key: cord-1024033-8iggqgl2
authors: Kayı, İlker; Madran, Bahar; Keske, Şiran; Karanfil, Özge; Arribas, Jose Ramon; Psheniсhnaya, Natalia; Petrosillo, Nicola; Gönen, Mehmet; Ergönül, Önder
title: The seroprevalence of SARS-CoV-2 antibodies among health care workers before the Era of vaccination: A systematic review and meta-analysis
date: 2021-06-08
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.05.036
sha: 6b29c3bef083a5459359c553759539f915caff26
doc_id: 1024033
cord_uid: 8iggqgl2

BACKGROUND: The prevalence of SARS-CoV-2 infection among HCWs provide information to for the spread of COVID-19 within health care facilities, and to detect the risk groups. OBJECTIVE: We aimed to describe the rate of SARS-CoV-2 seroprevalence and its determinants among health care workers. DATA SOURCES: We used Web of Science, Scopus, MEDLINE, EBSCOhost and Cochrane Library. STUDY ELIGIBILITY CRITERIA: We included the reports of SARS-CoV-2 seroprevalence with a sample size of minimum 1,000 HCWs. METHODS: The study was registered at the International Prospective Register of Systematic Reviews (PROSPERO, no: CRD42021230456). We used PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. The keywords were “COVID-19, “SARS-Co-2”, “Coronavirus”, “seroprevalence”, “health care workers” and “risk factors”. RESULTS: In total 4329 reports were retrieved, the duplications were removed, after filtering according to the title and abstract 25 studies were selected. Risk of bias was assessed in 25 studies; it was low in 13 studies, medium in four studies, and high in eight studies. In meta-analysis by using the random effect model, the weighted average of seroprevalence was calculated as 8% (CI: 6%-10%). The pooled seroprevalence rates of the selected variables that have a rate over the average were male HCWs with 9% (95% CI 7%-11%); HCWs from ethnic minorities with 13% (95% CI: 9% - 17%); high exposure 9% (95% CI: %6 - %13); exposure to the virus outside the health care setting %22 (95% CI: %14 - %32). CONCLUSIONS: Our analysis indicate a SARS-CoV-2 seroprevalence rate of 8% among studies included >1,000 HCWs for the year 2020 before vaccinations started. The most common risk factors associated with higher seroprevalence rate were ethnicity, male gender, and having higher number of household contacts. Working as a frontline HCW was inconsistent in its association with higher seroprevalence.

Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) continues to spread worldwide since its first emergence in December 2019. Health care workers (HCWs) have been considered at high risk of contracting the virus and may also pose a significant risk of transmitting the virus to patients, colleagues and their social contacts [1] . According to World Health Organisation (WHO), one out of every seven patient (14%) is a HCW [2] . A study from the United Kingdom and the United States of America reported that frontline HCWs have a 3.4 times higher risk than people living in the community [3] . In a systematic review the hospitalization and mortality rate of HCWs were reported to be 15.1% and 1.5% respectively [4] . Inability to protect the safety of frontline HCWs poses a risk for the health care system to collapse as well as transmission of the virus from health care seetings to the community [5] . The rate of SARS-CoV-2 seroprevalence among HCWs varies between and within countries and even between institutions due to the variations in the infection control measures taken in health care settings, geographic areas, established health policies and procedures at national level along with individual behaviors of HCWs to adhere to these measures [6] .

The prevalence of SARS-CoV-2 infection among HCWs provide valuable information to understand the spread of COVID-19 within health care facilities, and to detect the risk groups for the infection [7] . In this study, we aimed to investigate the seroprevalence of SARS-CoV-2 among HCWs and related risk factors by including the studies published in 2020 which were conducted before the unpredictable effects of highly spreading new variants appeared and vaccination programs put in place in 2021.

This is a systematic review and meta-analysis that has been registered at the International Prospective Register of Systematic Reviews (PROSPERO) with a registration number of CRD42020159198. We have performed the review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (PRISMA checklist, Supplementary Table 2 for the search strategy that included variations of the following terms "COVID-19, "SARS-Co-2", "Coronavirus", "seroprevalence", "health care workers" and "risk factors". The librarian provided the list of articles after eliminating the duplicate files. We have also searched Google for non-peer reviewed publications and also the list of references of all relevant articles and previous reviews.

J o u r n a l P r e -p r o o f

We included antibody screening studies among HCWs with over a 1,000 participants. We excluded surveys, preprint reports, diagnostic or screening studies performed primarily by using polymerase chain reaction (PCR) for viral RNA, and the studies that included only suspected or confirmed cases.

There were two phases of selection process. In the first phase, two reviewers (BM and İK) independently screened the titles and abstracts of each study. Two other reviewers (ŞK and ÖK) conducted another screening to double check the first reviewers which yielded consistent results.

