Covid 19: Wastewater Surveillance to Prevent SARS-CoV2 Infection in Nursing Homes

BAA 75D301-20-R-68024 Subtopic 3.1 Assess utility of COVID-19 symptom monitoring and SARS-CoV-2 testing for patients or residents in identifying COVID-19 cases Wastewater Surveillance to Prevent SARS-CoV2 Infection in Nursing Homes People living in long-term care facilities have experienced disproportionate morbidity and mortality from COVID-19. As of mid-June over 50,000 COVID-19 deaths had occurred in nursing home residents in the United States, an estimated 43% of all US COVID-19 deaths in a group that makes up less than 1% of the US population.1 In Kentucky 63% of all reported COVID-19 deaths were nursing home residents and an estimated 59% (169/288) of long-term care facilities have reported at least one confirmed infection.2 Once SARS-CoV2 infection is introduced into congregate living settings it can spread rapidly due to resident density and the frequent and often physically proximal interactions between residents and staff. Nursing home residents are vulnerable to severe COVID-19 disease because of their age and comorbid conditions. Efforts to prevent COVID-19 disease in these settings have focused on enhanced infection prevention activities, such as limiting visitors, use of personal protective equipment (PPE), and physical distancing.3 However, even with increased infection prevention activities, COVID-19 continues to devastate long-term care facilities resulting in substantial loss of life. Early detection of infection in staff or residents is another strategy to mitigate SARS- CoV2 transmission. The CDC recommends temperature and symptom screening of employees prior to each shift and of residents daily. However, there is no evidence that this approach is effective at identifying people with SARS-CoV2 infection or in preventing spread of COVID-19 illness in congregate living settings, and employees and residents may be infectious while presymptomatic or even asymptomatically infected with SARS-CoV2. As part of the “reopening process” CDC guidance encourages one-time viral testing of all nursing home healthcare personnel and residents with weekly testing of asymptomatic personnel thereafter. It is unclear if this resource-intensive approach is feasible given current viral testing bottlenecks and if in conjunction with testing of symptomatic personnel and residents it will identify infections with the expediency needed to prevent future nursing home outbreaks. Wastewater surveillance provides an alternative strategy for SARS-CoV2 detection by evaluating samples of wastewater for the presence of viral biomarkers like RNA. SARS-CoV2 is shed in the stool of infected people and has been detected in the wastewater of several urban areas.4–6 Although historically wastewater surveillance has been limited, it effectively identified a sub-clinical polio virus outbreak in Israel, leading to a focused immunization campaign.7 In response to the COVID-19 pandemic, several cities in the US are implementing city-level wastewater surveillance. We propose implementing wastewater surveillance at nursing homes for the early detection of SARS-CoV2 infection, which if detected would trigger facility-wide clinical testing and enhanced infection prevention measures to prevent COVID-19 infections and deaths. Our team is currently working to simplify the process of extracting and stabilizing SARS- CoV2 RNA from wastewater. We are also studying the stability of SARS-CoV2 RNA under various environmental conditions. We have expertise in wastewater engineering, the development of 1 RNA-based diagnostic platforms, surveillance system design and evaluation (EIS training), and public health response measures to COVID-19. Additionally, we have the resources of a land grant research institution and a formal partnership with the local health department. The objective of our applied research project is to prevent SARS-CoV2 infection in vulnerable people living in nursing homes. To achieve this objective, we propose a pragmatic cluster randomized trial of wastewater surveillance for SARS-CoV2 in long-term care facilities. Aim 1. Monitor wastewater effluent from nursing homes for SARS-CoV2 virus to trigger testing of residents and staff and enhanced infection prevention and control measures. Hypothesis: Wastewater surveillance for SARS-CoV2 will detect circulating virus before symptom-based screening and will trigger timely individual viral testing, mitigate viral spread, and reduce COVID-19 mortality. We will recruit 24 nursing homes in central Kentucky and randomly assign 6 to the intervention and 18 to the control group. These nursing homes follow state reopening guidance, which includes standard infection prevention practices, one-time viral testing of staff and residents, and the development of a facility-specific COVID-19 response plan that addresses issues such as PPE supply, quarantine units, and employee screening. Inclusion criteria are facilities with more than 50 residents and with wastewater infrastructure that permits effluent monitoring specific to the facility. The intervention facilities will receive daily wastewater surveillance for the presence of SARS-CoV2 viral RNA in the facility’s effluent. We will place an automated sampling device in the effluent sewer of the facility. This device will take a preprogrammed volume of wastewater at a specified frequency from the sewer. We will obtain composite 24-hour effluent samples to increase the sensitivity of detecting SARS-CoV2 RNA. To develop the appropriate sampling frequency for each facility, we will flush a standardized SARS-CoV2 RNA load within a toilet in the facility and obtain repeated effluent samples over time to understand the durability of the RNA in the facility’s wastewater system. Effluent samples will be refrigerated and transported to the study team’s lab for processing8 and tested for SARS-CoV2 RNA via RT-qPCR using CDC primers. When a facility has a wastewater sample that tests positive for SARS-CoV2, we will immediately notify facility leadership and support SARS-CoV2 viral testing of all willing residents and employees with a PCR-based test. We will use the SARS-CoV2 testing approach described by the facility in their specific COVID-19 response plan. Additionally, we will review the facility’s COVID-19 infection prevention plan and ensure that staff are using appropriate PPE and that residents are physically distancing as is feasible. The facility’s response to a positive viral test in resident or staff member will be guided by CDC recommendations and the person’s clinical situation to include isolating residents who test positive, the use of enhanced PPE to care for infected residents, and excluding SARS-CoV2-infected employees from work. Once a facility has a positive wastewater test for SARS-CoV2, we anticipate the presence of SARS-CoV2 RNA in the wastewater for days to weeks because infected individuals may have prolonged fecal shedding of SARS-CoV2 RNA.9 Quantitative RT-PCR will aid in understanding the infectious burden in the facility. 