Bénédicte Neven

IRCCS Istituto G. Gaslini, Genova, Liguria, Italy

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Publications (179)

  • Brigitte Bader-Meunier · Bénédicte Neven
    [Show abstract] [Hide abstract] ABSTRACT: The monogenic autoinflammatory diseases (AIDs) are characterized by episodic or persistent, seemingly unprovoked inflammation. They are caused by abnormal activation of the cells that mediate innate immunity, resulting from dysregulation of the physiological alarm responses to foreign or endogenous danger signals. Many of the affected genes that have been initially reported are directly or indirectly involved in the regulation of the Interleukin-1 (IL-1) cytokine signaling pathway in AID. Typically, there is no evidence of high-titer autoantibodies or antigen-specific T lymphocytes. However, some recently reported AIDs enlarge the autoinflammation spectrum by having features of immunodeficiency and autoimmunity, and by implicating other cytokines than IL-1, such as interferon α. Molecular insights have provided the basis for therapeutic interventions, comprising mostly IL-1 inhibitors.
    Article · Dec 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Absent T cell immunity resulting in life-threatening infections provides a clear rationale for hematopoetic stem cell transplantation (HSCT) in patients with severe combined immunodeficiency (SCID). Combined immunodeficiencies (CID) and “atypical” SCID show reduced, not absent T-cell immunity. If associated with infections or autoimmunity, they represent profound CID (P-CID), for which outcome data are insufficient for unambiguous early transplant decisions.
    Article · Sep 2016
  • [Show abstract] [Hide abstract] ABSTRACT: 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.
    Article · Sep 2016 · Nature Immunology
  • M. Rodero · M. Frémond · L. Van Eyck · [...] · B. Neven
    Article · Sep 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Background. Early diagnosis and treatment are crucial in invasive fungal diseases (IFD). Serum (1-3)-β-d-glucan (BG) is believed to be an early IFD marker, but its diagnostic performance has been ambiguous, with insufficient data regarding sensitivity at the time of IFD diagnosis (TOD) and according to outcome. Whether its clinical utility is equivalent for all types of IFD remains unknown. Methods. We included 143 patients with proven or probable IFD (49 invasive candidiasis, 45 invasive aspergillosis [IA], and 49 rare IFD) and analyzed serum BG (Fungitell) at TOD and during treatment. Results. (1-3)-β-d-glucan was undetectable at TOD in 36% and 48% of patients with candidemia and IA, respectively; there was no correlation between negative BG results at TOD and patients' characteristics, localization of infection, or prior antifungal use. Nevertheless, patients with candidemia due to Candida albicans were more likely to test positive for BG at TOD (odds ratio = 25.4, P = .01) than patients infected with other Candida species. In 70% of the patients with a follow-up, BG negativation occurred in >1 month for candidemia and >3 months for IA. A slower BG decrease in patients with candidemia was associated with deep-seated localizations (P = .04). Thirty-nine percent of patients with rare IFD had undetectable BG at TOD; nonetheless, all patients with chronic subcutaneous IFD tested positive at TOD. Conclusions. Undetectable serum BG does not rule out an early IFD, when the clinical suspicion is high. After IFD diagnostic, kinetics of serum BG are difficult to relate to clinical outcome.
    Full-text Article · Jun 2016 · Open Forum Infectious Diseases
  • [Show abstract] [Hide abstract] ABSTRACT: LRBA (lipopolysaccharide-responsive and beige-like anchor protein) deficiency associates immune deficiency, lymphoproliferation, and various organ-specific autoimmunity. To date, prevalent symptoms are autoimmune cytopenias and enteropathy, and lymphocytic interstitial lung disease. In 2 siblings from a consanguineous family presenting with early onset polyautoimmunity, we presumed autosomal recessive inheritance and performed whole exome sequencing. We herein report the first case of early-onset, severe, chronic polyarthritis associated with LRBA deficiency. A novel 1bp insertion in the LRBA gene, abolishing protein expression, was identified in this family. Among the 2 brothers homozygous for LRBA mutation, one developed Evans syndrome and deceased at age 8.5 from complications of severe autoimmune thrombocytopenia. His brother, who carried the same homozygous LRBA mutation, early-onset erosive polyarthritis associated with chronic, bilateral, anterior uveitis and early onset type 1 diabetes mellitus. This report widens the clinical spectrum of LRBA deficiency and, in lights of the variable phenotypes described so far, prompts us to screen for this disease in patients with multiple autoimmune symptoms in the family, including severe, erosive, polyarticular juvenile arthritis.
