key: cord-0785446-zd8c1no7 authors: Danis, Kostas; Epaulard, Olivier; Bénet, Thomas; Gaymard, Alexandre; Campoy, Séphora; Bothelo-Nevers, Elisabeth; Bouscambert-Duchamp, Maude; Spaccaferri, Guillaume; Ader, Florence; Mailles, Alexandra; Boudalaa, Zoubida; Tolsma, Violaine; Berra, Julien; Vaux, Sophie; Forestier, Emmanuel; Landelle, Caroline; Fougere, Erica; Thabuis, Alexandra; Berthelot, Philippe; Veil, Raphael; Levy-Bruhl, Daniel; Chidiac, Christian; Lina, Bruno; Coignard, Bruno; Saura, Christine title: Cluster of coronavirus disease 2019 (Covid-19) in the French Alps, 2020 date: 2020-04-11 journal: Clin Infect Dis DOI: 10.1093/cid/ciaa424 sha: 245319b9ff57c43cd0d2d027218c842a7c87ce3a doc_id: 785446 cord_uid: zd8c1no7 BACKGROUND: On 07/02/2020, French Health authorities were informed of a confirmed case of SARS-CoV-2 coronavirus in an Englishman infected in Singapore who had recently stayed in a chalet in the French Alps. We conducted an investigation to identify secondary cases and interrupt transmission. METHODS: We defined as a confirmed case a person linked to the chalet with a positive RT-PCR sample for SARS-CoV-2. RESULTS: The index case stayed 4 days in the chalet with 10 English tourists and a family of 5 French residents; SARS-CoV-2 was detected in 5 individuals in France, 6 in England (including the index case), and 1 in Spain (overall attack rate in the chalet: 75%). One pediatric case, with picornavirus and influenza A coinfection, visited 3 different schools while symptomatic. One case was asymptomatic, with similar viral load as that of a symptomatic case. Seven days after the first cases were diagnosed, one tertiary case was detected in a symptomatic patient with a positive endotracheal aspirate; all previous and concurrent nasopharyngeal specimens were negative. Additionally, 172 contacts were monitored, including 73 tested negative for SARS-CoV-2. CONCLUSIONS: The occurrence in this cluster of one asymptomatic case with similar viral load as a symptomatic patient, suggests transmission potential of asymptomatic individuals. The fact that an infected child did not transmit the disease despite close interactions within schools suggests potential different transmission dynamics in children. Finally, the dissociation between upper and lower respiratory tract results underscores the need for close monitoring of the clinical evolution of suspect Covid-19 cases. A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) causing respiratory infections (coronavirus disease 2019, was first detected in Wuhan, China in December 2019 (1) (2) (3) . Within weeks, the virus spread to all provinces of China, and to a growing number of countries in five continents (China accounting for >99% of cases) (4) (5) . The first reported case series featured a high proportion of severe disease (acute respiratory distress syndrome in 17-29% of the cases) (6-7). On 24/01/2020, the first 3 confirmed Covid-19 cases were detected in France, being the first reported in Europe (8) (9) ; as of 07/02/2020, a total of 6 cases had been detected: 4 among individuals coming or returning from China and 2 among non-travelers in contact with cases in France. On 07/02/2020, the French health authorities were informed via the European Early Warning and Response System (EWRS) of a confirmed Covid-19 case in the United-Kingdom on 06/02/2020, and who had recently stayed in France. During 18/01-23/01/2020, the index case had attended a conference in Singapore linked to Covid-19 confirmed cases, the first of whom was from Wuhan, China. On 24/01/2020, he flew from London to Geneva for a skiing holiday in France. He stayed for one night in Saint-Gervais-les-Bains,Haute-Savoie and then in a chalet in the ski resort of Contamines-Montjoie, Haute-Savoie. On 28/01/2020, he flew back to the UK from Geneva. He developed moderate symptoms during the night of 24/01/2020 and was symptomatic during the rest of his stay in France. On 07/02/2020, we initiated an investigation to detect potential secondary Covid-19 cases, identify their contacts and prevent transmission. A c c e p t e d M a n u s c r i p t 7 In accordance with the 07/02/2020 surveillance case definition (10) , we defined as a confirmed case a person with a positive SARS-CoV-2 RT-PCR on respiratory samples and a direct or indirect epidemiological link with the chalet in Contamines-Montjoie. A