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. 2021 Aug 20:10:e70458.
doi: 10.7554/eLife.70458.

SARS-CoV-2 shedding dynamics across the respiratory tract, sex, and disease severity for adult and pediatric COVID-19

Paul Z Chen  1 , Niklas Bobrovitz  2   3   4 , Zahra A Premji  5 , Marion Koopmans  6 , David N Fisman  7 , Frank X Gu  1   8
Affiliations

SARS-CoV-2 shedding dynamics across the respiratory tract, sex, and disease severity for adult and pediatric COVID-19

Paul Z Chen et al. Elife. .

Abstract

Background: Previously, we conducted a systematic review and analyzed the respiratory kinetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Chen et al., 2021). How age, sex, and coronavirus disease 2019 (COVID-19) severity interplay to influence the shedding dynamics of SARS-CoV-2, however, remains poorly understood.

Methods: We updated our systematic dataset, collected individual case characteristics, and conducted stratified analyses of SARS-CoV-2 shedding dynamics in the upper (URT) and lower respiratory tract (LRT) across COVID-19 severity, sex, and age groups (aged 0-17 years, 18-59 years, and 60 years or older).

Results: The systematic dataset included 1266 adults and 136 children with COVID-19. Our analyses indicated that high, persistent LRT shedding of SARS-CoV-2 characterized severe COVID-19 in adults. Severe cases tended to show slightly higher URT shedding post-symptom onset, but similar rates of viral clearance, when compared to nonsevere infections. After stratifying for disease severity, sex and age (including child vs. adult) were not predictive of respiratory shedding. The estimated accuracy for using LRT shedding as a prognostic indicator for COVID-19 severity was up to 81%, whereas it was up to 65% for URT shedding.

Conclusions: Virological factors, especially in the LRT, facilitate the pathogenesis of severe COVID-19. Disease severity, rather than sex or age, predicts SARS-CoV-2 kinetics. LRT viral load may prognosticate COVID-19 severity in patients before the timing of deterioration and should do so more accurately than URT viral load.

Funding: Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, NSERC Senior Industrial Research Chair, and the Toronto COVID-19 Action Fund.

Keywords: COVID-19 severity; SARS-CoV-2 replication; epidemiology; global health; infectious disease; infectious disease epidemiology; microbiology; none; pathogenesis of severe COVID-19; pediatric infections; prognostic indicator.

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Conflict of interest statement

PC, NB, ZP, MK, FG No competing interests declared, DF reports serving on advisory boards of Seqirus, Sanofi Pasteur, Pfizer, and AstraZeneca, and consulting for the Ontario Nurses Association, Elementary Teachers' Federation of Ontario, JP Morgan­Chase, WE Foundation, and Farallon Capital, outside the submitted work.