    Article · Apr 2016 · Clinical Immunology
  • [Show abstract] [Hide abstract] ABSTRACT: Introduction: PFAPA syndrome is the most frequent periodic fever syndrome in non-Mediterranean patients. The pathogenesis is unclear and the treatment is purely symptomatic and not standardized. The aim of this study was to assess colchicine's efficacy as prophylactic treatment in PFAPA syndrome and to identify factors able to predict response to treatment. Methods: We performed a retrospective, multicentric, cohort study of PFAPA patients under colchicine prophylaxis. PFAPA diagnosis was established according to Feder's criteria. Medical records were reviewed and analyzed for demographic, clinical and laboratory data. We distinguished one responder's group, defined as patients who had no more or twice fewer crises under colchicine and another one of non-responders. Subgroup analyses were performed using non-parametric Mann-Whitney test for quantitative data and calculating odds ratio and confidence interval for qualitative data. Difference between the two groups was considered significant for P-value<0.05 or a confidence interval different from 1. Results-conclusion: Twenty children, 65% of whom were boys, were analyzed. Their mean age at disease onset was 2.3±1.5 years. Among the nine responder patients, five were MEFV (71%) heterozygotes: M694V mutation in four and V726A once. Heterozygous MEFV gene mutation tended to be more frequent in the responders group (71% versus 43%; OR=0.3 [0.03-2.7]). Non-responder patients had more chronic fatigue (82% versus 33%; OR=9 [1,14-71]) and had more oral aphtosis (82% versus 11%; OR=36 [1,7-141]) than the responders ones. Although not significant, colchicine treatment appeared more effective in patients with less complete PFAPA phenotype and MEFV heterozygosity.
    Article · Apr 2016 · Joint, bone, spine: revue du rhumatisme
  • Article · Apr 2016 · The Journal of allergy and clinical immunology
  • Elodie Elkaim · Benedicte Neven · Julie Bruneau · [...] · Sven Kracker
    [Show abstract] [Hide abstract] ABSTRACT: Activated PI3-kinase delta syndrome 2 (APDS2/PASLI-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α and p50α) of class IA PI3-kinases.
    Article · Apr 2016 · Journal of Allergy and Clinical Immunology
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    Full-text Article · Mar 2016
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    Alexandre Amin · Philippe Bourget · Bénédicte Neven · [...] · Stéphane Blanche
    [Show abstract] [Hide abstract] ABSTRACT: Abstract published in Blood;126 (23); page 4326; December 3, 2015 http://www.bloodjournal.org/content/126/23/4326.full.pdf Introduction: Busulfan (Bu) is recognized worldwide as the cornerstone for HSCT conditioning regimens (CR). It has a narrow therapeutic window (TW), and graft rejection or toxicity are related to Bu exposure. In very young children, Bu exhibits large pharmacokinetic (PK) variability, and its metabolic clearance is non-linearly related to body weight (BW). In this setting, Bu dosage is stratified according to BW and commonly monitored once after the 1st of 16 total 2-hr infusions and finally, 96-hr exposure to this major alkylating agent. Given the narrow TW of Bu in relation to clinical outcomes and to better understand its PK/PD relationship, it is important to attempt to optimize both the duration and the intensity of exposure to Bu in children undergoing HSCT, whatever their BW and pathologies. Study objective: To optimize Bu duration/intensity exposure in children undergoing HSCT, we studied the possible contribution of double TDM of IV Bu dosing in children receiving Bu-based CR for HSCT, by comparing the expected targeted values of exposure after performing 1 PK (1st dose, PK1) and finally 2 PK (1st dose, PK1, and 9th dose, PK2). Patients and methods: In this single-centre* prospective observational study (05/2012-07/2015), the PK of Bu was performed using the NONMEM® software; a one-compartment PK model suitably fitted the concentrations vs. time data. The PK of Bu was assessed on 6 plasma samples (3 samples/PK) using a validated LC-MS/MS method, with area under the concentration-time curve (AUC) calculation from the 1st and 9th doses. AUC calculated after the 1st dose and extrapolated to the 16th one were compared intraindividually by the non-parametric Wilcoxon signed-rank test to the sum of AUC1-6 with TDM1 applied from the 7th dose with or without TDM2 applied from the 13th or 14th dose; p≤0.025 was considered statistically significant. 