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Hematopoietic stem cell transplantation and gene therapy are the only curative therapies for severe combined immunodeficiency (SCID). In patients lacking a matched donor, TCRαβ/CD19-depleted haploidentical family donor transplant (TCRαβ-HaploSCT) is a promising strategy. Conditioned transplant in SCID correlates to better myeloid chimerism and reduced immunoglobulin dependency. We studied transplant outcome in SCID infants according to donor type, specifically TCRαβ-HaploSCT, and conditioning, through retrospective cohort analysis of 52 consecutive infants with SCID transplanted between 2013 and 2020. Median age at transplant was 5.1 months (range, 0.8–16.6). Donors were TCRαβ-HaploSCT (n = 16, 31.4%), matched family donor (MFD, n = 15, 29.4%), matched unrelated donor (MUD, n = 9, 17.6%), and matched unrelated cord blood (CB, n = 11, 21.6%). Forty-one (80%) received fludarabine/treosulfan-based conditioning, 3 (6%) had alemtuzumab only, and 7 (14%) received unconditioned infusions. For conditioned transplants (n = 41), 3-year overall survival was 91% (95% confidence interval, 52–99%) for TCRαβ-HaploSCT, 80% (41–98%) for MFD, 87% (36–98%) for MUD, and 89% (43–98%) for CB (p = 0.89). Cumulative incidence of grade II–IV acute graft-versus-host disease was 11% (2–79%) after TCRαβ-HaploSCT, 0 after MFD, 29% (7–100%) after MUD, and 11% (2–79%) after CB (p = 0.10). 9/10 patients who received alemtuzumab-only or unconditioned transplants survived. Myeloid chimerism was higher following conditioning (median 47%, range 0–100%) versus unconditioned transplant (median 3%, 0–9%) (p n = 29/36, 81% vs n = 4/9, 54%) (p

The hyper-IgE syndromes (HIES) are a heterogeneous group of inborn errors of immunity sharing manifestations including increased infection susceptibility, eczema, and raised serum IgE. Since the prototypical HIES description 55 years ago, areas of significant progress have included description of key disease-causing genes and differentiation into clinically distinct entities. The first two patients reported had what is now understood to be HIES from dominant-negative mutations in signal transduction and activator of transcription 3 (STAT3-HIES), conferring a broad immune defect across both innate and acquired arms, as well as defects in skeletal, connective tissue, and vascular function, causing a clinical phenotype including eczema, staphylococcal and fungal skin and pulmonary infection, scoliosis and minimal trauma fractures, and vascular tortuosity and aneurysm. Due to the constitutionally expressed nature of STAT3, initial reports at treatment with allogeneic stem cell transplantation were not positive and treatment has hinged on aggressive antimicrobial prophylaxis and treatment to prevent the development of end-organ disease such as pneumatocele. Research into the pathophysiology of STAT3-HIES has driven understanding of the interface of several signaling pathways, including the JAK-STAT pathways, interleukins 6 and 17, and the role of Th17 lymphocytes, and has been expanded by identification of phenocopies such as mutations in IL6ST and ZNF341. In this review we summarize the published literature on STAT3-HIES, present the diverse clinical manifestations of this syndrome with current management strategies, and update on the uncertain role of stem cell transplantation for this disease. We outline key unanswered questions for further study.