The studies which does not fulfill the eligibility criteria were excluded. Studies with promising titles but missing abstracts were included in the full text screening. Reference lists of included studies were searched to identify further studies. In the second phase, two reviewers (BM and İK) read the fulltext of the articles remained from the first phase and discrepencies in selection were resolved via a consensus discussion among the review team.

The data extracted from each article included authors, location, dates of starting and ending terms of screening, sample size, setting, study design, antibody tests, sensitivity and spesifity of antibody tests, risk factors associated with seroprevalence of SARS-CoV-2 antibodies. The data required for the pooled analysis was extracted for the variables of gender, race/ethnicity, job 

In order to evaluate the systematic errors in each study one of the authors (İK) has assessed the Risk of Bias (RoB) by using the Joanna Briggs Institute (JBI) critical appraisal tools for prevalence studies. This is a nine-point scale where a score of 8-9 indicates low risk of bias whereas a score of 5-7 indicates moderate and ≤ 4 indicates high risk of bias [9] . As we have included studies with over 1,000 participants, the sample size item on the JBI scale was considered as fulfilled, but we have evaluated the item about response rate as low if it was less than 50% and unclear if it was not mentioned or we were unable to calculate according to the number of target population provided.

Primary outcome measure was the rate of pooled seroprevalence rate obtained from the articles and pooled seroprevalence rate for selected risk factors. Heterogeneity assessment was done using the I 2 test. The estimation for the pooled seroprevalence for SARS-CoV-2 was carried out whenever appropriate with 95% Confidence Interval (CI). We performed meta-analysis on prevalence rates using both fixed effect model and random effects model under logit transformation. Statistical analyses were done using meta package in R [10] . The outcome of this analysis was visualized by using Forest Plots.

Our literature review yielded 4,329 reports in total. After removal of duplications and initial screening according to the title and abstract we had 35 articles for fulltext review. Finally we had J o u r n a l P r e -p r o o f 25 studies that met the eligibility criteria (PRISMA flowchart, Figure 1 ). According to the RoB assessment 13 studies showed low RoB , 5 medium RoB, and 7 high RoB (See Supplement 2). Table 1 shows the main characteristics of the studies, seroprevalence rates and risk factors investigated in each study. The earliest time of starting data collection dates to March 2020 [11] and the latest time of finishing date to August 2020 [12] . The mean duration of data collection time was 45.8 days (min. 8 days [13] and max. 181 days [14] . The majority of the participants were female in each study with the range of 64-85%, except one in India with the rate of 34.6%.

The range of the mean age was 37.0 and 49.4 years. Fourteen studies were performed in one center, whereas, 11 study was conducted as a multicenter inquiry. The lowest rate of seroprevalence was 1.1 % reported in May from US [15] . The highest seroprelance rate was reported as 35.4% in May from USA [16] . Risk factors described in 25 studies were summarized in Table 2 .

In total, data extracted for 168,200 HCWs were included. The lowest sample size was 1,122 [12] , the highest one was 40,329 [17] (Figure 2 ). In meta-analysis by using the random effect model, the weighted average of seroprevalence was calculated as 8% (95% CI: 6%-10%) with a heterogeneity of I 2 =100% (p<0.001).

The pooled analysis of selected risk factors were presented in Table 3 (Fort he detailed forost plots please see Supplentary Figure 1 -12) . The pooled seroprevalence ra tes of the selected risk factors that have a rate over the average were male HCWs with 9% (95% CI 7%-11%); non-J o u r n a l P r e -p r o o f white HCWs with 13% (95% CI: 9% -17%); frontline HCWs with 9% (95% CI: %6 -%13); esposure to the virus outside the health care setting %22 (95% CI: %14 -%32).

Since the beginning of the pandemic HCWs were considered as the number one risk group for COVID-19, therefore our goal was to investigate seroprevalance rates among HCWs in scientific literature with over 1,000 participants in order to ensure high level representation of the source population. The timeframe of our study was from the start of the pandemic until the vaccination programs began. At the first phase of the pandemic, the aim of the seroprevalence studies was to have an idea about the level of asymptomatic cases, risk factors and herd immunity in the population. Therefore, the seroprevalence studies among HCWs proved to be valuable to understand the risk and related factors as well. Towards the end of 2020, the vaccination programs were in place starting with the HCWs. At the same time, there was increasingly another concern regarding the new variants of the virus, all of which halted the efforts to detect the antibodies among HCWs. Although vaccines have been stated to prevent the disease and severe illness, it is still under investigation whether the vaccines will prevent from the variants or acquiring and/or transmission the infection [18, 19] .