possible case was a patient with an acute respiratory illness, whatever the severity, and a direct or indirect epidemiological link with a confirmed case from the chalet. Confirmed cases were interviewed using bespoke questionnaires on exposure and clinical history, clinical characteristics and their contacts during the period of their clinical symptoms. Depending on the level of risk, we defined contacts as high/moderate, low, or negligible risk, as previously reported (8) . As per the French national guidance for contacts of Covid-19 cases (8), low risk contacts were asked to measure their body temperature twice a day during a 14-day period after their last exposure, and, in case of fever or respiratory symptoms to wear a surgical mask and contact the emergency hotline (SAMU-centre15). In addition, high/moderate risk contacts were isolated at home, and were actively followed up through daily calls. A c c e p t e d M a n u s c r i p t 8 Respiratory samples were either nasopharyngeal swabs (upper respiratory tract) (Sigma Virocult®, Medical Wire Instrument, UK) and endotracheal aspirates (lower respiratory tract). All samples were refrigerated and shipped to the National Reference Center for Respiratory Viruses (Hospices Civils de Lyon), where they were tested for SARS-CoV-2, but also for other respiratory pathogens. Details of the procedures of RNA extraction and real-time RT-PCR (rtRT-PCR) and of the viral load calculation are presented in the supplementary material. Investigations complied with the General Data Protection Regulation (Regulation (EU) 2016/679 and Directive 95/46/EC) and the French data protection law (Law n°78-17 on 06/01/1978 and Décret n°2019-536 on 29/05/2019). Informed consent to disclose information relevant to this publication was obtained from the confirmed cases in France. During 25/1-28/1, the index case stayed in the chalet with 10 other adult British tourists (apartment 1) and a British family of 2 adults and 3 children, residents in France (apartment 2) (Figure 1 ). Of these, 5 tested positive for SARS-CoV-2 in France, 6 were found positive in the UK (including the index case), and one in Spain, indicating an overall attack rate of 75% (12/16) among the tourists/residents in those apartments,82% (9/11) in apartment 1, and 60% (3/5) in apartment 2) (Figure 1-2 ). In addition, 5 other adult British tourists arrived in apartment 1 of the chalet after the index case had left (high risk contacts of the secondary A c c e p t e d M a n u s c r i p t 9 cases). On 07/02, four of those adult British tourists in apartment 1 and the two children of the family in apartment 2 were isolated in hospitals; one adult tourist had left for the UK before 07/02 and was followed up there. On 15/02, one of those adult tourists tested positive while being in hospital isolation in France; he had stayed in apartment 1 of the chalet together with three secondary cases (tertiary case). All cases were adults, apart from one 9 years old child who attended three different schools (school A, B, C) and one ski class while symptomatic. Of all cases, 75% were males. The dates of onset of symptoms of the confirmed cases, excluding the index case, ranged from 27/01 to 12/02 ( Figure 2 ). Of all 6 confirmed cases diagnosed in France, case 4 did not develop any sign or symptom, apart from muscle pain on 27/1/2020 following intense sport activities. Among the other 5 symptomatic confirmed cases, the following signs and symptoms were reported: fever (n=5), dry cough (n=5), wet cough (n=1), asthenia/fatigue (n=3), chills (n=2), sweats (n=2), rhinorrhea (n=3), and myalgia (n=1); four cases had those mild signs/symptoms one week before the first positive test on 07/02 (Figure 3-4) . At the time of diagnosis, they had these symptoms with an even lower intensity, and all had a benign clinical evolution. Case 13, a high-risk contact initially negative for SARS-CoV-2, developed fever and cough with respiratory crackles at auscultation on the fifth day of hospital isolation. A bilateral interstitial syndrome was identified at the CT-scan with bilateral ground-glass opacification predominating on the left. The symptoms of all cases resolved rapidly, without anti-viral treatment. A c c e p t e d M a n u s c r i p t 10 Virological findings of cases All 5 symptomatic confirmed cases were first tested between 6 to 10 days after symptoms