Clinical description and outcome of overall varicella-zoster virus-related organ dysfunctions admitted in intensive care units: the VAZOREA cohort study.

Encephalitis Immunocompromised host Intensive care units Pneumonia Varicella-Zoster virus

Journal

Annals of intensive care
ISSN: 2110-5820
Titre abrégé: Ann Intensive Care
Pays: Germany
ID NLM: 101562873

Informations de publication

Date de publication:
29 Mar 2024
Historique:
received: 12 12 2023
accepted: 23 02 2024
medline: 29 3 2024
pubmed: 29 3 2024
entrez: 29 3 2024
Statut: epublish

Résumé

Due to aging population and increasing part of immunocompromised patients, a raise in life-threatening organ damage related to VZV can be expected. Two retrospective studies were already conducted on VZV in ICU but focused on specific organ injury. Patients with high-risk of VZV disease still must be identified. The objective of this study was to report the clinical features and outcome of all life-threatening VZV manifestations requiring intensive care unit (ICU) admission. This retrospective cohort study was conducted in 26 French ICUs and included all adult patients with any life-threatening VZV-related event requiring ICU admission or occurring in ICU between 2010 and 2019. One-hundred nineteen patients were included with a median SOFA score of 6. One hundred eight patients (90.8%) were admitted in ICU for VZV disease, leaving 11 (9.2%) with VZV disease occurring in ICU. Sixty-one patients (51.3%) were immunocompromised. Encephalitis was the most prominent organ involvement (55.5%), followed by pneumonia (44.5%) and hepatitis (9.2%). Fifty-four patients (45.4%) received norepinephrine, 72 (60.5% of the total cohort) needed invasive mechanical ventilation, and 31 (26.3%) received renal-replacement therapy. In-hospital mortality was 36.1% and was significantly associated with three independent risk factors by multivariable logistic regression: immunosuppression, VZV disease occurring in ICU and alcohol abuse. Hierarchical clustering on principal components revealed five phenotypically distinct clusters of patients: VZV-related pneumonia, mild encephalitis, severe encephalitis in solid organ transplant recipients, encephalitis in other immunocompromised hosts and VZV disease occurring in ICU. In-hospital mortality was highly different across phenotypes, ranging from zero to 75% (p < 0.001). Overall, severe VZV manifestations are associated with high mortality in the ICU, which appears to be driven by immunosuppression status rather than any specific organ involvement. Deciphering the clinical phenotypes may help clinicians identify high-risk patients and assess prognosis.

Sections du résumé

BACKGROUND BACKGROUND
Due to aging population and increasing part of immunocompromised patients, a raise in life-threatening organ damage related to VZV can be expected. Two retrospective studies were already conducted on VZV in ICU but focused on specific organ injury. Patients with high-risk of VZV disease still must be identified. The objective of this study was to report the clinical features and outcome of all life-threatening VZV manifestations requiring intensive care unit (ICU) admission. This retrospective cohort study was conducted in 26 French ICUs and included all adult patients with any life-threatening VZV-related event requiring ICU admission or occurring in ICU between 2010 and 2019.
RESULTS RESULTS
One-hundred nineteen patients were included with a median SOFA score of 6. One hundred eight patients (90.8%) were admitted in ICU for VZV disease, leaving 11 (9.2%) with VZV disease occurring in ICU. Sixty-one patients (51.3%) were immunocompromised. Encephalitis was the most prominent organ involvement (55.5%), followed by pneumonia (44.5%) and hepatitis (9.2%). Fifty-four patients (45.4%) received norepinephrine, 72 (60.5% of the total cohort) needed invasive mechanical ventilation, and 31 (26.3%) received renal-replacement therapy. In-hospital mortality was 36.1% and was significantly associated with three independent risk factors by multivariable logistic regression: immunosuppression, VZV disease occurring in ICU and alcohol abuse. Hierarchical clustering on principal components revealed five phenotypically distinct clusters of patients: VZV-related pneumonia, mild encephalitis, severe encephalitis in solid organ transplant recipients, encephalitis in other immunocompromised hosts and VZV disease occurring in ICU. In-hospital mortality was highly different across phenotypes, ranging from zero to 75% (p < 0.001).
CONCLUSION CONCLUSIONS
Overall, severe VZV manifestations are associated with high mortality in the ICU, which appears to be driven by immunosuppression status rather than any specific organ involvement. Deciphering the clinical phenotypes may help clinicians identify high-risk patients and assess prognosis.