2 Since this is a pragmatic study, the 18 facilities in the control arm will follow standard, CDC-recommended employee and resident symptom monitoring, infection prevention practices and instigate individual or facility-wide clinical testing per institutional policy and the guidance of local and state public health agencies. If a control facility identifies a SARS-CoV2-infected resident or employee, we anticipate an institutional response similar to the intervention facilities and in accordance with local, state, and CDC guidance. The primary outcome for this applied research project is the SARS-CoV2 infection rate in nursing home residents. Secondary outcomes are COVID-19 hospitalization and mortality rates in nursing home residents. We estimate that a sample size of 6 intervention and 18 control facilities with an average of 85 residents each will have 78% power to detect an infection probability of 5% in the intervention arm and 35% in the control arm. Nursing homes are mandated to report SARS-CoV2 infections and deaths to the state health department. We will obtain weekly nursing home census figures to calculate the number of residents at risk. Our analysis will use generalized estimating equations to study the effect of wastewater surveillance on resident infection, hospitalization, and mortality rates. We anticipate a study duration of 18 months. Note: We are open to modifying this proposal with the addition of a second intervention arm in order to study the effect of weekly viral testing of nursing home staff on preventing COVID-19 mortality in nursing home residents. The control group would remain the same. We also have interest in serial serological testing of nursing home residents in a subset of the intervention facilities to understand the sensitivity of wastewater surveillance or weekly viral testing in identifying SARS-CoV2 infection. Interval development of positive SARS-CoV2 serology in a resident during a period when wastewater surveillance or clinical tests were negative would suggest that the surveillance method missed infections. Adding another intervention arm or serologic testing would increase the estimated budget of the project by 30-50%. Aim 2. Advance SARS-CoV2 wastewater surveillance technology by adapting ESP (exclusion- based sample preparation) to simplify viral RNA extraction Hypothesis: ESP will simplify wastewater sample preparation, increase RT-qPCR viral assay sensitivity, and enhance feasibility of routine facility-level wastewater surveillance. ESP is a new technology that has successfully isolated viral RNA in minimal-resource settings.10 We have demonstrated that this isolation process significantly stabilizes viral RNA. Given that the half-life of coronavirus RNA in wastewater is estimated to be only 4.8-7.2 hours,11 processes that stabilize RNA “in the field” and not after shipping to a central lab should significantly enhance the sensitivity of wastewater surveillance. We will collect paired wastewater samples from long-term care facilities. One sample will be sent to the lab and processed as in Aim 1. The other sample will be stabilized at the point-of-collection using ESP, and the ESP-extracted RNA will be analyzed in the lab via RT- qPCR. We will compare the RT-qPCR measurements of each paired samples to quantify the advantage of ESP stabilization. Point of contact: James Keck, MD MPH at [email protected] Rough order of magnitude cost estimate: $980,000 3 Estimated timeline to complete the project: Months Activities 1-3 IRB, enroll facilities Install effluent autosamplers in intervention nursing homes Spike facility wastewater systems to inform sampling frequency Review facility generated COVID-19 response plan with each nursing home 4-18 Facility wastewater surveillance for SARS-CoV2 RNA Clinical viral testing of residents and staff per wastewater surveillance and ad hoc Comparison of ESP technology to standard RNA extraction Analysis and dissemination of results References 1. As U.S. Nursing-Home Deaths Reach 50,000, States Ease Lockdowns - WSJ.https://www.wsj.com/articles/coronavirus-deaths-in-u-s-nursing-long-term-care- facilities-top-50-000-11592306919. Accessed June 22, 2020. 2. kycovid19.ky.gov. https://govstatus.egov.com/kycovid19. Accessed June 22, 2020. 3. Responding to Coronavirus (COVID-19) in Nursing Homes | CDC. https://www.cdc.gov/coronavirus/2019-ncov/hcp/nursing-homes-responding.html. Accessed June 22, 2020. 4. Wurtzer S, Marechal V, Mouchel J-M, Moulin L. Time course quantitative detection of SARS-CoV-2 in Parisian wastewaters correlates with COVID-19 confirmed cases. medRxiv. April 2020:2020.04.12.20062679. 5. Medema G, Heijnen L, Elsinga G, Italiaander R, Brouwer A. Presence of SARS-Coronavirus- 2 in sewage. medRxiv. March 2020:2020.03.29.20045880. 6. Ahmed W, Angel N, Edson J, et al. First confirmed detection of SARS-CoV-2 in untreated wastewater in Australia: A proof of concept for the wastewater surveillance of COVID-19 in the community. Sci Total Environ. April 2020:138764. 7. Brouwer AF, Eisenberg JNS, Pomeroy CD, et al. Epidemiology of the silent polio outbreak in Rahat, Israel, based on modeling of environmental surveillance data. Proc Natl Acad Sci U S A. 2018;115(45):E10625-E10633. 8. Wu F, Xiao A, Zhang J, et al. SARS-CoV-2 titers in wastewater are higher than expected from clinically confirmed cases. medRxiv. April 2020:2020.04.05.20051540. 9. Wu Y, Guo C, Tang L, et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol. 2020;5:434-435. 10. Berry SM, Pezzi HM, Williams ED, et al. Using Exclusion-Based Sample Preparation (ESP) to Reduce Viral Load Assay Cost. PLoS One. 2015;10(12). 11. Hart OE, Halden RU. Computational analysis of SARS-CoV-2/COVID-19 surveillance by wastewater-based epidemiology locally and globally: Feasibility, economy, opportunities and challenges. Sci Total Environ. 2020;730:138875. 4