Evidence of innate lymphoid cell redundancy in humans.

Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common γ-chain cytokine receptor subunit IL-2Rγ or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved.

ATM germline pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies.

Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene. Children with A-T are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order 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 eight (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% 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). Germline 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 (HR=14.11, 95% CI 1.36-146.31; p=.029). Patients with A-T and leukemia/lymphoma may benefit from de-escalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

Allogeneic stem cell transplantation compared to conservative management in adults with inborn errors of immunity.

Allogeneic hematopoietic stem cell transplantation (alloSCT) is curative for severe inborn errors of immunity (IEIs), with recent data suggesting alloSCT in adulthood is safe and effective in selected patients. However, questions remain regarding the indications for and optimal timing of transplant. We retrospectively compared outcomes of transplanted vs matched nontransplanted adults with severe IEIs. Seventy-nine patients (aged ≥ 15 years) underwent alloSCT between 2008 and 2018 for IEIs such as chronic granulomatous disease (n = 20) and various combined immune deficiencies (n = 59). A cohort of nontransplanted patients from the French Centre de Référence Déficits Immunitaires Héréditaires registry was identified blindly for case-control analysis, with ≤3 matched controls per index patient, without replacement. The nontransplanted patients were matched for birth decade, age at last review greater than index patient age at alloSCT, chronic granulomatous disease or combined immune deficiencies, and autoimmune/lymphoproliferative complications. A total of 281 patients were included (79 transplanted, 202 nontransplanted). Median age at transplant was 21 years. Transplant indications were mainly lymphoproliferative disease (n = 23) or colitis (n = 15). Median follow-up was 4.8 years (interquartile range, 2.5-7.2). One-year transplant-related mortality rate was 13%. Estimated disease-free survival at 5 years was higher in transplanted patients (58% vs 33%; P = .007). Nontransplanted patients had an ongoing risk of severe events, with an increased mean cumulative number of recurrent events compared with transplanted patients. Sensitivity analyses removing patients with common variable immune deficiency and their matched transplanted patients confirm these results. AlloSCT prevents progressive morbidity associated with IEIs in adults, which may outweigh the negative impact of transplant-related mortality.

Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants.

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.

Protecting children and adults with primary antibody deficiencies against common and emergent pathogens and non-infectious complications.

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.

Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.

Pregnancy in primary immunodeficiency diseases: The PREPI study.

BACKGROUND: Primary immunodeficiencies (PID) are a heterogeneous group of rare inborn immunity defects. As management has greatly improved, morbidity and mortality are reduced in this population, while our knowledge on pregnancy's unfolding and outcome remains scarce. OBJECTIVE: We conducted a retrospective monocentric study to study pregnancy outcomes in women with PID. METHODS: The study cohort consisted of women over 18 included in the national registry for PID (CEREDIH), living in the greater Paris area, reporting ≥1 pregnancy. Data were collected through a standardized questionnaire and medical records. We analyzed PID features, pregnancy course and outcome, and neonatal features (NCT04581460). RESULTS: We studied 93 women with PID (27 combined immunodeficiencies, 51 predominantly antibody deficiencies, and 15 innate immunodeficiencies) and their 222 pregnancies (67, 119, and 36 in each group, respectively). One hundred fifty-four (69%) of 222 pregnancies led to 157 live births, including 4 severe preterm births (3%), in the range of pregnancy outcome in the French general population. In a multivariate model, poor obstetrical outcome (fetal loss or pregnancy termination) was associated with history of severe infection (adjusted odds ratio 0.28, 95% confidence interval 0.11-0.67, P = .005). Only 59% pregnancies were led with optimal anti-infective prophylaxis; severe infections were reported in only 2 pregnancies (1%). One infant died during the neonatal period. CONCLUSION: Pregnancy is achievable in women with a wide group of PID. Prematurity is increased and history of severe infection is associated with significant increase of fetal loss/pregnancy termination. Adjustment of care during pregnancy needs to be better delivered.

