Rapid tests for quantification of infectiousness are urgently required in patients with COVID-19
Authors: Daniel Pan, Shirley Sze, Shalin Abraham, Caroline M Williams, Julian W Tang, Mike R Barer, Manish Pareek
Journal: The Lancet Microbe (2021)

Muge Cevik and colleagues1Cevik M Tate M Lloyd O Maraolo AE Schafers J Ho A SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis.Lancet Microbe. 2020; 2: e13-e22Summary Full Text Full Text PDF PubMed Scopus (744) Google Scholar report that for SARS-CoV-2, no study was able to culture live virus from any respiratory samples taken after day 8 or beyond day 9 of symptoms, despite persistently high viral RNA loads.1Cevik M Tate M Lloyd O Maraolo AE Schafers J Ho A SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis.Lancet Microbe. 2020; 2: e13-e22Summary Full Text Full Text PDF PubMed Scopus (744) Google Scholar This is a striking finding because, unlike SARS-CoV and MERS-CoV, for which symptom severity correlates to infectiousness, most patients with COVID-19 continue to have worsening symptoms beyond day 9, but might become progressively less infectious.2Min CK Cheon S Ha NY et al.Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity.Sci Rep. 2016; 6: 1-12Crossref PubMed Scopus (281) Google Scholar, 3Lau JTF Tsui H Lau M Yang X SARS transmission, risk factors, and prevention in Hong Kong.Emerg Infect Dis. 2004; 10: 587-592Crossref PubMed Scopus (171) Google Scholar We would like to make two comments about this study.1Cevik M Tate M Lloyd O Maraolo AE Schafers J Ho A SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis.Lancet Microbe. 2020; 2: e13-e22Summary Full Text Full Text PDF PubMed Scopus (744) Google Scholar First, none of the 11 studies that attempted to isolate live SARS-CoV-2 in this data synthesis included patients who were severely immunosuppressed. There is emerging evidence showing long-term SARS-CoV-2 culture positivity in this specific cohort (up to 119 days after symptom onset; table), with emergence of mutations that are identical to those found in the South African B.1.351, Brazilian P.1, and Kent B.1.1.7 variants.4Avanzato VA Matson MJ Seifert SN et al.Case study: prolonged infectious SARS-CoV-2 shedding from an asymptomatic immunocompromised individual with cancer.Cell. 2020; 183: 1901-1912Summary Full Text Full Text PDF PubMed Scopus (442) Google Scholar, 5Decker A Welzel M Laubner K et al.Prolonged SARS-CoV-2 shedding and mild course of COVID-19 in a patient after recent heart transplantation.Am J Transplant. 2020; 20: 3239-3245Summary Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 6Aydillo T Gonzalez-Reiche AS Aslam S et al.Shedding of viable SARS-CoV-2 after immunosuppressive therapy for cancer.N Engl J Med. 2020; 383: 2586-2588Crossref PubMed Scopus (273) Google Scholar, 7Baang JH Smith C Mirabelli C et al.Prolonged severe acute respiratory syndrome coronavirus 2 replication in an immunocompromised patient.J Infect Dis. 2020; 223: 23-27Crossref Scopus (174) Google Scholar, 8Walsh KA Spillane S Comber L et al.The duration of infectiousness of individuals infected with SARS-CoV-2.J Infect. 2020; 81: 847-856Summary Full Text Full Text PDF PubMed Scopus (86) Google Scholar Increased vigilance is needed to protect immunosuppressed individuals, as well as their close contacts, from being infected.TableExamples of emerging primary reports about long-term SARS-CoV-2 positivity in immunosuppressed individualsType of immunosuppressionDuration of positive quantitative RT-PCR or NAAT, daysDuration of positive culture, daysAvanzato et al (2020)4Avanzato VA Matson MJ Seifert SN et al.Case study: prolonged infectious SARS-CoV-2 shedding from an asymptomatic immunocompromised individual with cancer.Cell. 2020; 183: 1901-1912Summary Full Text Full Text PDF PubMed Scopus (442) Google ScholarOne patient with chronic lymphocytic leukaemia and acquired hypogammaglobulinaemia10570Decker et al (2020)5Decker A Welzel M Laubner K et al.Prolonged SARS-CoV-2 shedding and mild course of COVID-19 in a patient after recent heart transplantation.Am J Transplant. 2020; 20: 3239-3245Summary Full Text Full Text PDF PubMed Scopus (48) Google ScholarOne patient who had a heart transplant, and was receiving cyclosporine A, mycophenolate mofetil, and prednisolone3521Aydillo et al (2020)6Aydillo T Gonzalez-Reiche AS Aslam S et al.Shedding of viable SARS-CoV-2 after immunosuppressive therapy for cancer.N Engl J Med. 2020; 383: 2586-2588Crossref PubMed Scopus (273) Google Scholar18 recipients of haematopoietic stem-cell transplants or chimeric antigen receptor T-cell therapy, and two patients with lymphoma78*Maximum reported duration. (IQR 24–64)8, 17, 25,26, and 61†Values are from five individual patients.Baang et al (2020)7Baang JH Smith C Mirabelli C et al.Prolonged severe acute respiratory syndrome coronavirus 2 replication in an immunocompromised patient.J Infect Dis. 2020; 223: 23-27Crossref Scopus (174) Google ScholarOne patient with mantle cell lymphoma who was receiving CD20 bispecific antibody with cyclophosphamide, doxorubicin, and prednisolone156119Data show the number of days after COVID-19 symptom onset that patients were positive for SARS-CoV-2. NAAT=nucleic acid amplification test.