Publications by authors named "Nizar Mahlaoui"

116 Publications

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

J Clin Immunol 2021 Sep 3. Epub 2021 Sep 3.

The Royal Hospitals & Queen's University, Belfast, UK.

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).
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http://dx.doi.org/10.1007/s10875-021-01090-8DOI Listing
September 2021

Toward a transitional care from childhood and adolescence to adulthood in surgical neurooncology? A lesson from the Necker-Enfants Malades and the Sainte-Anne Hospitals collaboration.

J Neurosurg Pediatr 2021 Jul 30:1-7. Epub 2021 Jul 30.

1Service de Neurochirurgie, GHU Paris-Hôpital Sainte-Anne, Paris.

Objective: Transitional care in surgical neurooncology is poorly studied. However, this period is pivotal, since it allows the patient to be empowered in his or her disease management. Here, the authors describe the experience of the Necker-Enfants Malades and the Sainte-Anne Hospital collaboration.

Methods: The mixed transitional consultations started in September 2019 in a dedicated space for transitional care, named the "La Suite" department, located in the Necker-Enfants Malades Hospital, Paris, France. The authors organized planned consultations to schedule the clinical and radiological follow-up in the adult neurosurgical department but also emergency consultations to manage tumor recurrence in young adult patients. Transitional care was performed jointly by pediatric and adult neurosurgeons who have developed clinical and research skills in the field of surgical neurooncology. Neuropathological analysis was performed by a neuropathologist who is specialized in pediatric and adult neurooncology.

Results: Fourteen patients benefited from a mixed transitional consultation. All of them accepted to start their management in an adult neurosurgical environment. Eleven patients (78.6%) for whom the disease was controlled benefited from a planned consultation. Three patients (21.4%) required rapid neurosurgical management for a tumor recurrence (n = 2) or for a new primary CNS tumor (n = 1) and benefited from an emergency consultation.

Conclusions: For adult patients harboring a brain tumor during childhood or adolescence, the authors suggest that neurosurgeons specialized in adult surgical neurooncology with a full knowledge in pediatric neurooncology will combine the required skills to optimize care management for these patients within a dedicated multidisciplinary organization framework.
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http://dx.doi.org/10.3171/2021.3.PEDS2141DOI Listing
July 2021

Impact of Early Versus Late Antiretroviral Treatment Initiation on Naive T Lymphocytes in HIV-1-Infected Children and Adolescents - The-ANRS-EP59-CLEAC Study.

Front Immunol 2021 22;12:662894. Epub 2021 Apr 22.

Unité Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Paris, France.

Background: The early initiation of antiretroviral therapy (ART) in HIV-1-infected infants reduces mortality and prevents early CD4 T-cell loss. However, the impact of early ART on the immune system has not been thoroughly investigated in children over five years of age or adolescents. Here, we describe the levels of naive CD4 and CD8 T lymphocytes (CD4/CD8T), reflecting the quality of immune reconstitution, as a function of the timing of ART initiation (early (<6 months) versus late (≥24 months of age)).

Methods: The ANRS-EP59-CLEAC study enrolled 27 children (5-12 years of age) and nine adolescents (13-17 years of age) in the early-treatment group, and 19 children (L-Ch) and 21 adolescents (L-Ado) in the late-treatment group. T lymphocytes were analyzed by flow cytometry and plasma markers were analyzed by ELISA. Linear regression analysis was performed with univariate and multivariate models.

Results: At the time of evaluation, all patients were on ART and had a good immunovirological status: 83% had HIV RNA loads below 50 copies/mL and the median CD4 T-cell count was 856 cells/µL (interquartile range: 685-1236 cells/µL). In children, early ART was associated with higher CD8T percentages (medians: 48.7% vs. 31.0%, = 0.001), and a marginally higher CD4T (61.2% vs. 53.1%, = 0.33). In adolescents, early ART was associated with low CD4T percentages and less differentiated memory CD8 T cells. CD4T and CD8T levels were inversely related to cellular activation and gut permeability.

Conclusion: In children and adolescents, the benefits of early ART for CD8T were clear after long-term ART. The impact of early ART on CD4T appears to be modest, because pediatric patients treated late respond to HIV-driven CD4 T-lymphocyte loss by the production of T cells in the thymus. Our data also suggest that current immune activation and/or gut permeability has a negative impact on T levels.

Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02674867.
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http://dx.doi.org/10.3389/fimmu.2021.662894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100053PMC
April 2021

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

J Allergy Clin Immunol 2021 Apr 23. Epub 2021 Apr 23.

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jaci.2021.04.015DOI Listing
April 2021

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.

J Exp Med 2021 07;218(7)

Pediatric Medicine Unit, University Hospital of Besançon, Besançon, France.

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
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http://dx.doi.org/10.1084/jem.20210554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077172PMC
July 2021

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

J Clin Immunol 2021 Aug 21;41(6):1266-1271. Epub 2021 Apr 21.

Necker-Pasteur Center for Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Université de Paris, 149 Rue de Sèvres, 75015, Paris, France.

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.
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http://dx.doi.org/10.1007/s10875-021-01043-1DOI Listing
August 2021

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

J Clin Immunol 2021 01 4;41(1):185-193. Epub 2020 Nov 4.

Department of Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, AP-HP, Paris, France.

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.
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http://dx.doi.org/10.1007/s10875-020-00901-8DOI Listing
January 2021

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

Pediatr Allergy Immunol 2021 04 22;32(3):576-585. Epub 2020 Nov 22.

Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Charité Universitätsmedizin -Berlin University Hospital Center, Berlin, Germany.

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.
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http://dx.doi.org/10.1111/pai.13402DOI Listing
April 2021

The Development of a New Questionnaire to Measure the Burden of Immunoglobulin Treatment in Patients with Primary Immunodeficiencies: The IgBoT-35.

Patient Prefer Adherence 2020 3;14:1567-1584. Epub 2020 Sep 3.

French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux De Paris, Paris, France.

Purpose: 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.
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http://dx.doi.org/10.2147/PPA.S234669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490431PMC
September 2020

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study.

J Allergy Clin Immunol 2021 Feb 24;147(2):520-531. Epub 2020 Sep 24.

Istituto Molecolare "A Nocivelli," Department of Experimental and Clinical Sciences, University of Brescia & Asst Spedali civili, Brescia, Italy.

Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense.

Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2.

Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI.

Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.

Conclusions: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jaci.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832563PMC
February 2021

Nocardiosis Associated with Primary Immunodeficiencies (Nocar-DIP): an International Retrospective Study and Literature Review.

J Clin Immunol 2020 11 12;40(8):1144-1155. Epub 2020 Sep 12.

Department of Infectious Diseases and Tropical Medicine, Centre d'Infectiologie Necker -Pasteur, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades University Hospital, Université de Paris, Paris, France.

Purpose: Nocardiosis is a life-threatening infectious disease. We aimed at describing nocardiosis in patients with primary immunodeficiency diseases (PID).

Methods: This international retrospective cohort included patients with PID and nocardiosis diagnosed and/or published from Jan 1, 2000, to Dec 31, 2016. To identify nocardiosis cases, we analyzed PID databases from the French National Reference Center for PID (Paris, France) and the National Institute of Health (NIH, United States of America) and we performed a literature review on PubMed.

Results: Forty-nine cases of nocardiosis associated with PID were included: median age at diagnosis of nocardiosis was 19 (0-56) years and most cases were observed among chronic granulomatous disease (CGD) patients (87.8%). Median time from symptoms to diagnosis of Nocardia infection was 20 (2-257) days. Most frequent clinical nocardiosis presentation was pneumonia (86.7%). Twelve-month mortality rate was 4.2%, and 11.9% of patients experienced a possible recurrence of infection. Nocardiosis more frequently led to the diagnosis of PID among non-CGD patients than in CGD patients. Non-CGD patients experienced more cerebral nocardiosis and more disseminated infections, but mortality and recurrence rates were similar. Highest incidences of nocardiosis among PID cohorts were observed among CGD patients (0.0057 and 0.0044 cases/patient-year in the USA and in France, respectively), followed by IL-12p40 deficiency.

Conclusions: Among 49 cases of nocardiosis associated with PID, most patients had CGD and lung involvement. Both mortality and recurrence rates were low.
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http://dx.doi.org/10.1007/s10875-020-00866-8DOI Listing
November 2020

Correction to: A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

J Clin Immunol 2020 Jul;40(5):786-787

Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker Pasteur, Hôpital Universitaire Necker-EnfantsMalades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.

