You are here

  • Home
  • Archive
  • Volume 8, Issue 1
  • COVID-19 infection among patients with autoinflammatory diseases: a study on 117 French patients compared with 1545 from the French RMD COVID-19 cohort: COVIMAI – the French cohort study of SARS-CoV-2 infection in patient with systemic autoinflammatory d…

Article Text

Article menu

Download PDFPDF

Autoinflammatory disorders
Short report
COVID-19 infection among patients with autoinflammatory diseases: a study on 117 French patients compared with 1545 from the French RMD COVID-19 cohort: COVIMAI – the French cohort study of SARS-CoV-2 infection in patient with systemic autoinflammatory diseases
  1. Rim Bourguiba1,
  2. Maeva Kyheng2,
  3. Isabelle Koné-Paut3,
  4. Diane Rouzaud4,
  5. Jerome Avouac5,
  6. Mathilde Devaux6,
  7. Nassim Ait Abdallah7,
  8. Bruno Fautrel8,
  9. Nicole Ferreira-Maldent9,
  10. Vincent Langlois10,
  11. Emmanuel Ledoult11,
  12. Hubert Nielly12,
  13. Viviane Queyrel13,
  14. Jérémie Sellam14,
  15. Nathalie Tieulie15,
  16. Pascal Chazerain16,
  17. Philippe Evon17,
  18. Julien Labreuche18,
  19. Léa Savey1,
  20. Veronique Hentgen19,
  21. Gilles Grateau1 and
  22. Sophie Georgin-lavialle1
  23. FAI2R/SFR/SNFMI/SOFREMIP/CRI/IMIDIATE consortium and contributors
    1. 1Sorbonne University, AP-HP, Tenon Hospital, Internal Medicine Department, 4 rue de la Chine, 75020, Paris, France; national Reference center for autoinflammatory diseases and AA amyloidosis (CEREMAIA), Tenon Hospital, Paris, France
    2. 2Univ. Lille, CHU Lille, ULR 2694 - METRICS : évaluation des technologies de santé et des pratiques médicales, F-59000 Lille, France, CHU Lille, Département de Biostatistiques, F-59000 Lille, France, Université de Lille, Lille, France
    3. 3Service de Rhumatologie Pédiatrique, Centre de Référence des Maladies Auto-Inflammatoires de l’enfant, Hôpital Bicêtre, AP HP, Université Paris Sud, Bicètre, France
    4. 4Department of internal medicine, Bichat hospital, Paris, France, Bichat Hospital, Paris, France
    5. 5Université de Paris, Service de Rhumatologie, Hôpital Cochin, AP-HP.CUP, Paris, France, Hôpital Cochin, Paris, France
    6. 6CHI Poissy-Saint-Germain-en-Laye, Saint-Germain-en-Laye, France
    7. 7Unité de Médecine Interne: Maladies Auto-immunes et Pathologie Vasculaire (UF 04), Centre de Reference des Maladies autoimmunes systemiques Rares d’Ile-de-France MATHEC, AP-HP, Hopital Saint-Louis, Paris, France, Université de Paris, IRSL, Recherche clinique appliquée à l’hématologie, EA, Paris, France, Hôpital Saint-Louis, Paris, France
    8. 8Sorbonne Université – Assistance Publique Hôpitaux de Paris, Pitié Salpêtrière University Hospital, Dept of Rhumatology, Reference Center for Rare Diseases CEREMAIA (ERN RITA), Paris, France. ii) Pierre Louis Institute of Epidemiology and Public Health, INSERM UMRS 1136, PEPITES team, Assistance Publique-Hopitaux de Paris, Paris, France
    9. 9Internal Medecine, CHU Tours, Tours, France
    10. 10GH du Havre-Hôpital Jacques Monod, Le Havre, France
    11. 11Service de Médecine Interne, Centre de Référence des Maladies Auto-immunes et Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), CHU Lille, F-59000 Lille, France 2- Inserm, U1286, F-59000 Lille, France, CHRU de Lille, Lille, France
    12. 12Hôpital d'Instructions des Armées Bégin, Saint Mande, France
    13. 13Rheumatology department, CHU de Nice, Nice, France
    14. 14Rheumatology, INSERM UMRS_938, Sorbonnes Université UPMC Univ Paris 06, St-Antoine Hospital, DHU i2B, Paris, France
    15. 15Service de Rhumatologie, Hôpital Pasteur, Centre Hospitalier Universitaire, Université de Nice Sophia Antipolis, Nice, France
    16. 16Internal Medicine and Rheumatology, Groupe Hospitalier Diaconesses Croix Saint Simon, Paris, France
    17. 17Internal Medecine department, CH de Bar-Le-Duc, Bar-le-Duc, France
    18. 18Univ Lille, Lille, France
    19. 19CeReMAI-Departement of Pediatrics Department of general pediatrics, Andre Mignot hospital, Versailles, CEREMAIA, France, Hôpital Mignot, Le Chesnay, France
    1. Correspondence to Dr Sophie Georgin-lavialle; sophie.georgin-lavialle{at}aphp.fr

    Abstract

    Objective There is little known about SARS-CoV-2 infection in patients with systemic autoinflammatory disease (SAID). This study aimed to describe epidemiological features associated with severe disease form and death. Mortality between patients with and without SAID hospitalised for SARS-CoV-2 infection was compared.

