Criteria for discharge of patients with Ebola virus diseases in high-income countries
Authors: Nazario Bevilacqua, Emanuele Nicastri, Pierangelo Chinello, Vincenzo Puro, Nicola Petrosillo, Antonino Di Caro, Maria Rosaria Capobianchi, Simone Lanini, Francesco Vairo, Michel Pletschette, Alimuddin Zumla, Giuseppe Ippolito
Journal: The Lancet Global Health (2015)

During the recent epidemic of Ebola virus disease (EVD) in west Africa,1WHOEbola virus diseases outbreak.http://www.who.int/csr/disease/ebola/en/Google Scholar several health-care and aid workers infected with EVD were evacuated to Europe and the USA, where local transmission occurred in occupationally exposed health-care workers. Preparation for discharge requires an organised and evidence-based approach to ensure that the patient, health-care workers, family, and community are protected at all times. The risk of infection to others after discharge in the community and of unexpected late clinical events for the patient make discharge policies difficult to formulate.2O'Dempsey T Khan SH Bausch DG Rethinking the discharge policy for Ebola convalescents in an accelerating epidemic.Am J Trop Med Hyg. 2015; 92: 238-239Crossref PubMed Scopus (14) Google Scholar To suggest a framework for developing international consensus on criteria for safe discharge of EVD patients from hospital in high-income countries, we searched the websites of WHO, the US Centers for Disease Control and Prevention (CDC), the European Centre for Disease Prevention and Control (ECDC), and Public Health England (PHE) for hospital discharge criteria using the search terms “EVD discharge”, “EVD management”, “Ebola discharge”, and “Ebola management”. We also searched Pubmed, ProMed, and EMBASE for all published clinical reports on EVD patients cared for out of Africa during the current EVD outbreak using the search terms (“Ebola” OR “EVD”) AND (“case” OR “cases” OR “case-report” OR “report” OR “patient” OR “patients”) in the title or abstract. The search dates were January, 2014, to July, 2015. We also added unpublished data about EVD patients treated at the National Institute for Infectious Diseases (INMI) Lazzaro Spallanzani in Rome, Italy. WHO guidelines recommended that, in west Africa, the discharge of an EVD case be based on improvement of the clinical conditions together with, if laboratory testing is available, a negative blood RT-PCR for Ebola virus RNA.3WHOClinical management of patients with viral haemorrhagic fever: a pocket guide for the front-line health worker.http://www.who.int/csr/resources/publications/clinical-management-patients/en/Google Scholar The US CDC listed eight criteria to consider when deciding whether to discharge people under investigation for Ebola virus disease, but no guideline was provided for confirmed cases.4Centers for Disease Control and PreventionConsiderations for discharging people under investigation (PUIs) for Ebola virus disease (EVD).http://www.cdc.gov/vhf/ebola/healthcare-us/evaluating-patients/discharging.htmlGoogle Scholar The criteria included resolution of all symptoms and having no clinical laboratory results consistent with EVD. The ECDC has currently removed from the public access domain of its website a previously published expert opinion document on EVD discharge criteria for EU countries. This document recommended that EVD cases should remain in isolation until recovery from clinical symptoms of EVD and two consecutive antigen capture or RT-PCR tests on blood specimens are negative.5ECDC Expert OpinionPrevention and control of Ebola virus disease in healthcare settings.https://extranet.ecdc.europa.eu/publichealthevents/ebola/clinicians/Shared%20Documents/Reference%20documents%20for%20discussion%20forum/ECDC_EVDPrevConInHC.pdfGoogle Scholar We did not find any PHE document providing formal criteria for discharge of patients with confirmed EVD. Thus, none of these widely referenced health agencies provide recommendations for discharging EVD patients cared for outside Africa. Of 22 patients with EVD discharged from hospitals in Europe and the USA, discharge criteria were available for 14 cases (table). Different virological criteria for discharge were applied between and within the same country, ranging from two consecutive blood specimens testing negative for Ebola virus RNA by RT-PCR assay to the absence of Ebola virus in cell culture of several biological samples. In all but one patient, negative RT-PCR assays on biological samples were considered as common minimum requirements for discharging patients in the community. Patient 9, according to the German guidelines, was released from the hospital only when no infectious virus was isolated in cell culture. At the INMI Lazzaro Spallanzani in Rome, Italy, patients 12 and 13 were considered to be convalescent at day 28 and 17 from illness onset, respectively, since clinical symptoms resolved completely and RT-PCR on the blood became negative.6Bausch DG Towner JS Dowell SF et