The original version of the article contained error regarding the presentation of the institutional authors in the PDF and html versions.
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http://dx.doi.org/10.1007/s10875-020-00793-8DOI Listing
July 2020

Chronic Granulomatous Disease with the McLeod Phenotype: a French National Retrospective Case Series.

J Clin Immunol 2020 07 19;40(5):752-762. Epub 2020 Jun 19.

Pediatric Immuno-Hematology and Rheumatology Unit, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades University Hospital, Paris, France.

Background: X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype.

Methods: We retrospectively collected data from the medical records of 8 patients with CGD and the McLeod phenotype registered at the French National Reference Center for blood types.

Results: The median age at diagnosis of CGD was 1.2 years, the median age at diagnosis of the McLeod phenotype was 4.5 years, and the median length of follow-up was 15.2 years. Four patients displayed allo-immunization, with anti-KEL20 and anti-XK1 (formerly known as anti-KL) antibodies. Five of the 6 patients with available blood smears had acanthocytosis. Neuropsychiatric, muscle-related, and ocular manifestations were present in 4, 2, and 1 of the patients, respectively. Three of the 4 patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) are alive. Overall, 5 patients are alive, and 3 are alive and well.

Conclusion: This is the largest yet descriptive study of a series of patients with X-linked CGD and the McLeod phenotype. Although this disease combination is rare, the timely, accurate diagnosis of the McLeod phenotype is critical because of the serious post-transfusion complications. However, HSCT can be considered in these patients.
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http://dx.doi.org/10.1007/s10875-020-00791-wDOI Listing
July 2020

Devastating Gynecological Infections in Women with STAT3 Deficiency.

Clin Infect Dis 2020 10;71(7):e186-e190

Paris University, Necker-Pasteur Center for Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, University Hospital Institute (IHU)  Imagine, Paris, France.

We provide the first description of a series of 9 severe gynecological infections (mastitis and pelvic cellulitis) occurring in the French national cohort of women with STAT3 deficiency. Each episode had unique features in terms of clinical presentation, microbial documentation, location, treatment duration, and related persistent esthetic damage.
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http://dx.doi.org/10.1093/cid/ciaa020DOI Listing
October 2020

Primary immunodeficiency-related bronchiectasis in adults: comparison with bronchiectasis of other etiologies in a French reference center.

Respir Res 2019 Dec 4;20(1):275. Epub 2019 Dec 4.

Service de Pneumologie, Hôpital Foch, Suresnes, France.

Background: Bronchiectasis is a heterogeneous disease depending on etiology. It represents the most frequent non-infectious pulmonary complication of primary immunodeficiencies (PID). We investigated whether bronchiectasis associated with PID had a distinct course in comparison to bronchiectasis of other causes.

Methods: Retrospective single-center study of adult patients diagnosed with non-cystic fibrosis bronchiectasis with more than 5 years of follow-up and at least 4 pulmonary functional tests available at one year apart. They were divided into three groups: PID- related bronchiectasis, idiopathic/post infectious-related bronchiectasis and other causes of bronchiectasis. Respiratory functional data and clinical outcomes were compared.

Results: Of 329 patients with bronchiectasis diagnosed in Foch Hospital (Suresnes, France), 98 patients fulfilled the selected criteria (20 PID-related cases, 39 idiopathic or post-infectious cases, and 39 cases with other causes). Median time of follow-up was 9.5 years. Groups were similar concerning initial characteristics (female 70.4%, never smokers 59.2%, mild severity bronchiectasis according to the FACED score and median FEV1 at diagnosis 73.5% predicted values [Q1-Q3: 53.75-90.5]), except PID patients who were younger (median age of 51.5 vs 62 years, p = 0.02). Eighty-five percent of PID patients received immunoglobulin substitution (median trough level was measured at 10.5 g/dl [10;10.92]). Global median FEV1 annual decline was 25.03 ml/year [8.16;43.9] and 19.82 ml/year [16.08;48.02] in the PID patients group. Forty-five percent of patients had bacterial colonization, pneumoniae occurred in 56% of patients and median exacerbation annual rate was 0.8 [0.3-1.4]. Hemoptysis occurred in 31.6% of patients. Global mortality rate was 11.2%. We did not record any significant difference for all clinical and functional outcomes between patients with PID and other etiologies. The median decline in FEV1 was similar in the three groups.