Hematopoietic stem cell transplantation and gene therapy are the only curative therapies for severe combined immunodeficiency (SCID). In patients lacking a matched donor, TCRαβ/CD19-depleted haploidentical family donor transplant (TCRαβ-HaploSCT) is a promising strategy. Conditioned transplant in SCID correlates to better myeloid chimerism and reduced immunoglobulin dependency. We studied transplant outcome in SCID infants according to donor type, specifically TCRαβ-HaploSCT, and conditioning, through retrospective cohort analysis of 52 consecutive infants with SCID transplanted between 2013 and 2020. Median age at transplant was 5.1 months (range, 0.8-16.6). Donors were TCRαβ-HaploSCT (n = 16, 31.4%), matched family donor (MFD, n = 15, 29.4%), matched unrelated donor (MUD, n = 9, 17.6%), and matched unrelated cord blood (CB, n = 11, 21.6%). Forty-one (80%) received fludarabine/treosulfan-based conditioning, 3 (6%) had alemtuzumab only, and 7 (14%) received unconditioned infusions. For conditioned transplants (n = 41), 3-year overall survival was 91% (95% confidence interval, 52-99%) for TCRαβ-HaploSCT, 80% (41-98%) for MFD, 87% (36-98%) for MUD, and 89% (43-98%) for CB (p = 0.89). Cumulative incidence of grade II-IV acute graft-versus-host disease was 11% (2-79%) after TCRαβ-HaploSCT, 0 after MFD, 29% (7-100%) after MUD, and 11% (2-79%) after CB (p = 0.10). 9/10 patients who received alemtuzumab-only or unconditioned transplants survived. Myeloid chimerism was higher following conditioning (median 47%, range 0-100%) versus unconditioned transplant (median 3%, 0-9%) (p 0.001), as was the proportion of immunoglobulin-free long-term survivors (n = 29/36, 81% vs n = 4/9, 54%) (p 0.001). TCRαβ-HaploSCT has comparable outcome to MUD and is a promising alternative donor strategy for infants with SCID lacking MFD. This study confirms that conditioned transplant offers better myeloid chimerism and immunoglobulin freedom in long-term survivors.

Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.

Major histocompatibility class I deficiency, due to genetic lesions in TAP1, TAP2, TAPBP, or B2M, manifests with recurrent sinopulmonary infections and granulomatous skin ulceration, and is predominately treated with antimicrobial prophylaxis and chest physiotherapy. One previous report of hematopoietic stem cell transplantation has been described in the literature, demonstrating cure of the immune defect without significant graft-versus-host disease. In this report, we expand the literature on HSCT in MHC-I deficiency with follow-up of the original patient, demonstrating maintained resolution of normal immune function and regression of the granulomatous rash 15 years post-transplant, and describe a further patient with mycobacterial disease whose transplant course was complicated by severe graft-versus-host disease.

Homozygous mutations in cytochrome b-245 chaperone 1 (CYBC1) have been recently described as causing recurrent infections and inflammatory disease in an Icelandic cohort and a patient from Saudi Arabia, by destabilising the dimerisation of gp91phox with p22phox, manifesting as phenotypic chronic granulomatous disease (CGD). Haematopoietic stem cell transplantation is the treatment of choice in CGD, though experience of transplantation in this subtype of CGD is limited to a brief description in one patient. We provide clinical and transplant data for two Icelandic brothers with CGD due to homozygous p.Tyr2Ter mutations in CYBC1, demonstrating maintained cure of the immune defect 11 years post-transplant in one brother, and death in the peri-transplant period for the other.

