Clinical and Microbiological Assessments of COVID-19 in Healthcare Workers: A Prospective Longitudinal Study

Bal, Antonin; Brengel‐Pesce, Karen; Gaymard, Alexandre; Quéromès, Grégory; Guibert, Nicolas; Frobert, Emile; Bouscambert‐Duchamp, Maude; Trabaud, Mary‐Anne; Allantaz-Frager, Florence; Oriol, Guy; Cheynet, Valérie; d’Aubarede, Constance; Massardier-Pilonchéry, Amélie; Buisson, Marlyse; Lupo, Julien; Pozzetto, Bruno; Poignard, Pascal; Lina, Bruno; Fassier, Jean‐Baptiste; Morfin-Sherpa, Florence; Assant, Sophie

doi:10.2139/ssrn.3724866

Cited by 3 publications

(6 citation statements)

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“…At the full-text stage, reference lists were reviewed for study inclusion. Inconsistencies were resolved by discussion and consensus, and 26 studies met the inclusion criteria ( Bal et al, 2020 ; Benotmane et al, 2020 ; Biguenet et al, 2021 ; Fajnzylber et al, 2020 ; Han et al, 2020 ; Hirotsu et al, 2020 ; Hurst et al, 2020 ; Iwasaki et al, 2020 ; L’Huillier et al, 2020 ; Lavezzo et al, 2020 ; Pan et al, 2020 ; Peng et al, 2020 ; Shrestha et al, 2020 ; Sun et al, 2020 ; To et al, 2020 ; van Kampen et al, 2021 ; Vetter et al, 2020 ; Wölfel et al, 2020 ; Wyllie et al, 2020 ; Xu et al, 2020a ; Yazdanpanah, 2021 ; Yilmaz et al, 2021 ; Yonker et al, 2020 ; Zhang et al, 2021 ; Zheng et al, 2020 ; Zou et al, 2020 ). Additional details on study selection can be found in our previous protocol ( Chen et al, 2021a ).…”

Section: Methodsmentioning

confidence: 99%

“…of adult cases (nonsevere; severe) No. of pediatric cases (nonsevere; severe) URT specimens (ascertained † for age, sex, disease severity) LRT specimens (ascertained † for age, sex, dis-ease severity) Reported treatment (type) ‡ Volume of VTM reported Specimen type (adjusted rVL) § Risk of bias ¶ Bal et al, 2020 France H, N, A, S 39 (38; 1) 0 47 (47; 47; 47) 0 N/A No NPS (yes) ***** Benotmane et al, 2020 France H, A, S 37 (19; 18) 0 47 (47; 47; 47) 0 Yes (azithromycin, other antibiotics, azole antifungals, lopinavir-ritonavir, hydroxychloroquine, tocilizumab, high-dose corticosteroid, mycophenolate mofetil withdrawal, mycophenolic acid withdrawal, calcineurin inhibitors withdrawal, mammalian target of rapamycin withdrawal, delayed belatacept administration) No NPS (yes) ****** Biguenet et al, 2021 France H, N, A, S 453 (406; 47) 0 453 (453; 453; 453) 0 Yes (antibiotics, oseltamivir, hydroxychloroquine, corticosteroids, lopinavir-ritonavir, remdes...…”

Section: Appendix 1—tablementioning

confidence: 99%

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

Chen

Bobrovitz

Premji

et al. 2021

eLife

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Appendix 1—tablementioning

confidence: 99%

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

Chen

Bobrovitz

Premji

et al. 2021

eLife

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“…Specific viral loads likely to be infectious for each specimen type have not been established (27), partly because Ct values are not comparable across assays(28, 29) and culture methods differ. However, as a general reference, viral loads of >10 4 -10 7 RNA copies/mL are associated with the presence of replication-competent virus in culture (16,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40), and these values have been used in outbreak simulations (35,39,(41)(42)(43). The enormous range (>4 orders of magnitude) in observed viral loads that correspond with infectiousness emphasizes why quantitative measurements of viral loads in different specimen types are needed to make robust predictions about tests that will detect the pre-infectious and infectious periods.…”

Section: Introductionmentioning

confidence: 99%

Extreme differences in SARS-CoV-2 viral loads among respiratory specimen types during presumed pre-infectious and infectious periods

Winnett

Akana

Shelby

et al. 2022

Preprint

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Background. Screening testing, often via self-collected specimens, remains a key strategy to detect infections early and prevent SARS-CoV-2 transmission, and to enable earlier initiation of treatment. However, which specimen type best detects the earliest days of infection remains controversial. Further, the analytical sensitivity of diagnostic tests must also be considered, as viral loads below a test's limit of detection (LOD) are likely to yield false-negative results. Comparisons of quantitative, longitudinal SARS-CoV-2 viral-load timecourses in multiple specimen types can determine the best specimen type and test analytical sensitivity for earliest detection of infection. Methods. We conducted a COVID-19 household transmission study between November 2021 and February 2022 that enrolled 228 participants and analyzed 6,825 samples using RT-qPCR to quantify viral-load timecourses in three specimen types (saliva [SA], anterior-nares swab [ANS], and oropharyngeal swab [OPS]). From this study population, 14 participants enrolled before or at the incidence of infection with the Omicron variant. We compared the viral loads in specimens collected from each person at the same timepoint, and the longitudinal viral load timecourses from each participant. Using these viral loads, we inferred the clinical sensitivity of each specimen type to detect infected, pre-infectious and infectious individuals (based on presumably infectious viral load levels) using assays with a range of analytical sensitivities. We also inferred the clinical sensitivity of computationally contrived specimen types representing combinations of single specimen types. Results. We found extreme differences (up to 109 copies/mL) in viral loads between paired specimen types in the same person at the same timepoint, and that longitudinal viral load timecourses across specimen types did not correlate. Because of this lack of correlation, infectious viral loads were often observed in different specimen types asynchronously throughout the course of the infection. In the first 4 days of infection, no single specimen type was inferred to achieve >95% detection of infected or infectious individuals, even with the highest analytical sensitivity assays. In nearly all participants (11/14), a rise in ANS viral loads was delayed (as many as 7 days) relative to SA and OPS. We also observed that ANS and OPS had the most complementary viral load timecourses, resulting in optimal inferred performance with a computationally contrived combined anterior nares-oropharyngeal (AN-OP) swab specimen type. The combination AN-OP swab had superior inferred clinical sensitivity the first 8 days of infection with both high- and low-analytical-sensitivity assays. This AN-OP swab was also inferred to significantly improve detection of pre-infectious and infectious individuals over any single specimen type. Conclusion. Our work demonstrates that the viral load in one specimen type cannot reliably predict the viral load in another specimen type. Combination specimen types may offer a more robust approach for earliest detection of new variants and respiratory viruses when viral kinetics are still unknown.

