Shedding of infectious virus in hospitalized patients with coronavirus disease-2019 (COVID-19): duration and key determinants

van Kampen, J. J. A.; van de Vijver, D. A. M. C.; Fraaij, P. L. A.; Haagmans, B. L.; Lamers, M. M.; Okba, N.; van den Akker, J. P. C.; Endeman, H.; Gommers, D. A. M. P. J.; Cornelissen, J. J.; Hoek, R. A. S.; van der Eerden, M. M.; Hesselink, D. A.; Metselaar, H. J.; Verbon, A.; de Steenwinkel, J. E. M.; Aron, G. I.; van Gorp, E. C. M.; van Boheemen, S.; Voermans, J. C.; Boucher, C. A. B.; Molenkamp, R.; Koopmans, M. P. G.; Geurtsvankessel, C.; van der Eijk, A. A.

Background Long-term shedding of viral RNA in COVID-19 prevents timely discharge from the hospital or de-escalation of infection prevention and control practices. Key questions are the duration and determinants of infectious virus shedding. We assessed these questions using virus cultures of respiratory tract samples from hospitalized COVID-19 patients as a proxy for infectious virus shedding. Methods Clinical and virological data were obtained from 129 hospitalized COVID-19 patients (89 intensive care, 40 medium care). Generalized estimating equations were used to identify if viral RNA load, detection of viral subgenomic RNA, serum neutralizing antibody response, duration of symptoms, or immunocompromised status were predictive for a positive virus culture. Findings Infectious virus shedding was detected in 23 of the 129 patients (17,8%). The median duration of shedding was 8 days post onset of symptoms (IQR 5-11) and the probability of detecting infectious virus dropped below 5% after 15,2 days post onset of symptoms (95% confidence interval (CI) 13,4-17,2). Multivariate analyses identified viral loads above 7 log10 RNA copies/mL (odds ratio [OR]; CI 14,7 (3,57-58,1; p<0,001) as independently associated with isolation of infectious SARS-CoV-2 from the respiratory tract. A serum neutralizing antibody titre of at least 1:20 (OR of 0,01 (CI 0,003-0,08; p<0,001) was independently associated with non-infectious SARS-CoV-2. Interpretation Infection prevention and control guidelines should take into account that patients with severe or critical COVID-19 may shed infectious virus for longer periods of time compared to what has been reported for in patients with mild COVID-19. Infectious virus shedding drops to undetectable levels below a viral RNA load threshold and once serum neutralizing antibodies are present, which warrants the use of quantitative viral RNA load assays and serological assays in test-based strategies to discontinue or de-escalate infection prevention and control precautions.