key: cord-0745249-y6ypbdtu authors: Fajnzylber, J. M.; Regan, J.; Coxen, K.; Corry, H.; Wong, C.; Rosenthal, A.; Worrall, D.; Giguel, F.; Piechocka-Trocha, A.; Atyeo, C.; Fischinger, S.; Chan, A.; Flaherty, K. T.; Hall, K.; Dougan, M.; Ryan, E. T.; Gillespie, E.; Chishti, R.; Li, Y.; Jilg, N.; Hanidziar, D.; Baron, R. M.; Baden, L.; Tsibris, A. M.; Armstrong, K. A.; Kuritzkes, D. R.; Alter, G.; Walker, B. D.; Yu, X.; Li, J.; Readiness, Massachusetts Consortium for Pathogen title: SARS-CoV-2 Viral Load is Associated with Increased Disease Severity and Mortality date: 2020-07-17 journal: nan DOI: 10.1101/2020.07.15.20131789 sha: 2a1f3eb9a049a1ad5975196b0a6d8cb58f296ee9 doc_id: 745249 cord_uid: y6ypbdtu The relationship between SARS-CoV-2 viral load and risk of disease progression remains largely undefined in coronavirus disease 2019 (COVID-19). We quantified SARS-CoV-2 viral load from participants with a diverse range of COVID-19 severity, including those requiring hospitalization, outpatients with mild disease, and individuals with resolved infection. SARS-CoV-2 plasma RNA was detected in 27% of hospitalized participants and 13% of outpatients diagnosed with COVID-19. Amongst the participants hospitalized with COVID-19, higher prevalence of detectable SARS-CoV-2 plasma viral load was associated with worse respiratory disease severity, lower absolute lymphocyte counts, and increased markers of inflammation, including C-reactive protein and IL-6. SARS-CoV-2 viral loads, especially plasma viremia, were associated with increased risk of mortality. SARS-CoV-2 viral load may aid in the risk stratification of patients with COVID-19 and its role in disease pathogenesis should be further explored. We enrolled 88 hospitalized participants with COVID-19, 94 symptomatic individuals who were 81 evaluated in a respiratory infection clinic, of whom 16 were diagnosed with COVID-19 by 82 standard clinical testing of nasopharyngeal swabs, and 53 participants diagnosed with COVID-19 83 who had symptomatically recovered. Table 1 shows baseline demographic information, disease 84 severity and hospital outcomes. Hospitalized participants were significantly older than both 85 symptomatic outpatients and individuals recovered from COVID-19 (Kruskal-Wallis P<0.001). 86 Participants recruited in the outpatient setting had the shortest time between the start of 87 symptoms and the time of sample collection (median 5 days) compared to hospitalized 88 individuals (median 13 days) and recovered participants (median 27 days). 89 We report SARS-CoV-2 viral load analysis both as a continuous variable and analyzed as 90 a categorical variable (detectable versus undetectable) given that only qualitative commercial 91 qPCR testing is available for clinical care. Amongst hospitalized individuals, the majority still 92 had detectable SARS-CoV-2 RNA at the time of initial sample collection, including 50% with variable, individuals with detectable plasma, nasopharyngeal or sputum viral loads had 124 significantly lower absolute lymphocyte counts, and higher CRP and IL-6 levels compared to 125 those without detectable plasma viremia (Fig 2b-d) . Plasma, nasopharyngeal and/or 126 oropharyngeal viral loads were also significantly associated with increased levels of the 127 inflammatory cytokines IL-8, IP-10, MCP1, IFN-γ, and IL-1RA (Fig 2a) . Compared to individuals who were discharged from the hospital, those who eventually died had 131 significantly higher levels of plasma viremia at the time of initial sampling (median plasma viral 132 load 1.0 vs 2.0 log10 RNA copies/mL, P = 0.009, Fig 3a) , which occurred a median 11 days 133 before death. For hospitalized individuals with initial detectable viremia, 32% died vs 8% of 134 those without initial viremia (OR 5.5, P = 0.02, Fig 3e) . We performed a sensitivity analysis to 135 assess whether plasma viremia may also predict mortality in those with the most severe disease. For participants who were on ventilatory support at the time of initial sample collection, 43% of 137 those with detectable plasma viremia died compared to 17% of those without detectable plasma 138 viremia, although this comparison did not reach statistical significance (OR 3.8, P = 0.11). We 139 also performed an analysis in older participants as the majority of participants who died were at 140 least 70 years old. In those ≥70 years old with initial plasma viremia, 6 of 7 died (86%) vs 2 of 9 141 (22%) without initial viremia (OR 21, P = 0.02). Levels of SARS-CoV-2 viral load in respiratory 142 secretions were also higher in those who eventually died (Fig 3b-d) , although the presence or 143 absence of detectable respiratory secretion viral RNA were not significantly associated with 144 increased risk of death (Fig 3f-h) . Logistic regression analysis was also performed with viral 145 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 17, 2020. almost all participants, regardless of eventual participant outcome (Fig 4) . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 17, 2020. . https://doi.org/10.1101/2020.07.15.20131789 doi: medRxiv preprint DISCUSSION 151 We report a comprehensive analysis of SARS-CoV-2 respiratory tract, plasma, and urine viral 152 loads of 235 participants who were either hospitalized with COVID-19, evaluated as 153 symptomatic outpatients, or had recovered from COVID-19 disease. The results show a 154 relatively high prevalence of SARS-CoV-2 plasma viremia in hospitalized individuals with 155 severe disease, but plasma viremia was also detected in symptomatic non-hospitalized 156 participants. Levels of SARS-CoV-2 viremia was also associated with markers of inflammation 157 and disease severity, including low lymphocyte counts, and elevated CRP and IL-6 levels. To 158 our knowledge, this is also the first report that SARS-CoV-2 viral loads, especially detectable 159 plasma viremia, predicted the risk of death. In contrast to prior reports suggesting that the SARS-CoV-2 viral infection is largely Additional studies of plasma viral load dynamics early in the course of disease are needed. In summary, we report that SARS-CoV-2 plasma viremia is commonly detected in (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 17, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 17, 2020. . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 17, 2020. . https://doi.org/10.1101/2020.07.15.20131789 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 17, 2020. . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 17, 2020. . Recovered individuals included participants who had previously been diagnosed with COVID-19, but whose symptoms have since resolved. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 17, 2020. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 17, 2020. . https://doi.org/10.1101/2020.07.15.20131789 doi: medRxiv preprint There were no deaths in participants with undetectable sputum viral loads All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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