onset. For 4 cases, a low viral load detected (often under the limit of quantification of 1 log10 copies/1000 cells) (Figure 3 Because of the large number of contacts of the pediatric case (case 6), particular attention was paid to detect tertiary cases in children in the three schools the child attended while symptomatic. On 08/02, a public meeting was held to inform the parents of two schools (A and B); the parents of school C were informed by telephone. As a precaution, the first two schools were closed for two weeks and the third for one week (end of follow-up period; the pediatric case visited that school on 31/01). On Sunday 09/02, infectious disease specialists A c c e p t e d M a n u s c r i p t 11 and epidemiologists evaluated the risk of 112 school contacts. All children and teachers who were in the same class as the symptomatic pediatric case were considered as high risk contacts and were isolated at home ( Table 2 ). All hospitals in the region implemented emergency plans to accommodate potential tertiary cases. Overall, 172 contacts were identified; 84 (49%) were classified as high/moderate risk and 88 (51%) as low risk (Table 1 ). Of those, 98% (n=169) were contacted; 70 (41%) had respiratory symptoms during the investigation and were thus classified as possible cases; 73 were tested; all tested negative for SARS-CoV-2 except for case 13 who tested positive during hospitalization. No additional cases were identified within the 14-day follow-up period of all the contacts. The movement history of the confirmed cases during their stay in France and their contact tracing is presented in the Supplementary material. Briefly, contacts of the other 5 cases that were monitored included teachers in another school, apartment staff and cleaners, staff in shops and restaurants, and passengers in four buses and three airplanes. Except for case 13 (tertiary case), no SARS-CoV-2 virus was detected in any of the contacts monitored. However, other seasonal respiratory viruses were detected in 64% (n=46) of the tested contacts, representing 62% and 67% of high and low risk contacts, respectively (Table 1) . Overall, 33% of the viral infections detected were due to influenza (75% of influenza A (H1N1)pdm09 virus and 25% of influenza B virus) and 18% were due to a picornavirus (rhinovirus or enterovirus). At school C, 30% (3/10) of contacts of the pediatric case had a picornavirus infection (Table 1 ). In addition, "classical" human coronaviruses such as HUK1 and NL63 were detected in 16% of contacts without any cross reactivity with SARS-CoV-2 molecular diagnostics. A c c e p t e d M a n u s c r i p t 12 In this international community cluster, all cases, but one (tertiary case), were high risk contacts of the index case, indicating that one case may have infected 11 other individuals. Transmission occurred only within the environment of the chalet, where the attack rate was very high. Studies suggested that the basic reproductive number (R0) for Covid-19 ranges (17) . A thorough study of those factors and environmental dynamics will be important to delineate their relative contribution to the phenomenon of super-spreading. As the majority of persons present in the chalet on 07/02 reported current or previous respiratory symptoms, they were all hospitalized and tested for SARS-CoV-2. Following several detailed interviews, it was confirmed that one case did not develop any symptoms. Anecdotal reports suggest the occurrence of asymptomatic cases of Covid-19. In recently published reports, SARS-CoV-2 was detected in asymptomatic travelers returning to A c c e p t e d M a n u s c r i p t 13 Germany from China (18) and in asymptomatic family members in two family clusters in China (19) (20) . The possibility of transmission from an asymptomatic individual is not clear. Recently published reports suggested potential transmission during the incubation period of the index patients (21) (22) . In line with another recently published study (23), our study indicated that an asymptomatic individual had similar viral load as a symptomatic case, both at low levels, suggesting a transmission potential of asymptomatic or minimally symptomatic cases. To confirm this finding, we used quantitative and normalization methods, to allow valid comparisons of the different specimens. As our tertiary case was exposed to two symptomatic and one