    Methods A national multicentric prospective cohort study was conducted from the French Rheumatic and Musculoskeletal Diseases (RMD) COVID-19 cohort. Patients with SAID were matched with patients with non-SAID on age±7 years, gender and number of comorbidities to consider important confounding factors. Impact of SAID on severity of SARS-CoV-2 infection was analysed using multinomial logistic regression for severity in three classes (mild, moderate and severe with mild status as reference). Fine-Gray regression model for length of hospital stay and binomial logistic regression model for risk of death at 30 days.

    Results We identified 117 patients with SAID (sex ratio 0.84, 17 children) and compared them with 1545 patients with non-autoinflammatory immune-mediated inflammatory disorders (non-SAID). 67 patients had a monogenic SAID (64 with familial Mediterranean fever). Other SAIDs were Behçet’ disease (n=21), undifferentiated SAID (n=16), adult-onset Still disease (n=9) and systemic-onset juvenile idiopathic arthritis (n=5). Ten adults developed severe form (8.6%). Six patients died. All children had a benign disease. After matching on age±7 years, sex and number of comorbidities, no significant difference between the two groups in length of stay and the severity of infection was noted.

    Conclusion As identified in the whole French RMD COVID-19 cohort, patients with SAID on corticosteroids and with multiple comorbidities are prone to develop more severe COVID-19 forms.

    • COVID-19
    • autoimmune diseases
    • biological therapy
    • familial Mediterranean fever
    http://creativecommons.org/licenses/by-nc/4.0/

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

    https://doi.org/10.1136/rmdopen-2021-002063

    Statistics from Altmetric.com

      Request Permissions

      If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

      WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?

      • As reported in the French RMD cohort, patients with inflammatory RMD are more likely to develop severe form when they have multiple comorbidities or they were under steroids over 10 mg/day.

      WHAT DOES THIS STUDY ADD?

      • Children display more likely mild signs of COVID-19 with excellent prognosis.

      • When comparing patients with systemic autoinflammatory disease (SAID) and non-SAID after matching on age, sex and number of comorbidities, no significant difference in severity of COVID-19 between the two groups was found.

      • Associated comorbidities are more important than the underlying SAID, for developing a severe form or dying.

      • Colchicine or biotherapies against Interleukine IL-6 or IL-1 do not seem to be associated with high risk of severe form of COVID-19.

      HOW MIGHT THIS IMPACT ON CLINICAL PRACTICE OR FUTURE DEVELOPMENTS?

      • In addition to common risk factors for severe COVID-19, patients with SAID on steroids should be considered of high risk for severe form.

      Introduction

      The pandemic related to SARS-CoV-2 infection has emerged since late 2019; Europe was affected in March 2020.1 The virus caused many deaths in all countries. Patients with immune disorders were a concern of developing a severe form of COVID-19 especially those with systemic autoinflammatory diseases (SAIDs) in which, the innate immune system is improperly activated. The most frequent SAID worldwide is familial Mediterranean fever (FMF); three other monogenic diseases are also classified in the historical hereditary recurrent fevers: cryopyrin-associated periodic syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). Others are polygenic such as Behçet’s disease and Still disease. It was initially difficult to predict if patients with SAID might develop an excessive inflammatory response when they contracted the virus.

      To our knowledge, except few studies on FMF2 and one on Behçet’s disease,3–7 little is known about both the risk factors and the diseases at risk of contracting a severe form of COVID-19.

      We took the opportunity of the French national prospective registry collecting cases of COVID-19 in patients with immune diseases including SAIDs.8 Our main question was to determine whether patients with SAIDs had an over-risk of severe form and death. Our secondary objectives were to assess whether the risk correlated to either the disease itself, the existence of comorbidities or the exposure to anti-inflammatory and immunosuppressive medications. In addition, we compared risk factors of patients with SAIDs with those with other inflammatory disorders included in the French RMD COVID-19 cohort.8

      Patients and methods

      Study design and patients

      This multicentre, national cohort study (COVIMAI) analysed data from the French RMD COVID-19 cohort, which has been previously described.8 Briefly, the French RMD COVID-19 cohort included paediatric and adult patients with confirmed inflammatory rheumatic and musculoskeletal diseases and highly suspected or a confirmed diagnosis of COVID-19. SAIDs were defined by the international criteria and included the four historical monogenic SAIDs (FMF, TRAPS, CAPS, MKD), undifferentiated SAIDs,9 adult onset Still diseases (AOSDs) and Behçet’s disease. We assessed and classified the severity of COVID-19 according to the level of care needed for each patient. Mild COVID-19 required ambulatory care; moderate COVID-19 required non-intensive hospital treatment and severe COVID-19 required admission to an intensive care unit or led to death. The study started on March 2020 and was done in compliance with the research methodology MR-004 (research not involving humans connected to studies and evaluations in the field of health), received legal approval from Lille University Hospital ULR 2694-METRICS (Lille, France) and was declared to the Commission Nationale de l’Informatique et des Libertés (reference DEC20-107).

