluate current treatment strategies. Methods Patients with a definitive diagnosis of XLA were included in this cross-sectional and retrospective analysis of clinical health outcomes. Data pertaining to diagnosis, infection incidence, IgG trough levels and lung function were collected and analysed. Results 99 patients with a median age of 29.02 years (IQR 12.83–37.41) and a total follow up of 1922 patient years, were included this study. The median age at diagnosis was 3.30 years (IQR 1.04–8.38) which decreased over time ( p  = 0.004). 40% of the cohort had radiological evidence of bronchiectasis. Risk of bronchiectasis was not significantly associated with clinical infection incidence ( p  = 0.880) or IgG trough levels ( p  = 0.407). Two patients demonstrated novel complications, namely persistent norovirus infection, leading to haemopoietic stem cell transplantation (HSCT). Conclusions Despite modern therapy, most XLA patients continue to experience complications, most notably bronchiectasis, likely due to absence of IgA/M in current therapies, but lack of B lymphocytes may also lead to additional sequalae. These data strongly support the need for further research, particularly that of curative modalities including HSCT and gene therapy.

A significant complication of HSCT is graft failure, although few studies focus on this problem in patients with inborn errors of immunity (IE). We explored outcome of second HSCT for IEI by a retrospective, single-centre study between 2002 and 2022. Four hundred ninety-three patients underwent allogeneic HSCT for severe combined immunodeficiency (SCID; n  = 113, 22.9%) or non-SCID IEI ( n  = 380, 77.1%). Thirty patients (6.0%) required second HSCT. Unconditioned infusion or no serotherapy at first HSCT was more common in patients who required second transplant. Median interval between first and second HSCT was 0.97 years (range: 0.19–8.60 years); a different donor was selected for second HSCT in 24/30 (80.0%) patients. Conditioning regimens for second HSCT were predominately treosulfan-based (with thiotepa: n  = 18, 60.0%; without, n  = 6, 20.0%). Patients received grafts from peripheral blood stem cell ( n  = 25, 83.3%) or bone marrow ( n  = 5, 16.7%) with median stem cell dose 9.5 × 10 6 CD34 + cells/kilogram (range: 1.4–32.3). Median follow-up was 1.92 years (0.22–16.0). Overall survival was 80.8% and event-free survival was 64.7%. Four patients died, two of early-transplant related complications, and two of late sepsis post-second HSCT. Three patients required third HSCT; all are alive with 100% donor chimerism. Cumulative incidence of acute graft-versus-host disease was 28.4%, (all grade I–II). Viral reactivation was seen in 13/30 (43.3%) patients, including HHV6 ( n  = 6), CMV ( n  = 4), and adenovirus ( n  = 2). At latest follow-up, 25/26 surviving patients have donor chimerism ≥ 90% and 16/25 (64.0%) have discontinued immunoglobulin replacement. Second HSCT offers IEI patients with graft failure curative treatment with good overall survival and immunological recovery.

Predisposition to mycobacterial infection is a key presenting feature of several rare inborn errors of intrinsic and innate immunity. Hematopoietic stem cell transplantation (HSCT) can be curative for such conditions, but published reports are few. We present a retrospective survey of the outcome of 11 affected patients (7 males, 4 females) who underwent HSCT between 2007 and 2019. Eight patients had disseminated mycobacterial infection prior to transplant. Median age at first transplant was 48 months (9 -192); three patients were successfully re-transplanted due to secondary graft failure. Donors were matched family (1), matched unrelated (3), and mismatched unrelated and haploidentical family (5 each). Stem cell source was peripheral blood (9), bone marrow (4), and cord blood (1). TCRαβ/CD19 + depletion was performed in 6. Conditioning regimens were treosulfan, fludarabine (4), with additional thiotepa (in 8), and fludarabine, melphalan (2); all had serotherapy with alemtuzumab (8) or anti T-lymphocyte globulin (6). Median hospital stay was 113 days (36–330). Three patients developed acute grade I-II skin and one grade IV skin graft versus host disease. Four patients had immune-reconstitution syndrome. Two reactivated cytomegalovirus (CMV), 1 Epstein-Barr virus, and 3 adenovirus post HSCT. Nine are alive, 1 died early post-transplant from CMV, and the other was a late death from pneumococcal sepsis. Patients with active mycobacterial infection at HSCT continued anti-mycobacterial therapy for almost 12 months. In conclusion, HSCT is a successful treatment for patients with mycobacterial susceptibility even with disseminated mycobacterial infection and in the absence of an HLA matched donor.

A Correction to this paper has been published: https://doi.org/10.1038/s41409-020-01175-9

Understanding the risks involved in hiring new faculty is becoming increasingly important. In Managing Risk in High-Stakes Faculty Employment Decisions Julee T. Flood and Terry Leap critically examine the landscape of US institutions of higher learning and the legal and human resource management practices pertinent to college and university faculty members. To help minimize the potential pitfalls in the hiring and promotion processes, Flood and Leap suggest ways that risk management principles can be applied within the unique culture of academia. Claims of workplace harassment and discrimination, violation of free speech and other First Amendment rights, social movements decrying unequal hiring practices, and the growing number of non-tenure track and adjunct faculty, require those involved in hiring and promotion decisions to be more knowledgeable about contract law, best practices in hiring, and risk management, yet many newly appointed administrators are often not sufficiently trained in these matters or in understanding how they might be applied in an academic setting. Human resource departments, hiring committees, department chairs, and academics seeking faculty jobs need resources such as Managing Risk in High-Stakes Faculty Employment Decisions now more than ever. Outlines critical issues affecting U.S. higher educationAnalyzes the social and psychological biases that can arise during hiring, promotion, and tenure decisionsDiscusses contract and constitutional law from the perspective of institutions of higher learningIllustrates complex interactions that shape contractual, constitutional, and collegial issues in institutions of higher learningExamines contract rights and controversies for tenured and tenure-track facultyDescribes how risk management processes can help to deal with these complicated, but critical, issuesAddresses constitutional issues associated with academic freedom and free speech on campusInvestigates the nebulous, but important, issue of collegialityDiscusses the future for institutions of higher learning in hiring faculty