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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

See all articles by Barnaby E. Young

Barnaby E. Young

National Centre for Infectious Diseases, Singapore

Sean Wei Xiang Ong

National Centre for Infectious Diseases; Tan Tock Seng Hospital

Lisa FP Ng

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

Danielle E. Anderson

Duke NUS Medical School

Wan Ni Chia

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

Po Ying Chia

National Centre for Infectious Diseases, Singapore; Tan Tock Seng Hospital; Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Li Wei Ang

Ministry of Health, Singapore; National Centre for Infectious Diseases

Tze-Minn Mak

National Centre for Infectious Diseases, Singapore

Shirin Kalimuddin

Singapore General Hospital - Department of Infectious Diseases; Duke NUS Medical School - Emerging Infectious Disease Program

Louis Yi Ann Chai

National University Health System (NUHS); National University of Singapore (NUS) - Yong Loo Lin School of Medicine

Surinder Pada

Ng Teng Fong General Hospital - Division of Infectious Diseases

Seow Yen Tan

Changi General Hospital

Louisa Sun

Alexandra Hospital

Purmina Parthasarathy

Khoo Teck Puat Hospital

Siew-Wai Fong

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN); National University of Singapore (NUS) - Department of Biological Sciences

Yi-Hao Chan

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

Chee Wah Tan

Duke NUS Medical School

Bernett Lee

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

Olaf Rötzschke

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

Ying Ding

National Centre for Infectious Diseases

Paul Tambyah

National University of Singapore (NUS)

Jenny GH Low

Singapore General Hospital; Duke NUS Medical School

Lin Cui

National Centre for Infectious Diseases, Singapore

Timothy Barkham

Tan Tock Seng Hospital; National University of Singapore (NUS) - Yong Loo Lin School of Medicine

Raymond Tzer Pin Lin

National Centre for Infectious Diseases

Yee-Sin Leo

National University of Singapore (NUS) - Department of Microbiology and Immunology

Laurent Renia

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

Lin-Fa Wang

Duke NUS Medical School

David Chien Lye

National Centre for Infectious Diseases; Tan Tock Seng Hospital; Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine; National University of Singapore (NUS) - Yong Loo Lin School of Medicine

Singapore 2019 Novel Coronavirus Outbreak Research Team

Independent

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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

Young, Barnaby E. and Ong, Sean Wei Xiang and Ng, Lisa FP and Anderson, Danielle E. and Chia, Wan Ni and Chia, Po Ying and Ang, Li Wei and Mak, Tze-Minn and Kalimuddin, Shirin and Chai, Louis Yi Ann and Pada, Surinder and Tan, Seow Yen and Sun, Louisa and Parthasarathy, Purmina and Fong, Siew-Wai and Chan, Yi-Hao and Tan, Chee Wah and Lee, Bernett and Rötzschke, Olaf and Ding, Ying and Tambyah, Paul and Low, Jenny GH and Cui, Lin and Barkham, Timothy and Lin, Raymond Tzer Pin and Leo, Yee-Sin and Renia, Laurent and Wang, Lin-Fa and Lye, David Chien and Team, Singapore 2019 Novel Coronavirus Outbreak Research, Immunological and Viral Correlates of COVID-19 Disease Severity: A Prospective Cohort Study of the First 100 Patients in Singapore (4/15/2020). Available at SSRN: https://ssrn.com/abstract=3576846 or http://dx.doi.org/10.2139/ssrn.3576846

Barnaby E. Young (Contact Author)

National Centre for Infectious Diseases, Singapore ( email )

Singapore

Sean Wei Xiang Ong

National Centre for Infectious Diseases

Singapore

Tan Tock Seng Hospital

11 Jalan Tan Tock Seng
308433
Singapore

Lisa FP Ng

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

1 Fusionopolis Way
#16-16 Connexis
Singapore, 138632
Singapore

Danielle E. Anderson

Duke NUS Medical School

Singapore

Wan Ni Chia

Duke-NUS Medical School - Programme in Emerging Infectious Diseases

Singapore

Po Ying Chia

National Centre for Infectious Diseases, Singapore

Singapore

Tan Tock Seng Hospital

11 Jalan Tan Tock Seng
308433
Singapore

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Singapore

Li Wei Ang

Ministry of Health, Singapore

College of Medicine
16 College Road
Singapore, 169854
Singapore

National Centre for Infectious Diseases

Singapore

Tze-Minn Mak

National Centre for Infectious Diseases, Singapore

Singapore

Shirin Kalimuddin

Singapore General Hospital - Department of Infectious Diseases

Singapore

Duke NUS Medical School - Emerging Infectious Disease Program

Singapore

Louis Yi Ann Chai

National University Health System (NUHS)

1E, Kent Ridge Road
119228
Singapore

National University of Singapore (NUS) - Yong Loo Lin School of Medicine

Singapore

Surinder Pada

Ng Teng Fong General Hospital - Division of Infectious Diseases

Singapore

Seow Yen Tan

Changi General Hospital

Singapore

Louisa Sun

Alexandra Hospital

Singapore

Purmina Parthasarathy

Khoo Teck Puat Hospital

Singapore

Siew-Wai Fong

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

1 Fusionopolis Way
#16-16 Connexis
Singapore, 138632
Singapore

National University of Singapore (NUS) - Department of Biological Sciences

14 Science Drive 4
Singapore, 117543
China

Yi-Hao Chan

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

1 Fusionopolis Way
#16-16 Connexis
Singapore, 138632
Singapore

Chee Wah Tan

Duke NUS Medical School

Singapore

Bernett Lee

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN) ( email )

1 Fusionopolis Way
#16-16 Connexis
Singapore, 138632
Singapore

Olaf Rötzschke

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

1 Fusionopolis Way
#16-16 Connexis
Singapore, 138632
Singapore

Ying Ding

National Centre for Infectious Diseases

Singapore

Paul Tambyah

National University of Singapore (NUS)

1E Kent Ridge Road
NUHS Tower Block Level 7
Singapore, 119228
Singapore

Jenny GH Low

Singapore General Hospital

Singapore, 169608
Singapore

Duke NUS Medical School

Singapore

Lin Cui

National Centre for Infectious Diseases, Singapore ( email )

Singapore

Timothy Barkham

Tan Tock Seng Hospital

11 Jalan Tan Tock Seng
308433
Singapore

National University of Singapore (NUS) - Yong Loo Lin School of Medicine

Singapore

Raymond Tzer Pin Lin

National Centre for Infectious Diseases

Singapore

Yee-Sin Leo

National University of Singapore (NUS) - Department of Microbiology and Immunology ( email )

5 Science Drive 2 Blk MD4, Level 3
117545
Singapore

Laurent Renia

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

1 Fusionopolis Way
#16-16 Connexis
Singapore, 138632
Singapore

Lin-Fa Wang

Duke NUS Medical School

Singapore

David Chien Lye

National Centre for Infectious Diseases

Singapore

Tan Tock Seng Hospital

11 Jalan Tan Tock Seng
308433
Singapore

Nanyang Technological University (NTU) - Lee Kong Chian School of Medicine

Singapore

National University of Singapore (NUS) - Yong Loo Lin School of Medicine

Singapore

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