key: cord-0869406-89ridgwd
authors: Kahlert, C. R.; Persi, R.; Guesewell, S.; Egger, T.; Leal-Neto, O. B.; Sumer, J.; Flury, D.; Brucher, A.; Lemmenmeier, E.; Moeller, C.; Rieder, P.; Stocker, R.; Vuichard-Gysin, D.; Wiggli, B.; Albrich, W. C.; Babouee Flury, B.; Besold, U.; Fehr, J.; Kuster, S. P.; McGeer, A.; Risch, L.; Schlegel, M.; Vernazza, P.; Friedl, A.; Kohler, P.
title: Non-occupational and occupational factors associated with specific SARS-CoV-2 antibodies among Hospital Workers - a multicentre cross-sectional study
date: 2020-11-13
journal: nan
DOI: 10.1101/2020.11.10.20229005
sha: a811c12102b439801d1d754d6bf13a32f9de0ef5
doc_id: 869406
cord_uid: 89ridgwd

Background Protecting healthcare workers (HCW) from Coronavirus Disease-19 (COVID-19) is critical to preserve the functioning of healthcare systems. We therefore assessed seroprevalence and identified risk factors for Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) seropositivity in this population. Methods Between June 22nd and August 15th 2020, employees from healthcare institutions in Northern/Eastern Switzerland were screened for SARS-CoV-2 antibodies. We recorded baseline characteristics, non-occupational and occupational risk factors. We used pairwise tests of associations and multivariable logistic regression to identify factors associated with seropositivity. Findings Among the 4664 included HCW from 23 healthcare facilities, 139 (3%) were seropositive. Non-occupational exposures independently associated with seropositivity were contact with a COVID-19 positive household (adjusted OR=54, 95%-CI: 31-97) and stay in a COVID 19 hotspot (aOR=2.2, 95%-CI: 1.1-3.9). Blood group 0 vs. non-0 (aOR=0.4, 95%-CI: 0.3-0.7), active smoking (aOR=0.5, 95%-CI: 0.3-0.9) and living with children <12 years (aOR=0.3, 95%-CI: 0.2-0.6) were associated with decreased risk. Occupational risk factors were close contact to COVID-19 patients (aOR=2.8, 95%-CI: 1.5-5.5), exposure to COVID-19 positive co-workers (aOR=2.0, 95%-CI: 1.2-3.1), poor knowledge of standard hygiene precautions (aOR=2.0, 95%-CI: 1.3-3.2), and frequent visits to the hospital canteen (aOR=1.9, 95%-CI: 1.2-3.1). Interpretation We identified several modifiable factors associated with SARS-CoV-2 seropositivity among our HCW. Living with COVID-19 positive households showed by far the strongest association. The lower risk among those living with children, even after correction for multiple confounders, is remarkable and merits further study. Funding Swiss National Sciences Foundation, Federal Office of Public Health, Health Department Canton of St. Gallen

Protecting healthcare workers (HCW) from Coronavirus Disease-19 is critical to preserve the functioning of healthcare systems. We therefore assessed seroprevalence and identified risk factors for Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS- seropositivity in this population.

Between June 22 nd and August 15 th 2020, employees from healthcare institutions in Northern/Eastern Switzerland were screened for SARS-CoV-2 antibodies. We recorded baseline characteristics, non-occupational and occupational risk factors. We used pairwise tests of associations and multivariable logistic regression to identify factors associated with seropositivity.

Among the 4'664 included HCW from 23 healthcare facilities, 139 (3%) were seropositive. Nonoccupational exposures independently associated with seropositivity were contact with a COVID-19 positive household (adjusted OR=54, 95%-CI: 31-97) and stay in a COVID-19 hotspot (aOR=2·2, 95%-CI: 1·1-3·9). Blood group 0 vs. non-0 (aOR=0·4, 95%-CI: 0·3-0·7), active smoking (aOR=0·5, 95%-CI: 0·3-0·9) and living with children <12 years (aOR=0·3, 95%-CI: 0·2-0·6) were associated with decreased risk. Occupational risk factors were close contact to COVID-19 patients (aOR=2·8, 95%-CI: 1·5-5·5), exposure to COVID-19 positive co-workers (aOR=2·0, 95%-CI: 1·2-3·1), poor knowledge of standard hygiene precautions (aOR=2·0, 95%-CI: 1·3-3·2), and frequent visits to the hospital canteen (aOR=1·9, 95%-CI: 1·2-3·1).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20229005 doi: medRxiv preprint

We identified several modifiable factors associated with SARS-CoV-2 seropositivity among our HCW. Living with COVID-19 positive households showed by far the strongest association. The lower risk among those living with children, even after correction for multiple confounders, is remarkable and merits further study.

