key: cord-0922722-4ghqpzgr
authors: Bahrs, Christina; Kimmig, Aurelia; Weis, Sebastian; Ankert, Juliane; Hagel, Stefan; Maschmann, Jens; Stallmach, Andreas; Steiner, Andrea; Bauer, Michael; Behringer, Wilhelm; Baier, Michael; Kesselmeier, Miriam; Richert, Cora; Zepf, Florian; Walter, Martin; Scherag, André; Kiehntopf, Michael; Löffler, Bettina; Pletz, Mathias W.
title: Prospective surveillance study in a 1,400‐bed university hospital: COVID‐19 exposure at home was the main risk factor for SARS‐CoV‐2 point seroprevalence among hospital staff
date: 2021-03-09
journal: Transbound Emerg Dis
DOI: 10.1111/tbed.14041
sha: 4b7ec25a21f177e942b206954b49831d4b839ef7
doc_id: 922722
cord_uid: 4ghqpzgr

The Co‐HCW study is a prospective cohort study among hospital staff, including healthcare workers (HCWs) and administration staff, at the Jena University Hospital (JUH), Germany. The objectives of this study were to assess SARS‐CoV‐2 IgG seroprevalence, individual exposure risk factors and compliance of HCWs to wear personal protective equipment (PPE). After the first nosocomial COVID‐19 outbreak at JUH, mandatory masking was implemented on 20th March 2020. We evaluated point seroprevalence using two IgG detecting immunoassays and issued a questionnaire to assess COVID‐19 exposure, clinical symptoms and compliance to wear PPE. Antibody retesting was offered to participants with a divergent result of both immunoassays 5–10 weeks after the first test. Between 19th May and 19th June 2020, we analysed 660 participants [out of 3,228; 20.4%]. Among them, 212 participants (32.1%) had received a previous COVID‐19 test. Four of them (1.9%) reported a positive test result. After recruitment, 18 participants (2.7%) had SARS‐CoV‐2 antibodies in at least one immunoassay. Overall, 21 participants (3.2%) had any evidence of a past or current SARS‐CoV‐2 infection. Among them, 13 (61.9%) were not aware of direct COVID‐19 exposure and 9 (42.9%) did not report any clinical symptoms. COVID‐19 exposure at home (adjusted OR (aOR) with 95% CI: 47.82 (5.49, 416.62)) was associated with SARS‐CoV‐2 seroprevalence. We observed no evidence for an association between seroprevalence and exposure at work (aOR 0.48 (0.13, 1.70)) or with COVID‐19 risk area according to the working place (aOR for intermediate‐risk vs. high‐risk: 1.97 (0.42, 9.22), aOR for low‐risk versus high‐risk: 2.10 (0.40, 11.06); p = .655). Reported compliance of HCWs to wear PPE differed (p < .001) between working in high‐risk (98.3%) and in intermediate‐risk areas (69.8%). In conclusion, compared to administration staff, we observed no additional risk to acquire SARS‐CoV‐2 infections by patient care, probably due to high compliance to wear PPE.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel beta coronavirus that was first identified in December 2019 in Wuhan, China . As of the beginning of 2020, the outbreak progressed and has been characterized as a pandemic in March 2020 (Abebe et al., 2020; Whitworth, 2020) . The clinical presentation of the disease caused by SARS-CoV-2, corona virus disease 2019 (COVID-19) (Abebe et al., 2020) , varies significantly and ranges from asymptomatic and mild to critical courses Guan et al., 2020; Pergolizzi et al., 2020) . As asymptomatic or pre-symptomatic patients can spread the virus (Furukawa et al., 2020; He et al., 2020; Long et al., 2020; Slifka & Gao, 2020) , it is challenging to timely identify and isolate respective cases. SARS-CoV-2 is highly transmissible from human to human mainly via inhalation of infectious respiratory droplets but also via close personal contact (shaking hands) and via touching contaminated surfaces . As a consequence, nosocomial transmission of insufficiently protected healthcare workers (HCWs) can occur during aerosol generating procedures Reychler et al., 2020) , in the regular patient contact particularly when exposed to patients with a delayed diagnosis of COVID-19 and also in close contact with asymptomatic but virus carrying colleagues (Baker et al., 2020; Taylor et al., 2020; Treibel et al., 2020; Zhao et al., 2020) .

