Incidence and Risk Factors of Illnesses Presumably Caused by A SARS-CoV-2 Infection in The General Population During The Lockdown Period: A Multi-Cohort Study.

Background Our main objectives were to estimate the incidence of illnesses presumably caused by SARS-CoV-2 infection during the lockdown period and to identify the associated risk factors. Methods Participants from 3 adult cohorts in the general population in France were invited to participate in a survey on COVID-19. The main outcome was possible COVID-19, dened as a sudden onset of cough, fever, dyspnea, ageusia and/or anosmia, that lasted more than 3 days and occurred during the 17 days before the survey. We used delayed-entry Cox models to identify associated factors. Results Between April 2, 2020 and May 12, 2020, 279,478 participants were invited, 116,903 validated the questionnaire and 106,848 were included in the analysis. Three thousand thirty-ve cases of possible COVID-19 were reported during 62,099 person-months of follow-up. The cumulative incidences of possible COVID-19 were 6.2% (95% Condence Interval (95%CI): 5.7%; 6.6%) on day 15 and 8.8% (95%CI 8.3%; 9.2%) on day 45 of lockdown. The risk of possible COVID-19 was lower in older age groups and higher in French regions with a high prevalence of SARS-CoV-2 infection, in participants living in cities >100,000 inhabitants (vs rural areas), when at least one child or adolescent was living in the same household, in overweight or obese people, and in people with chronic respiratory diseases, anxiety or depression or chronic diseases other than diabetes, cancer, hypertension or cardiovascular diseases. Conclusion The incidence of possible COVID-19 in the general population remained high during the rst two weeks of lockdown, and decreased signicantly thereafter. Modiable and non-modiable risk factors were identied.


Introduction
Following the identi cation of a novel coronavirus (SARS-CoV-2) in Wuhan, China in December 2019 and its worldwide spread, the rst imported COVID-19 cases were initially reported in France on January 24, 2020. Less than two months later, the French government declared a nationwide epidemic (phase 3) and a generalized lockdown procedure was set-up on March 17, 2020. Public health reports have shown that lockdown had a marked impact on the dynamics of the pandemic with a clear downward trend in new hospitalizations from April 1, 2020, and a consecutive decrease in the number of deaths from April 7, 2020. 1,2 Thus, the French government eased these restrictions on May 11th. Although there is obvious epidemiologic evidence that the lockdown period had a signi cant impact on severe COVID-19, estimates of its impact on mild-to-moderate COVID-19 are based on modelling studies, 3 and are not yet supported by clinical evidence.
Our main goals were 1) to estimate the incidence of illnesses presumably caused by SARS-CoV-2 infection during the lockdown period; 2) to identify the associated risk factors. We also described associated symptoms, preventive behaviors and healthcare in relation to these illnesses.

Design
The SAPRIS ("SAnté, Perception, pratiques, Relations et Inégalités Sociales en population générale pendant la crise COVID-19") survey was begun in March 2020 to evaluate the main epidemiological, social and behavioral challenges of the SARS-CoV2 epidemic in France in relation to social inequalities in health and healthcare. SAPRIS is based on a consortia of prospective cohort studies involving two childcohorts (not presented in this study) and three general population-based adult cohorts: CONSTANCES, a "general population" cohort including a representative sample of 215,000 adults (including 66,000 followed by internet) aged 18 to 69 at inclusion and recruited from 2012; 4 E3N / E4N, a multigenerational adult cohort based on a community of families with 113,000 participants (women recruited in 1990 and still actively followed-up, their offspring and the fathers of these offspring) among whom 90,000 have been invited to an internet follow-up; 5 and NutriNet-Santé a nutritional general population-based internet cohort started in 2009, with 170,000 included participants. 6 Ethics and public involvement Ethical approval and written informed consent was obtained from each participant before enrolment in the original cohort. According to French law, the present nested survey did not require speci c additional written consent from the participant. It was approved by the Inserm ethics evaluation committee (approval #20-672 dated March 30, 2020). Representatives of the participants tested and validated the questionnaires, but they did not contribute to other aspects related to the design, conduct, reporting or dissemination of the research.
All participants from the original cohorts with regular access to electronic (internet) questionnaires were invited to participate in the current SAPRIS survey ( gure 1). A rst self-administered questionnaire covered the lockdown period and was sent from April 1, 2020 and returned before May 12, 2020. A second questionnaire covered the post-lockdown period and was sent between May 5, 2020 and June 15, 2020. The present study used the data from the rst self-administered questionnaire, which included questions on socio-demographics, household size and composition, SARS-CoV2 diagnosis, a detailed description of the subject's symptoms in the two weeks before the questionnaire, comorbidities, healthcare use and treatment, employment, daily life, child care, alcohol, tobacco and cannabis use, social and sexual life, preventive measures, risk perception and beliefs.
Additional speci c socio-demographic and clinical characteristics were extracted from original cohort databases. Symptoms were reported if they had been present at least once in the last 14 days. If a symptom had been, but was no longer present when the questionnaire was completed, the duration was noted on a scale (less than 1 day, 1 to 3 days, 4 to 7 days, 8 to 14 days, >14 days). Finally, the total time (in days) between the onset of the rst symptoms and the questionnaire was reported. All visits outside the home and the use of preventive measures in the 7 days before the questionnaire were reported.