Swiss National Sciences Foundation, Federal Office of Public Health, Health Department Canton of St. Gallen . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020. 11 3, 4 . The recent massive re-emergence of cases in many European countries including Switzerland is putting further strain on healthcare systems and hospital workers.

Studies from different countries suggest that HCW are at increased risk to acquire Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) when compared to the general population.

A study among 72 symptomatic HCW from Wuhan showed that working on high-risk wards was associated with increased risk 5 . A seroprevalence study among over 2'000 HCW from a Hospital in Sweden depicted 19% to be seropositive, with higher proportions among those with patient contact and among those caring for COVID-19 patients, suggesting a relevant occupational risk 6 .

In the UK, HCW and their household contacts accounted for a sixth of all COVID-19 cases admitted to the hospital for those aged 18-65 years. This risk was increased for HCW involved in patient care 7 . In light of these data it is imperative to better understand risk factors for SARS-CoV-2 acquisition among HCW in order to better protect them from infection 8 .

In this multicentre study from Switzerland, we aimed to assess the prevalence of specific antibodies against SARS-CoV-2 among HCW with and without patient contact. In addition, we intended to identify non-occupational and occupational factors associated with seropositivity to inform prevention recommendations for this population.

We initiated a multicentre cross-sectional study between June 22 nd and August 15 th 2020 in healthcare institutions located in Northern and Eastern Switzerland. Acute care hospitals, rehabilitation clinics, geriatric and psychiatric clinics in the region were asked to participate.

Within every participating institution, employees aged 16 years or older were invited to enrol into the study via institutional webpages. Employees registered online and provided electronic consent. The study was approved by the ethics committee of Eastern Switzerland (#2020-00502).

We implemented a multi-modular digital baseline questionnaire for institutions and participants.

Questions about facility structure were asked in the institutional questionnaire (e.g. type and size of institution, and number of HCW). Participants were asked about place of residence, anthropometric data including body mass index (BMI), and baseline health including presumed risk factors for COVID-19 (i.e. comorbidities, smoking status, number of respiratory tract infections per year, blood group, seasonal influenza and Bacillus Calmette-Guérin [BCG] vaccination) 9, 10 . Questions related to non-occupational exposure included household structure (i.e. number, gender and age of household contacts), visits to COVID-19 hotspot regions in bordering countries during February or March 2020 (i.e. Northern Italy, Austrian ski resorts, Alsace), leisure activities (i.e. visits to restaurants and bars, participation in music groups or choirs, fitness centres, sport clubs, religious and cultural activities), number of shopping trips per week, adherence to protective measures, and exposure to non-occupational COVID-19 cases or symptomatic household contacts (i.e. people living in the same household or intimate partners).

Questions related to work included type of profession, medical department, employment rate, patient contact in general, contact to COVID-19 patients, close contact to COVID-19 patients (i.e. >15 minutes within 2 meters with or without personal protective measures [PPE]), . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20229005 doi: medRxiv preprint involvement in aerosol-generating procedures (AGP) defined according to national guidelines 11 , exposure to COVID-19 confirmed or symptomatic co-workers, knowledge of standard precautions, use of PPE while caring for COVID-19 patients (in case of multiple events the participants were asked to describe the event with the lowest protection) and frequency of visits to the hospital canteen or cafeteria. Poor knowledge of standard precautions was assumed for those who correctly identified less than 3 measures in a multiple choice question (among a choice of hand hygiene, surgical mask in case of respiratory symptoms, donning gowns in case of potential contamination with body fluids, cough etiquette, and vaccination). Low protection while caring for COVID-19 patients was assumed for those using less than 3 measures out of face masks, gloves, gowns, and goggles. Also, results of previously performed nasopharyngeal swabs for SARS-CoV-2 were asked.

Upon registration, participants provided a venous blood sample at time of inclusion, which was collected at local sites. After obtaining serum by standardized centrifugation, samples were analysed with an electro-chemiluminescence immunoassay (ECLIA, Roche Diagnostics, Rotkreuz, Switzerland, detection of total antibodies directed against the nucleocapsid-(N)-protein of SARS-CoV-2) run on a COBAS 6000 instrument, as described elsewhere 12 In press]. A subgroup of samples with a positive signal in the ECLIA (at a cut-off index, COI, > 1) were also tested with an Enzyme-linked Immunosorbent Assay (ELISA, Euroimmune, Germany, detection each of IgG and IgA antibodies against S1 domain of the spike-(S)-protein including the immunologically relevant receptor binding domain) 13 . Cut-offs for seropositivity . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20229005 doi: medRxiv preprint were applied as recommended by the manufacturers. Seropositivity was defined as positive result in the ECLIA followed by confirmation in the ELISA (either positive IgA or IgG).