Our analysis showed that the weighted average of the seroprevalance rate among HCWs in the selected studies was 8.0% (95% CI 6.0%-10.0%) and the seropositivity rate reported in the articles ranged from 1.1% [15] to 35.4% [16] . However in a meta-analysis at the population level which excluded HCWs Rostami et al. reported that SARS-CoV-2 seroprevelance rate was 3.38% J o u r n a l P r e -p r o o f (95% CI 3.05-3.72) and in their report the seroprevalence in the countries that we included in our analysis ranged from 0.36% in Greece to 15% in Sweden [20] .

In our sudy, there were reports with high seroprevalence rate (>20%) that required further explanation. One reason might be that two studies from USA, in which the seroprevalence rates were reported as 35.4% [16] and 19% [21] , representation of African-American population who already had higher rates of infection in the general population was high as 48.4 % [16] and 27.2% [21] respectively. Additionally, the variance in seropravelance rates reported in the studies was due to different commercial serological tests, statistical power or the studies, and the timing of the study that corresponds to the waves in the epidemic curve of each country or region. For example, Racine-Brazostek et al. [16] have conducted their study in the declining curve of the first wave in New York, USA meaning that there were too many patients and too much unknowns about the prevention of COVID-19. Another study by Grant et al. [22] similarly reported high level of seropositivity (31.6%) among HCWs and authors suggested that it may be due to the spacial constraints in the health care settings where exposures such as patient-to-HCWs or HCWs-to-HCWs might have played a role along with HCWs' awareness of and adherence to infection control measures. On the other hand, Brant-Zawadzki et al. [15] have found the seroprevalence rate among HCWs in California, USA as 1.1%, however the response rate in their research was below 50%. Xu et al. [23] reported a seroprelalence rate of 1.8% in Wuhan, China however their study was conducted after the first wave of the pandemic when the daily number of cases in China was below 100 per day during their data collection period and the study is also subject to selection bias. Regarding the different conditions and the methods of data collection it can be argued that the variance between studies is multifactorial.

Age It has been well documented that older ages carry a higher risk for severe illness and death [24] . [14] in UK have found that age was inversely associated with seropositivity. While their analysis depended on multivariate analysis, a similar statistically significant finding in univariate analysis by Goenka et al. [12] was diminished in the logistic regression model. Conversely, Xu et al. [23] in China found that seroprevalence significantly increased among HCWs over 65 years of age.

Lastly, other studies [5, 11, 16, [27] [28] [29] [30] [31] [32] [33] have found no significant association between seroprevalance rates and age. In a systematic review by Bandyopadhyay et al. [34] COVID-19 incidence rates at a global level were higher in older HCWs especially in the 50-59 years age group. However, the incidence reports depend on PCR tests which might represent active disease rather than the past one. Studies showing PCR screening results are out of our scope, however it has been shown that symptomatic cases increase with age [35] . Detecting COVID-19 cases with PCR has the potential to yield results of relatively older patients. However, serologic tests also convey past infections, which might have been asymptomatic or less symptomatic among younger populations. Hence, compared to PCR studies, seroprevalence studies can be expected to have a higher proportion of infected people from younger ages. On the other hand, studies showing significant association between lower age and seropositivity might be as a result of higher community transmission among younger adults and more active roles during patient care to protect older HCWs as well.

Gender Majority of the studies included in our review have found no association between gender and seroprevalence rates. While Goenka et al. [12] found that the significant association between gender and seroprevalance rates diminished in multivariate analysis, it was males in the study by Iversen et al. [13] and females in the study by Self et al. [32] that were significantly associated with higher seroprevalence rates. Our analysis shows that the pooled seroprevalence rates were %9 (95% CI: %7 -%11) for males and %8 (95% CI: %6 -%10) for females, which are very close to each other.

It has been shown that COVID-19 prevalance was higher among males due to several reasons including gender based roles such as males being more likely to be employed in essential jobs, which increases their exposure to virus. At the same time, males had a higher tendency to engage in risky behaviors including smoking [36] . Our findings from pooled analysis for gender data indicates a 1% higher seroprevalence for male HCWs. This slight difference is less likely to depend on gender roles as level of exposure to SARS-CoV-2 in health care settings might be a stronger determinant.

Studies mainly from USA and UK have assessed the associaton between race/ethnicity and seropositivity among HCWs and all [14-17, 21, 26, 27, 32] but one [11] has found significantly increased rate among HCWs of African-American, Hispanic, Asian or Indigenious populations. This finding is in line with the previous studies indicating higher COVID-19 incidences among ethnic minority groups [6, 37, 38] . Our pooled analysis for seroprevalence according to 