Late-onset enteric virus infection associated with hepatitis (EVAH) in transplanted SCID patients.

BACKGROUND: Allogenic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are potentially curative treatments for severe combined immunodeficiency (SCID). Late-onset posttreatment manifestations (such as persistent hepatitis) are not uncommon. OBJECTIVE: We sought to characterize the prevalence and pathophysiology of persistent hepatitis in transplanted SCID patients (SCIDH+) and to evaluate risk factors and treatments. METHODS: We used various techniques (including pathology assessments, metagenomics, single-cell transcriptomics, and cytometry by time of flight) to perform an in-depth study of different tissues from patients in the SCIDH+ group and corresponding asymptomatic similarly transplanted SCID patients without hepatitis (SCIDH-). RESULTS: Eleven patients developed persistent hepatitis (median of 6 years after HSCT or GT). This condition was associated with the chronic detection of enteric viruses (human Aichi virus, norovirus, and sapovirus) in liver and/or stools, which were not found in stools from the SCIDH- group (n = 12). Multiomics analysis identified an expansion of effector memory CD8+ T cells with high type I and II interferon signatures. Hepatitis was associated with absence of myeloablation during conditioning, split chimerism, and defective B-cell function, representing 25% of the 44 patients with SCID having these characteristics. Partially myeloablative retransplantation or GT of patients with this condition (which we have named as "enteric virus infection associated with hepatitis") led to the reconstitution of T- and B-cell immunity and remission of hepatitis in 5 patients, concomitantly with viral clearance. CONCLUSIONS: Enteric virus infection associated with hepatitis is related to chronic enteric viral infection and immune dysregulation and is an important risk for transplanted SCID patients with defective B-cell function.

Facilitated Subcutaneous Immunoglobulin Treatment in Patients with Immunodeficiencies: the FIGARO Study.

PURPOSE: The FIGARO study aims to provide insights on real-world utilization and tolerability of facilitated subcutaneous immunoglobulin (fSCIG) for primary immunodeficiency disease (PID) or secondary immunodeficiency disease (SID). METHODS: This prospective, multicenter, observational study, evaluated medical records, charts, and diaries of patients who had received at least 1 fSCIG infusion for PID or SID. Data were analyzed by cohort (PID, SID) and age groups (pediatric [< 18 years], adult [18-64 years], older adult [≥ 65 years]). Patients were followed up to 36 months. RESULTS: The study enrolled 156 patients: 15 pediatric, 120 adult, 21 older-adult. Twelve-month follow-up data were available for 128 patients. fSCIG was mainly prescribed for PID among patients aged < 65 years and for SID among older adults. At inclusion, 75.6% received their fSCIG infusion at home, and 78.7% self-administered. Adults were more likely to receive their initial infusion at home and self-administer (81.7% and 86.6%, respectively) than pediatric patients (53.3% each) and older adults (57.1% and 52.4%, respectively). At 12 months, the proportion of patients infusing at home and self-administering increased to 85.8% and 88.2%. Regardless of age, most patients self-administered the full fSCIG dose at home every 3-4 weeks and required a single infusion site. The tolerability profile was consistent with previous pivotal trials. Acute severe bacterial infections occurred in 0%-9.1% of patients during follow-up visits (full cohort). CONCLUSIONS: FIGARO confirms the feasibility, tolerability, and good infection control of fSCIG in PID and SID patients across the age spectrum in both the home-setting and medical facility. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03054181.

Current Transition Practice for Primary Immunodeficiencies and Autoinflammatory Diseases in Europe: a RITA-ERN Survey.