A recent analysis of more than 2 million community members and nearly 100,000 frontline HCWs in the United States and the UK found an increased risk of having a positive SARS-CoV-2 test result among HCWs (adjusted hazard ratio 3.40, 95% confidence interval 3.37-3.43) (Nguyen et al., 2020) . According to a recent meta-analysis including 127,480 HCWs, the estimated overall seroprevalence of SARS-CoV-2 antibodies was 8.7% (range: 0.0%-45.3%) and varied among continents (12.7% in North America, 8.5% in Europe, 8.2% in Africa, 4 .0% in Asia) (Galanis et al., 2021) . However, in the literature reported seroprevalence rates among HCWs show a high variability even within the countries: 1.6%-15.1% in Germany (Finkenzeller et al., 2020; Korth et al., 2020) , 4.0%-11.0% in Spain (Dacosta-Urbieta et al., 2020; Garcia-Basteiro et al., 2020) , 24.4%-31.6% in UK (Shields et al., 2020; Grant et al., 2020) , 6.0%-27.0% in United States (Self et al., 2020; Venugopal et al., 2021) and 0.0%-11.1% in India (Kumar, Sathyapalan et al., 2020; Kumar, Bhartiya et al., 2020) .

Although only moderate seroprevalence rates among HCWs were reported from China (1.3%-3.8%) , a rapid review and meta-analysis found that the proportion of nosocomial infections among confirmed COVID-19 cases was 44% in China during the early outbreak and that 33% of COVID-19 patients infected in hospitals were medical staff . (Chou et al., 2020) .

The primary objective of this study was to assess SARS-CoV-2

IgG seroprevalence among hospital staff of JUH, including HCWs (with patient contact) and administration staff (without patient contact 

Being a contracted staff member of JUH, working in a predefined hospital area and willing to sign a written informed consent were the only inclusion criteria. Predefined areas were as follows: Department Table S1 ). Individuals working outside these pre-categorized risk areas (namely laboratory personal where at least a proportion deals with COVID-19 related clinical specimens but has no patient contact), participating outside the planned study period or who did not provide a blood sample were excluded.

Participants were recruited between 19th May 2020 and 19th

June 2020. All eligible staff members were informed by a prior email.

Enrolment was conducted by on-site visit, and additionally, individual appointments were made possible for those who were out off duty during the on-site visit but willing to participate in the study.

After pseudonymization at the study centre, blood samples were sent to the Department of Clinical Chemistry and Laboratory Medicine (JUH) and the Institute of Medical Microbiology (JUH) for testing of IgG antibodies against SARS-CoV-2 by two different immunoassays (see below).

Pseudonymized questionnaires were digitalized with support of data management of the Institute of General Practice and Family Medicine (JUH). After digitalization, the whole data set was checked for plausibility and for missing data. In case of not plausible or missing data, original data included in the paper questionnaire were rechecked and manually added to the electronic data set (e.g. age missing or age <18 years or >65 years).

The questionnaire included questions on demographics, working area, individual exposure to confirmed COVID-19 cases, return from is identical to the WURSS-21 (Barrett et al., 2005) , except for the addition of the items assessing headache, body ache and fever.

Response options range from 0 to 7 (0 = do not have, 1 = very mildly, 3 = mildly, 5 = moderately, 7 = severely).

To evaluate the risk for nosocomial transmissions, HCWs with an individual face-to-face contact within 1 metre with a confirmed COVID-19 patient or at least with its surroundings received an extended questionnaire that also included questions on the compliance concerning use of personal protective equipment (PPE) as recently published by the WHO (https://apps.who.int/iris/bitst ream/ handl e/10665/ 33149 6/WHO-2019-nCov-HCW_risk_asses sment -2020.2-eng.pdf last accessed at 2nd February 2021). 

The primary outcome of the study was to assess the seroprevalence of SARS-CoV-2 antibodies in hospital staff of JUH using two IgG detecting immunoassays. Secondary outcomes were ( HCWs that had regular patient contact but did not routinely treat patients with confirmed or suspected SARS-CoV-2 infections. The high-risk group included HCWs working at areas with confirmed COVID-19 patients and areas that deal with a high number of suspected COVID-19 cases (see Table S1 ). Participants presented any evidence of past or current COVID19 infection if they were seropositive for SARS-CoV-2 IgG antibodies by at least one immunoassay after recruitment and/or reported evidence of a positive SARS-CoV-2 test (PCR or serology) prior recruitment.

As previous data on SARS-CoV-2 IgG seroprevalence rates of HCWs in Germany were sparse (Schwierzeck et al., 2020) , our intention was to conduct an exploratory study focussing on the precision of the prevalence estimate in the defined exposure groups (i.e. the group comparisons by hypothesis test was not the primary objective).

