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Persistent positivity and fluctuations of SARS-CoV-2 RNA in clinically-recovered COVID-19 patients

2020; Elsevier BV; Volume: 81; Issue: 3 Linguagem: Inglês

10.1016/j.jinf.2020.06.024

1532-2742

Valeria Cento, Luna Colagrossi, Alice Nava, Anna Lamberti, Sabrina Senatore, Giovanna Travi, Roberto Rossotti, Marta Vecchi, Ornella Casati, Elisa Matarazzo, Alessandra Bielli, Giorgia Casalicchio, Maria Antonello, Silvia Renica, Valentino Costabile, Francesco Scaglione, Roberto Fumagalli, Nicola Ughi, Oscar Massimiliano Epis, Massimo Puoti, Chiara Vismara, Marino Faccini, Diana Fanti, Claudia Alteri, Carlo Federico Perno,

COVID-19 Clinical Research Studies

As the COVID-19 pandemic slowly recedes, the number of clinically recovered subjects increases steadily. To minimize the risk of viral transmission in the community, several countries worldwide are currently endorsing a "test-based" strategy for hospital discharge and discontinuation of home-isolation, which requires 2 negative results of RT-PCR for SARS-CoV-2 RNA on nasopharyngeal swabs collected ≥24 h apart.1ECDCEuropean Centre for Disease Prevention and Control. Guidance for discharge and ending isolation in the context of widespread community transmission of COVID-19, 8 April 2020. Stockholm.in: ECDC. 2020https://www.ecdc.europa.eu/sites/default/files/documents/covid-19-guidance-discharge-and-ending-isolation-first%20update.pdfGoogle Scholar Emerging evidences are indicating that RT-PCR positivity may persist for several weeks after the resolution of symptoms,2Peng J. Wang M. Zhang G. Lu E Seven discharged patients turning positive again for SARS-CoV-2 on quantitative RT-PCR.Am J Infect Control. 2020 Apr 10; (PubMed PMID: 32317126. Pubmed Central PMCID: 7151314)Abstract Full Text Full Text PDF Scopus (32) Google Scholar, 3Fu W. Chen Q. Wang T Letter to the Editor: three cases of re-detectable positive SARS-CoV-2 RNA in recovered COVID-19 patients with antibodies.J Med Virol. 2020 May 5; (PubMed PMID: 32369214)Crossref Scopus (30) Google Scholar, 4Woodruff A COVID-19 follow up testing.J Infect. 2020 May 11; (PubMed PMID: 32407758. Pubmed Central PMCID: 7212964)Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 5Liu W.D. Chang S.Y. Wang J.T. Tsai M.J. Hung C.C. Hsu C.L. et al.Prolonged virus shedding even after seroconversion in a patient with COVID-19.J Infect. 2020 Apr 10; (PubMed PMID: 32283147. Pubmed Central PMCID: 7151379)Abstract Full Text Full Text PDF Scopus (185) Google Scholar while the decline in viral infectivity occurs rather quickly (i.e. within one or two weeks since symptoms onset).5Liu W.D. Chang S.Y. Wang J.T. Tsai M.J. Hung C.C. Hsu C.L. et al.Prolonged virus shedding even after seroconversion in a patient with COVID-19.J Infect. 2020 Apr 10; (PubMed PMID: 32283147. Pubmed Central PMCID: 7151379)Abstract Full Text Full Text PDF Scopus (185) Google Scholar, 6Wolfel R. Corman V.M. Guggemos W. Seilmaier M. Zange S. Muller M.A. et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020 Apr 1; (PubMed PMID: 32235945)Crossref PubMed Scopus (4646) Google Scholar, 7Bullard J. Dust K. Funk D. Strong J.E. Alexander D. Garnett L. et al.Predicting infectious SARS-CoV-2 from diagnostic samples.Clin Infect Dis: Off Publ Infect Dis Soc Am. 2020 May 22; (PubMed PMID: 32442256)Crossref Scopus (769) Google Scholar Whether the persistently-positive recovered patients might still shed infectious virus is thus uncertain, and this implies the risk for many of them to remain hospitalized, or in shelter-in-place, for a much longer time than necessary, with significant social distress and economic commitment. In order to help in estimating the burden, and the temporal extent, of persistent RT-PCR positivity, and thus support the design of sustainable follow-up protocols, we retrospectively analyzed 13,475 longitudinal SARS-CoV-2 molecular tests (performed from March 3 to June 4, 2020), of 7608 laboratory-confirmed and clinically recovered COVID-19 patients. Patients were tested at symptoms resolution while still hospitalized (N = 501; range of follow-up: 1–53 days), and/or after hospital discharge (N = 7127; range of follow-up post-discharge: 14–74 days); 50.6% of them were male, and median (IQR) age was 51 (41–59) years. At symptoms resolution, after a median (IQR) of 21 (15–28) days since their onset, nearly half of the 501 hospitalized patients tested (46.9%, N = 235) had detectable virus in nasopharyngeal swabs, in all cases with cycle-thresholds (Cts) values ≥24 (viral-load <1 × 106 by quantitative droplet-PCR). These patients had higher nasopharyngeal viral-load at hospital-admission, compared to those who tested negative (median [IQR] Cts: 27.2 [23.8–32.0] vs. 31.3 [25.2–42.1], respectively; p = 0.016 by Mann-Whitney test), and a shorter duration of disease, calculated from symptoms onset to clinical recovery (median [IQR]= 21 [15–28] vs. 28 [20–36] days; p 24.7Bullard J. Dust K. Funk D. Strong J.E. Alexander D. Garnett L. et al.Predicting infectious SARS-CoV-2 from diagnostic samples.Clin Infect Dis: Off Publ Infect Dis Soc Am. 2020 May 22; (PubMed PMID: 32442256)Crossref Scopus (769) Google Scholar All patients included in our analysis complied with one or both these criteria, ever since their first control after clinical recovery. The data published so far lead us to consider the contagiousness of our persistently positive (and persistently asymptomatic) patients rather unlikely, even if the risk of viral transmission should not be definitely rule out (especially at of few days after the symptoms resolution). Based on our data, the optimal post-recovery follow-up strategy should include an integrated approach between the exclusively ``symptom based'' one (as recommended by the CDC8CDC. Symptom-based strategy to discontinue isolation for persons with COVID-19. Accessed May 24, 2020. https://www.cdc.gov/coronavirus/2019-ncov/community/strategy-discontinue-isolation.html.Google Scholar) and the one based only on the evaluation of the negativity of the RT-PCR (as recommended by the ECDC1ECDCEuropean Centre for Disease Prevention and Control. Guidance for discharge and ending isolation in the context of widespread community transmission of COVID-19, 8 April 2020. Stockholm.in: ECDC. 2020https://www.ecdc.europa.eu/sites/default/files/documents/covid-19-guidance-discharge-and-ending-isolation-first%20update.pdfGoogle Scholar), possibly by integrating the latter with a quantitative evaluation of the viral load. A pressing clinical and social need to define a maximum time and viral load limit beyond which the positivity of the RT-PCR loses significance, is thus felt now more than ever, as this is the only way to allow their safe return to the community, and not to prolong their isolation beyond clinical and public-health utility. This work was supported by the Italian Ministry of Education, University and Research [PRIN grant: 20179JKAMZ].