key: cord-0740108-gsx20896
authors: Wang, Jiancong; Zhou, Mouqing
title: Issues to be considered when planning sero-epidemiological studies in regions with a low incidence of SARS-CoV-2
date: 2020-06-17
journal: Am J Infect Control
DOI: 10.1016/j.ajic.2020.06.176
sha: 5b4665f7840f6b489ac04b577eb9f79e0928f4aa
doc_id: 740108
cord_uid: gsx20896

nan

Letter to the Editor Issues to be considered when planning seroepidemiological studies in regions with a low incidence of SARS-CoV-2

The pandemic of coronavirus disease has substantially affected the healthcare systems, economy and society. 1 Research on the proportions of mild or asymptomatic cases and their roles in coronavirus transmission are ongoing worldwide. 2 Sero-epidemiological investigation of SARS-CoV-2 allows inferences about the extent of infection and the cumulative incidence of infection in the population. 3 However, there are some issues to be considered when planning sero-epidemiological studies in regions with a low incidence of SARS-CoV-2.

The first issue is study design. The World Health Organization (WHO) has recommended 3 design possibilities for implementation of sero-epidemiological investigation 3 : (1) one-time cross-sectional study; (2) repeated cross-sectional study; and (3) longitudinal cohort study. Current evidence has suggested that IgM and IgG antibodies to SARS-CoV-2 can be developed 6-15 days after infection onset. 2 Therefore, repeated cross-sectional and/or longitudinal cohort investigations are preferable for regions with a low incidence of SARS-CoV-2, as they are more likely to detect the seropositive mild or asymptomatic cases through the serial samplings approach. 3 In contrast, one-time cross-sectional investigation is tailored for the regions and countries with initial or subsequent peaks of transmission of epidemic waves (ie, Italy, Spain, and Wuhan). [3] [4] [5] The second issue is population selection. For regions with a low incidence of SARS-CoV-2, targeting specific population groups should be taken into account. There is still the question of which population to consider for detection: (1) seniors with underlying health conditions in nursing homes; (2) adults who have had close contact history with suspected or confirmed COVID-19 cases; or (3) people with suspected SARS-CoV-2 infection but with a negative reverse transcription polymerase chain reaction virus test results on their respiratory samples. The latter 2 targeted groups have been considered by an ongoing French sero-epidemiological study. 6 Furthermore, the WHO protocol suggests that all attempts should include participants across a range of ages, in order to determine and compare age-specific sero-prevalence. 3 Finally, instead of random sampling, convenience sampling from a selected population in the regions with a low incidence of SARS-CoV-2 has also been suggested, considering the better feasibilities for future follow-up as well as for tracking of long-term antibody dynamics.

The third issue is laboratory capacity and medical sources (ie, research funds). According to the available evidence, 3 detection of total antibodies or IgG of SARS-CoV-2 should be prioritized, serological testing should be carried out using enzyme-linked immunosorbent assay, and the confirmation of the presence of neutralizing antibodies should ideally be performed. 3 However, the laboratories in such regions with a low incidence of SARS-CoV-2 usually have limited capacities, that is lacking of biosafety level 3 laboratories and testing kits for SARS-CoV-2. Therefore, planners should take into account the need for well-trained specimen collectors, well-equipped facilities, and funding to cover the cost of shipping samples to an international reference laboratory for confirmation. 3 Meanwhile, we should be aware of the false positive test results, especially in regions that have a low incidence of SARS-CoV-2. This will result in an overestimation of the proportion of infected population in the community, and could also be potentially misled about antibody status for the individuals. 7 The fourth issue is sample size calculation, which is critical when planning sero-epidemiological studies in regions with a low incidence of SARS-CoV-2. The WHO offers online statistical tools for sample size calculation. 3 It is worthwhile to mention that household surveys, as a design feature, are likely to increase the required sample size of the study. 3 Bendavid and colleagues have confirmed the positive effect of this approach. When testing 3,285 adults, they asked each adult to bring 1 child from the same household with them (889 children registered) in order to increase the study power. 8 Last but not least, outcome indicators should be considered. The most interesting outcome indicator is to measure the seroprevalence of antibodies of SARS-CoV-2 in the general population in affected regions. However, for regions with a low incidence, it is meaningful to estimate the proportion of asymptomatic or pre-symptomatic/subclinical infections in the population. The number of asymptomatic cases can help determine whether a region is facing the risk of a potential epidemic wave. Recently, Wuhan conducted a mass COVID-19 nucleic acid tests on about 10 million people, and only 300 asymptomatic cases were discovered. It demonstrated that asymptomatic cases may have limited transmissibility, but more studies are needed to confirm this fact. 5 In addition to the issues presented above, some other factors should also be considered when planning sero-epidemiological studies in regions with a low incidence of SARS-CoV-2, including socioeconomics status, geographical factors, cultures, compliance and responses, ethical considerations, and so forth.

