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Georgina L Jones,1 Kate Williams,2 Mark Edmondson-Jones,2 Johan Prevot,3 Jose Drabwell,3 Leire Solis,3 Anna Shrimpton,4 Nizar Mahlaoui5– 7 1Department of Psychology, School of Social Sciences, Leeds Beckett University, Leeds, UK; 2PAREXEL International, London, UK; 3International Patient Organisation for Primary Immunodeficiencies, Downderry, Cornwall PL11 3LY, UK; 4Clinical Immunology and Allergy Unit, Northern General Hospital, Sheffield Teaching Hospitals and NHS Foundation Trust, Sheffield, UK; 5French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux De Paris, Paris, France; 6Pediatric Immuno-Haematology and Rheumatology Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux De Paris, Paris, France; 7IPOPI Medical Advisory Board, ChairCorrespondence: Georgina L JonesDepartment of Psychology, School of Social Sciences, Leeds Beckett University, Calverley Building, City Campus, Leeds, UKTel +44 113 8125106Email g.l.jones@leedsbeckett.ac.ukPurpose: To describe the development and psychometric testing of a new questionnaire to measure the burden of immunoglobulin treatment (Ig) from the perspective of patients with primary immunodeficiencies (PID).Patients and Methods: An online, cross-sectional survey was administered to PID patients across 10 countries (nine European and Canada) who were receiving either intravenous (IVIg) or subcutaneous (SCIg) immunoglobulin therapy. The range and distribution of the responses (ie, levels of missing data, floor and ceiling effects), exploratory factor analysis (using factor loadings of 0.4 or greater) and measures of internal consistency reliability (ie, Cronbach’s alpha coefficient, inter-item and item-total correlations) were used to identify the domain and item pool.Results: In total, 472 patients completed the questionnaire, of which 395 were included in the analysis (32% underwent IVIg and 67% underwent SCIg). The final instrument contained 34 items across eight domains of treatment burden (time, organisation and planning, leisure and social, interpersonal relationships, employment and education, travel, consequences of treatment and emotional) and an additional Ig treatment burden global question at the end of the measure. All the scales achieved good internal reliability (Cronbach’s alpha coefficient ranged from 0.70 to 0.85) and, with the exception of one item exceeded the minimum threshold of 0.35 for item-total correlations. Treatment burden was lower than anticipated across the different treatment routes and countries, although overall was more burdensome for patients undergoing IVIg compared to SCIg treatment.Conclusion: The IgBoT-35 appears to be a reliable, patient-generated questionnaire and may help to identify more individualised and preferred therapies for the PID patient when used in clinical practice. A new survey with a sample of US patients is currently being undertaken to further establish its validity and conceptual model. The overall Ig burden of treatment scores appeared to be low. PID patient preferences are important to guide treatment decisions and ensuring patients receive the right treatment at the right time.Keywords: intravenous immunoglobulins, subcutaneous immunoglobulins, primary immunodeficiency, treatment burden, patient preference, quality of life

Background: Paediatric cutaneous granuloma with primary immunodeficiency (PID) is a rare condition. The physiopathology is unclear, and treatment is challenging. We report on 17 paediatric cases and review the literature. Objectives: To make dermatologists and dermatopathologists aware of the diagnostic value of skin granulomas in paediatric PID. Methods: We collected data on 17 patients with cutaneous granulomas and PID registered with us and also reviewed 33 cases from the literature. Results: Cutaneous granuloma was the presenting feature of the PID in 15 of the 50 collated cases. The lesions presented as red‐brownish nodules and infiltrated ulcerative plaques, predominantly on the face and limbs. Scleroderma‐like infiltration on a single limb was observed in 10% of the cases. The associated PID was ataxia‐telangiectasia (52%), combined immunodeficiency (24%), cartilage‐hair hypoplasia (6%) and other subtypes (18%). The granulomas were mostly sarcoidal, tuberculoid, palisaded or undefined subtypes. In some patients, several different histopathologic granulomatous patterns were found in the same biopsy. Some granulomas were associated with the presence of a vaccine strain of rubella virus. Conclusion: Cutaneous granulomas associated with a PID have a variable clinical presentation. A PID can be suspected when crusty, brownish lesions are found on the face or limbs. The concomitant presence of several histological subtypes in a single patient is suggestive of a PID. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which focuses on the study on ichthyosis as the dermatological phenotype associated with tetratricopeptide repeat domain 7A gene (Ttc7) mutations.