al.Assessment of the risk of Ebola virus transmission from bodily fluids and fomites.J Infect Dis. 2007; 196: S142-S147Crossref PubMed Scopus (383) Google Scholar Despite this, the institute only discharged patients 12 and 13 after achieving negative RT-PCR assay on urine and other body fluids.TableDischarge criteria for 14 patients with Ebola virus disease managed at hospitals in Europe and the USACentreDay of Discharge*From onset of illness.Discharge criteriaComments1Atlanta302 negative RT-PCR for EBOV on blood 24 h apartPatient had positive urine RT-PCR for EBOV on day 28. Unspecified results on other biological fluids.2Atlanta292 negative RT-PCR for EBOV on blood 24 h apartPatient had repeated negativity of RT-PCR for EBOV in urine. Unspecified results on other biological fluids.3Atlanta44Negative blood and urine RT-PCR for EBOV on serial specimensAt discharge semen positive for EBOV on RT-PCR and culture4Dallas†Admitted to.Bethesda†Transferred to.15Repeated negative RT-PCR for EBOV on bloodThroat, rectal, vaginal, urine, and sweat samples negative for EBOV on RT-PCR5Dallas†Admitted to.Atlanta†Transferred to.14Repeated negative blood and urine RT-PCR for EBOVSkin and vaginal swabs negative for EBOV on RT-PCR6Omaha283 serial blood samples free of EBOVUnspecified result of tests in other biological specimens7Omaha203 serial blood samples free of EBOVUnspecified result of tests in other biological specimens8New York222 negative RT-PCR for EBOV on bloodUnspecified result of tests in other biological specimens9Hamburg40All cultures of RT-PCR positive samples of body fluids free of infectious virus for 20 daysAt discharge patient had negative RT-PCR in plasma and urine; positive RT-PCR on sweat10FrankfurtNARepeated negative blood RT-PCR for EBOVUrine and stool samples also negative RT-PCR for EBOV11Madrid34Repeated negative RT-PCR for EBOV of all body fluid samplesUnspecified body site and number of samples12Rome44Repeated negative RT-PCR for EBOV of all body fluid samples apart from semenPatient's throat, sweat, ocular, and stool samples negative for EBOV on RT-PCR13Rome31Repeated negative RT-PCR for EBOV of all body fluid samples apart from semenPatient's blood, urine, throat, sweat, ocular, sputum, and stool samples negative for EBOV on RT-PCR14Geneva19Repeated negative RT-PCR for EBOV of all body fluid samplesPatient's blood, urine, sweat, ocular, saliva, and stool samples negative for EBOV on RT-PCREBOV=Ebola virus RNA. Atlanta=Emory University Hospital, Atlanta, GA, USA. Dallas=Texas Health Presbyterian Hospital, Dallas, TX, USA. Bethesda=National Institutes of Health Clinical Center, Bethesda, MD, USA. Omaha=Nebraska Medical Center, Omaha, NE, USA. New York=Bellevue Hospital Center, New York, NY, USA. Hamburg=University Medical Center, Hamburg, Germany. Frankfurt=University Hospital, Frankfurt, Germany. Madrid=La Paz Carlos III University Hospital, Madrid, Spain. Rome=INMI Lazzaro Spallanzani, Rome, Italy. Geneva=Geneva University Hospitals, Geneva, Switzerland.* From onset of illness.† Admitted to.‡ Transferred to. Open table in a new tab EBOV=Ebola virus RNA. Atlanta=Emory University Hospital, Atlanta, GA, USA. Dallas=Texas Health Presbyterian Hospital, Dallas, TX, USA. Bethesda=National Institutes of Health Clinical Center, Bethesda, MD, USA. Omaha=Nebraska Medical Center, Omaha, NE, USA. New York=Bellevue Hospital Center, New York, NY, USA. Hamburg=University Medical Center, Hamburg, Germany. Frankfurt=University Hospital, Frankfurt, Germany. Madrid=La Paz Carlos III University Hospital, Madrid, Spain. Rome=INMI Lazzaro Spallanzani, Rome, Italy. Geneva=Geneva University Hospitals, Geneva, Switzerland. The key issues for further discussion are: (1) the clinical and virological criteria for discontinuing strict isolation and stepping down to routine hospital practice; (2) the clinical and virological criteria for discharge from hospital; (3) the virological criteria for resumption of household, community, and professional activities; (4) the follow-up of clinical and virological parameters during the convalescent phase; and (5) the definition of “cured”. The value of a positive biomolecular assay in the absence of data on the infectivity of the same biological sample remains unclear and discharge criteria need to be considered in the context of viral persistence after clinical recovery. Before discharging patients home, preliminary steps to scale down isolation precautions to routine in-hospital practices were applied differently in the reported cases; in most cases, negative Ebola virus blood RT-PCR and lack of gastrointestinal symptoms were considered the minimum required criteria. The persistence of Ebola virus in semen 9 months after the onset of disease7Christie A Davies-Wayne GJ Cordier-Lasalle T et al.Possible sexual transmission of Ebola virus—Liberia, 2015.MMWR Morb Mortal Wkly Rep. 2015; 64: 479-481PubMed Google Scholar, 8Deen GF Knust B Broutet DVMN et al.Ebola RNA persistence in