Combined epidemiological and molecular investigation of 3 nosocomial outbreaks of SARS-CoV-2 cross-infection

Background and rationaleDuring the Coronavirus disease 2019 (COVID-19) pandemic, 3 nosocomial outbreaks occurred in distinct sites in the Department of Rehabilitation and Geriatrics of Geneva University Hospitals. After enhancing infection prevention and control, the outbreaks were successfully controlled. Protection of healthcare workers (HCWs) is a key priority whilst caring for severe acute respiratory syndrome (SARS-CoV-2) infected patients. Similarly, preventing healthcare-associated COVID-19 among COVID-19 negative patients is key. Particular attention should be placed on vulnerable patients in long-term care facilities and geriatrics. In the outbreaks we describe, the complex interplay between and respective role of HCWs and patients in transmission remains unclear. Aim and objectives The overarching objective of this study is to reconstruct the outbreaks in each hospital site (A, B, C) combining epidemiological with genetic data, in order to understand transmission dynamics and improve infection control practices and consider additional preventive strategies.Specific aimsSpecific aims of the study include:•Compute the attack rate in the institution among patients and HCWs•Establish viral transmission pathways of the outbreak and reconstructing a transmission tree•Identify the directionality of transmission (i.e. HCW to HCW, HCW to patient, patient to HCW, community to HCW)•Identify risk factors for healthcare-associated SARS-CoV-2 infection and mortality among patients •Identify risk factors for HCW SARS-CoV-2 infection •Describe and analyse variation among infection control practices across the 3 sites•Identify and develop new strategies to prevent healthcare-associated COVID infection Study design and expected resultsThis is a retrospective cohort study of COVID-19 clusters involving 104 patients and 185 HCWs in 3 distinct hospital sites of the Geneva University Hospitals. We will obtain clinical and epidemiological data of all SARS-CoV-2 positive patients and HCWs. We will construct epidemic curves by ward for patients and HCWs, and compute attack rates and doubling times. These data will help to construct a putative transmission tree. We will perform a nested case-control study in one of the sites that will seek to establish risk factors of HCW infection by SARS-CoV-2. Exposure to COVID-19 patients and other HCWs is assessed, as well as potential community exposure. A nested case-control study will be performed in order to identify risk factors for healthcare-associated SARS-CoV-2 infection among patients, and a case-case-control study to identify risk factors for mortality among these patients.SARS-CoV-2 complete genome sequences will be generated using an amplicon-based next generation sequencing protocol. Complete viral genomes will be obtained after mapping reads to a SARS-CoV-2 reference sequence. We will combine epidemiologic and genetic data using the "outbreaker" package in R software. We will use a Bayesian framework, which will combine the distribution of the generation time, from which a probabilistic transmission tree is constructed, as well as a model of sequence evolution along the transmission chain. We will impute generation times from estimates available from the literature. The output from the model will allow us to estimate the dates of infection, mutation rates, multiple importation events, missed cases, as well as to reconstruct the transmission tree. Expected impactAnalysis of these nosocomial outbreaks will provide key insights into transmission dynamics of SARS-CoV-2 in the healthcare setting and will inform infection prevention guidelines in order to enhance protection of HCWs and patients. Furthermore, this study will demonstrate the added value of genome sequencing in elucidating the complex connectivity of SARS-CoV-2 dissemination in hospitals.