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Immunological and Viral Correlates of COVID-19 Disease Severity: A Prospective Cohort Study of the First 100 Patients in Singapore
34 Pages Posted: 20 May 2020
More...Abstract
Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide, causing severe infections and death with hitherto no proven therapy.
Methods: This was a prospective observational study of 100 patients with virologically confirmed 2019 novel coronavirus disease (COVID-19) admitted to public hospitals in Singapore from 22 January to 6 March 2020. Enrolled patients contributed clinical data from medical records, respiratory samples for SARS-CoV-2 polymerase chain reaction (PCR) and viral culture, serial serum samples for IgG and IgM SARS-CoV-2 serology and plasma samples for immune-profiling.
Findings: Of the 100 patients, mean age was 46 years (95% confidence interval [CI] 43-49), males comprised 56 (56%) and 38 (38%) had comorbidities. Median time from symptom onset to hospital admission was 5·3 days (inter-quartile range (IQR) 1·3-8). Fifty-seven (57%) developed viral pneumonia, of whom 20 (20%) required supplemental oxygen including 12 (12%) invasive mechanical ventilation. Viral culture from respiratory samples was positive for 14 of 73 patients (19%). PCR cycle threshold value ≤30 predicted viral isolation by culture or next-generation sequencing (p<0·0001). Average duration of viral shedding by PCR was 16·7 days (95% CI 15·2-18·3) which did not differ significantly by disease severity or treatment with lopinavir-ritonavir. Seroconversion occurred at a median of 12·5 days (IQR 9-18) for IgM and 15·0 days (IQR 12-20) for IgG; 49/51 patients (96.1%) 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.
Interpretation: Our findings of virus viability have implications on infectivity and infection control. The timing of seroconversion may guide use of rapid serological assays and convalescent plasma collection from donors. The identified overactive proinflammatory immune signatures suggest targets for host-directed immunotherapy which should be evaluated in randomised controlled trials.
Funding Statement: National Medical Research Council COVID research fund (COVID19RF-001). This work is supported in part by the Singapore NMRC grants STPRG-FY19-001 and COVID19RF-003, and Singapore NRF grant NRF2016NRF-NSFC002-013 and by a core fund by the Singapore Immunology Network, Agency for Science Technology and Research (A*STAR).
Declaration of Interests: BY reports personal fees from Roche and Sanofi, outside the submitted work. All other authors: no interest declared.
Ethics Approval Statement: Written informed consent was obtained from all study participants (study protocol at all sites approved by the National Healthcare Group Domain Specific Review Board, Study Reference 2012/00917; additional study protocol at Singapore General Hospital approved by the SingHealth Centralised Institutional Review Board, Study Reference 2018/3045).
Keywords: Coronavirus Disease 2019; COVID-19; severe acute respiratory syndrome coronavirus 2; SARS-CoV-2; severe; critical illness; IL-6; serology; viral culture
Suggested Citation: Suggested Citation