semen of Ebola virus disease survivors—preliminary report.N Engl J Med. 2015; (published online Oct 14.)http://dx.doi.org/10.1056/NEJMoa1511410Google Scholar necessitates condom use or avoidance of sexual intercourse, although the duration of these preventive measures have not been defined. No clear data on the virological criteria on the readmission of the convalescent person to the household, nor on commencement of social and professional activities are available. The definition of cure of the EVD patient is an ongoing debate: a viable Ebola virus was isolated in the aqueous humour of the eye of a US patient (patient 3, table) with acute panuveitis nine weeks after Ebola virus clearance from blood.9Varkey JB Shantha JG Crozier I et al.Persistence of Ebola Virus in ocular fluid during convalescence.N Engl J Med. 2015; 372: 2423-2427Crossref PubMed Scopus (323) Google Scholar In the longer term, further research is needed to assess the presence of infective viruses in EVD convalescent patients to establish evidence-based criteria and guidelines for discharge.10Osterholm MT Moore KA Kelley NS et al.Transmission of Ebola viruses: what we know and what we do not know.MBio. 2015; 6: e00137Crossref Scopus (7) Google Scholar An important need exists for the scientific community to reach a consensus and develop universal guidelines using the available evidence base to define the discharge criteria for EVD patients, taking into consideration the epidemic context and available resources in low-income and high-income countries. With this aim, the INMI Lazzaro Spallanzani is starting an international consultation on the critical issues of patients' discharge outside outbreak settings. This online publication has been corrected. The corrected version first appeared at thelancet.com/langh on Nov 23, 2015 This online publication has been corrected. The corrected version first appeared at thelancet.com/langh on Nov 23, 2015 Members of the INMI EBOV Team ID specialists: Nicola Petrosillo, Emanuele Nicastri, Nazario Bevilacqua, Evangelo Boumis, Stefania Cicalini, Pierangelo Chinello, Angela Corpolongo, Vincenzo Galati, Andrea Mariano, Silvia Rosati, Fabrizio Taglietti, Laura Vincenzi; Intensive care physicians: Mario Antonini, Ilaria Caravella, Gabriele Garotto, Luisa Marchioni, Micaela Maritti; Cardiologist: Gianluigi Biava; Radiologist: Elisa Busi Rizzi; Virology and Microbiology Laboratorians: Maria Rosaria Capobianchi, Antonino di Caro, Concetta Castilletti, Licia Bordi, Eleonora Lalle, Silvia Meschi, Daniele Lapa, Patrizia Marsella, Francesca Colavita, Roberta Chiappini, Antonio Mazzarelli, Serena Quartu, Chiara Agrati, Fabrizio Carletti, Federica Forbici, Maria Beatrice Valli, Isabella Abbate, Alessandra Amendola, Anna Rosa Garbuglia, Maria Grazia Paglia, Eugenio Bordi, Damiano Travaglini, Antonietta Toffoletti; Nurses: Gianni Battisti, Alessanda Coppola, Loredana De Marchis, Nicola De Marco, Paolo Giacomini, Fabio Di Gianbattista, Mario Guiducci, Antonio Marasco, Antonella Marzolini, Alessandro Mercuri, Paola Nieddu, Silvia Ondedei, Maurizio Vescovo, Laura Vitolo; Radiology Technician: Maurizio Morea; Drivers biocontainment ambulance: Gaetano Battisti, Marco Liguori. Members of the INMI Crisis unit: Nicola Petrosillo, Emanuele Nicastri, Francesco Nicola Lauria, Vincenzo Puro, Mario Antonini, Antonio Russo, Maria Rosaria Capobianchi, Antonino Di Caro, Paolo D'Aprile, Antonella Petrecchia, Evangelo Boumis, Marco Gentile, Damiano Travaglini, Silvia Pittalis, Lorena Martini, Concetta Castilletti, Francesco Maria Fusco, Simone Lanini, Andrea Antinori, Marina Cerimele, Giuseppe Ippolito, Valerio Fabio Alberti, Marta Branca. We declare no competing interests. Ebola: forgotten but not gone?On Oct 16, two new Ebola cases were reported in Guinea, indicating the continuing danger of Ebola virus even after progress in bringing the west African Ebola outbreak under control. The outbreak in Guinea, Liberia, and Sierra Leone caught the world badly unprepared during 2013–14, resulting in more than 11 000 deaths. WHO responded slowly to this major challenge in countries with sparse health provision, and disease control measures worked imperfectly. During 2015, lost ground has been made up by provision of care for those infected and at risk of infection, yet recent developments illustrate the continuing health risks for those who have been infected. Full-Text PDF Correction to Lancet Glob Health 2015; 3: e739–40Bevilacqua N, Nicastri E, Chinello P, et al, and the INMI Ebola Team. Criteria for discharge of patients with Ebola virus diseases in high-income countries. Lancet Glob Health 2015; 3: e739–40—In this Correspondence (December, 2015), the last sentence should have read: “With this aim, the INMI Lazzaro Spallanzani is starting an international consultation on the critical issues of patients' discharge outside outbreak settings.” This correction has been made to the online version as of Nov 23, 2015. Full-Text PDF Open Access