Background/Aims The range of approved immunosuppressive and immunomodulatory (IM) agents has grown considerably with an increasing list of indications across paediatric specialties. At present, there is limited evidence supporting best practice for prescribing and monitoring of IM agents in children and young people (CYP). We present a staged service development project exploring cross-specialty prescribing and monitoring of IM agents at a tertiary children’s hospital (Great North Children’s Hospital, GNCH) and data sharing with local hospitals across northeast England. Methods In Phase 1, we searched pharmacy databases and surveyed specialty teams in GNCH to identify clinicians regularly prescribing IM agents to CYP over a twelve-month period. Phase 2 was a cross-specialty retrospective case-notes review of prescribing, monitoring and infection surveillance in a representative sample of CYP on IM agents. Phase 3 explored information sharing with six other hospitals in the region and acute presentations to these sites involving CYP on IM agents. Results Phase 1 identified 9 paediatric and 2 adult specialties prescribing IM agents to 416 CYP. 32 discrete IM therapies were prescribed with significant between-specialty overlap in drugs prescribed but a wide range of prescribing and monitoring practices. Phase 2 assessed 77 CYP on IM agents in detail - 57% were prescribed >1 IM agent, 100% had FBC measured at least once (range once only to weekly), 18% developed lymphopenia at least once and 40% were prescribed prophylactic antibiotics. Previous varicella exposure had been assessed in 70%. Phase 3 data are summarised in Table 1. P011 Table 1:Information sharing and acute presentations to regional hospitals local to immunosuppressed patientsTotal number of patients141Mean age in years (range)11 (2 - 17)NDiagnosisJIA without uveitis108JIA with uveitis9Uveitis alone8Systemic JIA4Period fever4Behçet’s disease2Juvenile dermatomyositis2Scleroderma1Juvenile systemic lupus erythematosus1Mixed connective tissue disease1Granulomatosis with polyangiitis1Immunosuppressive or immunomodulatory agent usedAdalimumab65Methotrexate42Tocilizumab22Mycophenolate mofetil10Etanercept10Infliximab5Sulfasalazine5Prednisolone4Abatacept4Leflunomide4Canakinumab2Colchicine2Anakinra2Rituximab2Cyclophosphamide1Number of immunosuppressive or immunomodulatory agents per patient3 agents52 agents441 agent92Number of acute presentations by diagnosis or presenting complaint (n = 19)Fever4Chickenpox4Viral upper respiratory tract infection2Joint pain2Abdominal pain2Rash2Eye infection1Tonsilitis1Wheeze1Yes (%)No (%)Named local consultant (n = 129)3763Correct diagnosis recorded locally (n = 130)8020Correct immunosuppressive or immunomodulatory agent recorded locally (n = 130)5050Open access for febrile illness (n = 116)4159Reviewed in past 2 years for acute illness (n = 109)1783Note: presented numbers for immunosuppressive or immunomodulatory agents are not mutually exclusive. JIA, juvenile idiopathic arthritis Conclusion IM agents are central to modern paediatric clinical care across a wide range of diseases. This staged project identified significant variation in IM prescribing and monitoring practice between specialties at GNCH. Communication between specialty and local teams is inadequate. Particular areas of concern include limited diagnostic, blood monitoring and medication information sharing and limited local information governing management of intercurrent illness and vaccination. Although different disease processes can necessitate different advice and prescribing practices, sharing examples of good practice will minimise unnecessary variation. We propose the development of a regional immunosuppression working group to improve quality and safety across our region. Disclosure J.L. Bennett: None. C. Tsilifis: None. A. Flinn: None. T. Altmann: None. N. Jansen: None. H. Tumelty: None. K. Aitken: None. S. Bhopal: None. E. Harrison: None. S. Ravenscroft: None. E. Sen: None. E. Williams: None. T. Flood: None. S. Sampath: None. A. Battersby: None. F. McErlane: None.

Summary The Erwiniaceae are a family of gram-negative, aerobic coliforms which are pathogenic to a number of plants. Recently described within this family are the Pantoea, strains of which have been associated with infection in immunocompromised children and post-surgical meningitis but also colonisation of a healthy human subject's gastrointestinal tract, as well as a variety of agricultural diseases. In 2015, a further clade of this family was established as the genus Mixta. In this case report, we describe infection of the pleural space and lung parenchyma with members of Mixta in a term neonate following an anastomic leak post-primary repair of congenital trache-oesophageal fistula, causing a respiratory and cardiovascular deterioration. Mixta were identified by MALDI-TOF. The child made a full recovery with use of intravenous piperacillin-tazobactam. The Mixta genus must be added to a list of opportunistic pathogens responsible for infection following perforation of the gastrointestinal tract.