      Data collection

      Cases of patients with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19 were reported retrospectively. The individual data regarding diagnosis and specific ongoing treatments for inflammatory rheumatic and musculoskeletal diseases were captured from physicians via an electronic Case Report Form available online through a secured access. Data collected from patients’ medical records have previously been described elsewhere.8 All participants were followed until the worst COVID-19 outcome at the time of dataset lock. The present study was conducted on the database locked in 15 April 2021.

      Outcomes

      The primary outcome was to compare the severity of COVID-19 in patients with SAID with patients with non-SAID included in the French RMD COVID-19 cohort. The secondary outcomes were to compare frequency of deaths and duration of hospital stay in patients with or without SAID.

      Statistical analysis

      Quantitative variables were expressed as means (SD) in the case of normal distribution or medians (IQR) otherwise. Categorical variables were expressed as numbers (%). Normality of distributions was assessed using histograms and the Shapiro-Wilk test.

      To consider important confounding factors, patients with SAIDs were matched with patients with non-SAID from the French RMD COVID-19 cohort on age±7 years, gender and number of comorbidities.

      Impact of SAID on severity of SARS-CoV-2 infection was analysed, before and after matching, using multinomial logistic regression for severity in three classes (mild, moderate and severe with mild status as reference), Fine-Gray regression model for length of hospital stay (with death as competing event) and binomial logistic regression model (with link logit) for risk of death at 30 days.

      All statistical tests were done at the two-tailed α level of 0·05. Data were analysed using SAS V.9.4 (SAS Institute).

      This study is registered with ClinicalTrials.gov, NCT04353609.

      Results

      We included 117 patients with SAID and compared them with 1545 patients with non-SAID. The disease distribution of the 117 patients with SAID was respectively: monogenic SAID (n=67; 57.3%) including FMF (n=64) and CAPS (n=3), Behçet’s disease (n=21; 17.9%), undifferentiated SAID (n=15; 12.8%), AOSD (n=9; 7.7%) and Systemic Juvenile Idiopathic Arthritis (sJIA) (n=5; 4.3%) (online supplemental table 1). Seventeen children had COVID-19 at a median age of 12 years ranging from 3 to 16 years. Ten cases occurred during the first wave (March, April 2020) and seven cases from the second wave (September 2020 onwards). The diseases were FMF (n=7; 41%), PFAPA (n=2), CAPS (n=2), sJIA (n=3), unclassified SAID (n=2) and DADA2 (n=1). Symptoms of COVID-19 were benign in children; none had risk factors for severe COVID-19; seven patients were on colchicine; others were receiving biotherapies (anti-IL-1: n=4; anti-IL-6: n=1; anti TNF: n=2) (online supplemental table 2).

      The mean age in each group was 38.7±20.5 for SAID versus 54.7±17.5 for non-SAID. Among the SAIDs, there was a clear predominance of adults (85.5%) with most patients aged between 18 and 54 years (63.2%). The proportion of women was 54.7% in the SAID cohort and 67.2% in the non-SAID cohort. The proportion of patients with SAID with at least one known comorbidity of severe SARS-CoV-2 infection was 35%. Most patients were on colchicine (61.5%) in line with the high proportion of FMF among patients with SAID (table 1). In the SAID group, at least one comorbidity was noted in 35% versus 57% in the non-SAID group. Colchicine and anti-IL-1 biotherapy were, respectively, 61.5% and 10.3% in the monogenic SAID group, whereas in the non-SAID group, systemic corticosteroids under 10 mg/day (38.4%), methotrexate (35, 9%), anti-TNF (30.4%) and anti-IL-6R (3, 6%) were taken (table 1).

      View this table:
      Table 1

      In the SAID group, 90 patients (76.9%) displayed mild form, 17 patients (14.5%) with moderate form and 10 patients (8.6%) with severe form. When comparing the severity between the two groups, the difference was closed to the significant level (with mild form as reference p=0.064), patients with SAID displayed a significantly lower proportion of moderate forms (14.5% vs 22.5%, OR 0.56, 95% CI 0.33 to 0.95). Severe forms were not different between the two groups (8.6% vs 11.2%, OR 0.66, 95% CI 0.34 to 1.29). The days of hospitalisation were similar between the two groups (HR 0.83, 95% CI 0.51 to 1.36) and there were no differences on the death rate (OR 1.00 (95% CI 0.43 to 2.35)). After matching on age±7 years, sex and number of comorbidities, we could not find any significant difference between the two groups (table 2).

      View this table:
      Table 2

      Concerning the patients who died in the SAID group: two had severe FMF on colchicine and anakinra, one of them had AA amyloidosis; two had Behçet’s disease, including a 35-year-old patient; one elderly patient had Still’s disease and one had unclassified SAID. Half were on corticosteroids >10 mg/day. All had numerous comorbidities and 2/3 were over 65 years old (tables 3 and 4).

      View this table:
      Table 3
      View this table:
      Table 4

      Discussion

      Patients of all ages with SAID can contract COVID-19 and without surprise, more frequently those with FMF, because it is the most frequent monogenic SAID worldwide and those with Behçet’s disease, the most frequent polygenic SAID. Interestingly, neither patients with TRAPS nor MKD developed COVID-19 in this series, but some cases might be unreported.