Baseline information of institutions and participants was characterized using descriptive statistics. The relative frequency of participants with ELISA confirmed positive and negative serology was compared between levels of baseline characteristics, non-occupational risk factors and occupational risk factors. Fisher's exact test was used for dichotomous factors or factors with a reference level, comparing each level to the reference. Logistic regression was used for numeric and ordinal variables. Age, sex, BMI, smoking status, comorbidities as well as nonoccupational and occupational risk factors expected to influence seropositivity were entered into a multivariable logistic regression model to evaluate the effect of each risk factor after adjusting for all other factors in the model. For sensitivity analysis, we fitted two additional models including place of residence (7 predefined regions) and institution either as fixed effects or as random effects to assess whether spatial proximity or clustering of observations confounded the effects of the risk factors. Analyses were performed with R statistical software, version 4.0.2.

We included 17 institutions on 23 sites across Northern and Eastern Switzerland, thereof 19 inpatient sites (14 acute care; 1 geriatric clinic; 1 rehabilitation clinic; 3 psychiatric clinics) and 4 outpatient clinics (3 psychiatric facilities; 1 blood donation centre). The total of represented patient beds was 3'523 (thereof 106 ICU beds) ( Table 1) .

Of the 17'060 potentially eligible HCW, 4'664 (27%) participated in the study. Median age was 38 years (range 16-73); 3'654 (78%) were female. The majority were nurses (n=2'126; 46%) followed by physicians (n=776; 17%); 3'676 (79%) reported having patient contact ( Table 2) .

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Overall, seropositivity was 3·0% (139/4'664). Among these 139, 88 (63%) were also tested with the confirmatory ELISA and all 88 samples had either positive IgA or IgG. On the institutional level, seropositivity ranged between 0·5% and 4·2% for inpatient, and 0% and 2·3% for outpatient facilities ( Table 1) . Seropositivity by district (only districts with at least 10 participants) ranged from 0% to 13%. Seropositivity was lower in regions located in Eastern compared to Northern Switzerland (Figure 1) . 

Exposure to COVID-19 confirmed (55·7% vs. 2·1%, p<0·001) or symptomatic, not confirmed household contacts (5·5% vs. 1·9%, p<0·001) was strongly associated with seropositivity. Also, having visited a known COVID-19 hotspot in Austria (but not in Italy or France) was clearly associated with seropositivity (6·8% vs. 2·8%, p=0·002). Seroprevalence was lower among those with blood group 0 vs. non-0 (1·8% vs· 3·5%, p=0·002) and for those living with children aged 12 or younger (1·7% vs. 3·4%, p=0·002). The proportions of seasonal influenza vaccination 2019/2020 and previous BCG vaccination were not different between seropositive and seronegative participants ( Table 2) .

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The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20229005 doi: medRxiv preprint Nurses had a higher (3·9%), physicians a lower (1·0%) seropositivity rate; no differences according to medical speciality were noted. Seroprevalence was higher among those with patient contact (3·1% vs. 1·7%, p=0·037), particularly for those with contact to confirmed COVID-19 patients (4·1% vs. 1·7%, p<0·001). Workers indicating low protection while caring for COVID-19 patients (5·8% vs. 3·5%, p=0·019) and those with poor knowledge of hygiene standards had higher seropositivity (4·1% vs. 2·6%, p=0·018) (Figure 2, panels A and B) . The number of unprotected contacts to COVID-19 confirmed or symptomatic co-workers was associated with seropositivity ( Figure 2, panel C) . Also, workers who never or only occasionally visited the hospital canteen had a lower seroprevalence compared to those with weekly or daily visits (1·9% vs. 3·5%, p=0·004) (Figure 2, panel D) . This effect was consistent across institutions and professions (Table S1). HCW visiting bars and restaurants other than the hospital canteen did not have an increased risk for seropositivity ( Table 2) .

In multivariable analysis, exposure to a COVID-19 positive household member remained the strongest risk factor for seropositivity with an adjusted odds ratio (aOR) of 54 (95% CI 31-97) ( Figure 3, Table S2 ). Stay in a COVID-19 hotspot was associated with increased risk (aOR 2·2, 95% CI 1·1-3·9), whereas blood group 0 (aOR 0·4, 95% CI 0·3-0·7), active smoking (aOR 0·5, 95% CI 0·3-0·9) and living with children <12 years (aOR 0·3, 95% CI 0·2-0·6) were all associated with decreased risk after correcting for multiple confounder variables. The number of respiratory tract infections per annum was only marginally significant (aOR 1·6, 95% CI 1·0-2·5).