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The main outcome was possible COVID-19, de ned according to the European Centre for Disease Prevention and Control as at least one of a cough, a fever, a dyspnea, a sudden onset of anosmia, ageusia or dysgeusia, 7 that lasted more than 3 days and occurred during the at-risk period. Participants were also requested to report the occurrence of cough, fever or dyspnea before March 1, 2020 or between March 1 and the two weeks before the questionnaire, and whether they or any other household members had tested positive for SARS-CoV-2 since the beginning of the pandemic. The primary "at-risk period" was de ned as the 17 days before the self-administered questionnaire for each patient, corresponding to the 14 days to report the presence of symptoms, plus 3 days for the minimum duration of our de nition of possible COVID-19. In a rst sensitivity analysis, no restriction was made on the minimum duration of symptoms, extending our primary case-de nition of possible COVID-19 to illness that lasted less than 4 days. In a second sensitivity analysis, the at-risk period was de ned as between March 16, 2020 and the date of the questionnaire for all participants. This de nition made it possible to include all possible COVID-19 that occurred during the lockdown period.

Statistical methods
We determined that 100,000 subjects were needed to have a power of at least 80% to identify associations (Odds-Ratio, OR <0.9 or OR >1.1) between covariates and possible COVID-19 in a wide range of situations, assuming 10% of events and 10% to 90% exposure.
We used inverse probability weighting to correct for selection bias (when only a subgroup of the whole cohort was invited to participate by internet) and inverse probability weighting to correct for nonparticipation bias in those who were invited. Weights were estimated using logistic regression models, with selection or participation as the response variables, and socio-demographic characteristics as covariates. Unweighted and weighted daily incidence rates of possible COVID-19 and 95% con dence intervals were estimated with an exact method based on the Poisson distribution. Estimates of unweighted and weighted cumulative incidences on days 15 (March 30, 2020), 30 (April 14, 2020) and 45 (April 29, 2020) of lockdown were obtained as one minus the estimated probability of survival free of possible COVID-19 at that time.
To account for potential heterogeneity between the cohorts, left-truncation and censorship in the data, factors associated with the occurrence of possible COVID-19 were identi ed using unweighted data and delayed-entry Cox models with strati cation on the source cohort. The start of the at-risk period was de ned according to the calendar day for each participant and survival time was calculated as the time between that day and the day the questionnaire was lled-out in case of no symptom or the day the rst symptoms were reported in possible COVID-19 cases. Multivariable analysis was performed including all factors associated with possible COVID-19 cases on univariable analysis. All analyses were performed with SAS 9·4 software (SAS Institute Inc., Cary, North Carolina, USA). A P-value <.05 was considered to be statistically signi cant.
Eighty out of 189 participants who experienced possible COVID-19 and were tested reported a positive (RT-PCR) test result (supplementary table 1). Headaches, rhinorrhea and fatigue were frequently reported in addition to the symptoms de ning possible COVID-19. Seven-hundred and forty-nine (25%) participants with possible COVID-19 sought medical advice and a diagnosis of COVID-19 was considered to be very likely or likely by the physician in 375 (62%) of the rst 604 medical visits. Paracetamol was taken by 62% and antibiotics by 6% of participants with possible COVID-19. Only 8 participants used chloroquine or hydroxychloroquine. Forty percent participants stayed strictly con ned at home following symptoms onset. Table 2 presents the unweighted incidence rates of possible COVID-19 and the hazard ratios obtained from the univariable Cox models with strati cation on source cohort. Almost all tested factors were found to be associated with possible COVID-19. A positive RT-PCR in another household member was strongly associated with possible COVID-19 in the participant; this variable was not included in the multivariable analysis to avoid over tting. On multivariable analysis (Table 3), the risk of COVID-19 was lower in older age groups and was higher in the Ile-de-France and Grand-Est regions (compared to other French metropolitan regions), in those living in cities > 100,000 inhabitants (vs rural areas), when at least one child or adolescent was living in the same household, in overweight or obese participants, and in people with chronic respiratory diseases, anxiety or depression and chronic diseases other than diabetes, cancer, hypertension or other cardiovascular diseases. The observed associations were con rmed in the sensitivity analyses, except that male gender, living in a household of size 2 and being retired were negatively associated with the risk of possible COVID-19 in addition to factors identi ed in the primary analysis (supplementary Tables 2 & 3).