      Patients with SAID were younger compared with patients with non-SAID, and all children with SAID displayed a benign form of COVID-19 with excellent prognosis. Therefore, after matching with sex and age, there is no difference in the infection outcome: severe forms and deaths, between the two groups. Thus, the weight of comorbidities appeared more important than the underlying disease; indeed 41/117 (35%) patients with COVID-19+SAID displayed one or more comorbidities.

      Colchicine, taken as a daily treatment by 72/117 patients with SAID (61.5%), was not associated with the severity of infection. Even though the number of patients is relatively low, there was no signal on a higher sensitivity to COVID-19 of patients receiving biotherapies targeting either TNF (n=4) or IL-1 (n=8). Interestingly, three patients receiving daily steroids >10 mg/day died including two patients with Behçet’s disease. Chronic oral steroid intake has previously been reported to be associated with more severe COVID-197.

      Conclusion

      In conclusion, COVID-19 affected more likely patients with FMF in our cohort. Severe forms occurred more frequently among patients with multiple comorbidities, and chronic intake of oral steroids.

      Ethics statements

      Patient consent for publication

      Ethics approval

      This study involves human participants and was approved by CNIL DEC20-107. Participants gave informed consent to participate in the study before taking part.

      References

      1. ↵
        1. Chen G,
        2. Wu D,
        3. Guo W, et al
        . Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020;130:2620–9.doi:10.1172/JCI137244
        OpenUrlCrossRefPubMed
      2. ↵
        1. Kharouf F,
        2. Ishay Y,
        3. Kenig A, et al
        . Incidence and course of COVID-19 hospitalizations among patients with familial Mediterranean fever. Rheumatology 2021;60:keab577.doi:10.1093/rheumatology/keab577
      3. ↵
        1. Bourguiba R,
        2. Delplanque M,
        3. Vinit C, et al
        . Clinical course of COVID-19 in a cohort of 342 familial Mediterranean fever patients with a long-term treatment by colchicine in a French endemic area. Ann Rheum Dis 2020. doi:doi:10.1136/annrheumdis-2020-218707. [Epub ahead of print: 02 Nov 2020].pmid:http://www.ncbi.nlm.nih.gov/pubmed/33139307
      4. ↵
        1. Güven SC,
        2. Erden A,
        3. Karakaş Özlem, et al
        . COVID-19 outcomes in patients with familial Mediterranean fever: a retrospective cohort study. Rheumatol Int 2021;41:715–9.doi:10.1007/s00296-021-04812-8pmid:http://www.ncbi.nlm.nih.gov/pubmed/33611656
        OpenUrlPubMed
      5. ↵
        1. Nas K,
        2. Eryilmaz N,
        3. Geyik MF, et al
        . COVID-19 in patients with familial Mediterranean fever treated with colchicine: case based review. Rheumatol Int 2021;41:811–7.doi:10.1007/s00296-021-04809-3pmid:http://www.ncbi.nlm.nih.gov/pubmed/33611657
        OpenUrlPubMed
      6. ↵
        1. Stella A,
        2. Lamkanfi M,
        3. Portincasa P
        . Familial Mediterranean fever and COVID-19: friends or Foes? Front Immunol 2020;11:574593.doi:10.3389/fimmu.2020.574593pmid:http://www.ncbi.nlm.nih.gov/pubmed/33072117
        OpenUrlPubMed
      7. ↵
        1. Zouboulis CC,
        2. van Laar JAM,
        3. Schirmer M, et al
        . Adamantiades-Behçet's disease (Behçet's disease) and COVID-19. J Eur Acad Dermatol Venereol 2021;35:e541–3.doi:10.1111/jdv.17325pmid:http://www.ncbi.nlm.nih.gov/pubmed/33914986
        OpenUrlPubMed
      8. ↵
        1. FAI2R /SFR/SNFMI/SOFREMIP/CRI/IMIDIATE consortium and contributors
        . Severity of COVID-19 and survival in patients with rheumatic and inflammatory diseases: data from the French RMD COVID-19 cohort of 694 patients. Ann Rheum Dis 2021;80:527–38.doi:10.1136/annrheumdis-2020-218310
        OpenUrlAbstract/FREE Full Text
      9. ↵
        1. Papa R,
        2. Penco F,
        3. Volpi S, et al
        . Syndrome of undifferentiated recurrent fever (surf): an emerging group of autoinflammatory recurrent fevers. J Clin Med 2021;10:10.doi:10.3390/jcm10091963pmid:http://www.ncbi.nlm.nih.gov/pubmed/34063710
        OpenUrlPubMed

