Asymptomatic SARS-CoV-2 infection: A systematic review and meta-analysis

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Significance

Asymptomatic infections have been widely reported for COVID-19. However, many studies do not distinguish between the presymptomatic stage and truly asymptomatic infections. We conducted a systematic review and meta-analysis of COVID-19 literature reporting laboratory-confirmed infections to determine the burden of asymptomatic infections and removed index cases from our calculations to avoid conflation. By analyzing over 350 papers, we estimated that more than one-third of infections are truly asymptomatic. We found evidence of greater asymptomaticity in children compared with the elderly, and lower asymptomaticity among cases with comorbidities compared to cases with no underlying medical conditions. Greater asymptomaticity at younger ages suggests that heightened vigilance is needed among these individuals, to prevent spillover into the broader community.

Abstract

Quantification of asymptomatic infections is fundamental for effective public health responses to the COVID-19 pandemic. Discrepancies regarding the extent of asymptomaticity have arisen from inconsistent terminology as well as conflation of index and secondary cases which biases toward lower asymptomaticity. We searched PubMed, Embase, Web of Science, and World Health Organization Global Research Database on COVID-19 between January 1, 2020 and April 2, 2021 to identify studies that reported silent infections at the time of testing, whether presymptomatic or asymptomatic. Index cases were removed to minimize representational bias that would result in overestimation of symptomaticity. By analyzing over 350 studies, we estimate that the percentage of infections that never developed clinical symptoms, and thus were truly asymptomatic, was 35.1% (95% CI: 30.7 to 39.9%). At the time of testing, 42.8% (95% prediction interval: 5.2 to 91.1%) of cases exhibited no symptoms, a group comprising both asymptomatic and presymptomatic infections. Asymptomaticity was significantly lower among the elderly, at 19.7% (95% CI: 12.7 to 29.4%) compared with children at 46.7% (95% CI: 32.0 to 62.0%). We also found that cases with comorbidities had significantly lower asymptomaticity compared to cases with no underlying medical conditions. Without proactive policies to detect asymptomatic infections, such as rapid contact tracing, prolonged efforts for pandemic control may be needed even in the presence of vaccination.

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Most cited references 468

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Bias in meta-analysis detected by a simple, graphical test

Jos I. M. Egger, G D Smith, M. Schneider … (1997)

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COVID-19: consider cytokine storm syndromes and immunosuppression

Puja Mehta, Daniel McAuley, Michael Brown … (2020)

As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).

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A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

Jasper Chan, Shuofeng Yuan, Kin-Hang Kok … (2020)

Summary Background An ongoing outbreak of pneumonia associated with a novel coronavirus was reported in Wuhan city, Hubei province, China. Affected patients were geographically linked with a local wet market as a potential source. No data on person-to-person or nosocomial transmission have been published to date. Methods In this study, we report the epidemiological, clinical, laboratory, radiological, and microbiological findings of five patients in a family cluster who presented with unexplained pneumonia after returning to Shenzhen, Guangdong province, China, after a visit to Wuhan, and an additional family member who did not travel to Wuhan. Phylogenetic analysis of genetic sequences from these patients were done. Findings From Jan 10, 2020, we enrolled a family of six patients who travelled to Wuhan from Shenzhen between Dec 29, 2019 and Jan 4, 2020. Of six family members who travelled to Wuhan, five were identified as infected with the novel coronavirus. Additionally, one family member, who did not travel to Wuhan, became infected with the virus after several days of contact with four of the family members. None of the family members had contacts with Wuhan markets or animals, although two had visited a Wuhan hospital. Five family members (aged 36–66 years) presented with fever, upper or lower respiratory tract symptoms, or diarrhoea, or a combination of these 3–6 days after exposure. They presented to our hospital (The University of Hong Kong-Shenzhen Hospital, Shenzhen) 6–10 days after symptom onset. They and one asymptomatic child (aged 10 years) had radiological ground-glass lung opacities. Older patients (aged >60 years) had more systemic symptoms, extensive radiological ground-glass lung changes, lymphopenia, thrombocytopenia, and increased C-reactive protein and lactate dehydrogenase levels. The nasopharyngeal or throat swabs of these six patients were negative for known respiratory microbes by point-of-care multiplex RT-PCR, but five patients (four adults and the child) were RT-PCR positive for genes encoding the internal RNA-dependent RNA polymerase and surface Spike protein of this novel coronavirus, which were confirmed by Sanger sequencing. Phylogenetic analysis of these five patients' RT-PCR amplicons and two full genomes by next-generation sequencing showed that this is a novel coronavirus, which is closest to the bat severe acute respiatory syndrome (SARS)-related coronaviruses found in Chinese horseshoe bats. Interpretation Our findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings, and the reports of infected travellers in other geographical regions. Funding The Shaw Foundation Hong Kong, Michael Seak-Kan Tong, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, Sanming Project of Medicine (Shenzhen), and High Level-Hospital Program (Guangdong Health Commission).

