key: cord-268809-plgip4h6 authors: Bielecki, Michel; Züst, Roland; Siegrist, Denise; Meyerhofer, Daniele; Crameri, Giovanni Andrea Gerardo; Stanga, Zeno Giovanni; Stettbacher, Andreas; Buehrer, Thomas Werner; Deuel, Jeremy Werner title: Social distancing alters the clinical course of COVID-19 in young adults: A comparative cohort study date: 2020-06-29 journal: Clin Infect Dis DOI: 10.1093/cid/ciaa889 sha: doc_id: 268809 cord_uid: plgip4h6 BACKGROUND: Social distancing and stringent hygiene seem effective in reducing the number of transmitted virus particles, and therefore the infectivity, of coronavirus disease 2019 (COVID-19) and could alter the mode of transmission of the disease. However, it is not known if such practices can change the clinical course in infected individuals. METHODS: We prospectively studied an outbreak of COVID-19 in Switzerland among a population of 508 predominantly male soldiers with a median age of 21 years. We followed the number of infections in two spatially separated cohorts with almost identical baseline characteristics with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) before and after implementation of stringent social distancing. RESULTS: Of the 354 soldiers infected prior to the implementation of social distancing, 30% fell ill from COVID-19. While no soldier in a group of 154, in which infections appeared after implementation of social distancing, developed COVID-19 despite the detection of viral RNA in the nose and virus-specific antibodies within this group. CONCLUSIONS: Social distancing not only can slow the spread of SARS-CoV-2 in a cohort of young, healthy adults but can also prevent the outbreak of COVID-19 while still inducing an immune response and colonizing nasal passages. Viral inoculum during infection or mode of transmission may be key factors determining the clinical course of COVID-19. COVID-19 is a pandemic disease [1] transmitted from human to human [2] caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019 in Wuhan, mainland China [3] [4] [5] . COVID-19 can have a severe to fatal course, primarily in the elderly populations [6] , but it also affects children [7] and young adults [8] , in which the clinical course has been described to be mild or even asymptomatic [9] . Physical interventions such as social distancing [10, 11] , wearing face masks [12] and implementing strict hygiene measures [13] reduce the rate of infection by reducing the transfer of respiratory viruses from infectious to susceptible persons through contact, droplets, or aerosols [14] . These interventions not only lower the chance of infection but also quantitatively reduce the viral inoculum received by the recipient [15, 16] and may change the route of transmission [17] from direct droplet-transmission in close proximity to the infecting person [18] to indirect transmission via contaminated surfaces [19] ) . Higher nasal viral load is associated with worse clinical outcomes for severe acute respiratory syndrome [2, 20] , and higher initial viral exposure is associated with more severe disease [21] . To our knowledge, it is unknown if lowering the viral inoculum during infection with SARS-CoV-2 or altering the mode of infection by physical means can affect the clinical course of the disease. Here, we present an outbreak at a Swiss Army Base with two very similar groups infected prior and after the implementation of stringent social distancing and hygiene A c c e p t e d M a n u s c r i p t measures (SDHMs). While both groups show evidence of infection, the rate of symptomatic COVID-19 amongst the infected soldiers differed significantly amongst the two groups and was much lower in the cohort where infection happened after the implementation of these measures. We provide evidence that SDHMs not only are effective in reducing transmission but also can alter the clinical course of COVID-19 in infected individuals. We hypothesize that the difference in the clinical presentation of infected persons might be due to lower viral inoculum during infection or an altered mode of transmission of the virus, but further studies are needed to answer this question. A c c e p t e d M a n u s c r i p t We recruited soldiers stationed at a Swiss Army Base in Airolo between March 25 and April 14, 2020. Patients not feeling fit for service were required to report to our clinic and were promptly isolated and tested for COVID-19 by nasopharyngeal swabs. Additionally, asymptomatic soldiers were sampled cross-sectionally as indicated in We observed a COVID-19 outbreak at a Swiss Army base in Airolo. Three companies (508 soldiers) were stationed at the base (Table 1) (Table 1) were similar, with a median age of 20.4 years (range, 18-28 years). Due to a stringent recruitment process, soldiers with severe health-related constraints are generally excluded from military service. Company 1 consisted exclusively of male soldiers, while 12% of companies 2 and 3 were women. Some of the soldiers, instructors, and other personnel at the base were stationed in separate units and therefore grouped as "other". They were excluded from further analysis due to group heterogeneity and segmentation into various subgroups with a very low sample size each. A c c e p t e d M a n u s c r i p t On March 11, 2020, we diagnosed the first patient suffering from COVID-19 in company 3; we refer to this date as day 1 of the outbreak. In the following weeks, we observed an epidemic in companies 2 and 3 as depicted in figure 1A , while company 1 had no cases. On day 9, it became clear that the disease was widely spreading within companies 2 and 3; both units were put under quarantine, and hygiene measures were rigidly enforced across all three companies: Soldiers had to keep a distance of at least 2 m from each other at all times, and in situations where this could not be avoided (e.g., military training), they had to wear a surgical face mask. A distance of 2 m was enforced between the beds and during meals. All sanitary facilities were cleaned and disinfected twice daily. Symptomatic soldiers were immediately separated and required to report to our clinic where they were tested for COVID-19 using nasopharyngeal swabs. Strict separation of the unaffected company 1 from the other companies was enforced. Until