      Supplementary materials

      • Supplementary Data

        This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

      Footnotes

      • Collaborators FAI2R /SFR/SNFMI/SOFREMIP/CRI/IMIDIATE Consortium And Contributors: Florence Aeschlimann, Paris; Christian Agard, Nantes; Nassim, Ait-Abdallah Paris; Jean-David Albert, Rennes; Didier Alcaix, Le Havre; Jean-Sébastien Allain, Rennes; Yannick Allanore, Paris; Zahir Amoura, Paris; Adamah Amouzougan, Aint-Priest-En-Jarez; Emma Andre, Paris; Anaïs Arbault, Dijon; Jean-Benoît Arlet Paris; Laurent Arnaud, Strasbourg; Denis Arniaud, Marseille; Herliette Arty-Hue, Gap; Lucie Atlan, Amboise; Alexandra Audemard-Verger Tours; Christine Audoin-Pajot, Toulouse; Victor Audren, Paris; Gilles Avenel, Rouen; Jérôme Avouac, Paris; Maxime Bach-Bunner, Colmar; Hélène Bacquet-Deschryver, Dieppe; Brigitte Bader-Meunier, Paris; Nathalie Balandraud, Marseille; Jean-Charles Balblanc, Trevenans; Claire Ballot-Schmit, Besancon; Stéphane Bally, Chambery; Frédéric Banal, Saint-Mande; Béatrice Banneville, Paris; Pierre Barbery, Lisieux; Audrey Barrelet, Jossigny; Géraldine Bart, Rennes; André Basch, Caluire-Et-Cuire; Vincent Baumier, Clermont-Ferrand; Guillaume Bayer, Quincy-Sous-Senart; Sophie Bayle, Avignon; Catherine Beauvais, Paris; Rudie Beinat, Bordeaux; Véronique Belin, Thonon-Les-Bains; Rakiba Belkhir, Kremlin-Bicetre; Alexandre Belot, Bron; Aurélie Beltai, Narbonne; Ruben Benainous, Bobigny; Mohammed Benammar, Saint-Quentin; Chahinez Bendahmane, Pontoise; Mathilde Benhamou, Versailles; Ygal Benhamou, Rouen; Ahmed Benmansour, Chateauroux; Pascal Bennet, Bois-Guillaume; Brigitte Bernoux-Manat, Rennes; Elise Berthet, Clermont-Ferrand; Sabine Berthier, Dijon; Olivia Berthoud, Rennes; Emilie Berthoux, Lyon; Ewa Bertolini, annecy; Adrien Bigot, Tours; Aurélia Bisson-Vaivre, Castres, Gilles Blaison, Colmar; Gilles Bolla, Cannes; Olivier Bonidan, Agen; Christine Bonnet, Limoges; Raphaël Borie, Paris; Charlotte Borocco, Paris; Marie Bossert, Trevenans; Laurence Boudou, Saint-Chamond; Françoise Bouhour, Bron; Kévin Bouiller, Besancon; Laurence Bouillet, Grenoble; Bastien Bouldoires, Colmar; Thomas Bourree, Cholet; Ines Boussen, Paris; Karima Boussoualim, Saint-Priest-En-Jarez; Eric Bouvard, Paris; Brondino Regine, Pennes-Mirabeau; Pierre Buchlin, Mulhouse; Laurence Cabantous, Merignac; Patrice Cacoub, Paris; Simon Cadiou, Rennes; Alaine Cantagrel, Toulouse; Didier Caplanne, Bayonne; Aurélia Carbasse, Montpellier; Maurizio Carteni, Saint-Pierre-De-Coutances; Brice Castel, Tarbes; Pascal Cathebras, Saint-Priest-En-Jarez; Hervé Caumont, Troyes; Audrey Cayot-Bouillet, Dijon; Annalisa Celant, Metz; Aurélie Chaffin, Avranches; Benjamin Chaigne, Paris; Benoît Chaillous, Herbiers; Romuald Champy, Ecuelles; Agnès Charcot, Paris; Pierre Charles, Paris; Isabelle Charlot-Lambrecht, Reims; Caroline Charpin, Marseille; Emmanuel Chatelus, Strasbourg; Bernard Chaudier, Marseille; Pascal Chazerain, Paris; Pascale Chertok, Argenteuil; Xavier Chevalier, Creteil; Maxime Chevreau, Aix-Les-Bains; Emilie Chotard, Paris; Delphine Chu Miow Lin, Tours; Pascal Claudepierre, Creteil; Gaëlle Clavel, Paris; Cyril Clavel-Osorio, Saint-Martin; Marine Clay, Grenoble; Johanna Clet, Bordeaux; Fleur Cohen, Paris; Gregory Cohen, Avignon; Marie-Eve Colette-Cedoz, Bourgoin-Jallieu; Nived Collercandy, Tours; Antoine Colombey; Saint-Nazaire; Chloé Comarmond, Paris; Bernard Combe, Montpellier; Céline Comparon, Bobigny; Elodie Constant, Valence; Arnaud Constantin, Toulouse; Pascal Coquerelle, Beuvry; Justine Corli, Douai; Clémence Corre, Vannes; Nathalie Costedoat-Chalumeau, Paris; Marion Couderc, Lermont-Ferrand; Marie Couret, Bourg-En-Bresse, Natacha Courvoisier, Nogent-Sur-Marne; Fabienne