Conclusions: The course of PID-related bronchiectasis was similar to bronchiectasis of other causes. Provided that patients receive immunoglobulin replacement, the course of PID-related bronchiectasis seems to be independent of the underlying immune disorder.
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http://dx.doi.org/10.1186/s12931-019-1242-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894192PMC
December 2019

Universal Newborn Screening for Severe Combined Immunodeficiency (SCID).

Front Pediatr 2019 18;7:373. Epub 2019 Sep 18.

Division of Hematology-Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States.

Patients with severe combined immunodeficiency (SCID) are born with profound deficiency of functional T-lymphocytes. Early detection and diagnosis would allow for prompt institution of isolation from infection and referral for definitive treatment with allogeneic hematopoietic stem cell transplantation. Universal newborn screening for SCID, using an assay to detect T-cell receptor excision circles (TREC) in dried blood spots (DBS), is now being performed in all states in the United States. In this review, we discuss the development and outcomes of TREC screening, and continued challenges to implementation.
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http://dx.doi.org/10.3389/fped.2019.00373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759820PMC
September 2019

A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

J Clin Immunol 2019 10 10;39(7):702-712. Epub 2019 Aug 10.

Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker Pasteur, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.

Purpose: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles.

Methods: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included.

Results: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04).

Conclusion: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.
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http://dx.doi.org/10.1007/s10875-019-00658-9DOI Listing
October 2019

The NEW ESID online database network.

Bioinformatics 2019 12;35(24):5367-5369

Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI).

Summary: Primary Immunodeficiencies (PIDs) belong to the group of rare diseases. The European Society for Immunodeficiencies (ESID) operates an international research database application for continuous long-term documentation of patient data. The system is a web application which runs in a standard browser. Therefore, the system is easy to access from any location. Technically, the system is based on Gails backed by MariaDB with high standard security features to comply with the demands of a modern research platform.

Availability And Implementation: The ESID Online Database is accessible via the official website: https://esid.org/Working-Parties/Registry-Working-Party/ESID-Registry. A demo system is available via: https://cci-esid-reg-demo-app.uniklinik-freiburg.de/EERS with user demouser and password Demo-2019.
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http://dx.doi.org/10.1093/bioinformatics/btz525DOI Listing
December 2019

Functional classification of ATM variants in ataxia-telangiectasia patients.

Hum Mutat 2019 10 17;40(10):1713-1730. Epub 2019 May 17.

CHU de Nancy, Service de Neurologie, Nancy, France.

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.
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http://dx.doi.org/10.1002/humu.23778DOI Listing
October 2019

Clinical and economic aspects of newborn screening for severe combined immunodeficiency: DEPISTREC study results.

Clin Immunol 2019 05 1;202:33-39. Epub 2019 Apr 1.

Laboratoire d'Immunologie, CHU Nantes, Nantes, France.

Purpose: Severe combined immunodeficiency (SCID) refers to a group of genetic disorders characterized by greatly compromised cellular and humoral immunity. Children with SCID are asymptomatic at birth, but they die from infections within the first months of life if not treated. Quantification of T-cell receptor excision circles is an extremely sensitive screening method for detecting newborns who may have SCID.The goal of the DEPISTREC study was to evaluate the feasibility of nationwide newborn screening for severe T-cell lymphopenia in France as well as its economic and clinical utility.

Methods: The test universally used for neonatal screening for SCID was the quantification of TRECs on Guthrie cards. We compared a group of 190,517 babies from 48 maternities across the country who underwent newborn SCID screening with a control group of 1.4 million babies out of whom 28 were diagnosed with SCID without such screening during the course of the study.

Results: Within the screening group, 62 babies were found to be lymphopenic, including three with SCID. The cost of screening ranged from 4.7€ to €8.15 per newborn. The average 18-month cost was €257,574 vs €204,697 in the control group.

Conclusions: In this large-scale study, we demonstrate that routine SCID screening is feasible and effective. This screening offers the additional benefit of aiding in the diagnosis of non-SCID lymphopenia. Economic evaluation allowed us to calculate the cost per test. Newborn screening may also prevent death by SCID before any curative treatment can be administered. The difference in cost between screened and control children could not be ascertained because of the very low numbers and death of one of the children tested.
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http://dx.doi.org/10.1016/j.clim.2019.03.012DOI Listing
May 2019

Spectrum of Pulmonary Aspergillosis in Hyper-IgE Syndrome with Autosomal-Dominant STAT3 Deficiency.