Significant occupational factors included close contact with a COVID-19 patient (aOR 2·8, 95% CI 1·5-5·5), exposure to a COVID-19 positive co-worker (aOR 2·0, 95% CI 1·2-3·1), poor knowledge of standard precautions (aOR 2·0, 95% CI 1·3-3·2), as well as having weekly/daily (vs. rarely/never) meals in the hospital canteen (aOR 1·9, 95% CI 1·2-3·1). Low protection while . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20229005 doi: medRxiv preprint caring for COVID-19 patients was marginally not significant. Both models in the sensitivity analysis did not show any relevant impact of geographic region or institution on the significance level of the variables in the original model (Table S2) .

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The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20229005 doi: medRxiv preprint

In this cross-sectional study including 4'664 HCW from Northern and Eastern Switzerland, 3% of participants had specific SARS-CoV-2 antibodies. Our main findings are that exposure to a COVID-19 positive household member is by far the strongest risk factor for seropositivity, and that living with children under the age of 12 -even after correction for multiple confounders -is clearly associated with decreased risk. Furthermore, we identified several exposures associated with seropositivity which might serve as leverage to further decrease the risk of SARS-CoV-2 acquisition among HCW.

We confirm findings from other studies showing that COVID-19 positive household contacts are probably the main source of SARS-CoV-2 infection for HCW 14, 15 . Our findings are also in line with a Dutch study analysing viral genomes of HCW and patients from the same hospital. The authors concluded that nosocomial transmissions seemed rather uncommon and that multiple hospital introductions from the community are probably responsible for the large part of COVID-19 cases among patients and HCW, at least in a low prevalence setting 16 . Of course, this association might be overestimated given that the directionality of virus transmission cannot be definitely assessed with our study design. It therefore must be assumed that a certain proportion of household contacts was in fact infected by the HCW, and not vice versa.

An important finding of our study is that participants living with children under the age of 12 were clearly less likely to be seropositive. A large study among over 300'000 HCW households from Scotland has recently found a similar association 17 . In contrast to the Scottish study, we corrected our result for important confounders, including age of HCW, full-time working, and leisure activities. An intriguing hypothesis for this finding is that certain childhood infections, particularly those with endemic coronaviruses such as HCoV-OC43 or HCoV-HKU1, might confer partial immunity (i.e. cross-immunity) to SARS-CoV-2. In line with this hypothesis, . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20229005 doi: medRxiv preprint adults aged 15 to 44 years (having presumably an increased probability of living with young children) have been shown to have higher antibody titers against the HCoV-OC43 N protein than older adults 18 . Also, supporting the notion of a rather immunological than a purely epidemiological phenomenon, a German study among over 4'000 COVID-19 patients suggested a less complicated disease course for those with frequent contact to children 19 . This hypothesis was partially confirmed by a recent study that demonstrated pre-existing humoral immunity (including neutralizing antibodies) to be particularly prevalent in children and adolescents 20 . This should be confirmed in prospective studies using immunologic assays that demonstrate humoral and cellular immunity against endemic coronaviruses and evaluate their protective role against SARS-CoV-2. If proven to be protective, this could represent a paradigm change for COVID-19 preventive measures in daycare, primary schools and in contact with grandparents.

We specifically asked the participants in our study about staying in geographic regions and places with high COVID-19 activity. Interestingly, stay in an Austrian ski resort where at least one COVID-19 superspreading event had occurred in February/March 2020 was indeed an independent risk factor for seropositivity 21 . Several studies have by now identified an association between the AB0 blood group system and acquisition of COVID-19. Quite consistently, blood group 0 is considered to have a protective effect as shown in our study, whereas people with a non-0 blood group (mostly A) seem to carry an increased risk [22] [23] [24] [25] [26] . Whether the blood group also determines the course of the disease is less clear 24, 27 . We also observed a lower seroprevalence among active smokers, confirming findings of other studies, including a living rapid review and meta-analysis 28, 29 . Possible explanations for this observation include biological effects of tobacco smoke on virus receptors on epithelial cells, or increased physical distancing from people who actively smoke. However, although susceptibility for SARS-CoV-2 might indeed be reduced in this population, the disease course seems to be negatively impacted by smoking 28 .