Coury-Lucas, Pierre-Benite; Cécile Coutarel, Clermont-Ferrand; Fabrice Coutier, Vesoul; Richard Damade, Chartres; Laurence Daver-Malaterre, Marseille; Claire De Moreuil, Brest; Marijke Decrock, Perpignan; Michel Delahousse, Suresnes; Emilie Delattre Barrois, Quingey; Christophe Deligny, Fort-De-France; Delphine Denarie, Roanne; Amélie Denis, Le Mans; Camille Deprouw, Courbevoie; Emanuelle Dernis, Le Mans; Alban Deroux, Grenoble; Renaud Desbarbieux, Boulogne-Sur-Mer; Elise Descamps, Paris; Alexandra Desdoits, Caen; Chantal Deslandre, Paris; Marie Desmurs, Mulhouse; Jacques Despaux, Montelimar; Marie Desplats, Lambersart; Frédérick Detree, Reims; Valérie Devauchelle-Pensec, Brest; Mathilde Devaux, Poissy; Robin Dhote, Bobigny; Harmonie Diaz, Narbonne; Philippe Dieude, Paris; Yannick Dieudonne, Strasbourg; Elisabeth Diot, Tours; Guillaume Direz, Le Mans; Djamal-Dine Djeddi, Amiens; Fanny Domont, Paris; Sarah Douvier, Aix-Les-Bains; Béatrice Drouet, Pau; Jean-Jacques Dubost, Clermont-Ferrand; Catherine Duc, Romans-Sur-Isere; Angélique Ducornet, Saint-Brieuc; Carine Dufauret-Lombard, Limoges; Cécile Dumaine,Paris; Anne-Elisabeth Dumel, Cernay; Chantal,Dumoulin-Richez Merignac; Agnès Duquesne, Bron; Géraldine Durand, Poitiers; Mariane Durandin-Truffinet, Paris; Pierre-Marie Duret, Colmar; Stéphanie Durieux-Mehlman, Saint_Cloud; Perrine Dusser-Benesty, Paris; Maïka Duval, Antibes; Mikaël Ebbo, Marseille; Esther Ebstein, Paris; Andra Economu-Dubosc, Sucy-En-Brie; Soumaya El Mahou, Tourcoing; Stéphanie Emilie, Villeneuve-Saint-Georges; Romain Euvrard, Bourg-En-Bresse; Philippe Evon, Bar-Le-Duc; Claire Eymard-Gibert, Lyon; Sylvie Fabre, Montpellier; Dorothée Fagedet, Gap; Dominique Farge-Bancel, Paris; Meryem Farhat, Lille; Marion Fauconier, Reims; Bruno Fautrel, Paris; Jacques Echtenbaum, Pantin; Renaud Felten, Strasbourg; Nicole Ferreira-Maldent, Tours; Elodie Feurer, Lyon; Amandine Fichet, Trevenans; Françoise Flaisler, Nimes; René-Marc Flipo, Lille; Nans Florens, Lyon; Violaine Foltz, Paris; Elisabeth Fontanges, Lyon; Jennifer Foret, Dax; Anne-Claire Fougerousse, Saint-Mande; Anne Fouque-Aubert, Lyon; Catherine Foutrier-Morello, Plan-De-Cuques; Hélène Francois-Pradier, Paris; Léa Frantzen, Mulhouse; Marie-Louise Fremond, Paris; Pierre Fritz, Paris; Antoine Froissart, Creteil; Jean Fulpin, Piera Toulon; Fuzibet, Orleans; Francis Gaches, Toulouse; Laurence Gagneux-Lemoussu, Reims; Mélanie Gahier Penhoat, Saint-Nazaire;Joris Galland, Paris; Frédérique Gandjbakhch, Paris; Anaïs Gardette, Vichy; Nicole Garnier, Plaisance-Du-Touch; Thomas Garraud, Nantes; Jean-François Garrot, Semur-En-Auxois; Romain Gastaldi, Grenoble; Philippe Gaudin, Grenoble; Véronique Gaud-Listrat, Saint-Michel-Sur-Orge; Maud Gauthier-Prieur, Louviers; Loraine Gauzere, Saint-Denis; Dana Georgescu, Vienne; Sophie Georgin-Lavialle, Paris; Nathalie Gerard, Dijon; Elisabeth Gervais, Poitiers; Christelle Gibert, Valence; Eric Gibert, Paris; Ghislaine Gill, Paris; Jérôme Gillard, Lons-Le-Saunier; Mélanie Gilson, Grenoble; Pauline Gimonnet, Epernay; Jeanine-Sophie Giraudet-Le Quintrec, Paris; Aude Giraud-Morelet, Ecully; Baptiste Glace, Vichy; Camille Glanowski, Saint-Mande; Bertrand Godeau, Creteil; Bruno Gombert, La Rochelle; Camille Gonnet-Gracia, La Rochelle; Tiphaine Goulenok, Paris; Philippe Goupille, Tours; Olivier Gourmelen, Aix-Les-Bains; Sophie Govindaraju-Audouard, Vesoul; Franck Grados, Amiens; Martine Grall-Lerosey, Rouen; Bruno Grardel, Arras; Anne Grasland, Colombes; Gilles Grateau, Paris; Monica Groza, Colmar; Pascal Guggenbuhl, Rennes; Isabelle Guichard, Saint-Priest-En-Jarez; Constance Guillaud, Creteil; Sévenrine Guillaume-Czitrom, Kremlin-Bicetre; Caroline Guillibert, Marseille; Xavier Guillot, Saint-Denis; Philippe