Optimal staging and evaluation of residual lesions of invasive fungal infections (IFIs) are major challenges in the immunocompromised host. Preliminary data have suggested that [18F]fluorodeoxyglucose ([18F]FDG) uptake may be observed in the course of active invasive fungal infections. The aim of this study was to assess the role of positron emission tomography with [18F]FDG ([18F]FDG-PET) in the diagnosis and staging of IFI. A prospective monocentric study evaluating [18F]FDG-PET in 30 consecutive adults and children with European Organization for Research and Treatment of Cancer/Mycoses Study Group probable or proven IFI was performed. Twenty males and ten females (median age, 45 years (range 6-75 years)) were enrolled. Twenty-six were immunocompromised, as follows: haematological malignancy (18) with allogeneic stem cell transplantation (16/18), solid tumour (three), solid organ transplantation (two), diabetes mellitus (two) and cystic fibrosis (one). IFIs were acute invasive aspergillosis (ten), chronic disseminated candidiasis (ten), zygomycosis (two), black grains eumycetoma (two), pulmonary Histoplasma capsulatum var. capsulatum histoplasmosis (two), and Phomopsis sp. osteoarthritis, Scedosporium apiospermum and Candida krusei spondylodiscitis, and acute pulmonary coccidioidomycosis in one case each. An increased uptake of [18F]FDG was observed in all areas previously identified by computed tomography and/ or magnetic resonance imaging to be involved by IFI. In 4/10 chronic disseminated candidiasis cases, [18F]FDG-PET revealed small splenic abscesses that were unapparent on the corresponding computed tomography scan. [18F]FDG uptake disappeared after 6 months of antifungal therapy in three patients with chronic disseminated candidiasis for whom the [18F]FDG-PET was performed to assess the evolution of the disease. [18F]FDG-PET could potentially be useful for the initial diagnosis and staging of IFI. Whether or not [18F]FDG-PET might be useful for assessing the optimal duration of IFI therapy should now be assessed in a specific prospective study. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Familial hemophagocytic lymphohistiocytosis is a genetically determined condition that is characterized by unremitting CD8 T lymphocyte and macrophage activation and leads to death in the absence of therapy. On the basis of the immunologic pathophysiology of familial hemophagocytic lymphohistiocytosis, we propose a therapy with a combination of antithymocyte globulins with corticosteroids, cyclosporin A, and intrathecal injections of methotrexate. METHODS: We retrospectively analyzed the outcome of antithymocyte globulin-based therapy that was performed in 38 consecutive patients who had familial hemophagocytic lymphohistiocytosis and were treated in a single center between 1991 and 2005. Overall, they received 45 courses of antithymocyte globulin (5-10 mg/kg per day for 5 days). RESULTS: This regimen was associated with infections after 10 of 45 courses of antithymocyte globulin. There were 6 events after 11 antithymocyte globulin courses given as second-line therapy against 4 after 34 antithymocyte globulin courses in patients who were treated primarily with antithymocyte globulin. Antithymocyte globulin administration led to rapid and complete response of familial hemophagocytic lymphohistiocytosis in 73% of cases, partial response in 24%, and no response only once. When hematopoietic stem cell transplantation was performed early after complete or partial response induction, it led to a high rate of cure, in 16 of 19 cases. Overall survival was 21 of 38 with 4 toxic deaths. CONCLUSION: Antithymocyte globulin based immunotherapy of familial hemophagocytic lymphohistiocytosis is efficient and carries an acceptable toxicity when used as a first treatment of familial hemophagocytic lymphohistiocytosis. [ABSTRACT FROM AUTHOR]