BACKGROUND: Due to the absence of curative treatments for inborn errors of immunity (IEI), children born with IEI require long-term follow-up for disease manifestations and related complications that occur over the lifespan. Effective transition from pediatric to adult services is known to significantly improve adherence to treatment and long-term outcomes. It is currently not known what transition services are available for young people with IEI in Europe. OBJECTIVE: To understand the prevalence and practice of transition services in Europe for young people with IEI, encompassing both primary immunodeficiencies (PID) and systemic autoinflammatory disorders (AID). METHODS: A survey was generated by the European Reference Network on immunodeficiency, autoinflammatory, and autoimmune diseases Transition Working Group and electronically circulated, through professional networks, to pediatric centers across Europe looking after children with IEI. RESULTS: Seventy-six responses were received from 52 centers, in 45 cities across 17 different countries. All services transitioned patients to adult services, mainly to specialist PID or AID centers, typically transferring up to ten patients to adult care each year. The transition process started at a median age of 16-18 years with transfer to the adult center occurring at a median age of 18-20 years. 75% of PID and 68% of AID centers held at least one joint appointment with pediatric and adult services prior to the transfer of care. Approximately 75% of PID and AID services reported having a defined transition process, but few centers reported national disease-specific transition guidelines to refer to. CONCLUSIONS: Transition services for children with IEI in Europe are available in many countries but lack standardized guidelines to promote best practice.

B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen.

Neutrophils use immunoglobulins to clear antigen, but their role in immunoglobulin production is unknown. Here we identified neutrophils around the marginal zone (MZ) of the spleen, a B cell area specialized in T cell-independent immunoglobulin responses to circulating antigen. Neutrophils colonized peri-MZ areas after postnatal mucosal colonization by microbes and enhanced their B cell-helper function after receiving reprogramming signals, including interleukin 10 (IL-10), from splenic sinusoidal endothelial cells. Splenic neutrophils induced immunoglobulin class switching, somatic hypermutation and antibody production by activating MZ B cells through a mechanism that involved the cytokines BAFF, APRIL and IL-21. Neutropenic patients had fewer and hypomutated MZ B cells and a lower abundance of preimmune immunoglobulins to T cell-independent antigens, which indicates that neutrophils generate an innate layer of antimicrobial immunoglobulin defense by interacting with MZ B cells.

An appraisal of the frequency and severity of noninfectious manifestations in primary immunodeficiencies: A study of a national retrospective cohort of 1375 patients over 10 years.

BACKGROUND: Noninfectious manifestations-allergy, autoimmunity/inflammation, lymphoproliferation, and malignancies-are known to exist in many primary immunodeficiency diseases (PID) and to participate in prognosis. OBJECTIVE: To obtain a global view on their occurrence, we retrieved data from a retrospective cohort of 1375 patients included in the French National Reference Center for Primary Immune Deficiencies (CEREDIH) for whom we had a 10-year follow-up since inclusion in the registry. METHODS: These patients were followed for 10 years (2009-2018) by specialized centers in university hospitals. This study showed that 20.1% of patients without prior curative therapy (n = 1163) developed at least 1 manifestation (event) encompassing 277 events. RESULTS: Autoimmune/inflammatory events (n = 138) and malignancies (n = 85) affected all age classes and virtually all PID diagnostic groups. They were associated with a risk of death that occurred in 195 patients (14.2%) and were found to be causal in 43% of cases. Malignancies (odds ratio, 5.62; 95% confidence interval, 3.66-8.62) and autoimmunity (odds ratio, 1.9; 95% confidence interval, 1.27-2.84) were clearly identified as risk factors for lethality. Patients who underwent curative therapy (mostly allogeneic hematopoietic stem cell transplantation, with a few cases of gene therapy or thymus transplantation) before the 10-year study period (n = 212) had comparatively reduced but still detectable clinical manifestations (n = 16) leading to death in 9.4% of them. CONCLUSION: This study points to the frequency and severity of noninfectious manifestations in various PID groups across all age groups. These results warrant further prospective analysis to better assess their consequences and to adapt therapy, notably indication of curative therapy.