Guilpain, Montpellier; Aline Gury, Angers; Pauline Guyader, Ploemeur; Marie-Hélène Guyot, Roubaix; Eric, Hachulla Lille; Cécile Hacquard-Bouder,Yvetot; Marie-Noelle Havard, Argenteuil; Jean-Pierre Hellier, Arles; Pascal Hennequin, Epinal; Basile Henriot, Dinan; Julien Henry, Kremlin-Bicetre; Véronique Hentgen, Le Chesnay; Marion Hermet, Vichy; Julie Hernandez, Montauban; Miguel Hie, Paris; Pascal Hilliquin, Corbeil-Essonnes; Olivier Hinschberger, Mulhouse; Ambre Hittinger-Roux, Reims; Jan Holubar, Montpellier; Elsa How Shing Koy, Saint-Priest-En-Jarez; Charlotte Hua, Nîmes; Christophe Hudry, Paris; Serge Huguenel, Sarrebourg; Clara Jaccard, Clermont-Ferrand; Jean-Michel Jacquemier, Cornebarrieu;Bénédicte Jamard, Toulouse;Catherine Jan, Bar-Le-Duc;Sylvie Jean, Rennes; Laurie Joffres, Saint-Benoît; Sandrine Jousse-Joulin, Brest; Mathieu Jouvray, Arras; Pierre-Antoine Juge, Paris; Laurent Juillard, Lyon; Denis Jullien,Lyon; Abdelkrim Kabchou, Vichy; Ludovic Karkowski, Lyon; Françoise Karman, Pontault-Combault; Farid Kemiche, Pontoise; Jérémy Keraen, Quimper; Pierre Kieffer, Mulhouse; Isabelle Kone-Paut, Kremlin-Bicetre; Abdeldajallil Koreichi, Lorient; Marie Kostine, Bordeaux; Stéphanie Krebs, Ploemer; Sylvain La Batide Alanore, Paris; Valentin Lacombe, Angers; Pierre Lafforgue, Marseille; Sophie Lahalle,PARIS;M arc Lambert, Lille; Isabelle Lambrecht, Reims; François Lamer, Rennes; Vincent Langlois, Le Havre; Sylvain Lanot, Alencon; Aurélia Lanteri, Antibes; Jean-Paul Larbre, Ierre-Benite; Augustin Latourte, Paris; Christian Lavigne, Angers; Noémie Le Gouellec, Valenciennes; Sophie Le Guen Guegan, Contamine-Sur-Arve; Guillaume Le Guenno, Clermont-Ferrand; Agnès Lebrun, Paris; Emmanuel Ledoult, Tourcoing / Lille; Nathalie Legoupil, Paris; Erick Legrand, Angers; Diane Leguy, Roubaix; Olivier Leloire, Ronchin; Christophe Leroux, Dreux; Rémi Leroy, Dunkerque; Marie Leroy-Gouix, Vannes; Charles Leske, Cholet; Tifenn Leturcq, Paris; Amélie Leurs, Dunkerque; Céline Leveque Michaud, Valence; François-Xavier Limbach, Saverne; Frédéric Liote, Paris; Anne, Lohse Trevenans; Pierre Lozac'h, Le Mans; Charlotte Lucas, Rennes; Etienne Mabrut, Pierre-Benite; Aurélie Madelon, Grenoble; Nadine Magy-Bertrand, Besancon; Matthieu Mahevas, Creteil; Hélène Maillard, Lille; Thibault Maillet, Macon; François Maillot, Tours; Sandrine Malochet-Guinamand, Clermont-Ferrand; Quentin Mangon, Aurillac; Julie Mankikian, Tours; Sylvie Marchou_Lopez, Crolles; Nathalie Margarit, Portet-Sur-Garonne; Thierry Marhadour, Brest; Alexandre Maria, Montpellier; Xavier Mariette, Kremlin-Bicetre; Hubert Marotte; Saint-Priest-En-Jarez; Claire Martin, A Rochelle; Thierry Martin, Strasbourg; Alexis Mathian, Paris; François Maurier, Metz; Frédéric Maury, Beuvry; Betty Mazet-Guillaume, Angers; Arnaud Mazouyez, Contamine-Sur-Arve; Hassan Mazyad, Poissy; Nadia Mehsen-Cetre, Bordeaux; Arsène Mekinian, Paris; Isabelle Melki, Paris; Jean-Camille Meric, Ales; Laurent Messer, Colmar; Martin Michaud, Toulouse; Catherine Michel, Mulhouse; Matthias Michel, Sangatte; Mathilde Michon, Courbevoie; Anne-Marie Milesi-Lecat, Vichy; Anna Molto, Paris; Olivier Moranne, Nimes; Gautier Morel, Valenciennes; Hugo Morel, Dijon; Jacques Morel, Montpellier; Franck Morin, Saint-Pierre-De-Coutances; Laurence Moulinier, Paris; Guillaume Moulis, toulouse; Bertrand Moura,Paris; Claudine Naude, Saint-Jean-De-Maurienne; Minh Nguyen, Paris; Sabine Nicolas-Vullierme, Chatillon; Hubert Nielly, Saint-Mande; Gaétane Nocturne, Kremlin-Bicetre; Aurore Nottez, Dunkerque; Henri-Olivier Ollagnon, Villeurbanne; Eric Oziol, Beziers; Isabelle Pacaud-Vitoux, Guilherand-Granges; Guillaume Padern, Montpellier; Anne Pagnier, Grenoble; Caroline Paris, Marseille; Antoine