63 patients (Pts) undergoing HSCT were included with median follow up of 14 months [1-39]. Median age was 17 months [1-193] and BW 11 kg [3-59]. Most Pts had non-malignant diseases, received allogenic HSCT and Bu-based CR in combination with Flu (morphometric, disease and CR details will be provided). *one of the 14 French Pediatric BMT units, involved in the therapeutic monitoring of IV Bu dosing in children undergoing HSCT. Results: 63 Pts (37 males (59%) and 26 females (41%)) were included. According to the EBMT-ESID recommendations, a median Bu posology of 1 mg/kg 4x/day for 4 days [0.6-1.3 mg/kg] was given. We demonstrate that: (a) estimated total AUC obtained from 2 PK differ significantly from those calculated after none (p=8.6455 E-7) or PK1 alone (p=7.2157 E-8), (b) double TDM allows achieving no difference between the expected AUC [20,706-23,180 mmol/min] desired by the medical staff in view of diseases vs. estimated AUC (p=0.5285). In 2/63 (3.2%) Pts, PK analysis did not lead to change Bu dosage. In 11/63 (18%) and 15/63(24%) Pts, dosage was modified after PK1 (TDM1 Group) or PK2 alone, respectively. In 35/63 (56%) Pts, changes were required twice, after the 2 PK (Double-TDM Group). The mean total dose of Bu were as follows: (a) a theoretical value of 220.80 mg (20.11 mg/kg) would have been given through 16 consecutive infusions without any TDM, (b) 199.35 mg (18.08 mg/kg) were administered in the TDM1 Group (16 doses), (c) 246.00 mg (19.46 mg/kg) were administered in the Double-TDM Group, avoiding the infusion of 24.00 mg of Bu vs. PK1 alone in these Pts. In 16/63 (25%) Pts, a decision of discontinuation of Bu exposure was taken. Indeed, the value that was desired by the medical staff was achieved after 13 (6 Pts) or 14 (10 Pts) doses; the mean total amounts of Bu were 273.22 mg (14.96 mg/kg) and 225.88 mg (16.16 mg/kg), respectively, vs. 336.27 mg (18.45 mg/kg) and 262.56 mg (18.60 mg/kg) theoretically after TDM1 alone. Conclusion: In this large paediatric cohort, the double TDM of Bu is a relevant and feasible option to better control Bu exposure and to potentially minimize the risk of overexposure. Correlations with toxicities (VOD, aGVH), CR, OS are under analysis. Based on these data, the double-TDM procedure is routinely applied in our centre.
    Full-text Conference Paper · Dec 2015
  • Benjamin Fournier · Julien Hogan · Bénédicte Neven
    Article · Dec 2015
  • Article · Dec 2015 · Annales de Dermatologie et de Vénéréologie
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    [Show abstract] [Hide abstract] ABSTRACT: Objective: Our aims were to validate the pediatric diagnostic criteria in a large international registry and to compare them with the performance of previous criteria for the diagnosis of familial Mediterranean fever (FMF). Methods: Pediatric patients with FMF from the Eurofever registry were used for the validation of the existing criteria. The other periodic fevers served as controls: mevalonate kinase deficiency (MKD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome (CAPS), aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA), and undefined periodic fever from the same registry. The performances of Tel Hashomer, Livneh, and the Yalcinkaya-Ozen criteria were assessed. Results: The FMF group included 339 patients. The control group consisted of 377 patients (53 TRAPS, 45 MKD, 32 CAPS, 160 PFAPA, 87 undefined periodic fevers). Patients with FMF were correctly diagnosed using the Yalcinkaya-Ozen criteria with a sensitivity rate of 87.4% and a specificity rate of 40.7%. On the other hand, Tel Hashomer and Livneh criteria displayed a sensitivity of 45.0 and 77.3%, respectively. Both of the latter criteria displayed a better specificity than the Yalcinkaya-Ozen criteria: 97.2 and 41.1% for the Tel Hashomer and Livneh criteria, respectively. The overall accuracy for the Yalcinkaya-Ozen criteria was 65 and 69.6% (using 2 and 3 criteria), respectively. Ethnicity and residence had no effect on the performance of the Yalcinkaya-Ozen criteria. Conclusion: The Yalcinkaya-Ozen criteria yielded a better sensitivity than the other criteria in this international cohort of patients and thus can be used as a tool for FMF diagnosis in pediatric patients from either the European or eastern Mediterranean region. However, the specificity was lower than the previously suggested adult criteria.
