Mounting evidence of impaired viral control in severe COVID-19

Substantial gaps in knowledge regarding the evolution and pathogenesis of COVID-19 remain after 1 year of the SARS-CoV-2 pandemic. At the start of the pandemic, a biphasic model to explain the physiopathology of COVID-19 became popular. This model divided the disease course into an initial viral response phase, followed by the inflammatory response phase.1Siddiqi HK Mehra MR COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal.J Heart Lung Transplant. 2020; 39: 405-407Summary Full Text Full Text PDF PubMed Scopus (1121) Google Scholar, 2Sundararaj Stanleyraj J Sethuraman N Gupta R Thiruvoth S Gupta M Ryo A Treating COVID-19: are we missing out the window of opportunity?.J Antimicrob Chemother. 2021; 76: 283-285Crossref PubMed Scopus (18) Google Scholar In the inflammatory response phase, the virus is thought to have a minor role, and host inflammatory responses are the predominant mediators of pathophysiology, by triggering tissue damage leading to acute respiratory distress syndrome.1Siddiqi HK Mehra MR COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal.J Heart Lung Transplant. 2020; 39: 405-407Summary Full Text Full Text PDF PubMed Scopus (1121) Google Scholar, 2Sundararaj Stanleyraj J Sethuraman N Gupta R Thiruvoth S Gupta M Ryo A Treating COVID-19: are we missing out the window of opportunity?.J Antimicrob Chemother. 2021; 76: 283-285Crossref PubMed Scopus (18) Google Scholar Growing evidence from our group and others suggest that this model might need revising. Patients with the most severe forms of the disease show the highest viral RNA loads in respiratory samples3Liu Y Yan L-M Wan L et al.Viral dynamics in mild and severe cases of COVID-19.Lancet Infect Dis. 2020; 20: 656-657Summary Full Text Full Text PDF PubMed Scopus (1134) Google Scholar and prolonged viral shedding.4Zhou F Yu T Du R et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062Summary Full Text Full Text PDF PubMed Scopus (17663) Google Scholar Most critically ill patients with COVID-19 show SARS-CoV-2 RNAaemia, with viral RNA load in plasma correlating with the degree of severity and the risk of mortality.5Bermejo-Martin JF González-Rivera M Almansa R et al.Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19.Crit Care. 2020; 24: 691Crossref PubMed Scopus (146) Google Scholar, 6Martin-Vicente M Almansa R Martínez I et al.Absent or insufficient anti-SARS-CoV-2 S antibodies at ICU admission are associated to higher viral loads in plasma, antigenemia and mortality in COVID-19 patients.medRxiv. 2021; (published online March 8.) (preprint).https://doi.org/10.1101/2021.03.08.21253121Google Scholar Non-survivors show more frequent antigenaemia.6Martin-Vicente M Almansa R Martínez I et al.Absent or insufficient anti-SARS-CoV-2 S antibodies at ICU admission are associated to higher viral loads in plasma, antigenemia and mortality in COVID-19 patients.medRxiv. 2021; (published online March 8.) (preprint).https://doi.org/10.1101/2021.03.08.21253121Google Scholar Furthermore, autopsies from COVID-19 patients demonstrate viral dissemination by the presence of viral particles and viral RNA in different organs.7Recalde-Zamacona B García-Tobar L Argueta A et al.Histopathological findings in fatal COVID-19 severe acute respiratory syndrome: preliminary experience from a series of 10 Spanish patients.Thorax. 2020; 75: 1116-1118Crossref PubMed Scopus (19) Google Scholar All these findings suggest that the virus is a key driver of pathogenesis in severe COVID-19. Some immunological signatures denote an impaired ability to control viral replication in patients with severe COVID-19; in critically ill patients, absent or insufficient specific anti-SARS-CoV-2 S antibodies correlate with the presence of antigenaemia, high viral RNA loads in plasma, and mortality.6Martin-Vicente M Almansa R Martínez I et al.Absent or insufficient anti-SARS-CoV-2 S antibodies at ICU admission are associated to higher viral loads in plasma, antigenemia and mortality in COVID-19 patients.medRxiv. 2021; (published online March 8.) (preprint).https://doi.org/10.1101/2021.03.08.21253121Google Scholar Patients with severe COVID-19 also show impaired interferon type I response, which is associated with a persistent blood viral load (appendix p 1).8Hadjadj J Yatim N Barnabei L et al.Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients.Science. 