Viral dynamics and immune correlates of COVID-19 disease severity

Young, Barnaby E; Ong, Sean W X; Ng, Lisa F P; Anderson, Danielle E; Chia, Wan Ni; Chia, Po Ying; Ang, Li Wei; Mak, Tze-Minn; Kalimuddin, Shirin; Chai, Louis Yi Ann; Pada, Surinder; Tan, Seow Yen; Sun, Louisa; Parthasarathy, Purnima; Fong, Siew-Wai; Chan, Yi-Hao; Tan, Chee Wah; Lee, Bernett; Rötzschke, Olaf; Ding, Ying; Tambyah, Paul; Low, Jenny G H; Cui, Lin; Barkham, Timothy; Lin, Raymond Tzer Pin; Leo, Yee-Sin; Renia, Laurent; Wang, Lin-Fa; Lye, David Chien

BACKGROUND: Key knowledge gaps remain in the understanding of viral dynamics and immune response of SARS-CoV-2 infection. METHODS: We evaluated these characteristics and established their association with clinical severity in a prospective observational cohort study of 100 patients with PCR-confirmed SARS-CoV-2 infection (mean age 46 years, 56% male, 38% with comorbidities). Respiratory samples (n=74) were collected for viral culture, serum samples for measurement of IgM/IgG levels (n=30), and plasma samples for levels of inflammatory cytokines and chemokines (n=81). Disease severity was correlated with results from viral culture, serologic testing, and immune markers. RESULTS: 57 (57%) patients developed viral pneumonia, of whom 20 (20%) required supplemental oxygen including 12 (12%) invasive mechanical ventilation. Viral culture from respiratory samples was positive for 19 of 74 patients (26%). No virus was isolated when the PCR cycle threshold (Ct) value was >30 or >14 days after symptom onset. Seroconversion occurred at a median of 12.5 days (IQR 9-18) for IgM and 15.0 days (IQR 12-20) for IgG; 54/62 patients (87.1%) sampled at day 14 or later seroconverted. Severe infections were associated with earlier seroconversion and higher peak IgM and IgG levels. Levels of IP-10, HGF, IL-6, MCP-1, MIP-1α, IL-12p70, IL-18, VEGF-A, PDGF-BB and IL-1RA significantly correlated with disease severity. CONCLUSION: We found virus viability was associated with lower PCR Ct value in early illness. A stronger antibody response was associated with disease severity. The overactive proinflammatory immune signatures offers targets for host-directed immunotherapy which should be evaluated in randomised controlled trials.