J Allergy Clin Immunol Pract 2019 Jul - Aug;7(6):1986-1995.e3. Epub 2019 Mar 13.

Service de Maladies Infectieuses et Tropicales, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (APHP), Université Paris Descartes, Paris, France; Institut Pasteur, CNRS, Centre National de Référence Mycoses Invasives et Antifongiques, Unité de Mycologie Moléculaire, Paris, France. Electronic address:

Background: Autosomal-dominant signal transducer and activator of transcription 3 (STAT3) deficiency predisposes to recurrent bacterial pneumonia, complicated by bronchiectasis and cavitations. Aspergillosis is a major cause of morbidity in these patients. However, its diagnosis, classification, and treatment are challenging.

Objective: We aimed to assess the prevalence and describe the clinical, mycological, and radiological presentation and related therapy and outcome of Aspergillus infections of the respiratory tract in the STAT3-deficient patients of the National French cohort.

Methods: We performed a retrospective study of all pulmonary aspergillosis cases in STAT3-deficient patients (n = 74). Clinical and mycological data were collected up to October 2015 and imaging was centralized.

Results: Twenty-one episodes of pulmonary aspergillosis in 13 (17.5%) STAT3-deficient patients were identified. The median age at first episode was 13 years (interquartile range, 10-26 years). Ninety percent of patients had previous bronchiectasis or cavitations. Infections were classified as follows: 5 single aspergilloma, 9 chronic cavity pulmonary aspergillosis, 5 allergic bronchopulmonary aspergillosis-like disease, and 2 mixed forms of concomitant allergic bronchopulmonary aspergillosis-like disease and chronic cavity pulmonary aspergillosis. No invasive aspergillosis cases were identified. Aspergillus species were isolated in 71% of episodes and anti-Aspergillus antibodies in 93%. Eleven episodes were breakthrough infections. Antifungal treatment was prolonged, with a median of 13 months, and 6 patients (7 episodes) required surgery, with a high rate of postsurgical complications. One patient died and 6 had a relapse.

Conclusions: Chronic and allergic forms of aspergillosis occurred in 17.5% of STAT3-deficient patients, mostly in lung cavities. Almost half had recurrences, despite prolonged antifungal treatment and/or surgery.
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http://dx.doi.org/10.1016/j.jaip.2019.02.041DOI Listing
September 2020

Genotype-phenotype correlations in ataxia telangiectasia patients with c.3576G>A and c.8147T>C mutations.

J Med Genet 2019 05 28;56(5):308-316. Epub 2019 Feb 28.

Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: Ataxia telangiectasia (A-T) is a neurodegenerative disorder. While patients with classic A-T generally die in their 20s, some patients with variant A-T, who have residual ataxia-telangiectasia mutated (ATM) kinase activity, have a milder phenotype. We noticed two commonly occurring mutations that appeared to be associated with prolonged survival and decided to study patients carrying one of these mutations.

Methods: Data were retrospectively collected from the Dutch, Italian, German and French A-T cohorts. To supplement these data, we searched the literature for patients with identical genotypes.

Results: This study included 35 patients who were homozygous or compound heterozygous for the c.3576G>A; p.(Ser1135_Lys1192del58) mutation and 24 patients who were compound heterozygous for the c.8147T>C; p.(Val2716Ala) mutation. Compared with 51 patients with classic A-T from the Dutch cohort, patients with c.3576G>A had a longer survival and were less likely to develop cancer, respiratory disease or immunodeficiency. This was also true for patients with c.8147T>C, who additionally became wheelchair users later in life and had fewer telangiectasias. The oldest patient with A-T reported so far was a 78-year-old patient who was compound heterozygous for c.8147T>C. ATM kinase activity was demonstrated in cells from all patients tested with the c.8147T>C mutant protein and only at a low level in some patients with c.3576G>A.

Conclusion: Compared with classic A-T, the presence of c.3576G>A results in a milder classic phenotype. Patients with c.8147T>C have a variant phenotype with prolonged survival, which in exceptional cases may approach a near-normal lifespan.
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http://dx.doi.org/10.1136/jmedgenet-2018-105635DOI Listing
May 2019

Lymphoproliferative disease in patients with Wiskott-Aldrich syndrome: Analysis of the French Registry of Primary Immunodeficiencies.