Hematopoietic cell transplantation in severe combined immunodeficiency: The SCETIDE 2006-2014 European cohort.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. OBJECTIVE: We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. METHODS: HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. RESULTS: Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P < .001). The 2-year event-free survival (EFS) was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (P < .001). Genetic subgroups did not differ in 2-year OS (P = .1) and EFS (P = .073). In multivariate analysis, pretransplantation infections and use of MMRDs were associated with less favorable OS and EFS. With a median follow-up of 6.2 years (range, 2.0-11.8 years), 73 of 152 patients in the IR cohort were alive and well without Ig dependency. IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor-deficient SCID, myeloablative conditioning, matched donor HSCT, and naive CD4 T lymphocytes >0.5 × 10e3/µL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. CONCLUSION: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.

Inborn errors of immunity caused by defects in the DNA damage response pathways: Importance of minimizing treatment-related genotoxicity.

Several primary immunodeficiencies are caused by defects in the general DNA repair machinery as exemplified by the T-B- radiosensitive SCID condition owing to impaired resolution of programmed DNA double-strand breaks introduced by RAG1/2 during V(D)J recombination. The genome instability generally associated with these conditions results in an increased propensity to develop malignancies requiring genotoxic-based anti-cancer treatments. Moreover, the extent of immune deficiency often calls for hematopoietic stem cell transplantation as a definitive treatment, also requiring genotoxic-based conditioning regimen prior to transplantation. In both cases, the underlying general DNA repair defect may result in catastrophic iatrogenic consequences. It is, therefore, of paramount importance to assess the functionality of the DNA repair apparatus prior to any genotoxic treatment when the exact molecular cause of the disease is unknown. For this purpose, two simple assays can be used on patients derived peripheral blood lymphocytes: (1) the PROMIDISα biomarker, based on the next-generation sequencing analysis of the TCRα repertoire, will highlight specific signatures of DNA repair deficiencies; (2) direct analysis of the sensitivity of peripheral lymphocytes to ionizing radiation will formally identify patients at risk to develop toxicity toward genotoxic-based treatments.

Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations.

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations. OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts. METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered. RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years. CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Infections in Patients with Chronic Granulomatous Disease Treated with Tumor Necrosis Factor Alpha Blockers for Inflammatory Complications.

PURPOSE: Management of inflammatory complications of chronic granulomatous disease (CGD) is challenging. The aim of this study was to assess safety, with a focus on infections, and effectiveness of tumor necrosis factor alpha (TNF-α) blockers in CGD patients. METHODS: A retrospective, single-center cohort study of CGD patients treated by anti-TNF-α agents at Necker-Enfants Malades University Hospital (Paris, France) and registered at the French National Reference Center for Primary Immunodeficiencies (CEREDIH). RESULTS: Between 2006 and 2019, 14 (X-linked: n = 10, 71.4%; autosomal-recessive: n = 4, 28.6%) CGD patients with gastrointestinal (n = 12, 85.7%), pulmonary (n = 10, 71.4%), cutaneous (n = 3, 21.4%), and/or genitourinary (n = 2, 14.3%) inflammatory manifestations received one or more doses of infliximab because of steroid-dependent (n = 7, 50%), refractory (n = 4, 28.6%) inflammatory disease or as first-line drug (n = 2, 14.3%; missing data, n = 1). All patients received adequate antimicrobial prophylaxis. Infliximab achieved complete (n = 2, 14.3%) or partial (n = 9, 64.3%) response in 11 (78.6%) patients. Seven (50%) patients were switched to adalimumab. During anti-TNF-α treatment, 11 infections (pneumonia, adenitis, invasive candidiasis, each n = 2; intra-abdominal abscess, bacteremic salmonellosis, Pseudomonas aeruginosa-related folliculitis, cat-scratch disease, proven pulmonary mucormycosis, each n = 1) occurred in 7 (50%) patients. All infectious complications had a favorable outcome. Anti-TNF-α treatment was definitively stopped because of infection in two patients. Nine (64.3%) patients finally underwent hematopoietic stem cell transplantation. No death occurred during follow-up. CONCLUSIONS: Anti-TNF-α treatment could improve the outcome of severe inflammatory complications in CGD patients, but increases their risk of infections. We suggest that anti-TNF-α treatment might be of short-term benefit in selected CGD patients with severe inflammatory complications awaiting hematopoietic stem cell transplantation.