Figures

Figure 1.
Figure 1.. Study selection.
Figure 1—figure supplement 1.
Figure 1—figure supplement 1.. Summary of respiratory viral loads in the systematic dataset.
(A) Upper respiratory tract (URT) respiratory viral loads (rVLs) for adult coronavirus disease 2019 (COVID-19) cases (from –3 to 10 days from symptom onset [DFSO], n = 0, 3, 12, 71, 145, 159, 176, 152, 114, 123, 161, 125, 110, and 117 samples per DFSO). (B) Lower respiratory tract (LRT) rVLs for adult COVID-19 cases (from –3 to 10 DFSO, n = 0, 0, 1, 0, 0, 1, 8, 10, 18, 23, 31, 39, 40, and 40 samples per DFSO). (C) URT rVLs for pediatric COVID-19 cases (from –3 to 10 DFSO, n = 1, 1, 2, 8, 17, 20, 11, 14, 16, 25, 26, 20, 17, and 14 samples per DFSO). Data were collected within the estimated infectious period of SARS-CoV-2 (−3 to 10 DFSO). The systematic search found no quantitative specimen measurements from the LRT for pediatric COVID-19. Open circles show rVL data. Filled circles and bars depict mean estimates and 95% CIs, respectively.
Figure 2.
Figure 2.. Comparison of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding in the upper respiratory tract (URT) across severity, sex, and age groups.
(A–C) URT shedding for severe and nonsevere adult (aged 18 years or older) coronavirus disease 2019 (COVID-19) (A), for nonsevere pediatric (aged 0–17 years) and nonsevere adult COVID-19 (B) and for nonsevere pediatric and severe adult COVID-19 (C). Open circles represent respiratory viral load (rVL) data and were offset from their day from symptom onset (DFSO) for visualization. Lines and bands show regressions and their 95% CIs, respectively. (D and E) Comparisons of URT shedding levels at 1 DFSO (D) and URT shedding dynamics (E) between severity, age, and sex groups for COVID-19. (F and G) Comparisons of URT shedding levels at 1 DFSO (F) and URT shedding dynamics (G) between pediatric and adult groups for COVID-19. The black line in (E) and (G) depicts 0, the threshold for no significant trend in SARS-CoV-2 clearance. Linear regression analyses with interaction determined p-values and compared shedding levels and dynamics between the two groups in each row.
Figure 2—figure supplement 1.
Figure 2—figure supplement 1.. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding in the upper respiratory tract (URT) for adult coronavirus disease 2019 (COVID-19).
(A–D) URT shedding for male and female adult (aged 18 years or older) cases with nonsevere COVID-19 (A), for male and female adult cases with severe COVID-19 (B), for older (aged 60 years or older) and younger (aged 18–59 years) adults with nonsevere COVID-19 (C) and for older and younger adults with severe COVID-19 (D). Open circles represent respiratory viral load (rVL) data and were offset from their day from symptom onset (DFSO) for visualization. Lines and bands show regressions and their 95% CIs, respectively.
Figure 2—figure supplement 2.
Figure 2—figure supplement 2.. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding in the upper respiratory tract (URT) for pediatric coronavirus disease 2019 (COVID-19).
(A) URT shedding for male and female pediatric (aged 0–17 years) cases with nonsevere COVID-19. Open circles represent respiratory viral load (rVL) data and were offset from their day from symptom onset (DFSO) for visualization. Lines and bands show regressions and their 95% CIs, respectively. (B) Estimated distributions at 2, 6, and 10 DFSO of URT shedding for adult (aged 18 years or older) and pediatric cases with nonsevere COVID-19.
Figure 3.
Figure 3.. Comparison of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding in the lower respiratory tract (LRT) across severity and age groups and the upper respiratory tract (URT).
(A–C). Shedding in the LRT for severe and nonsevere adult (aged 18 years or older) COVID-19 (A), in the LRT and URT nonsevere adult COVID-19 (B) and in the LRT and URT severe adult COVID-19 (C). Open circles represent respiratory viral load (rVL) data and were offset from their day from symptom onset (DFSO) for visualization. Lines and bands show regressions and their 95% CIs, respectively. (D and E) Comparisons of shedding levels at 4 DFSO (D) and URT shedding dynamics (E) between severity and age groups in the LRT and between the LRT and URT. The black line in (E) depicts 0, the threshold for no significant trend in SARS-CoV-2 clearance. Linear regression analyses with interaction determined p-values and compared shedding levels and dynamics between the two groups in each row.
Figure 3—figure supplement 1.
Figure 3—figure supplement 1.. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding in the lower respiratory tract (LRT) for adult coronavirus disease 2019 (COVID-19).
(A and B) LRT shedding for older (aged 60 years or older) or younger (aged 18–59 years) adult cases with severe COVID-19 (A) and male adult (aged 18 years or older) cases with severe COVID-19 (B). Open circles represent respiratory viral load (rVL) data and were offset from their day from symptom onset (DFSO) for visualization. Lines and bands show regressions and their 95% CIs, respectively.
Figure 4.
Figure 4.. Heterogeneity in, and severity prognostication from, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding for adult coronavirus disease 2019 (COVID-19).
(A–D) Upper respiratory tract (URT) analyses. (A) Estimated distributions at 2, 4, 7, and 10 days from symptom onset (DFSO) of URT shedding for adults (aged 18 years or older) with nonsevere or severe COVID-19. (B) Overlapped or separated areas under the curve for the distributions in (A). (C) Estimated accuracy for using URT shedding of SARS-CoV-2 as a prognostic indicator for COVID-19 severity. (D) Cumulative distributions of URT shedding for adults with nonsevere or severe COVID-19 at various DFSO. (E–H) Lower respiratory tract (LRT) analyses. (E) Estimated distributions at 5, 6, 8, and 10 DFSO of LRT shedding for adults with nonsevere or severe COVID-19. (F) Overlapped or separated areas under the curve for the distributions in (E). (G) Estimated accuracy for using LRT shedding of SARS-CoV-2 as a prognostic indicator for COVID-19 severity. (H) Cumulative distributions of LRT shedding for adults with nonsevere or severe COVID-19 at various DFSO. Arrows in (A) and (E) denote the 80th case percentiles, in terms of respiratory viral load (rVL), for each group. For (D) and (H), the proportion of cases to the left of a given prognostic threshold are predicted to have nonsevere COVID-19, while those to the right of it are predicted to have severe disease. Sensitivity and specificity can then be estimated using the nonsevere and severe distributions. The dotted lines in (D) and (H) denote 50% accuracy.
Figure 4—figure supplement 1.
Figure 4—figure supplement 1.. Few cases carry the majority of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) copies in the upper respiratory tract (URT) and lower respiratory tract (LRT).
(A–D) Cumulative distribution of URT SARS-CoV-2 copies harbored in adults with nonsevere or severe COVID-19 at 2 (A), 4 (B), 7 (C), and 10 (D) days from symptom onset (DFSO). (E–H) Cumulative distribution of LRT SARS-CoV-2 copies harbored in adults with nonsevere or severe COVID-19 at 5 (A), 6 (B), 8 (C), and 10 (D) DFSO. These curves were based on the fitted Weibull distributions in copies/ml and estimate the proportion of cases that carry the total amount of SARS-CoV-2 in the URT or LRT. The dotted lines denote when the upper case percentiles harbor 80% of copies.
Figure 4—figure supplement 2.
Figure 4—figure supplement 2.. Estimated sensitivity and specificity of upper respiratory tract (URT) shedding as a prognostic indicator for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
(A–D) Metrics for the accuracy of SARS-CoV-2 quantitation from the URT as a prognostic indicator for coronavirus disease 2019 (COVID-19) severity. Estimated true positive, true negative, false positive, and false negative (top) or sensitivity and specificity (bottom) at 2 (A), 4 (B), 7 (C), and 10 (D) days from symptom onset (DFSO) across SARS-CoV-2 respiratory viral loads as the prognostic threshold. As depicted throughout this study, these plots show respiratory viral loads (rVLs, viral RNA concentration in the respiratory tract) rather than specimen concentrations (viral RNA concentration quantitated from a respiratory specimen).
Figure 4—figure supplement 3.
Figure 4—figure supplement 3.. Estimated sensitivity and specificity of lower respiratory tract (LRT) shedding as a prognostic indicator for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
(A–D) Metrics for the accuracy of SARS-CoV-2 quantitation from the LRT as a prognostic indicator for coronavirus disease 2019 (COVID-19) severity. Estimated true positive, true negative, false positive, and false negative (top) or sensitivity and specificity (bottom) at 2 (A), 4 (B), 7 (C), and 10 (D) days from symptom onset (DFSO) across SARS-CoV-2 respiratory viral loads (rVLs) as the prognostic threshold. As depicted throughout this study, these plots show rVLs (viral RNA concentration in the respiratory tract) rather than specimen concentrations (viral RNA concentration quantitated from a respiratory specimen).
Author response image 1.
Author response image 1.. Respiratory viral loads from serially sampled asymptomatic cases.
Each set of connect dots represents a separate individual, except for one adult case which had paired NPS and Spu specimens. The data were overlaid on the regression lines for severe adult cases, nonsevere adult cases and nonsevere pediatric cases (Figure 2A-B). Data between 1-10 DFSO, as defined in the reviewer comment, is shown. The pediatric case with unchanged rVLs was below the detection limit for that study in the included DFSO. NPS, nasopharyngeal swab; Spu, sputum.
See this image and copyright information in PMC