• Highly active antiretroviral therapy (HAART) coverage was > 98%. • HAART mainly included dolutegravir or protease inhibitors. • > 80% of individuals receiving HAART for > 6 months were virologically suppressed. • Virological success was more frequently achieved in international adoptees. To assess the outcome of HIV-infected individuals attending one of the largest French pediatric HIV centers in 2016–2017 and to compare the rates of antiretroviral coverage and virological suppression with the UNAIDS targets. The clinical and immuno-virological status of 163 HIV-1-infected children and adolescents attending Necker Hospital in Paris, France, were investigated. Virological suppression was defined as an HIV-1 viral load < 50 copies/mL for at least six months. All genotypic resistance tests performed since birth were analyzed. Most patients were born in Sub-Saharan African countries (41.7%) or in France (38.0%). Their median age was 14 years [IQR 7.3–17.0]. Although 33.7% of individuals had a history of AIDS-defining clinical event(s), 86.5% of children/adolescents were free from HIV-related symptoms at their most recent evaluation. Antiretroviral coverage was high (98.2%; mainly including one integrase inhibitor [42.3%] or one protease inhibitor [23.9%]). At the last visit, most patients (82.8%) had normal CD4 T lymphocytes counts (≥ 25%). Although 61.7% of antiretroviral-experienced children had resistance to ≥ 1 drug class and 9.2% had triple-class resistance, 80.3% of patients receiving antiretrovirals for ≥ 6 months (126/157) were virologically suppressed. International adoptees were more frequently virologically suppressed than other patients (96.0% versus 74.6%, P = 0.02). Antiretroviral coverage exceeded the second UNAIDS 90 target aimed at ending the AIDS epidemic. The rate of virological suppression, one of the highest reported in children in high-income countries, is approaching the third UNAIDS 90 target and the rate observed in French HIV-infected adults on antiretrovirals. [ABSTRACT FROM AUTHOR]

Background: Subcutaneous immunoglobulin (SCIg) replacement therapy is indicated for patients with hypogammaglobulinemia caused by primary (PID) and secondary immunodeficiencies (SID)., Objective: To compare healthcare resource utilization (HCRU) and related direct medical costs of patients in France treated with weekly conventional SCIg (cSCIg) vs monthly hyaluronidase-facilitated SCIg (fSCIg)., Methods: This retrospective study of Ig-naïve patients with PID or SID newly receiving a SCIg between 2016 and 2018, extracted from the French National Healthcare reimbursement database (SNDS), analyzed the SCIg-related HCRU and reimbursed costs generated from in-hospital (hospitalizations and SCIg doses) or at-home (nurse visits [NV] and pump provider visits [PPV], drug doses) SCIg administration., Results: Overall, 2,012 patients (PID:534; SID:1,478) were analyzed. The follow-up duration varied between 7.5 and 8.7 months according to sub-groups. Compared with fSCIg-treated patients, monthly mean rates of NV and PPV were respectively 2.5 and 3.1 times higher in PID, and 1.6 and 3.1 times higher in SID cSCIg-treated patients. Monthly mean rates for SCIg administration-related hospitalizations were lower overall, while their costs were 1.6 and 1.8 times higher for cSCIg than fSCIg subgroups, in PIDs and SIDs respectively; these results are due to more frequent hospitalizations with fSCIg being mainly shorter, without stayover. Total HCRU costs from the French NHI's perspective were estimated to be lower with fSCIg vs cSCIg, in PIDs and SIDs., Conclusion: This study provides real-world evidence of SCIg administration in a large French population. Patients with PID or SID treated with fSCIg had fewer at-home HCRU and lower overall costs for in-hospital or at-home SCIg administration compared with cSCIg-treated patients., Competing Interests: G. Lefèvre reports consulting or advisory fees from Shire-Takeda and research grant and travel and accommodation expenses from Octapharma, Shire-Takeda, CSL Behring, and LFB. I. Borget has no conflict of interest to declare. C. Maherzi, C. Lefèvre, A. Nucit, and M. Hennaoui are full-time employees of Takeda. A. Schmidt, H. Lennon, Benjamin. G, and Florent. D are full-time employees of HEVA, a consultancy company paid by Takeda to conduct data analyses. N. Mahlaoui reports consultancy and unrestricted financial support from the national reference center for PID (CEREDIH).” This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2025 Lefèvre et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: Conflicts of interest None disclosed.