Our systematic review indicates that there has been a significantly increased seroposisitivity rate for HCWs in contact with patients either working in frontline service or COVID-19 unit [5, 22, 25, 26, 28, 41] . For example, Rudberg et al. [5] have shown that patient related work has increased the risk 2.3 times compared to other occupational groups. Moreover, even among the same occupational category the ones with higher contact with patients had increased rates of seropositivity. It can be due to frequent contacts with the patients during the early stages of the J o u r n a l P r e -p r o o f disease, when they were more contagious. However, some similar studies [11, 17, 30, 33] did not report significant associations. While it is plausible that prolonged contact with patients, especially COVID-19 patients, increases the risk of transmission of the virus, some other studies that have found no association between patient contact or work location and SARS-CoV-2 seropositivity rate indicate a contextual phenomenon [11, 17, 30, 31, 33] . Our pooled analysis results for level of exposure are in line with these findings. While HCWs with high level of exposure to the virus have a higher pooled seropositivity rate (9% with 95%CI 6%-13%) than average (8% with 95% CI 6%-10%), the ones with low level of exposure have a lower pooled seropositivity rate (7%; 95% CI 4%-12%). As we have labeled high level of exposure for the ones with increased patient contact such a result indicates that the risk of contracting the disease lies with the group of HCWs who are spending more time at the clinical encounters.

Another inquiry among the studies was the location of exposure. For example, Dimcheff et al. [30] and Steensels et al. [33] have shown no significant association between seropositivity rate and occupational factors but there was only increased seropositivity rate among the HCWs who had been exposed to a COVID-19 patient outside of the health care system. Eyre et al. [27] reported the household contact as the greatest risk factor for increased seropositivty among HCWs. Our pooled analysis for the seroprevalence rate based on location of exposure supports these findings. It is more likely that the infection control measures and strict requirements to use PPE could have prevented the patient-to-HCW as well as HCW-to-HCW transmission of SARS-CoV-2 in health care settings. However it should not be underestimated that HCWs have the risk J o u r n a l P r e -p r o o f to get infected in the community settings especially when the number of cases are in the rise [42] .

Four studies from USA in our review have conveyed different results for the association of seropositivity and work place in health care setting. While Jeremias et al. [11] , Self et al. [32] and Moscola et al. [17] have presented results showing low seropositivity rates in ICUs, there were no significant difference between departments. On the other hand, Sydney et al. [21] have found that seropositivity was significantly higher in EDs and significantly lower in ICUs. Similarly

Eyre et al. [27] and Grant et al. [22] have found significantly lower rates of seropositivity in ICUs. The lower rates in ICUs might be the result of several factors such as robust safety trainings for precedures in these units, availiability of gowns and other superior PPEs, strict adherence to preventive measures, and well-ventilated wards [6, 43] . Moreover, symptoms such as coughing or sneezing are limited in ICUs as patients due to ventilators, and lastly aerosol generating procedures might contain lower amounts of virus as the patient admission to ICUs are at a latter phase of the disease progression when the viable virus secretion decreases [44] .

This review is subject to several limitations. As each study has reported varying levels of sensitivity and specifity levels for their test kits, it is hard to ensure standard measurement across studies. Therefore seroprevalence reported in studies might be subject to overestimation as well as underestimation. Also, there were limited studies from developing countries. Lastly, the risk factors associated with seroprevalence rates were not standard. However, as a first step we have included studies with over 1,000 participants to minimize the bias and ensure generalizability of J o u r n a l P r e -p r o o f SARS-CoV-2 seroprelance among HCWs. Second, we have presented the outcomes of our analysis according to RoB assessment to illustrate the variation in seroprelance rates.

This study brings together the studies with high sample size to ensure a representative sample of the HCWs from the targeted health care settings. However the unavailability of high quality studies with low RoB especially from developing countries makes it difficult to understand the true level of seropositivity among HCWs and related factors. Nevertheless, our analysis indicate that SARS-CoV-2 seroprevalence rate was 8.0% (95% CI 6.0%-10.0%) and seropositivity was higher among HCWs who have been exposed to the virus outside of the health care setting, the ones with high level of exposure to the virus, and HCWs from ethnic minorities. Decreasing the burden of COVID-19 among HCWs depends on ensuring high adherence to infection control measures, early detection of infection in the health care settings along with prevention of transmission of the virus to HCWs in the community. There is also a need for high quality seroprevalence studies among HCWs in the future phases of the pandemic especially from developing countries to understand the real burden of COVID-19 and assess the efficacy of the vaccines and effectiveness of the vaccination programs.

We are thankful to Ertaç Nebioğlu from Koç University Health Sciences Library for his detailed literature search.

İK and BM contributed equally as the first author J o u r n a l P r e -p r o o f All authors contributed to the development of the selection criteria, the risk of bias assessment strategy and data extraction criteria made by İK, BM and ŞK.

The manuscrip drafted by İK, ŞK, BM, ÖK and ÖE.

All authors developed the search strategy.

MG and ÖE provided statistical expertise. ÖE, JRA, NP 7 and NP 8 provided expertise on SARS CoV-2 seroprevalence.

All authors read, provided feedback and approved the final manuscript. 

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