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Association of SARS-CoV-2 Clades with Clinical, Inflammatory and Virologic Outcomes: An Observational Study

33 Pages Posted: 5 Jan 2021

See all articles by Barnaby E. Young

Barnaby E. Young

National Centre for Infectious Diseases

Wycliffe E. Wei

National Public Health and Epidemiology Unit, National Centre for Infectious Diseases

Siew-Wai Fong

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

Tze-Minn Mak

National Centre for Infectious Diseases

Danielle E. Anderson

Duke NUS Medical School

Yi-Hao Chan

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

Rachael Pung

Ministry of Health, Singapore

Cheryl SY Heng

Ministry of Health, Singapore

Li Wei Ang

National Public Health and Epidemiology Unit, National Centre for Infectious Diseases

Kang Eng Zheng

Duke NUS Medical School

Bernett Lee

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

Shirin Kalimuddin

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

Surinder Pada

Ng Teng Fong General Hospital - Division of Infectious Diseases

Paul A. Tambyah

National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore

Purnima Parthasarathy

Khoo Teck Puat Hospital

Seow-Yen Tan

Changi General Hospital - Department of Infectious Diseases

Louisa Sun

Alexandra Hospital

Gavin JD Smith

Duke-NUS Medical School

Raymond Tzer Pin Lin

National Centre for Infectious Diseases

Yee-Sin Leo

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

Laurent Renia

Agency for Science, Technology and Research (A*STAR) - Infectious Diseases Horizontal Technology Centre

Lin-Fa Wang

Duke NUS Medical School

Lisa F.P. Ng

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

Sebastian Maurer-Stroh

National Centre for Infectious Diseases

David Chien Lye

National Centre for Infectious Diseases

Vernon J. Lee

Ministry of Health, Singapore

More...

Abstract

Background: Host determinants of severe coronavirus disease 2019 include advanced age, comorbidities and male sex. Virologic factors may also be important in determining clinical outcome and transmission rates, but limited patient-level data is available.

Methods: We conducted an observational cohort study at seven public hospitals in Singapore. Clinical and laboratory data were collected and compared between individuals infected with different SARS-CoV-2 clades. Firth’s logistic regression was used to examine the association between SARS-CoV-2 clade and development of hypoxia, and quasi-Poisson regression to compare transmission rates. Plasma samples were tested for immune mediator levels and the kinetics of viral replication in cell culture were compared.

Findings: 319 patients with PCR-confirmed SARS-CoV-2 infection had clinical and virologic data available for analysis. 29 (9%) were infected with clade S, 90 (28%) with clade L/V, 96 (30%) with clade G (containing D614G variant), and 104 (33%) with other clades ‘O’ were assigned to lineage B.6. After adjusting for age and other covariates, infections with clade S (adjusted odds ratio (aOR) 0·030 (95% confidence intervals (CI): 0·0002-0·29)) or clade O (B·6) (aOR 0·26 (95% CI 0·064-0·93)) were associated with lower odds of developing hypoxia requiring supplemental oxygen compared with clade L/V. Patients infected with clade L/V had more pronounced systemic inflammation with higher concentrations of pro-inflammatory cytokines, chemokines and growth factors. No significant difference in the severity of clade G infections was observed (aOR 0·95 (95% CI: 0·35-2·52). Though viral loads were significantly higher, there was no evidence of increased transmissibility of clade G, and replicative fitness in cell culture was similar for all clades.

Interpretation: Infection with clades L/V was associated with increased severity and more systemic release of pro-inflammatory cytokines. Infection with clade G was not associated with changes in severity, and despite higher viral loads there was no evidence of increased transmissibility.

Funding Statement: This study was funded by grants from the Singapore National Medical Research Council (COVID19RF- 001, COVID19RF2-0001, COVID19RF-007, and COVID19RF-60) and Biomedical Research Council (project number H20/04/g1/006).

Declaration of Interests: No conflicts of interest declared.