Parrot, Paris; Tristan Pascart, Lille; Yasmina Pascaud-Mansour, Angers; Lætitia Paulin, Bourgoin-Jallieu; Stephan Pavy, Kremlin-Bicetre; Judith Payet, Saint-Denis; Laurent Perard, Lyon; Céline Pereira-Gillion, Tours; Yves-Marie Pers, Montpellier; Edouard Pertuiset, Pontoise; Micheline Pha, Paris; Thao Pham, Marseille; Maud Pichon, Argenteuil; Audrey Pierreisnard, Merignac; Gabrielle Pizana, Fougeres; Sylvaine Poignant, Nantes; Elsa Poix, Quint-Fonsegrives; Agnès Portier, Paris; Jacques Pouchot, Paris; Antoine Poulet, Marseille; Nicolas Poursac, Bordeaux; Grégory Pugnet, Toulouse; Déborah Puyraimond-Zemmour, Paris; Pierre Quartier-Dit-Maire, Paris; Quenet Marion, Saint-Brieuc; Viviane Queyrel, Nice; Loïc Raffray, Saint-Denis; Jérôme Razanamahery, Dijon; Philippe Remy, Creteil; Myriam Renard, Aix-Les-Bains; Jessica Rene, Tours; Sabine Revuz, Metz; Bénédicte Rey, Lyon; Gaëlle Richard-Colmant, Lyon; Olivier Richer, Bordeaux; Christophe Richez, Bordeaux; Elodie Riviere, Kremlin-Bicetre; Etienne Riviere, Bordeaux; Sébastien Riviere, Paris; Sophie Robin, Elbeuf; Julien Rohmer, Suresnes; Isabelle Roitg, Perpignan; Michel Rolland, Saint-Etienne; Mélanie Roriz, Agen; Carole Rosenberg, Argenteuil; Linda Rossi, Kremlin-Bicetre; Olivier Roth, Marseille; Sid-Ahmed Rouidi, Dreux; Mathilde Roumier, Suresnes; Mickaël Rousiere, Paris; Clémentine Ousselin, Valenciennes; Bénédicte Rouviere, Brest; Christian Roux, Nice; Fabienne Roux, Paris; Marielle Roux, Bourgoin-Jallieu; Nicolas Roux, Metz;Diane Rouzaud, Paris; Sylvie Rozenberg, Paris; Ruyssen-Witrand Adeline, Toulouse; Sacco Isabelle, Paris; Sadji Fatiha, Poissy; Laurent Sailler, Toulouse; Carine Salliot, Orleans; Jean-Hugues Salmon, Reims; Charlotte Samaille, Lille; Maxime Samson, Dijon; Alain Saraux, Brest; Léa Savey, Paris; Jean Schmidt, Amiens; Julie Seguier, Marseille; Jérémie Sellam, Paris; Eric Senbel, Marseille; Thomas Sene, Paris; Patricia Senet, Paris ;Raphaële Seror, Kremlin-Bicetre;Amélie Servettaz, Reims; Pascal Seve, Lyon; Aurélie Sicaud, Le Pont-De-Beauvoisin; Nadia Sivova, Tourcoing; Smets, Clermont-Ferrand; Vincent Sobanski, Lille; Christelle Sordet, Strasbourg; Elisabeth Sornay-Rendu, La Tour-Du-Pin; Martin Soubrier, Clermont-Ferrand; Odile Souchaud-Debouverie, Poitiers; Gaëlle Sourisseau-Diverres, Gujan-Mestras; Lætitia Sparsa, Mulhouse; Lionel Spielmann, Colmar; Chloé Stavris, Marseille; Sarah Steib, Marseille; Catherine Straus, Elancourt; Victor Strotz, Antony; Sylvain Mathieu, Clermont-Ferrand; Séverine Taffignon-Clave, Ecully; Déborah Talmud, Orleans; Chloé Taraud, Niort; Nora Tenenbaum, Paris; Claire Theillac, Benoît Pierre-Benite; Thomachot, Gardanne; Thierry Thomas, Saint-Priest-En-Jarez; Nathalie Tieulie, Nice; Soizic Tiriau, Nantes; Alice Tison, Bordeaux; Anne Tournadre, Clermont-Ferrand; Eric Toussirot, Besancon; Ludovic Trefond, Clermont-Ferrand; Sophie Trijau, Marseille; Sébastien Trouillier, Aurillac; Anne-Priscille Trouvin, Paris; Marie-Elise Truchetet, Bordeaux; Florence Uettwiller,Tours; Florence Ulrich, Valenciennes; Yurdagul Uzunhan, Bobigny; Isabelle Valls-Bellec, Brest; Jacques Vaquier, Limoges; Eric Veillard, Saint-Malo;Laurent Veillon, Orleans; Guillaume Vial, Bordeaux; Jean-François Viallard, Bordeaux; Judith Victor, Bordeaux; Claire Vidon, Aix_Les_Bains; Vidon, Creteil; Camille Vigne, Pierre-Benite; Alexandre Virone, Kremlin-Bicetre; Ursula Warzocha, Bobigny; Daniel Wendling, Besancon; Claude Werle, Haguenau; Cécile Wibaux, Seclin; Michel Wisniewski, Saint-Amand-Les-Eaux; Juliette Woessner, Avignon; Bernadette Xerri-Campano, Saint-Maur-Des-Fosses.

      • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

      • Competing interests None declared.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.