Thus, we assumed a true prevalence of 5%. One-hundred and fifty participants per group should be targeted to get 95% confidence intervals (for the proportion) with a precision (half width of confidence interval) of about 3.5%.

Characteristics of participants are summarized (overall, stratified by test result) as absolute and relative frequencies or as median together with first and third quartile (Q1, Q3). Point seroprevalence of SARS-CoV-2 in hospital staff is described with absolute and relative frequencies together with 95% Clopper-Pearson confidence intervals (CIs). To compare seroprevalence rates between participants working at different COVID-19 risk areas, to analyse clinical symptoms and to identify potential risk factors for seropositive compared to seronegative participants, we apply uni-and multivariable logistic regression modelling with the seropositivity as dependent variable and the investigated factor as independent variable. In the multivariable models, we first adjusted for age and sex and, then, additionally for returning from a COVID-19 risk area since February 2020 (see Tables 1 and S4) . As sensitivity analysis, we repeated the logistic regression modelling with any evidence of a past or current SARS-CoV-2 infection as dependent variable (see Tables S3 and S5) .

We provide (adjusted) odds ratios (OR) together with 95% CI and p-value. Compliance of HCWs (in high and intermediate-risk areas) to wear PPE is assessed with Fisher's exact test. We compare those

HCWs who stated to always or mostly wear PPE to those who stated not to wear PPE or did not provide information on this issue.

We applied a two-sided significance level of 0.05 and did not correct for multiple testing as all analyses were considered exploratory.

Clopper-Pearson CIs were calculated with Microsoft Excel 2016.

All other analyses were done with SPSS Statistics version 25.0 for Windows (IBM Corp., Armonk, NY, USA).

We identified 3,228 hospital staff members who were eligible for study inclusion. Among them, 721 participants (22.3%) were included, and 660 of 721 participants (91.5%) could be analysed (see Table 1 .

Among the Note: The number of participants (n) is provided. Median together with first and third quartile or absolute and relative frequencies are provided. Furthermore, results from uni-and multivariable logistic regression modelling (odds ratio (OR) and adjusted OR with 95% confidence interval (CI) and p-value) comparing participants with detectable SARS-CoV-2 IgG antibodies by at least one immunoassay and participants without detectable SARS-CoV-2 by both immunoassays are given. The reference category (ref.) is provided, if necessary. The adjusted OR was calculated adjusting for age, sex and returning from a COVID-19 risk area. The complete results are provided in Table S4 . Participants with a borderline test result by EDI ELISA IgG and a negative Elecsys Roche test (n = 15) are included in the overall characterization but were neither classified as seronegative nor as seropositive.

For detailed results of this subgroup, see Table S2 .

Abbreviations: -, not applicable. a Information on profession is missing for 7 participants. 'other profession' excluded from logistic regression analysis due to sample size issues in the two groups. b Information missing on one participant.

c Multiple answers possible.

d 'Other place' excluded from logistic regression analysis due to sample size issues in the two groups.

reported PCR and serology results, cumulative SARS-CoV-2 infection rate in our participants was 3.2% (95% CI 2.0%-4.8%). Among the 18 participants with detectable SARS-CoV-2 IgG antibodies, only 9 (50.0%) reported clinical symptoms within the last two months (see Table 2 ). 

As shown in Table 1 , we did not observe evidence for an association of antibody positivity with the demographics, the professions or These results are similar to our sensitivity analysis results for any evidence of a past or current SARS-CoV-2 infection (see Tables S3 and S5). 

The main findings of our study were as follows: Altogether, (a) seroprevalence rate of SARS-CoV-2 IgG and cumulative SARS-CoV-2 infection rate among hospital staff were low (2.7% and 3.2%), (b)

we did not detect an association between seroprevalence rate and risk area according to the hospital workplace, but (c) participants with a SARS-CoV-2 IgG seroprevalence reported more frequently F I G U R E 1 Flow chart of the Co-HCW study. The number of hospital staff members (n) is provided. Reasons for exclusions are given. Hospital staff members, including healthcare workers and administration staff, working at predefined areas at Jena University Hospital (JUH) were eligible for study inclusion. Working areas were classified into three categories according to the risk to deal with COVID-19 positive patients (see Table S1 for the definition). Note that we decided not to assign laboratory personal to a pre-categorized risk area because a proportion dealt with COVID-19 related clinical specimens but there was no patient contact et al., 2020) , the majority of studies in HCWs found SARS-CoV-2 seroprevalence rates above 5% (Finkenzeller et al., 2020; Garcia-Basteiro et al., 2020; Grant et al., 2020; Iversen et al., 2020; Kumar, Bhartiya et al., 2020; Self et al., 2020; Shields et al., 2020; Venugopal et al., 2021) . Moreover, some of those studies with higher seroprevalence rates also found an increased risk for a higher seroprevalence in HCWs working in a COVID-19 unit (Grant et al., 2020; Iversen et al., 2020; ) , whereas other studies including ours did not find this association (Garcia-Basteiro et al., 2020; Korth et al., 2020) .