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“…(i) First, in the common view, the LOD of the Ag-RDT aligns with the infectious viral load threshold (IVLT) (Fig 7D), though there is no fundamental reason why the LOD should align perfectly with the IVLT. Replication-competent virus has been reliably isolated from specimens with viral loads of 10 4 copies/mL and above, 25,[32][33][34][35][36][37][38][39][40] whereas the LOD of Ag-RDTs span several orders of magnitude (from approximately 10 5 copies/mL to 10 7 copies/mL). The Ag-RDT we evaluated in this study was inferred to have an approximate LOD of 7.6x10 6 copies/mL.…”

Section: Discussionmentioning

confidence: 99%

“…55 Predicted results were used to calculate inferred positive percent agreement (Fig 3A-C . Individuals were presumed to be infectious at all timepoints between the first timepoint where at least one specimen type had a viral load above a specified infectious viral-load threshold (IVLT) of 10 4 , 10 5 , 10 6 , or 10 7 copies/mL (based on viral culture literature 16,25,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] ), until the last timepoint where at least one specimen type had a viral load above the IVLT.…”

Section: Statistical Analysesmentioning

confidence: 99%

Why Daily SARS-CoV-2 Nasal Rapid Antigen Testing Poorly Detects Infected and Infectious Individuals

Winnett

Akana

Shelby

et al. 2022

Preprint

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Background. To limit viral transmission, COVID-19 testing strategies must evolve as new SARS-CoV-2 variants (and new respiratory viruses) emerge to ensure that the specimen types and test analytical sensitivities being used will reliably detect individuals during the pre-infectious and infectious periods. Our accompanying work demonstrated that there are extreme differences in viral loads among paired saliva (SA), anterior-nares swab (ANS) and oropharyngeal swab (OPS) specimens collected from the same person and timepoint. We hypothesized that these extreme differences may prevent low-analytical-sensitivity assays (such as antigen rapid diagnostic tests, Ag-RDTs) performed on a single specimen type from reliably detecting pre-infectious and infectious individuals. Methods. We conducted a longitudinal COVID-19 household-transmission study in which 228 participants collected SA, ANS, and OPS specimens for viral-load quantification by RT-qPCR, and performed an ANS Ag-RDT (Quidel QuickVue At-Home OTC COVID-19 Test) daily. We evaluated the performance of the Ag-RDT (n=2215 tests) to detect infected individuals (positive results in any specimen type by RT-qPCR) and individuals with presumed infectious viral loads (at or above thresholds of 10^4, 10^5, 10^6, or 10^7 copies/mL). Results. Overall, the daily Ag-RDT detected 44% (358/811) timepoints from infected individuals. From 17 participants who enrolled early in the course of infection, we found that daily Ag-RDT performance was higher at timepoints when symptoms were reported, but symptoms only weakly correlated with SARS-CoV-2 viral loads, so ANS Ag-RDT clinical sensitivity remained below 50%. The three specimen types exhibited asynchronous presumably-infectious periods (regardless of the infectious viral-load threshold chosen) and the rise in ANS viral loads was delayed relative to SA or OPS for nearly all individuals, which resulted in the daily ANS Ag-RDT detecting only 3% in the pre-infectious period and 63% in the infectious period. We evaluated a computationally-contrived combined AN-OP swab based on viral loads from ANS and OPS specimens collected at the same timepoint; when tested with similar analytical sensitivity as the Ag-RDT, this combined swab was predicted to have significantly better performance, detecting up to 82% of infectious individuals. Conclusion. Daily ANS rapid antigen testing missed virtually all pre-infectious individuals, and more than one third of presumed infectious individuals due to low-analytical-sensitivity of the assay, a delayed rise in ANS viral loads, and asynchronous infectious viral loads in SA or OPS. When high-analytical-sensitivity assays are not available and low-analytical-sensitivity tests such as Ag-RDTs must be used for SARS-CoV-2 detection, an AN-OP combination swab is predicted to be most effective for detection of pre-infectious and infectious individuals. More generally, low-analytical-sensitivity tests are likely to perform more robustly using oral-nasal combination specimen types to detect new SASR-CoV-2 variants and emergent upper respiratory viruses.

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Clinical and Microbiological Assessments of COVID-19 in Healthcare Workers: A Prospective Longitudinal Study

Cited by 3 publications

References 0 publications

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

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

Extreme differences in SARS-CoV-2 viral loads among respiratory specimen types during presumed pre-infectious and infectious periods

Why Daily SARS-CoV-2 Nasal Rapid Antigen Testing Poorly Detects Infected and Infectious Individuals

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