* Maximum reported duration.† Values are from five individual patients. Open table in a new tab Data show the number of days after COVID-19 symptom onset that patients were positive for SARS-CoV-2. NAAT=nucleic acid amplification test. Second, the authors mention in their discussion that repeat RNA PCR testing in clinical practice might not be indicated to classify patients as no longer infectious. We strongly agree with this statement. Current National Institute for Health and Care Excellence guidance suggests that patients with COVID-19 awaiting an urgent operation can have the procedure postponed if they have a recent positive PCR test.9NICECOVID-19 rapid guideline: arranging planned care in hospitals and diagnostic services.https://www.nice.org.uk/guidance/ng179/resources/covid19-rapid-guideline-arranging-planned-care-in-hospitals-and-diagnostic-services-pdf-66141969613765Date: 2020Date accessed: December 22, 2020Google Scholar Some countries also require passengers from the UK to have a negative PCR test before flying.10British AirwaysCOVID-19 entry requirements.https://www.britishairways.com/en-gb/information/incident/coronavirus/entry-requirements#entryDate: 2020Date accessed: December 22, 2020Google Scholar We would recommend modifying such criteria to state that patients who have recovered from COVID-19 can have an operation or fly 10 days after their first positive swab, or 10 days after clear symptom onset, with exceptions for those who had severe symptoms or are heavily immunosuppressed. This guidance will require further updating as the evidence evolves, as has been done with the recent removal of repeat testing for hospitalised patients with COVID-19 before discharge to long-term care facilities in December, 2020.11Public Health EnglandGuidance for the stepdown of infection control precautions and discharging COVID-19 patients.https://www.gov.uk/government/publications/covid-19-guidance-for-stepdown-of-infection-control-precautions-within-hospitals-and-discharging-covid-19-patients-from-hospital-to-home-settings/guidance-for-stepdown-of-infection-control-precautions-and-discharging-covid-19-patientsDate: 2020Date accessed: December 22, 2020Google Scholar, 12Sze S Pan D Williams CML et al.The need for improved discharge criteria for hospitalised patients with COVID-19—implications for patients in long-term care facilities.Age Ageing. 2020; 50: 16-20Crossref Scopus (11) Google Scholar Future studies should focus on simpler and faster methods of quantifying the infectiousness of an individual with COVID-19 beyond viral cultures, which are labour intensive and require laboratory facilities with high biosafety levels (ie, category 3 or biosafety level 3 facilities), and for which a cytopathic effect can take 3–6 days to be observed. Cycle threshold values that indirectly provide a quantitative PCR value are not interchangeable between assays, and can be affected by the gene target or targets being assayed, the nucleic acid extraction system, and the PCR amplification biochemistry. One possible strategy could be to sample virus from exhaled breath rather than the nasopharyngeal tract using specialised matrices embedded within facemasks.13Williams CM Pan D Decker J et al.Exhaled SARS-CoV-2 quantified by face-mask sampling in hospitalised patients with COVID-19.J Infect. 2021; (published online March 24.)https://doi.org/10.1016/j.jinf.2021.03.018Summary Full Text Full Text PDF Scopus (25) Google Scholar The rapid identification of infectious individuals in the community, as well as in hospitals, will be crucial for effective contact tracing of future respiratory virus outbreaks with pandemic potential. DP is supported by a National Institute for Health Research (NIHR) Academic Clinical Fellowship. SS is supported by an NIHR Clinical Lectureship in Cardiology. CMWs supported by an NIHR Clinical Lectureship in Infectious Diseases and Microbiology. JWT has given talks on general aspects of COVID-19 (including transmission) at meetings sponsored by Thea Pharmaceuticals, Thornton & Ross, and Landsec, and received grants from Sanofi Pasteur outside the submitted work commented on here. MRB received funding from the UK National Core Study (PROTECT; transmission and the environment). MP is a member of the Health Data Research UK COVID-19 Taskforce, and is supported by a NIHR Development and Skills Enhancement Award, a grant from UK Research and Innovation, Medical Research Council, and NIHR (MR/V027549/1), and the NIHR Leicester Biomedical Research Centre. SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysisAlthough SARS-CoV-2 RNA shedding in respiratory and stool samples can be prolonged, duration of viable virus is relatively short-lived. SARS-CoV-2 titres in the upper respiratory tract peak in the first week of illness. Early case finding and isolation, and public education on the spectrum of illness and period of infectiousness are key to the effective containment of SARS-CoV-2. Full-Text PDF Open Access