Identifiants

pubmed: 38548917
doi: 10.1186/s13613-024-01270-w
pii: 10.1186/s13613-024-01270-w
doi:

Types de publication

Journal Article

Langues

eng

Pagination

44

Informations de copyright

© 2024. The Author(s).

Références

Heininger U, Seward JF, Varicella. Lancet. 2006;368:1365–76.
pubmed: 17046469 doi: 10.1016/S0140-6736(06)69561-5
Gnann JW, Whitley RJ. Herpes zoster. N Engl J Med. 2002;347:340–6.
pubmed: 12151472 doi: 10.1056/NEJMcp013211
Gershon AA, Breuer J, Cohen JI, Cohrs RJ, Gershon MD, Gilden D et al. Varicella zoster virus infection. Nature Reviews Disease Primers [Internet]. 2015 [cited 2020 Jan 15];1. Available from: http://www.nature.com/articles/nrdp201516 .
Heininger U, Braun-Fahrländer C, Desgrandchamps D, Glaus J, Grize L, Wutzler P et al. Seroprevalence of varicella-zoster virus immunoglobulin G antibodies in Swiss adolescents and risk factor analysis for seronegativity: the Pediatric Infectious. Disease J. 2001;775–8.
Wiese-Posselt M, Siedler A, Mankertz A, Sauerbrei A, Hengel H, Wichmann O, et al. Varicella-Zoster virus seroprevalence in children and adolescents in the pre-varicella vaccine era, Germany. BMC Infect Dis. 2017;17:356.
pubmed: 28525973 pmcid: 5438501 doi: 10.1186/s12879-017-2461-2
Cohen JI. Herpes Zoster. Solomon CG, editor. New England Journal of Medicine. 2013;369:255–63.
Vigneron C, Charpentier J, Wislez M, Mira J-P, Lefebvre A, Fournel L, et al. Short-term and long-term outcomes of patients with Lung Cancer and Life-threatening complications. Chest. 2021;160:1560–4.
pubmed: 33961832 doi: 10.1016/j.chest.2021.04.056
Sehn LH, Salles G. Diffuse large B-Cell lymphoma. N Engl J Med. 2021;384:842–58.
pubmed: 33657296 pmcid: 8377611 doi: 10.1056/NEJMra2027612
Rossi D, Bertoni F, Zucca E. Marginal-Zone Lymphomas. N Engl J Med. 2022;386:568–81.
pubmed: 35139275 doi: 10.1056/NEJMra2102568
Locke FL, Miklos DB, Jacobson CA, Perales M-A, Kersten M-J, Oluwole OO, et al. Axicabtagene Ciloleucel as Second-Line therapy for large B-Cell lymphoma. N Engl J Med. 2022;386:640–54.
pubmed: 34891224 doi: 10.1056/NEJMoa2116133
Lemiale V, Pons S, Mirouse A, Tudesq J-J, Hourmant Y, Mokart D, et al. Sepsis and septic shock in patients with malignancies: a Groupe De Recherche Respiratoire en Réanimation Onco-Hématologique Study. Crit Care Med. 2020;48:822–9.
pubmed: 32317596 doi: 10.1097/CCM.0000000000004322
Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaître O, Cohen P, et al. Rituximab versus Azathioprine for maintenance in ANCA-Associated Vasculitis. N Engl J Med. 2014;371:1771–80.
pubmed: 25372085 doi: 10.1056/NEJMoa1404231
Mullooly JP, Riedlinger K, Chun C, Weinmann S, Houston H. Incidence of herpes zoster, 1997–2002. Epidemiol Infect. 2005;133:245–53.
pubmed: 15816149 pmcid: 2870243 doi: 10.1017/S095026880400281X
Yoshikawa TT, Schmader K. Herpes zoster in older adults. Clin Infect Dis. 2001;32:1481–6.
doi: 10.1086/320169
Rimland D, Moanna A. Increasing incidence of herpes zoster among veterans. Clin Infect Dis. 2010;50:1000–5.