What is the best timing for health care workers infected with COVID-19 to return to work?

The current COVID-19 pandemic has exposed the health care system to its greatest risk, evident with a rapid depletion of medical resources and draining of intensive care units' capacity. 1 Nosocomial transmissions, especially health care workers (HCWs) getting infected with COVID-19 in health care facilities, have been reported by many countries, for example, 20% in Lombardy (Italy) and 26% in Spain, respectively. 2 Wang et al 3 advocated a need to increase the awareness of personal protection (ie, sufficient personal protective equipment and appropriate hand hygiene) in order to minimize the impacts from the loss of the frontline workforces due to infections; however, the question of "what is the best timing for HCWs infected with COVID-19 to return to work" was not still addressed. Globally, monitoring and identification of HCWs with COVID-19 have raised concerns. The main 2 strategies that need urgent attention are: (1) symptom monitoring and screening of HCWs; (2) suitability of HCWs Return-to-Work postinfection. In general, policy-makers and researchers supported and agreed with the strategy of symptom monitoring and screening, which should include: (1) active self-monitoring (ie, self-reporting of signs and symptoms of COVID-19), (2) continuous screening (ie, cross-sectional serological testing), (3) detection of asymptomatic or mildly symptomatic cases among HCWs, and (4) conducting self-quarantine; even though strategy of symptom monitoring and screening poses significant administrative and financial challenges across countries. However, the best Returnto-Work strategy has been debated widely, when balancing between the health status of HCWs and capacities of health care services.

In the United States of America, symptom-based (at least 10 days have passed since symptoms first appeared) and test-based strategies (negative results for SARS-CoV-2 detections from at least 2 consecutive respiratory specimens collected ≥24 hours apart) are proposed by the Centers for Disease Control and Prevention as the Return-to-Work criteria. 4 In Canada, health authorities justified allowing COVID-19 positive HCWs to return to work 10 days from the start of them having symptoms. 5 In Germany, home quarantine periods are recommended 14 days after being tested negative or without respiratory symptoms; in the case of staff shortages, the criteria of minimum 48 hours without symptoms and with 2 consecutive negative testing are applied. 6 Although these recommendations are implemented with the aim to protect health care workforces, these measures remain a great challenge for developing countries (ie, Brazil) especially when the large number of HCWs infected with COVID-19 were on leave from work, resulting in the depletion of workforces. 7 Therefore, criteria of HCWs Return-to-Work in high-income countries may not be implementable and adoptable in the developing countries. As such, issues to consider are: (1) Should Return-to-Work strategy be based on HCWs who have recovered or had an asymptomatic infection but without risk of increased transmission?, (2) Should Returnto-Work strategy be based on confirmatory of negative polymerasechain-reaction (PCR) testing alone and/or in the combination with detection of either all negative antibodies or IgM (À) and IgG (+) for the signal of recovery?, (3) Should Return-to-Work strategy be based on longitudinal clinical observation of HCWs with protective immune response against SARS-CoV-2?, (4) Should Return-to-Work criteria be more or less restrictive?, and (5) How can Return-to-Work policies be adjusted to reduce the loss of health care workforces?

Based on current best available scientific evidence, the median of SARS-CoV-2 incubation period is 5.1 days (95% confidence interval 4.5-5.8 days), and 97.5% of those who develop symptoms will do so within 11.5 days (95% confidence interval 8.2-15.6 days) of infection. 8 Furthermore, current hypothesis has suggested that the population infected with COVID-19 are able to produce protective neutralizing antibodies, and the level of titer of which are related to whether it provides the protection from reinfection and the effects of inhibiting SARS-CoV-2 replication in mechanism. 9 Hence, ideally, the best recommended Return-to-Work strategy for COVID-19 positive HCWs would be 14 days of home quarantine, along with 2 consecutive negative PCR testing at a 48 hours interval, without clinical respiratory symptoms and CT imaging progress. However, in reality, in order to possibly reduce the loss of the frontline workforces, we propose that alternative strategies are also implemented in various regions/countries to address limited medical workforces, that is, allowing asymptomatic and mildly symptomatic HCWs with only 8-9 days of home quarantine, along with both 2 negative PCR testing at a 48 hours interval, and detection of either all negative antibodies or IgM (À) and IgG (+) of SARS-CoV-2, before returning to work. Other infection control measures should be stringently applied, that is, self-active monitoring, temperature surveillance, hand hygiene practices, appropriate personal protective equipment, appropriate face masking, and social distancing.

More research (ie, repeated cross-sectional sero-epidemiological study) is urgently needed for policy-makers to make an informed decision on the best timing for HCWs infected with COVID-19 to Return-to-Work. In-depth analysis and knowledge are required to understand the effectiveness and safety of shortening home quarantine when combined with other infection control measures, which should take into consideration immune response and possibly

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