Understanding COVID-19: what does viral RNA load really mean?
Authors: Gavin M Joynt, William KK Wu
Journal: The Lancet Infectious Diseases (2020)

In The Lancet Infectious Diseases, Francois-Xavier Lescure and colleagues1Lescure F-X Bouadma L Nguyen D et al.Clinical and virological data of the first cases of COVID-19 in Europe: a case series.Lancet Infect Dis. 2020; (published online March 27.)https://doi.org/10.1016/S1473-3099(20)30200-0Summary Full Text Full Text PDF PubMed Scopus (795) Google Scholar describe the first cases of coronavirus disease 2019 (COVID-19) in Europe, which were reported in France. The detailed clinical features of five patients with COVID-19 are aligned with the quantitative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA load from nasopharyngeal and other selected sampling sites. Previous studies in patients with SARS, Middle East respiratory syndrome (MERS), and COVID-19 generally provide insufficient detail to allow examination of the relationship between individual patient clinical course and viral RNA load.2Peiris JS Chu CM Cheng VC et al.Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study.Lancet. 2003; 361: 1767-1772Summary Full Text Full Text PDF PubMed Scopus (1986) Google Scholar, 3Oh MD Park WB Choe PG et al.Viral load kinetics of MERS coronavirus infection.N Engl J Med. 2016; 375: 1303-1305Crossref PubMed Scopus (143) Google Scholar, 4Zou L Ruan F Huang M et al.SARS-CoV-2 viral load in upper respiratory specimens of infected patients.N Engl J Med. 2020; (published online Feb 19.)DOI:10.1056/NEJMc200173Crossref Scopus (3452) Google Scholar Although patient numbers are small, the authors provide the first COVID-19 time series correlating viral RNA load and detailed clinical manifestations.1Lescure F-X Bouadma L Nguyen D et al.Clinical and virological data of the first cases of COVID-19 in Europe: a case series.Lancet Infect Dis. 2020; (published online March 27.)https://doi.org/10.1016/S1473-3099(20)30200-0Summary Full Text Full Text PDF PubMed Scopus (795) Google Scholar Importantly, the dataset is provided in sufficient detail so it could be readily combined with future similar studies for deeper analysis. Although the authors make a case for COVID-19 presenting as three distinct clinical patterns, we believe a distinction based on such small numbers is highly speculative. Nevertheless, based on the assumption that viral RNA load correlates with high levels of viral replication,5Bustin SA Mueller R Real-time reverse transcription PCR (qRT-PCR) and its potential use in clinical diagnosis.Clin Sci. 2005; 109: 365-379Crossref PubMed Scopus (387) Google Scholar there are important insights to be gained from this time-course analysis. Currently, our understanding of the relationship between viral RNA load kinetics and disease severity in patients with COVID-19 remains fragmented. Zou and colleagues reported that patients with COVID-19 with more severe disease requiring intensive care unit admission had high viral RNA loads at 10 days and beyond, after symptom onset.4Zou L Ruan F Huang M et al.SARS-CoV-2 viral load in upper respiratory specimens of infected patients.N Engl J Med. 2020; (published online Feb 19.)DOI:10.1056/NEJMc200173Crossref Scopus (3452) Google Scholar Unfortunately, it is unknown when in the course of their disease these patients deteriorated. By contrast, Lescure and colleagues report the viral RNA kinetics of two patients who developed late respiratory deterioration despite the disappearance of nasopharyngeal viral RNA. It would be interesting to know whether viral RNA load in lung tissue, or a surrogate sample such as tracheal aspirate, mirrors the decline in nasopharyngeal shedding. Nevertheless, this observation suggests that these late, severe manifestations might be immunologically mediated and has obvious implications for the potential to use immune-modulatory therapies for this subset of patients. This finding is consistent with recent reports that corticosteroids were beneficial for acute respiratory distress syndrome,6Villar J Ferrando C Martínez D et al.Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.Lancet Respir Med. 2020; 8: 267-276Summary Full Text Full Text PDF PubMed Scopus (708) Google Scholar and possibly those with COVID-19.7Wu C Chen X Cai Y et al.Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.JAMA Intern Med. 2020; (published online Mar 13.)DOI:10.1001/jamainternmed.2020.0994Crossref Scopus (5774) Google Scholar With more detailed data such as those provided by Lescure and colleagues, the use of viral RNA load to suggest potential clinical strategies to treat COVID-19 could be exploited. In a pandemic, prevention of disease transmission is key. Lescure and colleagues wisely note the implications for transmission from patients with few symptoms but high viral RNA load in the nasopharynx early in the course of disease. Individuals within the community, policy makers, and frontline health-care providers, especially general and emergency room practitioners, should be alert and prepared to manage this risk. Equally worrying is the persistently high nasopharyngeal viral RNA load, and the detection of viral RNA in blood and pleural fluid, of the older patient (aged 80 years) with severe multi-organ dysfunction. This finding broadly correlates with the severely ill group data reported by Zou and colleagues,4Zou L Ruan F Huang M et al.SARS-CoV-2 viral load in upper respiratory specimens of infected patients.N Engl J Med. 2020; (published online Feb 19.)DOI:10.1056/NEJMc200173Crossref Scopus (3452) Google Scholar and has important implications for therapy and infection control. Development and effective administration of antiviral therapy to critically ill patients throughout the course of disease is likely to remain important. Vigilance regarding the strict implementation of transmission precautions is required throughout the prolonged course of COVID-19 in patients who are critically ill, and ancillary staff responsible for collecting and disposing of bodily fluids or waste, who are at high risk during an outbreak,8Lau JT Yang X Leung PC et al.SARS in three categories of hospital workers, Hong Kong.Emerg Infect Dis. 2004; 10: 1399-1404Crossref PubMed Scopus (32) Google Scholar should be properly protected and trained.9Gomersall CD Tai DY Loo S et al.Expanding ICU facilities in an epidemic: recommendations based on experience from the SARS epidemic in Hong Kong and Singapore.Intensive Care Med. 2006; 32: 1004-1013Crossref PubMed Scopus (67) Google Scholar It is noteworthy that the presence of viral RNA in specimens does not always correlate with viral transmissibility. In a ferret model of H1N1 infection, the loss of viral culture positivity but not the absence of viral RNA coincided with the end of the infectious period. In fact, real-time reverse transcriptase PCR results remained positive 6–8 days after the loss of transmissibility.10Inagaki K Song MS Crumpton JC et al.Correlation between the interval of influenza virus infectivity and results of diagnostic assays in a ferret model.J Infect Dis. 2016; 213: 407-410Crossref PubMed Scopus (21) Google Scholar For SARS coronavirus, viral RNA is detectable in the respiratory secretions and stools of some patients after onset of illness for more than 1 month, but live virus could not be detected by culture after week 3.11Chan KH Poon LL Cheng VC et al.Detection of SARS coronavirus in patients with suspected SARS.Emerg Infect Dis. 2004; 10: 294-299Crossref PubMed Scopus (261) Google Scholar The inability to differentiate between infective and non-infective (dead or antibody-neutralised) viruses remains a major limitation of nucleic acid detection. Despite this limitation, given the difficulties in culturing live virus from clinical specimens during a pandemic, using viral RNA load as a surrogate remains plausible for generating clinical hypotheses. We declare no competing interests. Clinical and virological data of the first cases of COVID-19 in Europe: a case seriesWe illustrated three different clinical and biological types of evolution in five patients infected with SARS-CoV-2 with detailed and comprehensive viral sampling strategy. We believe that these findings will contribute to a better understanding of the natural history of the disease and will contribute to advances in the implementation of more efficient infection control strategies. Full-Text PDF