pubmed: 20178416 doi: 10.1086/651078
Strangfeld A. Risk of herpes zoster in patients with rheumatoid arthritis treated with Anti–TNF-α agents. JAMA. 2009;301:737.
pubmed: 19224750 doi: 10.1001/jama.2009.146
Trousseau A. Clinique médicale De l’Hôtel-Dieu de Paris. Paris: Hachette BNF; 1868.
Rawson H, Crampin A, Noah N. Deaths from chickenpox in England and Wales 1995-7: analysis of routine mortality data. BMJ. 2001;323:1091–3.
pubmed: 11701571 pmcid: 59681 doi: 10.1136/bmj.323.7321.1091
Weber DM. Varicella Pneumonia: study of Prevalence in Adult men. JAMA. 1965;192:572.
pubmed: 14284857 doi: 10.1001/jama.1965.03080190138035
Reid G, Lynch J, Weigt S, Sayah D, Belperio J, Grim S, et al. Herpesvirus Respiratory infections in Immunocompromised patients: Epidemiology, Management, and outcomes. Semin Respir Crit Care Med. 2016;37:603–30.
pubmed: 27486740 pmcid: 7171758 doi: 10.1055/s-0036-1584793
Stollenwerk N, Harper RW, Sandrock CE. Bench-to-bedside review: rare and common viral infections in the intensive care unit – linking pathophysiology to clinical presentation. Crit Care. 2008;12:219.
pubmed: 18671826 pmcid: 2575602 doi: 10.1186/cc6917
Mirouse A, Vignon P, Piron P, Robert R, Papazian L, Géri G et al. Severe varicella-zoster virus pneumonia: a multicenter cohort study. Critical Care [Internet]. 2017 [cited 2020 Jan 10];21. Available from: http://ccforum.biomedcentral.com/articles/ https://doi.org/10.1186/s13054-017-1731-0 .
Kramer AH. Viral encephalitis in the ICU. Crit Care Clin. 2013;29:621–49.
pubmed: 23830656 doi: 10.1016/j.ccc.2013.03.011
Mailles A, Argemi X, Biron C, Fillatre P, De Broucker T, Buzelé R, et al. Changing profile of encephalitis: results of a 4-year study in France. Infect Dis Now. 2022;52:1–6.
pubmed: 34896660 doi: 10.1016/j.idnow.2021.11.007
Herlin LK, Hansen KS, Bodilsen J, Larsen L, Brandt C, Andersen CØ, et al. Varicella Zoster Virus Encephalitis in Denmark from 2015 to 2019-A nationwide prospective cohort study. Clin Infect Dis. 2021;72:1192–9.
pubmed: 32103249 doi: 10.1093/cid/ciaa185
Buchan SA, Daneman N, Wang J, Garber G, Wormsbecker AE, Wilson SE, et al. Incidence of hospitalizations and Emergency Department Visits for Herpes Zoster in immunocompromised and immunocompetent adults in Ontario, Canada, 2002–2016. Clin Infect Dis. 2020;71:22–9.
pubmed: 31436814 doi: 10.1093/cid/ciz769
Mirouse A, Sonneville R, Razazi K, Merceron S, Argaud L, Bigé N, et al. Neurologic outcome of VZV encephalitis one year after ICU admission: a multicenter cohort study. Ann Intensive Care. 2022;12:32.
pubmed: 35380296 pmcid: 8982685 doi: 10.1186/s13613-022-01002-y
Proceedings of Reanimation, the French Intensive Care Society International Congress. 2023,. Ann Intensive Care. 2023;13:50.
Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-related problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22:707–10.
pubmed: 8844239 doi: 10.1007/BF01709751
Le Gall JR, Lemeshow S, Saulnier F. A new simplified Acute Physiology score (SAPS II) based on a European/North American multicenter study. JAMA. 1993;270:2957–63.