asymptomatic case in apartment 1 of the chalet, it was not possible to disentangle who of those was the source of infection. However, given that the virus can remain viable and infectious on surfaces up to days, environmental contamination via the index case cannot be excluded (24). Future seroprevalence studies will be warranted to estimate the prevalence of asymptomatic infections, and household and viral shedding studies to determine the transmission dynamics of asymptomatic individuals (25). All symptomatic cases of this cluster treated in France initially presented with mild respiratory symptoms and none of them showed signs of severe clinical illness. This mild clinical picture contrasts with the first reports of Covid-19 cases series, which featured a high proportion of severe pneumonia and a considerable case-fatality (6) (7) . This indicates that the proportion of mild SARS-CoV-2 may be higher than initially suspected. In our cluster, cases could continue their activities, including skiing (and schooling for the child) while symptomatic, and interacted with many other individuals, increasing possibilities for transmission. Despite those interactions, only one tertiary case was detected and linked to the chalet. It is unlikely that we missed symptomatic cases, as we monitored and tested all contacts that developed symptoms during the 14-day follow up period. However, we may have missed asymptomatic cases. Despite extensive contact tracing, some contacts were either impossible to trace (e.g. people sharing ski cabins or lifts, co-travelers in public transportations who did not book their tickets online) or evaluated as negligible because of short and/or distant contacts (e.g. casual contacts). Accidental events at risk of transmission in such occasions, such as an episode of cough of sneezing, cannot be ruled out. The High risk High risk 25 25 (100%) 10 (40%) 10 (40%) 0 (0%) 0 (0%) 0(0%) 1 IAV, 2IBV 0 (0%) 3 (30%) Low risk 1 1 (100%) 1 (100%) 1 (100%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (100%) High risk Case 2 to 6: all virological data were obtained from nasopharyngeal swabs. Case 4 was asymptomatic; for visual purposes, we arbitrarily assigned 31-January as D1, as it was the median of the days of onset of the other (symptomatic) cases. Case 13: virological data were obtained from endotracheal aspirates (ETA), all nasopharyngeal swabs being negative (before or during the period of positive ETA). All viral load are expressed as log10(copies/1 000 cells). Results below the quantification limit are positive but non quantifiable. *: D1 correspond to the date of Covid-19 symptoms onset Symptomatic period for each confirmed case and contact / Patient in the UK / : hospital discharge All virological data were obtained from nasopharyngeal swabs, unless specified. *: results on endotracheal aspirates Virological data are represented by +: positive and quantified, + NQ: positive but not quantifiable, -: negative, nd: not determined. A Novel Coronavirus from Patients with Pneumonia in China Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study Novel Coronavirus (2019-nCoV) situation reports European Centre Disease Prevention and Control. Situation update-worldwide Clinical features of patients infected with 2019 novel coronavirus in Wuhan Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study First cases of coronavirus disease 2019 (COVID-19) in France: surveillance, investigations and control measures Novel coronavirus (2019-nCoV) early-stage importation risk to Europe Covid-19, France et Monde First cases of COVID-19 in Europe: clinical and virological data The reproductive number of COVID-19 is higher compared to SARS coronavirus Transmission dynamics of the etiological agent of SARS in Hong Kong: impact of public health interventions Discovery of a novel coronavirus associated with the recent pneumonia outbreak in 2 humans and its potential bat origin. bioRxiv Membrane ectopeptidases targeted by human coronaviruses Super-spreaders in infectious diseases The Role of Super-Spreaders in Infectious Disease Evidence of SARS-CoV-2 Infection in Returning Travelers from Wuhan, China A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster Asymptomatic cases in a family cluster with SARS-CoV-2 infection Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany A c c e p t e d M a n u s c r i p t 19