key: cord-0779909-95s88jou
authors: Coelho, Julien; Micoulaud-Franchi, Jean-Arthur; Wiet, Anne-Sophie; Nguyen, Duc; Taillard, Jacques; Philip, Pierre
title: Circadian misalignment is associated with Covid-19 infection
date: 2022-03-26
journal: Sleep Med
DOI: 10.1016/j.sleep.2022.03.015
sha: 8953cb641eb476065a2b39d73c90d0d157aad77c
doc_id: 779909
cord_uid: 95s88jou

BACKGROUND: Circadian system contributes to the regulation of inflammatory processes, but the role of circadian misalignment as a risk factor for contracting Covid-19 has up to now been poorly studied. The aim of this study was to explore the relationship between circadian misalignment (chronic disturbance of the circadian system) and the risk of Covid-19 infection in a population of subjects suspected of contact or infection with SARS-CoV-2. METHODS: Cross-sectional single-center study conducted during a period without lockdown in winter 2021. Recruitment took place in a Covid-19 outpatient testing center. Subjects between 18 and 45 years old were included whether they were symptomatic or not, healthcare workers or not, in contact with a Covid-19 case or not. To determine social jetlag, a proxy of circadian misalignment, they were asked about their usual sleep-wake behaviors. Usual sleep duration and sleep-wake timing were explored on workdays and free days. Social jetlag was defined as at least 2 hours shift of circadian alignment (defined as the difference between mid-sleep on workdays and mid-sleep on free days, mid-sleep as the median between bedtime and rise time). RESULTS: One thousand fourteen subjects were included (sampling rate: 10.8%, 39% men, mean age 28± 8) with 56 subjects positive for Covid-19 (positivity rate: 5.5%). Usual mean sleep duration was equivalent in both groups (7h47 versus 7h49, p=0.733). Social jetlag greater than 2 hours comprised 33.3% of subjects in the Covid-19 group versus 20.6% in the control group (p=0.026). After adjustment on age, gender, BMI and work schedules, subjects presenting with social jetlag greater than 2 hours had a 2.07-fold higher likelihood to test positive than subjects who had identical sleep-wake timing on workdays and free days (OR=2.07, 95%CI= [1.12-3.80], p=0.024). CONCLUSION: Circadian misalignment not only is present in subjects infected by Covid-19 but could also be responsible for a higher likelihood of being infected. The chronobiological impact on the immune system or a higher likelihood of being exposed to social contacts during nocturnal activities could explain our findings, which need to be confirmed in a future large cohort study. Regular sleep-wake timing could ultimately become a target for preventing Covid-19 infection.

-Circadian misalignment is associated with Covid-19 infection (OR=2.07 [1.12-3.80]) 23 -Mean sleep duration was not associated with Covid-19 infection 24 -Appropriate schedules could help to reduce the risk of Covid-19 infection 25

Circadian system contributes to the regulation of inflammatory processes, but the role of 27 circadian misalignment as a risk factor for contracting Covid-19 has up to now been poorly 28 studied. The aim of this study was to explore the relationship between circadian misalignment 29 (chronic disturbance of the circadian system) and the risk of Covid-19 infection in a population 30 of subjects suspected of contact or infection with SARS-CoV-2. 31

Cross-sectional single-center study conducted during a period without lockdown in winter 33 2021. Recruitment took place in a Covid-19 outpatient testing center. Subjects between 18 and 34 45 years old were included whether they were symptomatic or not, healthcare workers or not, 35 in contact with a Covid-19 case or not. To determine social jetlag, a proxy of circadian 36 misalignment, they were asked about their usual sleep-wake behaviors. Usual sleep duration 37 and sleep-wake timing were explored on workdays and free days. Social jetlag was defined as 38 at least 2 hours shift of circadian alignment (defined as the difference between mid-sleep on 39 workdays and mid-sleep on free days, mid-sleep as the median between bedtime and rise time). 40

One thousand fourteen subjects were included (sampling rate: 10.8%, 39% men, mean age 42 28± 8) with 56 subjects positive for Covid-19 (positivity rate: 5.5%). Usual mean sleep duration 43 was equivalent in both groups (7h47 versus 7h49, p=0.733). Social jetlag greater than 2 hours 44 comprised 33.3% of subjects in the Covid-19 group versus 20.6% in the control group 45 (p=0.026). After adjustment on age, gender, BMI and work schedules, subjects presenting with 46 social jetlag greater than 2 hours had a 2.07-fold higher likelihood to test positive than subjects 47 who had identical sleep-wake timing on workdays and free days (OR=2.07, 95%CI= [1.12-48 3.80], p=0.024). 49

Circadian misalignment not only is present in subjects infected by Covid-19 but could also be 51 responsible for a higher likelihood of being infected. The chronobiological impact on the 52 immune system or a higher likelihood of being exposed to social contacts during nocturnal 53 activities could explain our findings, which need to be confirmed in a future large cohort study. 54

The Covid-19 epidemic has massively disrupted sleep-wake behaviors in western society (1). 57