pubmed: 8254858 doi: 10.1001/jama.1993.03510240069035
Société française d’alcoologie. Mésusage de l’alcool: dépistage, diagnostic et traitement. Recommandation de bonne pratique. [Internet]. [cited 2024 Feb 6]. Available from: https://www.alcoologie-et-addictologie.fr/index.php/aa/article/view/570 .
ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307:2526–33.
Venkatesan A, Tunkel AR, Bloch KC, Lauring AS, Sejvar J, Bitnun A, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 2013;57:1114–28.
pubmed: 23861361 pmcid: 3783060 doi: 10.1093/cid/cit458
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus definitions for Sepsis and septic shock (Sepsis-3). JAMA. 2016;315:801.
pubmed: 26903338 pmcid: 4968574 doi: 10.1001/jama.2016.0287
Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112:18–35.
pubmed: 27995906 doi: 10.1038/ajg.2016.517
Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification of acute pancreatitis–2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62:102–11.
pubmed: 23100216 doi: 10.1136/gutjnl-2012-302779
Section 2. AKI Definition. Kidney Int Supplements. 2012;2:19–36.
doi: 10.1038/kisup.2011.32
Stahl JP, Azouvi P, Bruneel F, De Broucker T, Duval X, Fantin B, et al. Guidelines on the management of infectious encephalitis in adults. Med Mal Infect. 2017;47:179–94.
pubmed: 28412044 doi: 10.1016/j.medmal.2017.01.005
Lo Presti C, Curti C, Montana M, Bornet C, Vanelle P. Chickenpox: an update. Méd Mal Infect. 2019;49:1–8.
pubmed: 29789159 doi: 10.1016/j.medmal.2018.04.395
Tyler KL. Acute viral encephalitis. N Engl J Med. 2018;379:557–66.
pubmed: 30089069 doi: 10.1056/NEJMra1708714
Sonneville R, de Montmollin E, Contou D, Ferrer R, Gurjar M, Klouche K et al. Clinical features, etiologies, and outcomes in adult patients with meningoencephalitis requiring intensive care (EURECA): an international prospective multicenter cohort study. Intensive Care Med. 2023.
Styczynski J, Reusser P, Einsele H, de la Camara R, Cordonnier C, Ward KN et al. Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia. Bone Marrow Transplant. 2009;43:757–70.
Vink P, Ramon Torrell JM, Sanchez Fructuoso A, Kim S-J, Kim S-I, Zaltzman J, et al. Immunogenicity and safety of the Adjuvanted recombinant zoster vaccine in chronically immunosuppressed adults following renal transplant: a phase 3, Randomized Clinical Trial. Clin Infect Dis. 2020;70:181–90.
pubmed: 30843046
L’Huillier AG, Hirzel C, Ferreira VH, Ierullo M, Ku T, Selzner N, et al. Evaluation of recombinant herpes zoster vaccine for primary immunization of Varicella-seronegative transplant recipients. Transplantation. 2021;105:2316–23.
pubmed: 33528118 doi: 10.1097/TP.0000000000003621
Jaquet P, de Montmollin E, Dupuis C, Sazio C, Conrad M, Susset V, et al. Functional outcomes in adult patients with herpes simplex encephalitis admitted to the ICU: a multicenter cohort study. Intensive Care Med. 2019;45:1103–11.
pubmed: 31292686 doi: 10.1007/s00134-019-05684-0
Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306:2594–605.