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Background In 2016, the NICE clinical guideline 95 (’Chest pain of recent onset: assessment and diagnosis’) was updated to include coronary CT angiography (CCTA) as the first-line imaging modality for stable chest pain, and to suggest that fractional flow reserve CT (FFRCT) should also be considered as an option. NICE state FFRCT reduces cath lab utilisation due to better diagnostic performance at detecting significant coronary artery disease (CAD) compared to CCTA, and does not involve additional CT scanner time, radiation or contrast. This technology is not currently available at City Hospitals Sunderland. Local and international data suggest that CCTA overestimates disease severity compared to findings at invasive cardiac catheterisation (ICC). We investigated the role of including FFRCT in investigation of stable chest pain, including theoretical cost and service utilisation savings, and identified the concordance in grading of CAD between CCTA and ICC. Method Data on disease grading were collected from reports of CCTAs done between 1 st January 2016 and 31 st December 2017. Data were also collected for those patients who subsequently underwent ICC. For the patients who underwent both CCTA and ICC, the CCTA reports and images were individually reviewed by a consultant cardiologist with experience in CCTA to assess concordance between both studies. A financial model was then created, using cost data quoted by NICE. Results A total of 163 patients underwent CCTA in the time period. Of these, 113 (68%) had mild-moderate CAD and so were managed medically. The remaining 50 (32%) patients underwent ICC due to either findings of moderate-severe CAD; anatomical aberrancies; or artefact. Of these 50 ICCs, 33 (66%, showing normal arteries or mild CAD) could have been avoided if there was a more sensitive test. 8 patients went on to undergo revascularisation. Financial modelling estimated that using FFRCT prior to referral for ICC would lead to a cost saving of £22 290 per year (£136.74 per patient per year) and result in more efficient utilisation of the angiography suite, reducing waiting list lengths. CCTA and ICC agreed on disease grading in 37/47 of cases, which correlates with data in the literature showing high sensitivity but relatively poor specificity. Conclusion CCTA is the NICE-recommended fist-line investigation for stable chest pain, and is sensitive and clinically useful. However, poor specificity causes unnecessary cardiac catheterisation. This relates to overestimation of luminal stenoses (e.g. due to arterfact from calcium). Use of FFRCT at City Hospitals Sunderland would reduce unnecessary angiograms and the risks associated with these, and would provide better utilisation of the angiography suite for interventional procedures, at a cost saving to the Trust. Introduction of guidelines such as CAD-RADS (coronary artery disease reporting and data system) would standardise terminology used in reporting and further improve reliability and specificity.

To the Editor, In 2011, Moratto et al. [1]. identified age at haematopoietic stem cell transplantation (HSCT) as a risk modifier for complications inWiskott-Aldrich syndrome (WAS); of note, complications appear to be 1.5 times more likely in children transplanted at ages 2–5, compared to younger than 2 (RR = 1.53; CI, 0.90–2.58; P = 0.130). This reinforces the importance of prompt recognition, diagnosis and assessment for HSCT in patients with suspected WAS. We evaluated the presenting features in boys with WAS mutations transplanted at the Great North Childrens’ Hospital, Newcastle-upon-Tyne between 1989 and 2015 in order to identify any delay in diagnosis and causative factors, including misdiagnosis, and clarify the role of mean platelet volume in making a diagnosis of WAS. We sought to identify key discriminating diagnostic features in order to aid timely diagnosis and transplantation of these patients. Data was collected retrospectively from written and electronic medical records of 20 boys with WAS mutations, for which all families had given prior written consent. Information regarding date and nature of symptom onset, time elapsed until diagnosis, mean platelet volume at presentation, age at transplantation and outcome were recorded in an anonymised spreadsheet. Symptomatology was coded as one or more of the following: infectious and immunological, including autoimmunity; eczema; bruising and petechiae; and bleeding. No differentiation was made between WAS and XLT due to no significant difference in platelet counts, platelet size and bleeding episodes in these conditions. Median age at symptom onset was 2 months (birth – 9 months) and at diagnosis was 1 year (2 months – 14.1 years). Median interval between symptom onset and diagnosis was 8 months (2 weeks – 13.8 years). The most common presenting symptom was bleeding (13 reports, 65 %). The subsequent most common symptoms were bruising (11, 55 %); eczema and skin disease (9, 45 %) and immunological and infectious (7, 35 %). Initial documented impressions included nonaccidental injury [1], congenital cytomegalovirus infection [1] and suspected ITP [2]. The most common combination of symptoms at presentation was bruising with eczema, in 7 (35 %), bleeding and bruising, 5 (25 %); bleeding and eczema, 5 (25 %); bleeding and infective/immunological, 4 (20 %); bruising and infective or immunological, 4 (20 %), infective or immunological and eczema, 1 (5 %) patient. There was no documented family history of WAS or XLT. Eight patients (40 %) had a recorded mean platelet volume (MPV) following presentation to our unit. Median MPV was 4.85 fl (range: 3.6–21); only 3 patients had a volume < 5 fl (Fig. 1). One result was recorded as Blow^ and so was omitted from analysis. Our results show a lag between onset of symptoms and confirmed diagnosis of WAS of 8 months. A diagnostic delay in WAS (and other primary immunodeficiency disorders) of * Christo Tsilifis ctsilifis@gmail.com