Social distancing has disturbed daily life routines, increasing worry, isolation, stress, and screen 58 time, which are known contributors to impaired sleep (2,3). However, circadian clocks 59 contribute to the regulation of inflammatory processes (control the function of our immune 60 system, virus replication and the severity of infections) which are particularly important in this 61 context of a pandemic (4). Indeed, a recent study found that the expression of 30% of 332 62 human proteins that interact with SARS-CoV-2 proteins shows circadian oscillation (5), and 63 that most potential drug targets exhibit robust 24-hour oscillation in at least one organ or tissue 64 in mammalian systems (6). Moreover, people with circadian misalignment/disruption (a 65 chronic disturbance of the circadian system) due to internal (age, blindness) or external (shift 66 work, social jetlag) have a weaker immune system and could be more susceptible to such viral 67 respiratory diseases (6). Social jetlag is a chronic misalignment between internal circadian 68 clocks and external time (social time). Taken together, these results support the hypothesis that 69 circadian misalignment could promote SARS-CoV-2 infection (6-8). Nevertheless, usual 70 circadian misalignment as a risk factor for contracting Covid-19 has up to now been poorly 71 studied. Only a 2021 study showed that night work, which involves circadian disruption, was 72 associated with an 1.85-fold increased risk of Covid-19 infection (9). Therefore, the aim of this 73 study was to explore the relationship between usual circadian misalignment (describe by social and sleep-wake behaviors were compared between the Covid-19 group and the control group 98 using a X 2 test for qualitative variables or the t-test for quantitative variables. Adjusted odds-99 ratio (OR), 95% confidence interval (CI) and p-value were then assessed using a logistic 100 regression with age, gender, BMI, and work schedules as covariates. The threshold of 0.05 was 101 used to determine significance. 102 J o u r n a l P r e -p r o o f Population: Out of 9,419 patients (41% of men, mean age of 28±8) tested in the center during 104 the study period and meeting the inclusion criteria, 1,014 participants were included since they 105 were tested and interviewed during the work shifts of the student nurses assigned to the project 106 (sampling rate: 10.8%). The population interviewed was representative of the whole sample in 107 terms of age and sex (39% men, mean age 28± 8). Out of the 1,014 subjects recruited, 56 108 participants tested positive for Covid-19 (5.5%). This positivity rate was similar to the 109 department's data over the period (from 4.3% on March 12 to 7.5% on April 23). Table 1  110 describes socio-demographic and clinical patterns of the Covid-19 group and the control group. 111 A total of 20.6% of participants were overweight, including 6% obese, 27.5% had shifted 112 schedules including 18.3% with consecutive hours of more than 12 hours, 29.1% were 113 healthcare workers and 39.5% were students. Cough, fatigue, fever, headache, sore throat, 114 aches, loss of taste and/or smell, shortness of breath and chest pain were more frequent in the 115

Covid-19 group than in the control group. Presence of at least one chronic disease was 116 equivalent in both groups (10.7% versus 10.2%). 117

Circadian misalignment: Two-hundred eleven participants (20.8%) had social jetlag. The lack of association in this sample may be due to the low prevalence of significant 147 deprivation (sleep duration less than 6 hours per night on workdays: 5.2% versus 35.9% in a 148 2019 French study conducted before the outbreak (21)). Indeed, sleep duration has increased 149 significantly since the beginning of the Covid-19 epidemic in western society (22). 150

The study has some limitations. First, the subjects were included on a voluntary basis, although 151 their characteristics were quite similar to the source population, except for a high proportion of 152 students. However, supplementary analyses showed that the association between social jetlag 153 and Covid-19 infection was consistent across both groups (students: 31.6% of social jetlag in 154 the Covid-19 group versus 21.2% in the control group and non-students: 34.3% versus 20.1%). 155

Second, the design was cross-sectional, although we focused on usual sleep-wake timing, which 156 limited reverse causality. A large cohort study is now required to confirm our findings. Finally, 157 the formula used to calculate social jetlag does not take into account sleep latency as described 158 by Roenneberg et al. and could lead to an erroneous estimate (11). 159

In conclusion, circadian misalignment, i.e., a chronic disturbance of the circadian system 160 observed frequently in shift workers and evening subjects with sleep-wake timing constrained 161 by work, could prove to be another risk factor for Covid-19 infection in the general population 162 due to continuing social constraints. Defining the most appropriate schedules for (tele)-working 163 or staying at home to maintain a healthy body and circadian clock could help to reduce the risk 164 of infection and rapid transmission and manage the dynamics of the current pandemic and 165 future ones. Thus, 'temporal' social interventions need to be considered along with 'spatial' J o u r n a l P r e -p r o o f 

3. Ford MB. Social distancing during the COVID-19 pandemic as a predictor of daily 191 psychological, social, and health-related outcomes

Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity

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COVID-19 management in light of the circadian clock

COVID-19, circadian rhythms and sleep: from virology to chronobiology

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Circadian disturbances, sleep 202 difficulties and the COVID-19 pandemic

Shift work is 204 associated with increased risk of COVID-19: Findings from the UK Biobank cohort

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All persons who have made substantial contributions to the work reported in the manuscript (e.9., technical help, writing and editing assistance, general support), but who do not meet the criteria for authorship, are named in the Acknowledgements and have given us their written permission to be named. If we have not included an Acknowledgements, then that indicates that we have not received substantial contributions ftom non-authors.