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (hwp): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 24 August 2021

Publication date (Electronic): 10 August 2021

Publication date PMC-release: 10 August 2021

Volume: 118

Issue: 34

Electronic Location Identifier: e2109229118

Affiliations

[1] ^aCenter for Infectious Disease Modeling and Analysis, Yale School of Public Health , New Haven, CT 06520;

[2] ^bCenter for Vaccine Development and Global Health, University of Maryland School of Medicine , Baltimore, MD 21201;

[3] ^cAgent-Based Modelling Laboratory, York University , Toronto, ON M3J 1P3, Canada;

[4] ^dEmerging Pathogens Institute, University of Florida , Gainesville, FL 32610

Author notes

¹To whom correspondence may be addressed. Email: bhsinger@ 123456epi.ufl.edu .

Contributed by Burton H. Singer, July 8, 2021 (sent for review May 19, 2021; reviewed by David Fisman and Claudio Jose Struchiner)

Author contributions: P.S., M.C.F., S.M.M., and A.P.G. designed research; P.S., M.C.F., C.F.Z., E.A., L.J.-K., S.M.M., B.H.S., and A.P.G. performed research; P.S., M.C.F., C.F.Z., E.A., L.J.-K., S.M.M., and A.P.G. analyzed data; and P.S., M.C.F., S.M.M., B.H.S., and A.P.G. wrote the paper.

Reviewers: D.F., University of Toronto; and C.J.S., Fundacao Getulio Vargas.

Author information

Pratha Sah https://orcid.org/0000-0001-8936-5871

Burton H. Singer https://orcid.org/0000-0002-5295-5971

Article

Publisher ID: 202109229

DOI: 10.1073/pnas.2109229118

PMC ID: 8403749

PubMed ID: 34376550

SO-VID: 0c3849f8-7206-47a2-8b00-2eb28cb20845

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This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

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Pages: 12

Funding

Funded by: DH | NIHR | Health Services and Delivery Research Programme (HS&DR) 501100002001

Award ID: 1KO1A141576 - 01

Award Recipient : Meagan Fitzpatrick

Funded by: Gouvernement du Canada | Canadian Institutes of Health Research (CIHR) 501100000024

Award ID: OV4-170641

Award Recipient : Seyed Moghadas

Funded by: National Science and Engineering Council of Canada

Award ID: No Number

Award Recipient : Seyed Moghadas Award Recipient : Alison P Galvani

Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) 100000060

Award ID: 1RO1A1151176-01

Award Recipient : Alison P Galvani

Funded by: NSF RAPID

Award ID: 202775

Award Recipient : Seyed Moghadas Award Recipient : Alison P Galvani

Funded by: NSF CCF

Award ID: 1918784

Award Recipient : Seyed Moghadas Award Recipient : Alison P Galvani

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change-history-updated-date August 27, 2021

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Keywords: asymptomatic fraction,presymptomatic,silent transmission,novel coronavirus,comorbidity

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Keywords: asymptomatic fraction, presymptomatic, silent transmission, novel coronavirus, comorbidity

Asymptomatic SARS-CoV-2 infection: A systematic review and meta-analysis

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Novel Coronavirus Disease COVID-19

Most cited references 468

Bias in meta-analysis detected by a simple, graphical test

COVID-19: consider cytokine storm syndromes and immunosuppression

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

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