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- Israni, Muskan, et al.
(author)
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Current Transition Practice for Primary Immunodeficiencies and Autoinflammatory Diseases in Europe: a RITA-ERN Survey.
- 2023
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In: Journal of clinical immunology. - : Springer Science and Business Media LLC. - 0271-9142 .- 1573-2592. ; 43:1, s. 206-216
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Journal article (peer-reviewed)abstract
- 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.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).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.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 16-18years with transfer to the adult center occurring at a median age of 18-20years. 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.Transition services for children with IEI in Europe are available in many countries but lack standardized guidelines to promote best practice.
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2. |
- Maccari, Maria Elena, et al.
(author)
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Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity.
- 2023
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In: The Journal of allergy and clinical immunology. - 1097-6825. ; 152:4
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Journal article (peer-reviewed)abstract
- Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking.This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS.Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs.The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS.APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.
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3. |
- Manry, Jérémy, et al.
(author)
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The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.
- 2022
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:21
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Journal article (peer-reviewed)abstract
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
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4. |
- Matuozzo, Daniela, et al.
(author)
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Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.
- 2023
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In: Genome medicine. - 1756-994X. ; 15:1
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Journal article (peer-reviewed)abstract
- We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in~80% of cases.We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1×10-4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1×10-4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4×10-3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7×10-8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68×10-5).Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60years old.
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5. |
- Vallée, Tanja C, et al.
(author)
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Wiskott-Aldrich Syndrome: A study on 577 patients defining the genotype as a predictive biomarker for disease severity.
- 2024
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In: Blood. - 0006-4971 .- 1528-0020. ; 143:24, s. 2504-2516
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Journal article (peer-reviewed)abstract
- WAS is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% CI 78-87) at 15 years and 70% (61-80) at 30 years of age. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hotspot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared to 71% (62-81) and 48% (34-68) in patients with any other variant (class II; p<0.0001). The cumulative incidence rates of disease-related complications such as severe bleeding (p=0.007), life-threatening infection (p<0.0001), and autoimmunity (p=0.004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (p=0.6) was not different between classes I and II. This study represents the largest cohort of WAS patients studied so far. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of variant is a biomarker to predict the outcome for WAS patients.
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