In this prospective cohort study, we assessed symptomatic and asymptomatic SARS-CoV-2 infections in HCWs in a large tertiary hospital in Mainz, Germany. The seroprevalence of anti-SARS-CoV-2 antibodies ranged from 2.7% at baseline to 3.8% at the end of follow-up. Reported seroprevalence of SARS-CoV-2 among HCWs vary across and within settings, which could reflect differences in background community transmission. A recent meta-analysis reported a pooled seroprevalence in HCWs of 8.7%, with the rates ranging from 4% in Asia to 12.7% in the US.8 In Northern Germany, a prospective study during the early phases of the pandemic reported comparable seroprevalence of anti-SARS-CoV-2 IgG antibodies to our study (4.4%).9 During the same period, lower seroprevalences rates were reported in some regions,10,11 whereas a German region with high background rate had an estimated seroprevalence of 15.1%.12 Cross-sectional studies that were conducted against a background of high epidemic activity consistently reported higher seroprevalence, such as in Spain (~ 17% to ~ 32% 13–15), the UK (32% 16), and Sweden (19.1% 17).
In our university hospital, the seroprevalence among blood donors was estimated to be 0.4%.18 Another study from Germany reported similarly low seroprevalence rates among regular blood donors in three different regions.19 A large cross-sectional study in Central Denmark reported seroprevalence of 3.7% and 0.6–1.2% among HCWs and blood donors, respectively. 20. These results indicate the increased risk of SARS-CoV-2 infection in HCWs.
Our study provided some insights on the duration of anti-SARS-CoV-2 antibody response after natural infection, with apparent waning of antibody titers over time. Out of 98 HCWs who were seropositive at baseline, ~ 11% and ~ 15% seroreverted by weeks 6 and 12 of follow-up, respectively. In contrast, only one seroreversion occurred among the 33 HCWs who seroconverted by the 2nd visit. Assuming all seropositive subjects at baseline converted just prior to enrolment, the seroreversion rate in our population would be at most 2.3 per 1000 person-months. A longitudinal study from Italy reported a mean 17% reduction in IgG titers among seropositive HCWs within 8 weeks of testing negative for viral RNA.21 Another study from Spain reported 68.3% and 3.1% of seropositive HCWs seroreverted for IgM and IgG, respectively, after three months of follow-up.22
Between August 2020 - January 2021, we observed an increasing rate of SARS-CoV-2 infection, with 33 (0.9%) and 35 (1.2%) seroconversions at the 2nd and 3rd follow-up visits, respectively. These rates translate to ~ 1.5-2 weekly seroconversions per 1000 persons. Among HCWs with complete follow-up, the overall seroconversion rate in our study would be 2.3% (68/2925). With the cumulative incidence rate of COVID-19 in our study estimated to be 14.5 per 1000 persons, our findings are consistent with a concurrent regional increase in the background rates of COVID-19. Data reported to the Robert Koch-Institute in Germany indicated a ten-fold increase in the cumulative incidence of COVID-19 cases in the Rheinland-Pfalz region (where Mainz is located), from 2.6 per 1000 population in September 2020 to 17.6 per 1000 population in December 2020.23
Our study is one of adequately-powered few that were based on prospective design. Our observed seroconversion rate is consistent with findings from the largest prospective study to date, which followed > 12,500 HCWs in the UK over a median of 200 days and reported a seroconversion rate of 0.8%.24 Studies from similar settings that reported higher rates were likely underpowered. For example, two relatively small studies from Germany and Denmark reported seroconversion rates of 4.7% and 4.2%, respectively.25–26
Approximately 19% of HCWs who seroconverted in our study did not report any symptoms. Higher estimates of asymptomatic SARS-CoV-2 infections among HCWs were previously reported. A prospective study in Egypt reported that 64% of HCWs who seroconverted were asymptomatic.27 However, this was based on a single follow-up visit with no active surveillance in-between. In Spain, two cross-sectional studies reported that 49%-68% of seropositive HCWs were asymptomatic.14,15 Cross-sectional seroprevalence studies may not be suitable to estimate the true proportion of asymptomatic SARS-CoV-2 infections, given the variable incubation period thereof. Moreover, early clinical presentation of SARS-CoV-2 infection is non-specific, and knowledge and awareness thereof are likely to improve over time. Although a low-threshold active surveillance is more sensitive in detecting asymptomatic infections,, this approach is resource intensive and may not be suitable in most settings. For example, we had to test ~ 32 episodes using RT-PCR to detect one COVID-19-positive episode. Not surprisingly, an even lower proportion (10.2%) of asymptomatic infections was reported where both symptomatic and asymptomatic HCWs were screened.24
The majority (87.3%) of COVID-19-positive episodes comprised two or more symptoms with varying combinations, which invariably included smell or taste dysfunction. On the other hand, COVID-19 negative episodes were more likely to report single symptoms with relatively short durations, the most common of which was cough. This is consistent with data from other studies. A cross-sectional study on HCWs in Sweden reported up to 28-fold association between smell or taste dysfunction and seropositive status.17
Most COVID-19 cases in our study were nurses with reported direct contact with confirmed COVID-19 cases. In two Scandinavian studies, nurses had the highest risk of infection, and > 3-fold association was estimated between SARS-CoV-2 infection and direct contact with COVID-19 patients.17,20 Similarly, HCWs in Cairo who reported contact with confirmed COVID-19 cases were > 2-fold at higher risk of infection than those who did not (hazard ratio: 2.2).27 None of the COVID-19 cases in our study met either case definition of severe disease, and only one case (1.8%) required hospitalization. One meta-analysis demonstrated that the risk of severe or critical disease in HCWs was significantly lower than that in non-HCW COVID-19 patients (9.9% vs. 29.4%, respectively). However, higher prevalence of comorbidities may lead to higher rates of severe disease. In a recent systematic literature review, a higher prevalence of comorbidities in HCWs (18.4%) could explain an eight-fold higher prevalence of hospitalizations (~ 15%) compared to our study.28
A number of limitations need to be mentioned. First, the sampling method was convenience-based, and therefore selection bias could not be ruled out. Reporting of symptoms relied on self-reporting, which may have resulted in recall bias and/or missing data. However, the study team received automated alerts via centralized monitoring system to notify subjects with multiple missing reports. Second, ~ 18% of study subjects did not have their scheduled 3rd follow-up visit by the time of the data lock point of this analysis. However, we believe our estimates of seroprevalence and seroconversion at visit 3 are likely conservative, given that more than a third of incident COVID-19 cases occurred shortly before. Last, due to low case positive counts, we could not statistically assess risk factors of SARS-CoV-2 infection, including known sociodemographic and occupational factors which were reported previously.29 In addition, the low case count hindered reliable modelling to identify the symptoms most predictive of COVID-19. However, our results suggest that active case finding based on smell or taste dysfunction, with or without other symptoms, would help detect the majority of symptomatic infections.
In conclusion, our findings indicate increasing rates of COVID-19 disease among HCWs in a setting of increased background community transmission. Although we observed an apparent waning in humoral immune response against SARS-CoV-2, we did not detect evidence of reinfections – particularly among those who were seropositive at baseline. We also observed lower than expected rates of asymptomatic infections, which highlight the importance of cautious interpretation of reported estimates from cross-sectional studies. With the current rolling out of vaccination programs in a setting of increased but region-specific transmission of SARS-CoV-2 variants of concern, continued monitoring of infection rates is paramount.