Abstract: Predominantly antibody deficiencies have an estimated prevalence of >1 in 25 000. Their classical phenotype entails the association of autoimmune manifestations with increased susceptibility to infections. Up to 8% of these patients ultimately develop immune thrombocytopenic purpura (ITP). Reducing the risk for infections and considering nonimmunosuppressive treatments, such as thrombopoietin receptor agonists (TPO-RAs), are important considerations for these patients. This nationwide retrospective case series assessed the outcomes and safety of TPO-RAs as treatment for ITP in adults diagnosed with predominantly antibody deficiencies. Response and complete response to treatment were defined as platelet count reaching 30 × 109/L and 100 × 109/L, respectively. We analyzed data from 28 patients. The median follow-up time after introduction of the first TPO-RAs was 33 months (range, 2 weeks to 10.6 years). After 6 weeks of follow-up, response was achieved in 24 of the 28 patients (85.7%), and among those, 21 patients (75%) displayed a complete response. At the last available follow-up visit, only 7 patients (25%) needed second-line therapies for ITP, and among those, only 5 patients (17.9%) received immunosuppressants. Only 3 patients (10.7%) reported laboratory-confirmed hepatobiliary adverse events of light or mild severity and 3 patients (10.7%) reported thrombotic events. In conclusion, TPO-RAs seemed to be an effective and safe option of treatment in these case series. Our results suggest that eltrombopag or romiplostim should be considered as second-line therapy for ITP related to predominantly antibody deficiencies., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: Significant improvements in the prognosis for young patients with Primary Immunodeficiency Diseases (PID) and Autoinflammatory Disorders (AID), which together make up the majority of Inborn Errors of Immunity (IEI), have resulted in the need for optimisation of transition and transfer of care to adult services. Effective transition is crucial to improve health outcomes and treatment compliance among patients. Evaluations of existing transition programmes in European health centres identified the absence of disease-specific transition guidelines for PID and AID, as a challenge to the transition process. This research aimed to establish expert consensus statements for the transition of young patients with PID and AID to adult services., Methods: This project used the Delphi method to establish mutual agreement for the proposed recommendations. A draft set of statements was developed following a literature review of existing transition programmes. Then the ERN RITA Transition Working Group convened to review the drafted recommendations and develop them into a survey. This survey was circulated among healthcare professionals to determine consensus using a five-point Likert scale, with the level of agreement set to 80% or greater. Statements that did not reach consensus were revised by the Working Group and recirculated among respondents., Results: The initial survey received 93 responses from 68 centres across 23 countries, while the following survey outlining revised recommendations received 66 responses. The respondents agreed upon recommendations detailing the structure and administration of transition programmes, collaborative working with social systems, and contraindications to transfer of care., Conclusion: This paper sets out a comprehensive set of recommendations to optimise transitional care for PID and AID., Competing Interests: Declarations. Competing Interests: MC1 has received grant support from the National Institute of Health Research, the Royal Free Charity, Primary Immunodeficiency Association, PIDUK, and IDUK, financial support to attend symposia from CSL Behring, Grifols, BPL, and Biotest, a service development grant from CSL Behring, and honoraria for speaking engagements from BioCryst, Shire and Takeda; VD has received grant support from ZonMw for studies on immunogenicity of COVID-19 vaccines in IEI patients, equipment from Pharming NV for in vitro studies, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pharming NV, Takeda, CSL Behring, AstraZeneca, and Pfizer; LS is employed at the International Patient Organisation for Primary Immunodeficiencies (IPOPI) who regularly receive support from a broad range of companies involved in the manufacture of immunoglobulin therapies and the field of primary immunodeficiencies (updated list available on www.ipopi.org ), and has received grants from Takeda for an intervention during the ID Masterclass on 6–7 November 2023 in Rotterdam (The Netherlands) and for a virtual presentation on Strategic Advocacy, on 13 December 2023; SB1 and PS-P have received speaking fees from Sobi to co-chair two Nordic Autoinflammatory meetings. The rest of the authors declare that they have no relevant conflicts of interest., (© 2024. The Author(s).)