Discussion
Lockdown was associated with a strong decrease in the incidence of possible COVID-19 in the French adult population that participated in this survey. This study shows that the cumulative incidence of possible COVID-19 on day 45 of lockdown ranged from 7.7-10.2% depending on the estimation method, that more than sixty percent of new cases occurred within the rst two weeks, and that the daily incidence remained at a sustained low level 1 month after lockdown and thereafter. In addition, we identi ed several risk factors of possible COVID-19 during this period, and have described the immediate consequences in terms of access to healthcare and treatment associated with these syndromes. To our knowledge this is the rst study to report the signs and symptoms of COVID-19 on a nationwide scale and during lockdown.
Considering the estimated 5-day median incubation time of COVID-19 and the appearance of symptoms within 12 days after infection, 9 a large proportion of participants who developed possible COVID-19 in the rst two weeks were probably infected before lockdown, most of them in the community or at the workplace. It is therefore not surprising to nd the association of mild-to-moderate possible COVID-19 in adults with decreasing age, 10 living in urban versus rural environments, 11 in highly prevalent French regions, 12 who are healthcare professionals, 13 all factors that were reported in other studies performed before lockdown. We also identi ed factors indicating potential secondary household-related transmission, 14 such as living with children or another person with a positive diagnosis of SARS-CoV-2.
However, it was impossible to determine a timeframe for the latter factor and identify whether the participant was the source of infection or was infected by a household member. Obesity has been found to be linked with the risk of severe possible COVID-19 in young patients, 15 and also suspected to increase the susceptibility to infection. 16 Different theories suggest that asthma, COPD and other respiratory diseases may be negatively or positively associated with the susceptibility to SARS-CoV-2 infection due to up or down regulation of angiotensin-converting enzyme-2 expression. However, all of these respiratory diseases have been shown to be associated with the severity of illness in infected persons. [17][18][19] Since 30-60% of SARS-CoV-2 infections are asymptomatic 20-23 and were not included in our possible COVID-19 cases, by de nition, it is not surprising to nd the presence of these conditions, which are known to be associated with more severe disease, in subjects with symptomatic SARS-CoV-2 infection.
Our study has several limitations. The most important limitation is the lack of virological con rmation of possible COVID-19 and the risk of misclassi cation of a SARS-CoV-2 infection and a disease from another etiology. During lockdown, French health authority recommendations limited SARS-CoV-2 testing with a RT-PCR test to patients with severe symptoms requiring hospitalization or to speci c situations (e.g. healthcare workers with symptoms). Thus, testing was not available to most participants.
Nevertheless, the in uenza season peaked on week 6 and ended on week 10 to 12, just before lockdown, which limits the risk of acute respiratory infection caused by an in uenza virus. In addition, 42% of the small group of participants who were tested for SARS-CoV-2 infection in our study reported a positive RT-PCR result. This positive rate was higher than that reported in the community (30% at its highest between March 23 and March 29, 2020). 24 However, a 15-20% seroprevalence of SARS-CoV-2 was reported in Spain in individuals from the general population who presented symptoms compatible with COVID-19. 23 It is therefore likely that the cause of illness was not SARS-CoV-2 infection in a signi cant proportion of our possible COVID-19 cases and only studies using sensitive and speci c virological methods can accurately quantify the extent of the SARS-CoV-2 epidemic. To avoid recall bias, which is another potential limitation of our study, we limited the questionnaire to the symptoms present in the past 14 days. Finally, although participation bias was accounted for with an appropriate weighting method, our ndings should not be considered to be strictly representative of the general adult population in France.
Nevertheless, the large number of subjects from all social categories allows us to draw robust conclusions on the factors associated with the occurrence of possible COVID-19 in France.

Conclusion
In conclusion, to our knowledge this is the rst study to quantify the incidence of possible COVID-19 in the general population on a nationwide scale and during a lockdown, and it shows the signi cant impact of lockdown on the dynamics of the incidence of infection. A follow-up study is ongoing and will be combined with SARS-CoV-2 serological tests of all participants to estimate the seroprevalence and identify the associated factors.

Strengths And Limitations Of This Study
Lockdown was associated with a strong decrease in the incidence of possible COVID-19 in the French adult population.
We identi ed several risk factors of possible COVID-19 during this period, and we described the immediate consequences in terms of access to healthcare and treatment.
The most important limitation was the lack of virological con rmation of possible COVID-19 and the risk of misclassi cation of a SARS-CoV-2 infection and a disease from another etiology.
Although participation bias was accounted for with an appropriate weighting method, our ndings should not be considered to be strictly representative of the general adult population in France Abbreviations OR: Odds-Ratio, CI: Con dence Intervals Declarations Ethics approval and consent to participate Ethical approval and written informed consent was obtained from each participant before enrolment in the original cohort. The study was approved by the Inserm ethics evaluation committee (approval #20-672 dated March 30, 2020). According to French law, the present nested survey did not require speci c additional written consent from the participant. Representatives of the participants tested and validated the questionnaires, but they did not contribute to other aspects related to the design, conduct, reporting or dissemination of the research.

Avaibility of data and materials
In regards to data availability, data of the study are protected under the protection of health data regulation set by the French National Commission on Informatics and Liberty (Commission Nationale de l'Informatique et des Libertés, CNIL). The data can be available upon reasonable request to the corresponding author (fabrice.carrat@iplesp.upmc.fr), after a consultation with the steering committee of the Sapris study. The French law forbids us to provide free access to Sapris data; access could however be given by the steering committee after legal veri cation of the use of the data. Sponsor and funding sources played no role in the study design, data collection, analysis, interpretation or drafting of the study. FC had full access to all data in the study and FC and NB made the nal decision to submit the study for publication.
This study