pubmed: 22187279 pmcid: 3361243 doi: 10.1001/jama.2011.1829
Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13:862–74.
pubmed: 24232462 pmcid: 4077177 doi: 10.1038/nri3552
Ong DSY, Bonten MJM, Spitoni C, Verduyn Lunel FM, Frencken JF, Horn J, et al. Epidemiology of multiple herpes viremia in previously immunocompetent patients with septic shock. Clin Infect Dis. 2017;64:1204–10.
pubmed: 28158551 doi: 10.1093/cid/cix120
Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, Neff MJ, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008;300:413–22.
pubmed: 18647984 pmcid: 2774501 doi: 10.1001/jama.2008.697
Solomon T, Michael BD, Smith PE, Sanderson F, Davies NWS, Hart IJ, et al. Management of suspected viral encephalitis in adults–association of British neurologists and British Infection Association National Guidelines. J Infect. 2012;64:347–73.
pubmed: 22120595 doi: 10.1016/j.jinf.2011.11.014
Gacouin A, Tadie JM, Uhel F, Sauvadet E, Fillâtre P, Letheulle J, et al. At-risk drinking is independently associated with ICU and one-year mortality in critically ill nontrauma patients*. Crit Care Med. 2014;42:860–7.
pubmed: 24201172 doi: 10.1097/CCM.0000000000000041
Gacouin A, Painvin B, Coirier V, Quelven Q, Delange B, Joussellin V, et al. Impact on ICU mortality of moderate alcohol consumption in patients admitted with infection. J Crit Care. 2020;57:91–6.
pubmed: 32062291 doi: 10.1016/j.jcrc.2020.02.008
Prescott HC, Langa KM, Liu V, Escobar GJ, Iwashyna TJ. Increased 1-year healthcare use in survivors of severe sepsis. Am J Respir Crit Care Med. 2014;190:62–9.
pubmed: 24872085 pmcid: 4226030 doi: 10.1164/rccm.201403-0471OC
Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304:1787–94.
pubmed: 20978258 pmcid: 3345288 doi: 10.1001/jama.2010.1553
Hammond NE, Finfer SR, Li Q, Taylor C, Cohen J, Arabi Y, et al. Health-related quality of life in survivors of septic shock: 6-month follow-up from the ADRENAL trial. Intensive Care Med. 2020;46:1696–706.
pubmed: 32676679 doi: 10.1007/s00134-020-06169-1
Angriman F, Rosella LC, Lawler PR, Ko DT, Wunsch H, Scales DC. Sepsis hospitalization and risk of subsequent cardiovascular events in adults: a population-based matched cohort study. Intensive Care Med. 2022;48:448–57.
pubmed: 35142896 doi: 10.1007/s00134-022-06634-z
Prescott HC, Angus DC. Enhancing recovery from Sepsis: a review. JAMA. 2018;319:62.
pubmed: 29297082 pmcid: 5839473 doi: 10.1001/jama.2017.17687
Lenfant T, L’Honneur A-S, Ranque B, Pilmis B, Charlier C, Zuber M, et al. Neurological complications of varicella zoster virus reactivation: prognosis, diagnosis, and treatment of 72 patients with positive PCR in the cerebrospinal fluid. Brain Behav. 2022;12:e2455.
pubmed: 35040287 pmcid: 8865153 doi: 10.1002/brb3.2455
Guiraud V, Burrel S, Luyt C-E, Boutolleau D. Prevalence and clinical relevance of VZV lung detection in intensive care unit: a retrospective cohort study. J Clin Virol. 2023;164:105470.
pubmed: 37120914 doi: 10.1016/j.jcv.2023.105470