Prevention and treatment of infections are primary goals of treatment of children and adults with primary immune deficiencies due to decreased antibody production. Approaches to these goals include immunoglobulin replacement therapy, vaccination, and prophylactic treatment with antimicrobials. In this review, the infectious and non-infectious complications of antibody deficiencies will be discussed along with the limited number of studies that support the effective use of the available therapies and to drive the development of new therapies. Some illustrative case studies will be presented and the outlook for additional controlled clinical trials and potential for therapies driven by the underlying disease genetics will be considered., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abstract: Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21 (10%) with Hodgkin lymphoma and 8 (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI, 19.5-32.4). Germ line ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n = 110) were classified as having absent (n = 81) or residual (n = 29) ATM kinase activity. Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR = 0.362, 95% CI, 0.16-0.82; P = .009) and increased TRM (hazard ratio [HR] = 14.11, 95% CI, 1.36-146.31; P = .029). Patients with A-T and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Survival analysis (also referred to as time-to-event analysis) is the study of the time elapsed from a starting date to some event of interest. In practice, these analyses can be challenging and, if methodological errors are to be avoided, require the application of appropriate techniques. By using simulations and real-life data based on the French national registry of patients with primary immunodeficiencies (CEREDIH), we sought to highlight the basic elements that need to be handled correctly when performing the initial steps in a survival analysis. We focused on non-parametric methods to deal with right censoring, left truncation, competing risks, and recurrent events. Our simulations show that ignoring these aspects induces a bias in the results; we then explain how to analyze the data correctly in these situations using non-parametric methods. Rare disease registries are extremely valuable in medical research. We discuss the application of appropriate methods for the analysis of time-to-event from the CEREDIH registry. The objective of this tutorial article is to provide clinicians and healthcare professionals with better knowledge of the issues facing them when analyzing time-to-event data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Alligon, Mahlaoui and Bouaziz.)

Background: The contribution of genetic factors to the severity of adult hemophagocytic lymphohistiocytosis (HLHa) remains unclear., Objective: We sought to assess a potential link between HLHa outcomes and HLH-related gene variants., Methods: Clinical characteristics of 130 HLHa patients (age ≥ 18 years and HScore ≥ 169) and genotype of 8 HLH-related genes (LYST, PRF1, UNC13-D, STX11, STXBP2, RAB27A, XIAP, and SAP) were collected. A total of 34 variants found in only 6 genes were selected on the basis of their frequency and criteria predicted to impair protein function. Severity was defined by refractory disease to HLH treatment, death, or transfer to an intensive care unit., Results: HLHa-associated diseases (ADs) were neoplasia (n = 49 [37.7%]), autoimmune/inflammatory disease (n = 33 [25.4%]), or idiopathic when no AD was identified (n = 48 [36.9%]). Infectious events occurred in 76 (58.5%) patients and were equally distributed in all ADs. Severe and refractory HLHa were observed in 80 (61.5%) and 64 (49.2%) patients, respectively. HScore, age, sex ratio, AD, and infectious events showed no significant association with HLHa severity. Variants were identified in 71 alleles and were present in 56 (43.1%) patients. They were distributed as follows: 44 (34.4%), 9 (6.9%), and 3 (2.3%) patients carrying 1, 2, and 3 variant alleles, respectively. In a logistic regression model, only the number of variants was significantly associated with HLHa severity (1 vs 0: 3.86 [1.73-9.14], P = .0008; 2-3 vs 0: 29.4 [3.62-3810], P = .0002) and refractoriness (1 vs 0: 2.47 [1.17-5.34], P = .018; 2-3 vs 0: 13.2 [2.91-126.8], P = .0003)., Conclusions: HLH-related gene variants may be key components to the severity and refractoriness of HLHa., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs) 1,2 , conferring a predisposition to life-threatening COVID-19 pneumonia 3 . Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52 LOF /IκBδ GOF ). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52 LOF /IκBδ LOF ) or gain-of-function of p52 (hereafter, p52 GOF /IκBδ LOF ). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases., (© 2023. The Author(s).)