data censoring on day 54, 29% (102/354) of companies 2 and 3 suffered from PCR-confirmed symptomatic COVID-19. None of the 154 soldiers from company 1 was diagnosed with COVID-19 ( Figure 1A ). All soldiers with symptoms compatible with a respiratory infection, or who did not feel fit for service, were required to present at our clinic. Additionally, symptoms as well as vital parameters were assessed daily in the unaffected company 1. It is thus unlikely that we missed a symptomatic case of COVID-19. We tested 15 symptomatic soldiers from company 1 for COVID-19; all were negative. presented symptomatically in our clinic nor showed symptoms in our daily assessments during the following 19 days of follow-up despite daily assessment. Viral concentrations were lower than in symptomatic patients ( Figure 3 ) but still detectable. Since 29% of the soldiers of companies 2 and 3 had previously presented symptomatically for COVID-19, more than 30% of this population must have been infected asymptomatically but still developed a detectable immune response. Infection of these soldiers is likely to have happened after the implementation of SDHMs given that these measures were implemented 25 days prior to the testing date. The fraction of symptomatic patients with COVID-19 amongst all soldiers with evidence of exposure to SARS-CoV-2 either by PCR or serology was significantly lower (p=0.02, Fisher's exact test) in company 1 (0/13, 0%) than in companies 2 and 3 (45/113, 40%). A c c e p t e d M a n u s c r i p t companies also had a higher probability of developing COVID-19 when infected. More than 50% of the soldiers of all companies could be sampled, however, 36% of company 1 and 42% of companies 2 and 3 either refused to participate or were not available ( Figure 2 ). Our sample is likely to be representative for all companies, since we We treated more than 100 young, previously healthy, adult patients with COVID-19 at our clinic; all were treated symptomatically. No patient died, was admitted to the intensive care unit, or needed mechanical ventilation. One patient was referred to a hospital with interstitial pneumonia requiring oxygen supplementation for four days but recovered without obvious sequelae. Despite the high reported prevalence of thromboembolic complications among severely ill patients with COVID-19 [8] , we observed no thromboembolic complications in our population, although pharmacological thrombosis prophylaxis was only used in one case (the hospitalized patient). However, mechanical thrombosis prophylaxis was applied by encouraging physical training and involvement in cleaning and disinfection measures. We describe an outbreak of SARS-CoV-2 infections in young, healthy soldiers in two spatially separated groups with almost identical baseline characteristics but different clinical courses. While one cohort was heavily affected by COVID-19, with 102 cases of suffered from COVID-19. Strict enforcement of SDHMs prior to infection therefore reduced the rate of COVID-19 amongst those infected. Since we followed up the soldiers for 19 days after testing and soldiers were required to immediately report to our clinic if they became symptomatic during this period, we can exclude that any of the soldiers tested on that day later developed symptoms: 99% of cases become symptomatic before day 14 after infection [22] . While SDHMs reduce the reproductive number [23, 24] , these non-pharmacological interventions have to our knowledge not been known to reduce the fraction of patients suffering of COVID-19 amongst those who are infected prior to this study. A c c e p t e d M a n u s c r i p t Although all three companies were very similar demographically, all members of unaffected company 1 were male soldiers, but approximately 10% of the affected companies 2 and 3 were female. A key role for gender in the spread of the disease is unlikely as other studies have reported no differences in viral shedding between males and females [25] . The literature on the ratio of asymptomatic courses is controversial ranging from 4% of a highly selected and exposed group in Shanghai [26] , 18% on the Diamond Princess cruise ship [27] up to 75% [28, 29] of cross-sectional studies, some even reporting clusters of entirely asymptomatic cases [30] . This large range of the rate of symptomatic COVID-19 amongst infected might reflect the differential implementation of measures to prevent exposure to the virus or the mode of infection; as observed between the two groups reported in this study. The companies 2 and 3 showed high infection rates approaching the proposed level of herd immunity of 70% [31] . In company 1, infected after the implementation of SDHM, the infection rates remained significantly lower. The epidemic might have ceased not only due to the implementation of SDHM but also due to herd immunity since both factors effectively lower the reproductive number of the virus. SDHMs have been shown to quantitatively reduce the viral inoculum during infection [15, 16] . The route of transmission might also be changed by SDHMs [17] from direct droplet-transmission in close proximity to the infecting person [18] to indirect A c c e p t e d M a n u s c r i p t transmission via contaminated surfaces [19] , although the hygiene measures implemented involved regular disinfection of potentially contaminated surface. Our data show that SDHMs not only slow infection with SARS-CoV-2 but also can attenuate the clinical course by reducing the rate of symptomatic patients amongst those infected. These findings suggest, that reducing the viral inoculum might not only lead to a reduced probability of infection but also could cause favor an asymptomatic infection while still being able to induce an immunological response at least in a proportion of the infected. However, our study has not directly studied the effect of viral inoculum on the clinical course of an infection with SARS-CoV-2 but shows the profound effect SDHMs have thereon. Since our study population consisted of young predominantly male adults, our findings might not be applicable to the general population (especially to the elderly and co- M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t World Health Organization. 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