    Full-text Article · Nov 2015 · The Journal of Rheumatology
  • Alain Fischer · Luigi D. Notarangelo · Bénédicte Neven · [...] · Jennifer M. Puck
    [Show abstract] [Hide abstract] ABSTRACT: Severe combined immunodeficiencies (SCIDs) comprise a group of rare, monogenic diseases that are characterized by an early onset and a profound block in the development of T lymphocytes. Given that adaptive immunity is abrogated, patients with SCID are prone to recurrent infections caused by both non-opportunistic and opportunistic pathogens, leading to early death unless immunity can be restored. Several molecular defects causing SCIDs have been identified, along with many other defects causing profound, albeit incomplete, T cell immunodeficiencies; the latter are referred to as atypical SCIDs or combined immunodeficiencies. The pathophysiology of many of these conditions has now been characterized. Early, accurate and precise diagnosis combined with the ongoing implementation of newborn screening have enabled major advances in the care of infants with SCID, including better outcomes of allogeneic haematopoietic stem cell transplantation. Gene therapy is also becoming an effective option. Further advances and a progressive extension of the indications for gene therapy can be expected in the future. The assessment of long-term outcomes of patients with SCID is now a major challenge, with a view to evaluating the quality and sustainability of immune restoration, the risks of sequelae and the ability to relieve the non-haematopoietic syndromic manifestations that accompany some of these conditions.
    Article · Oct 2015
  • Article · Oct 2015 · Blood
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Obstructive sleep apnea syndrome (OSAS) is very common in mucopolysaccharidosis I (MPS I). Hematopoietic stem cell transplantation (HSCT) is the preferred treatment for patients with severe MPS I diagnosed early in life. The protective effect of HSCT on the development of long term OSAS is not known. Methods: Overnight polysomnography (PSG) and biomarker data were analyzed during the annual follow-up in consecutive MPS I patients treated with HSCT. Results: The data of 13 patients (6 boys) were analyzed. Median age at HSCT was 17 (range 14-19) months, median age at PSG was 9.0 (4.5-14.5) years, and median time elapsed since HSCT was 7.6 (2.4-13.2) years. A significant correlation was observed between time elapsed since HSCT and the apnea-hypopnea index (AHI, r(2)=0.493, p=+0.003) and the oxygen desaturation index (r(2)=0.424, p=+0.02). Patients older than 10years of age had a higher mean AHI (25.8/h vs 1.4/h, p=0.0008), a lower mean pulse oximetry (94.7% vs 97.2%, p=0.01) and a higher mean hypopnea index (18.8 vs 0.71/h, p=0.016) as compared to those younger than 10years of age. No correlation was observed between the AHI and the metabolic clearance, assessed by urine glycosaminoglycan (GAG) excretion and residual enzyme activity, although there was a positive trend for the urinary GAG/higher normal value for age ratio (p=0.09). Conclusion: HSCT does not offer long term protection against OSAS in MPS I with OSAS being documented in all patients after a time elapse since HSCT exceeding 10years. The potential benefit of additional enzyme replacement therapy needs to be assessed.
    Article · Oct 2015 · Molecular Genetics and Metabolism
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    Full-text Dataset · Sep 2015
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    [Show abstract] [Hide abstract] ABSTRACT: A boy with X-linked agammaglobulinemia experienced progressive global motor decline, cerebellar syndrome, and epilepsy. All standard polymerase chain reactions for neurotropic viruses were negative on cerebrospinal fluid and brain biopsy. Next-generation sequencing allowed fast identification of a new astrovirus strain (HAstV-VA1/HMO-C-PA), which led to tailor the patient's treatment, with encouraging clinical monitoring over 1 year.
    Full-text Article · Sep 2015 · Journal of the Pediatric Infectious Diseases Society
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    Full-text Article · Sep 2015 · Pediatric Rheumatology

Publication Stats

3k Citations


  • 2013
    • IRCCS Istituto G. Gaslini
      • Department of Experimental and Laboratory Medicine
      Genova, Liguria, Italy
    • Hôpital Universitaire Necker
      Lutetia Parisorum, Île-de-France, France
  • 2007-2013
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France