Viral dynamics of SARS-CoV-2 infection and the predictive value of repeat testing

Kissler, Stephen M; Fauver, Joseph R.; Mack, Christina; Olesen, Scott W.; Tai, Caroline; Shiue, Kristin Y.; Kalinich, Chaney; Jednak, Sarah; Ott, Isabel; Vogels, Chantal; Wohlgemuth, Jay; Weisberger, James; DiFiori, John; Anderson, Deverick J.; Mancell, Jimmie; Ho, David; Grubaugh, Nathan D.; Grad, Yonatan H.

BackgroundSARS-CoV-2 infections are characterized by viral proliferation and clearance phases and can be followed by low-level viral RNA shedding. The dynamics of viral RNA concentration, particularly in the early stages of infection, can inform clinical measures and interventions such as test-based screening. MethodsWe used prospective longitudinal RT-qPCR testing to measure the viral RNA trajectories for 68 individuals during the resumption of the 2019-20 National Basketball Association season. For 46 individuals with acute infections, we inferred the peak viral concentration and the duration of the viral proliferation and clearance phases. FindingsOn average, viral RNA concentrations peaked 2.7 days (95% credible interval [1.2, 3.8]) after first detection at a cycle threshold value of 22.4 [20.6, 24.1]. The viral clearance phase lasted longer for symptomatic individuals (10.5 days [6.5, 14.0]) than for asymptomatic individuals (6.7 days [3.2, 9.2]). A second test within 2 days after an initial positive PCR substantially improves certainty about a patients infection phase. The effective sensitivity of a test intended to identify infectious individuals declines substantially with test turnaround time. InterpretationSARS-CoV-2 viral concentrations peak rapidly regardless of symptoms. Sequential tests can help reveal a patients progress through infection stages. Frequent rapid-turnaround testing is needed to effectively screen individuals before they become infectious. FundingNWO Rubicon 019.181EN.004 (CBFV); clinical research agreement with the NBA and NBPA (NDG); Huffman Family Donor Advised Fund (NDG); Fast Grant funding from the Emergent Ventures at the Mercatus Center; George Mason University (NDG); the Morris-Singer Fund for the Center for Communicable Disease Dynamics at the Harvard T.H. Chan School of Public Health (YHG). Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSSARS-CoV-2 viral dynamics affect clinical and public health measures, informing patient care, testing algorithms, contact tracing protocols, and clinical trial design. We searched Web of Science using the search terms "ALL = ((SARS-CoV-2 OR COVID-19) AND (viral OR RNA) AND (load OR concentration OR shedding) AND (dynamic* OR kinetic* OR trajector*))" which returned 83 references. Of these, 22 were not pertinent to within-host SARS-CoV-2 viral dynamics. The remaining 61 studies tracked SARS-CoV-2 viral trajectories in a variety of geographic locations and patient populations. Together, these studies report that viral titers normally peak at or before the onset of symptoms and that a long tail of intermittent positive tests can follow a period of acute infection. Plasma but not nasopharyngeal viral concentration is associated with increased disease severity. Most studies tracked hospitalized patients after the onset of symptoms. Two of the studies tracked pre-symptomatic and/or asymptomatic patients, but these were too sparsely sampled to clearly discern viral dynamics during the earliest stage of infection. Added value of this studyWe implemented prospective longitudinal real time quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) testing for SARS-CoV-2 in a cohort of individuals during the resumption of the 2019-20 National Basketball Association season. This allowed us to explicitly measure viral titers during the full course of 46 acute infections. Consistent with other studies, we find that peak viral concentrations do not differ substantially between symptomatic and asymptomatic individuals but that symptomatic individuals take longer to clear the virus than asymptomatic individuals. For both symptomatic and asymptomatic individuals, viral titers normally peak within 3 days of the first positive test. This study is the first to describe the time course of viral concentrations during the earliest stage of infection when individuals are most likely to be infectious. Implications of all the available evidenceSymptomatic and asymptomatic individuals follow similar SARS-CoV-2 viral trajectories. Due to the rapid progression from first possible detection to peak viral concentration, frequent rapid-turnaround testing is needed to screen individuals prior to them becoming infectious.