Current Spectrum of Infections in Patients with X-Linked Agammaglobulinemia.

Outcome of patients with X-linked agammaglobulinemia (XLA) has improved with the widespread use of immunoglobulin replacement therapy (IgRT). There are few data on the spectrum of infections experienced by patients undergoing IgRT. We carried out a retrospective cross-sectional analysis of the records of XLA patients seen at Necker-Enfants Malades Hospital, Paris. For each infection, we evaluated infection site, microbial etiology, antibiotic prophylaxis, immunosuppressive treatment, IgRT route, and last known IgG trough level. Sixty patients were included, who cumulated a follow-up of 1470 patient-years. We recorded 188 infections, including 97 after initiation of IgRT. The rate of infection was highest before IgRT (0.66 vs. 0.06 per person-year (ppy), p < 0.001) and was higher after the age of 16 compared to before (0.14 vs. 0.05 ppy, p = 0.048). It was similar for patients receiving intravenous or subcutaneous Ig (0.09 vs 0.05 ppy, p = 0.54). The lungs and gastrointestinal tract accounted for 71% of infection sites. Forty-six (47%) infections occurred in patients receiving antibiotic prophylaxis. Sixteen (16.5%) infections occurred in patients receiving immunosuppressive therapy, which more frequently occurred after age 16 (35% vs. 2.4%, p < 0.001). The median IgG trough level prior to all infections was 8.4 g/L. Almost half (44.3%) of infections occurred with prior IgG trough levels > 8 g/L, and 16/97 (16.7%) in patients with trough levels > 10 g/L. Infection remains a significant issue in patients with XLA undergoing IgRT despite adequate IgG trough levels. Chronic inflammatory manifestations of X-linked agammaglobulinemia and immunosuppressive therapies may be significant drivers of infection during adulthood.

Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia.

Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).

Outcome of chronic granulomatous disease - Conventional treatment vs stem cell transplantation.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) can cure chronic granulomatous disease (CGD), but it remains debated whether all conventionally treated CGD patients benefit from HSCT. METHODS: We retrospectively analyzed 104 conventionally treated CGD patients, of whom 50 patients underwent HSCT. RESULTS: On conventional treatment, seven patients (13%) died after a median time of 16.2 years (interquartile range [IQR] 7.0-18.0). Survival without severe complications was 10 ± 3% (mean ± SD) at the age of 20 years; 85% of patients developed at least one infection, 76% one non-infectious inflammation. After HSCT, 44 patients (88%) were alive at a median follow-up of 2.3 years (IQR 0.8-4.9): Six patients (12%) died from infections. Survival after HSCT was significantly better for patients transplanted ≤8 years (96 ± 4%) or for patients without active complications at HSCT (100%). Eight patients suffered from graft failure (16%); six (12%) developed acute graft-vs-host disease requiring systemic treatment. Conventionally treated patients developed events that required medical attention at a median frequency of 1.7 (IQR 0.8-3.2) events per year vs 0 (IQR 0.0-0.5) in patients beyond the first year post-HSCT. While most conventionally treated CGD patients failed to thrive, catch-up growth after HSCT in surviving patients reached the individual percentiles at the age of diagnosis of CGD. CONCLUSION: Chronic granulomatous disease patients undergoing HSCT until 8 years of age show excellent survival, but young children need more intense conditioning to avoid graft rejection. Risks and benefits of HSCT for adolescents and adults must still be weighed carefully.