Ethics Approval Statement: The epidemiological investigation was conducted under the Infectious Diseases Act (Singapore). Study protocols were approved by ethics committees of the National Healthcare Group and SingHealth. Written informed consent was obtained from participants for clinical data and biological sample collection as part of the PROTECT study (2012/00917; 2018/3045). A waiver of informed consent for retrospective data collection only was granted for individuals admitted to the National Centre of Infectious Diseases (2020/01122). Healthy donor samples were collected under study numbers 2017/2806 and NUS IRB 04-140.

Suggested Citation

Young, Barnaby E. and Wei, Wycliffe E. and Fong, Siew-Wai and Mak, Tze-Minn and Anderson, Danielle E. and Chan, Yi-Hao and Pung, Rachael and Heng, Cheryl SY and Ang, Li Wei and Zheng, Kang Eng and Lee, Bernett and Kalimuddin, Shirin and Pada, Surinder and Tambyah, Paul A. and Parthasarathy, Purnima and Tan, Seow-Yen and Sun, Louisa and Smith, Gavin JD and Lin, Raymond Tzer Pin and Leo, Yee-Sin and Renia, Laurent and Wang, Lin-Fa and Ng, Lisa F.P. and Maurer-Stroh, Sebastian and Lye, David Chien and Lee, Vernon J., Association of SARS-CoV-2 Clades with Clinical, Inflammatory and Virologic Outcomes: An Observational Study. Available at SSRN: https://ssrn.com/abstract=3741264 or http://dx.doi.org/10.2139/ssrn.3741264

Barnaby E. Young (Contact Author)

National Centre for Infectious Diseases ( email )

Singapore

Wycliffe E. Wei

National Public Health and Epidemiology Unit, National Centre for Infectious Diseases ( email )

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

Tze-Minn Mak

National Centre for Infectious Diseases

Singapore

Danielle E. Anderson

Duke NUS Medical School ( email )

Yi-Hao Chan

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

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

Rachael Pung

Ministry of Health, Singapore

College of Medicine
16 College Road
Singapore, 169854
Singapore

Cheryl SY Heng

Ministry of Health, Singapore ( email )

Li Wei Ang

National Public Health and Epidemiology Unit, National Centre for Infectious Diseases ( email )

Kang Eng Zheng

Duke NUS Medical School ( email )

Bernett Lee

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

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

Shirin Kalimuddin

Singapore General Hospital - Department of Infectious Diseases

Singapore, 169608
Singapore

Duke NUS Medical School - Emerging Infectious Disease Program

Singapore

Surinder Pada

Ng Teng Fong General Hospital - Division of Infectious Diseases

Singapore

Paul A. Tambyah

National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore ( email )

Purnima Parthasarathy

Khoo Teck Puat Hospital ( email )

Seow-Yen Tan

Changi General Hospital - Department of Infectious Diseases ( email )

Singapore

Louisa Sun

Alexandra Hospital

Singapore

Gavin JD Smith

Duke-NUS Medical School ( email )

Raymond Tzer Pin Lin

National Centre for Infectious Diseases ( email )

Yee-Sin Leo

National Centre for Infectious Diseases ( email )

Singapore

Tan Tock Seng Hospital

11 Jalan Tan Tock Seng
308433
Singapore

National University of Singapore (NUS) - Saw Swee Hock School of Public Health

16 Medical Drive
#10-01
117597
Singapore

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

Singapore

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

Singapore

Laurent Renia

Agency for Science, Technology and Research (A*STAR) - Infectious Diseases Horizontal Technology Centre ( email )

Singapore

Lin-Fa Wang

Duke NUS Medical School

Singapore

Lisa F.P. Ng

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

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

Sebastian Maurer-Stroh

National Centre for Infectious Diseases ( email )

Singapore

David Chien Lye

National Centre for Infectious Diseases ( email )

Singapore

Vernon J. Lee

Ministry of Health, Singapore ( email )

College of Medicine
16 College Road
Singapore, 169854
Singapore

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