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References

    1. Argyropoulos KV, Serrano A, Hu J, Black M, Feng X, Shen G, Call M, Kim MJ, Lytle A, Belovarac B, Vougiouklakis T, Lin LH, Moran U, Heguy A, Troxel A, Snuderl M, Osman I, Cotzia P, Jour G. Association of initial viral load in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients with outcome and symptoms. The American Journal of Pathology. 2020;190:1881–1887. doi: 10.1016/j.ajpath.2020.07.001. - DOI - PMC - PubMed
    1. Bal A, Brengel-Pesce K, Gaymard A, Quéromès G, Guibert N, Frobert E. Clinical and Microbiological Assessments of COVID-19 in Healthcare Workers: A Prospective Longitudinal Study. medRxiv. 2020 doi: 10.1101/2020.11.04.20225862. - DOI
    1. Benotmane I, Gautier-Vargas G, Wendling MJ, Perrin P, Velay A, Bassand X, Bedo D, Baldacini C, Sagnard M, Bozman DF, Della-Chiesa M, Solis M, Gallais F, Cognard N, Olagne J, Delagrèverie H, Gontard L, Panaget B, Marx D, Heibel F, Braun-Parvez L, Moulin B, Caillard S, Fafi-Kremer S. In-depth virological assessment of kidney transplant recipients with COVID-19. American Journal of Transplantation. 2020;20:3162–3172. doi: 10.1111/ajt.16251. - DOI - PMC - PubMed
    1. Bernheim A, Mei X, Huang M, Yang Y, Fayad ZA, Zhang N, Diao K, Lin B, Zhu X, Li K, Li S, Shan H, Jacobi A, Chung M. Chest CT findings in coronavirus disease-19 (COVID-19): relationship to duration of infection. Radiology. 2020;295:200463. doi: 10.1148/radiol.2020200463. - DOI - PMC - PubMed
    1. Biguenet A, Bouiller K, Marty-Quinternet S, Brunel AS, Chirouze C, Lepiller Q. SARS-COV-2 respiratory viral loads and association with clinical and biological features. Journal of Medical Virology. 2021;93:1761–1765. doi: 10.1002/jmv.26489. - DOI - PubMed

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