J Allergy Clin Immunol 2019 06 20;143(6):2311-2315.e7. Epub 2019 Feb 20.

Clinical Hematology, Necker University Hospital, AP-HP, Paris, France; Paris Descartes University, Sorbonne Paris Cité University, Imagine Institute, Paris, France; INSERM UMR1163 & CNRS URL 8254, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutical implications, Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker University Hospital, AP-HP, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.01.046DOI Listing
June 2019

The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity.

J Allergy Clin Immunol Pract 2019 Jul - Aug;7(6):1763-1770. Epub 2019 Feb 15.

Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Patient registries are instrumental for clinical research in rare diseases. They help to achieve a sufficient sample size for epidemiological and clinical research and to assess the feasibility of clinical trials. The European Society for Immunodeficiencies (ESID) registry currently comprises information on more than 25,000 patients with inborn errors of immunity (IEI). The prerequisite of a patient to be included into the ESID registry is an IEI either defined by a defect in a gene included in the disease classification of the international union of immunological societies, or verified by applying clinical criteria. Because a relevant number of patients, including those with common variable immunodeficiency (CVID), representing the largest group of patients in the registry, remain without a genetic diagnosis, consensus on classification of these patients is mandatory. Here, we present clinical criteria for a large number of IEI that were designed in expert panels with an external review. They were implemented for novel entries and verification of existing data sets from 2014, yielding a substantial refinement. For instance, 8% of adults and 27% of children with CVID (176 of 1704 patients) were reclassified to 22 different immunodeficiencies, illustrating progress in genetics, but also the previous lack of standardized disease definitions. Importantly, apart from registry purposes, the clinical criteria are also helpful to support treatment decisions in the absence of a genetic diagnosis or in patients with variants of unknown significance.
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http://dx.doi.org/10.1016/j.jaip.2019.02.004DOI Listing
September 2020

Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study.

J Allergy Clin Immunol 2019 06 17;143(6):2238-2253. Epub 2019 Jan 17.

Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.

Background: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT).

Objective: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics.

Methods: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure.

Results: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%.

Conclusion: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.
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http://dx.doi.org/10.1016/j.jaci.2018.12.1010DOI Listing
June 2019

Genetic diagnosis of primary immunodeficiencies: A survey of the French national registry.

J Allergy Clin Immunol 2019 04 9;143(4):1646-1649.e10. Epub 2019 Jan 9.

French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Pediatric Immuno-Haematology and Rheumatology Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France; Collège de France, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.12.994DOI Listing
April 2019

Progressive Multifocal Leukoencephalopathy in Primary Immunodeficiencies.

J Clin Immunol 2019 01 14;39(1):55-64. Epub 2018 Dec 14.

Department of Haematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, France et Université Paris Descartes, 149 rue de Sèvres, 75015, Paris, France.

Purpose: Progressive multifocal leukoencephalopathy (PML) is a rare but severe demyelinating disease caused by the polyomavirus JC (JCV) in immunocompromised patients. We report a series of patients with primary immune deficiencies (PIDs) who developed PML.

Methods: Retrospective observational study including PID patients with PML. Clinical, immunological, imaging features, and outcome are provided for each patient.

Results: Eleven unrelated patients with PIDs developed PML. PIDs were characterized by a wide range of syndromic or genetically defined defects, mostly with combined B and T cell impairment. Genetic diagnosis was made in 7 patients. Before the development of PML, 10 patients had recurrent infections, 7 had autoimmune and/or inflammatory manifestations, and 3 had a history of malignancies. Immunologic investigations showed CD4 lymphopenia (median 265, range 50-344) in all cases. Six patients received immunosuppressive therapy in the year before PML onset, including prolonged steroid therapy in 3 cases, rituximab in 5 cases, anti-TNF-α therapy, and azathioprine in 1 case each. Despite various treatments, all but 1 patient died after a median of 8 months following PML diagnosis.

Conclusion: PML is a rare but fatal complication of PIDs. Many cases are secondary to immunosuppressive therapy warranting careful evaluation before initiation subsequent immunosuppression during PIDs.
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http://dx.doi.org/10.1007/s10875-018-0578-8DOI Listing
January 2019
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