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The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20229005 doi: medRxiv preprint An important question is whether HCW caring for COVID-19 patients are in fact at increased risk for acquiring the disease themselves. Digital surveillance data from the UK and the US indicate that frontline HCW are at increased risk for (self-reported) COVID-19 compared to the general population 30 . Also, frontline HCW in Denmark showed higher seroprevalence than other HCW 31 . Our study confirms these findings, at least for those with close contact to COVID-19 patients. A lower level of protection was not significantly associated with seropositivity in multivariable analysis, probably because of our restrictive definition of low protection. Due to the cross-sectional study design we cannot draw valid conclusions regarding the individual benefit of single protective measures such as gloves, gowns or goggles. However, participants performing AGPs as well as those working in intensive care or emergency rooms did not have an increased risk for COVID-19, suggesting that current safety measures are sufficient for these high-risk HCW. Of note, poor knowledge of standard hygiene precautions was associated with detection of SARS-CoV-2 antibodies, supporting efforts to continuously educate HCW regarding basic infection prevention concepts.

Apart from COVID-19 patients, we identified several easily modifiable occupational factors which might place HCW at increased risk for COVID-19. Exposure to ill co-workers is a known risk factor for respiratory illness in HCW, not only for COVID-19 but also for other respiratory viral diseases 32 . Although this signal was not evident in other HCW cohorts in countries with similar disease burden 14 , it is well conceivable that basic hygiene principles, such as physical distancing or hand hygiene are being neglected in contact with co-workers.

Across all participating institutions, we identified visits to the hospital canteen as potential risk factor for seropositivity, even after correction for multiple confounder variables. Visiting restaurants other than hospital canteens has previously been shown to be potentially associated with higher risk of SARS-CoV-2 acquisition 33,34 ; however, this was not the case in our data. This discrepancy could be explained by the fact that i) the visitor turnover of hospital canteens is . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20229005 doi: medRxiv preprint much higher than in other eating places and ii) that the probability of a HCW being infectious is higher than for an average visitor to other restaurants. We therefore suggest that hospitals should revisit and potentially reinforce the safety concepts of their canteens and food courts. This might include limiting the number of people in the area, limiting the duration of stay for each individual, or increasing distances between tables, but also increase adherence to hand washing recommendations before eating.

Our study has several limitations. First, causality cannot be inferred between exposures and seropositivity. Second, sampling bias (both on the institutional and on the individual level) may have arisen given that study participation was non-mandatory. Third, we relied on mostly selfreported data in our questionnaire which is subject to recall and other bias. For this exact reason, we decided not to include self-reported PCR results for the definition of positive and negative participants, thereby accepting a certain number of false negative serology results. Fourth, because of the low disease prevalence we have to assume that a certain proportion of our serology results might also be false positive. However, the reported specificity of >99% for the ECLIA 35 , the positive confirmatory results in our tested subsample and the overall low proportion of discordant results between PCR and serology supports the validity of our testing approach.

Strengths of the study are its large sample size, the inclusion of different types of healthcare institutions across a large geographic area, and consideration of not only occupational but a broad range of non-occupational risk factors. In particular the latter differentiates our study from most other seroprevalence studies performed among HCW.

To conclude, having a COVID-19 positive household member was by far the strongest predictor for SARS-CoV-2 seropositivity among our HCW. Furthermore, we identified several modifiable variables associated with seropositivity, including contact to COVID-19 co-workers, poor . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20229005 doi: medRxiv preprint knowledge of standard hygiene precautions, and possibly frequent visits to the hospital canteen.

Living with children below 12 years of age in the same household was independently associated with decreased risk, an extraordinary finding suggesting an increased role of cross-immunity.

We would like to warmly thank the large number of employees of the participating health care institutions who either took part in this study themselves or supported it. Furthermore, we thank the laboratory staff for shipment, handling and analysis of the blood samples. In particular, we acknowledge the organizational core team Simone Kessler and Susanne Nigg, who kept all strings between the participating centers and the laboratory and without whom this study would not have been possible.

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All authors contributed to the concept and conduct of the study. CRK, PV, and PK were responsible for funding. CRK, MS, PV and PK conceived and planned the study, CRK and PK directed the study. CRK, OL, TE and PK created the electronic database. TE was responsible for communication between study centers. SG performed the data analysis and prepared the figures.

CRK, RP and PK interpreted the results and prepared the manuscript, which was critically revised and approved by all authors.

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The copyright holder for this this version posted November 13, 2020. ; https://doi.org/10.1101/2020.11.10.20229005 doi: medRxiv preprint Figure 1 . SARS-CoV-2 seropositivity by district in Northern and Eastern Switzerland (in grey: no seroprevalence indicated for districts with less than 10 participants).

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