A Study Revealed That a High Percentage of Patients With Severe COVID-19 With Viral RNAaemia Had Significantly Worse Outcomes, and This Is the First Report About the Risk Factors of Viral RNAaemia in Patients With COVID-19: We Are Not Sure!

Li et al conclude that their study published in CHEST (April 2021) revealed that a high percentage of patients with severe COVID-19 complicated with viral RNAaemia had significantly worse outcomes. According to their knowledge, there are no reports about the risk factors of viral RNAaemia in patients with severe COVID-19. In fact, in a recent study, blood samples were collected. The molecular testing indicated increased viral loads. This increased viral RNAaemia was strongly correlated with the level of disseminated intravascular coagulation (DIC) as well the D-dimer levels and thus correlated with severity level. Clearly the study from Li et al is not the first to show a relationship between RNAaemia and level of severity. Regarding pathophysiology, whether the virus itself is responsible for this direct damage is unclear in the study by Dumache et al. Increased levels of RNAaemia inducing increase in DIC and D-dimers could induce more damage to various organs. In another recent study, detection of viral subgenomic RNA correlated poorly with shedding of infectious virus. These RNAs are produced only in actively infected cells and are not packaged into virions. Subgenomic RNAs were still detected when virus cultures turned negative. This could indicate that active replication continues in severely ill COVID-19 after seroconversion. Possibly, infectious virions are produced but are directly neutralized by antibodies. Conversely, the half-life of viral subgenomic RNAs is unknown in COVID-19 and may still be detected once replication has stopped. In other words, in their evaluation, the level of RNAaemia is not related to severity, because less than 5% of this RNAaemia is able to be infective. A very important issue raised by a new study was that digital polymerase chain reaction (PCR) more sensitive than quantitative PCR for the detection of SARS-CoV-2 RNAaemia in the plasma of the patients. Unfortunately, in the study of Li et al, they did used quantitative PCR and not digital PCR. In addition, prolonged shedding of SARS-CoV-2 furthermore occurs regardless of disease severity or development of virus-neutralizing antibodies. RNA viruses are capable of long-term persistence, possibly through poorly understood RNA structure-mediated effects on innate and adaptive host immune responses. The assumption that resolution of COVID-19 and the appearance of anti-SARS-CoV-2 IgG antibodies represents virus clearance and protection from reinfection, implicit, for example, in the susceptible-infected-recovered model used for epidemic prediction, should be rigorously reevaluated.