Contrary, in the present study, HCWs working at COVID-19 highrisk areas had the numerically lowest (1.5%) and administration staff had the numerically highest seroprevalence rates (3.3%). However, we found an association between seroprevalence or evidence of a patients identified household contact as the main setting for transmission of SARS-CoV-2 (10.3%) . Community acquisition is hence a major aspect that needs to be considered.

Another finding of the present study was a remarkable compliance of HCWs in the high-risk group regarding PPE administration. We assume that the awareness regarding personal protection was higher in those HCWs who are repeatedly exposed to COVID-19

patients. An increased awareness might lead to better adherence to other hygienic measurements as well (Houghton et al., 2020 . In a recently published report by Self et al. that included 3,248 frontline HCWs, seroprevalence of SARS-CoV-2 antibodies was lower among HCWs who reported always wearing a face covering while caring for patients compared to those who did not (6% vs. 9%) (Self et al., 2020) .

It is known, that pre-and asymptomatic COVID-19 infected persons can be contagious despite absence of any subjective feeling of illness. In a population-based study by Gudbjartsson et al. (2020) including 30,576 people from Iceland, nearly one third of the SARS-CoV-2 infections were asymptomatic and durability of SARS-CoV-2 antibody levels was over 4 months. In our study population, only The validity regarding sensitivity and specificity of SARS-CoV-2 serology testing has not yet been investigated entirely (Deeks et al., 2020) . According to the recently published IDSA guidelines on the diagnosis of COVID-19, there will be false positive and false negative tests, but the most reliable spot of measuring SARS-CoV-2 antibodies is 3-4 weeks after exposure to the virus/onset of clinical symptoms (Hanson et al., 2020 Table S1 acceptable agreement between both tests (Egger et al., 2020) . In our study, the Roche Elecsys assay did not identify asymptomatic COVID-19 cases, which was already observed in the CoNAN study mentioned above (Weis et al., 2020) . This assay was only positive in 2 participants (0.3%) who were tested at beginning of June 2020 and had developed a symptomatic COVID-19 disease in the second half of March 2020. In contrast, the EDI IgG ELISA was positive in 2.7% of participants (9 asymptomatic and 9 symptomatic cases) including the two persons with the positive Roche Elecsys assay. It is still a matter of debate to what extend seroprevalence of SARS-CoV-2 IgG can really reflect immunity and status after infection. Nonetheless, serological examination is a method, which is easily available and highly cost-effective compared to PCR (Alter & Seder, 2020) .

This study has the following limitations: Despite the high number of participants, the recruitment rate was below 10% of the total JUH staff and results of previous COVID-19 testing and compliance using PPE were only recorded by self-reports. We determined antibody titres repeatedly only in those with discrepant results. As SARS-CoV-2 infection generates two waves of antibodies, the provided data do not reflect long-lived immunity (Alter & Seder, 2020) .

In our study, reported contact with a COVID-19 patient was not found to be a risk factor for seroprevalence of SARS-CoV-2 antibodies, whereas contacts with infected family members were highly predictive. In line, we found a high awareness and compliance with PPE and no evidence for higher seroprevalence in HCWs caring for COVID-19 patients, whereas administration employees with no patient contacts had numerically higher seroprevalence rates. We conclude that for HCWs, community transmission may play a larger role for COVID-19 infection than professional exposure when using appropriate PPE.

We thank Stefanie Beier, Jana Schmidt, Stefanie Kolanos and

Monique Philippe for excellent technical support.

None to declare.

CB, AK and MWP had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of MWP and CB supervised the study.

The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to and the appropriate ethical review committee approval has been received by the local ethics committee of the Friedrich-Schiller-University Jena (ethical approval number 2020-1774). The research was conducted in accordance with the Declaration of Helsinki and national and institutional standards.

The data sets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Christina Bahrs https://orcid.org/0000-0002-4427-2839

Juliane Ankert https://orcid.org/0000-0001-6248-6307

Miriam Kesselmeier https://orcid.org/0000-0001-6462-2579

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