Auteurs

Jolan Malherbe (J)

Normandie Univ, UNICAEN, CHU de Caen Normandie, Médecine Intensive - Réanimation, Caen, 14000, France. malherbe-j@chu-caen.fr.

Pierre Godard (P)

Service de Médecine Intensive - Réanimation, CHU Bordeaux site Pellegrin, Bordeaux, France.

Jean-Claude Lacherade (JC)

Médecine Intensive - Réanimation, CH La Roche Sur Yon, La Roche Sur Yon, France.

Valentin Coirier (V)

Service de Médecine Intensive - Réanimation, CHU de Rennes, Rennes, 35000, France.

Laurent Argaud (L)

Service de Médecine Intensive - Réanimation, Hôpital Edouard Herriot, Hospices civils de Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon-Est, Lyon, France.

Hervé Hyvernat (H)

Service de Médecine Intensive - Réanimation, Université Côte d'Azur (UCA), CHU de Nice, 151 route Saint Antoine de Ginestière, Nice, 06200, France.

Francis Schneider (F)

Médecine Intensive - Réanimation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg et Unistra, Strasbourg, France.

Julien Charpentier (J)

Service de Médecine Intensive - Réanimation, Centre-Université Paris Cité, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, 75014, France.

Florent Wallet (F)

Médecine Intensive - Réanimation, CHU Lyon Sud, Pierre Benite, France.
RESHAPE Research on healthcare performance, U1290, Université Claude Bernard Lyon 1, Lyon, France.

Juliette Pocquet (J)

Médecine Intensive - Réanimation, CHR Orléans, Orléans, France.

Gaëtan Plantefeve (G)

Service de Réanimation, CH Argenteuil, Argenteuil, France.

Jean-Pierre Quenot (JP)

Department of Intensive Care, Burgundy University Hospital, Dijon, France.

Pierre Bay (P)

Service de Médecine Intensive - Réanimation, AP-HP Assistance Publique Hôpitaux de Paris, Hôpitaux universitaires Henri Mondor, DMU Médecine, Créteil, 94010, France.
UPEC Université Paris-Est Créteil, INSERM, Unité U955, Equipe 18, Créteil, 94010, France.

Agathe Delbove (A)

Service de réanimation polyvalente, CHBA Vannes, Vannes, France.

Hugues Georges (H)

Service de réanimation polyvalente, Centre hospitalier de Tourcoing, Tourcoing, 59200, France.

Tomas Urbina (T)

Service de Médecine Intensive - Réanimation, Hôpital Saint-Antoine, Assistance Publique- Hôpitaux de Paris, Paris, 75012, France.

David Schnell (D)

Réanimation Polyvalente et USC, CH Angoulême, Angoulême Cedex 9, Angoulême, 19959, France.

Charlène Le Moal (C)

Service Réanimation/USC, Centre Hospitalier du Mans, Le Mans, 72037, France.

Matthieu Stanowski (M)

Médecine Intensive - Réanimation, CHRU de Nancy, Nancy, France.

Corentin Muris (C)

Université de Poitiers, CHU de Poitiers, Médecine intensive Réanimation, 2 rue de la miletrie, Poitiers, 86000, France.

Maud Jonas (M)

Service Médecine Intensive - Réanimation/USC, Centre hospitalier de Saint-Nazaire, Saint-Nazaire, 44600, France.

Bertrand Sauneuf (B)

Service de Réanimation polyvalente, Centre Hospitalier Public du Cotentin, Cherbourg en Cotentin, 50100, France.

Olivier Lesieur (O)

Centre Hospitalier Saint-Louis, Réanimation polyvalente, La Rochelle, 17019, France.

Amaury Lhermitte (A)

Hôpital Universitaire Félix Guyon, Réanimation polyvalente, Allée des Topazes, Saint-Denis, La Réunion, 97400, France.

Laure Calvet (L)

Service de Médecine Intensive et Réanimation, CHU de Clermont-Ferrand, Clermont- Ferrand, France.

Ines Gueguen (I)

Service de réanimation médicale, CHRU de Lille, Lille, France.

Damien du Cheyron (D)

Normandie Univ, UNICAEN, CHU de Caen Normandie, Médecine Intensive - Réanimation, Caen, 14000, France.

Classifications MeSH