2020; (published online July 13.)https://doi.org/10.1126/science.abc6027Crossref PubMed Scopus (1713) Google Scholar Although inflammation appears to be a central pathogenic event in severe COVID-19 (as demonstrated by the success of steroids and interleukin (IL)-6 pathway blockers in clinical trials),9REMAP-CAP InvestigatorsInterleukin-6 receptor antagonists in critically ill patients with Covid-19.N Engl J Med. 2021; (published online Feb 25.)https://doi.org/10.1056/NEJMoa2100433Google Scholar we should not forget what drives the inflammatory process in these patients. Our results show a direct correlation between the concentrations of viral RNA in plasma and those of pro-inflammatory cytokines (C-X-C motif chemokine ligand 10, monocyte chemoattractant protein-1, IL-6, IL-15, and granulocyte-macrophage colony-stimulating factor) and anti-inflammatory or immunosuppressor mediators (IL-10 and programmed death-ligand 1).5Bermejo-Martin JF González-Rivera M Almansa R et al.Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19.Crit Care. 2020; 24: 691Crossref PubMed Scopus (146) Google Scholar Previous findings in SARS, H5N1 influenza, and pandemic H1N1 influenza already described a close connection between viral load, hypercytokinaemia, and disease severity. Consequently, hypercytokinaemia would be an additional clue supporting that severe COVID-19 patients have difficulties in controlling SARS-CoV-2 replication. Focusing exclusively on inflammation as a major driver of severe COVID-19 could lead to misconceptions that affect the design of therapeutic interventions. Anti-inflammatory drugs do not work for all patients with severe disease. For patients on ventilators, dexamethasone reduces mortality by about a third, and for patients requiring only oxygen, mortality is cut by about a fifth. Drugs that decrease viral replication could mediate complementary effect to those that modulate inflammation, because they could help to ameliorate pathogenic events potentially linked to a direct viral action, such as endothelitis10Varga Z Flammer AJ Steiger P et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418Summary Full Text Full Text PDF PubMed Scopus (4185) Google Scholar and its associated prothrombotic events. Moreover, by decreasing viral replication, antivirals could indirectly help to control hyperinflammation and its associated deleterious events. Monitoring plasma viral load or the presence of antigenaemia could represent a useful tool for early identification of patients at risk of deterioration. Quantification of viral load in respiratory samples has technical limitations (sample volume and heterogeneous composition), whereas plasma could represent a better option for monitoring viral load in patients with COVID-19 (fixed volume and more homogeneous composition). A pandemic is an opportunity to learn. We must build models on the evidence as it emerges and continue to change those pieces that do not explain all of the data. Models based on reductionist approaches lead to incorrect solutions. This is a viral disease, not an autoimmune one. In conclusion, the available evidence would support combined strategies to simultaneously control viral replication and deleterious inflammation, based on specific indicators or biomarkers of both pathophysiological processes. Effective antiviral treatments are nonetheless needed to achieve this goal. This online publication has been corrected. The corrected version first appeared at thelancet.com/microbe on April 27, 2021 This online publication has been corrected. The corrected version first appeared at thelancet.com/microbe on April 27, 2021 JFB-M, RA, APT, JME, AT, and DJK have a patent pending (EP20383140.9). AT reports grants from Instituto de Salud Carlos III. DJK reports grants from Canadian Institutes of Health Research, Research Nova Scotia, Atlantic Genome/Genome Canada, Li-Ka Shing Foundation, and Dalhousie Medical Research Foundation. AdlF declares no competing interests. Download .pdf (.16 MB) Help with pdf files Supplementary appendix Correction to Lancet Microbe 2021; published online April 15. https://doi.org/10.1016/S2666-5247(21)00084-7Bermejo-Martin JF, Almansa R, Tedim AP, et al. Mounting evidence of impaired viral control in severe COVID-19. Lancet Microbe 2021; published online April 15. https://doi.org/10.1016/S2666-5247(21)00084-7—The appendix of this Comment has been uploaded as of April 27, 2021. Full-Text PDF Open AccessCombining immunomodulators and antivirals for COVID-19We read with interest the Comment by Jesus Bermejo-Martin and colleagues1 on impaired viral control in severe COVID-19. They highlight the importance of ongoing research on plasma viral load monitoring and antiviral therapies, and we agree with these points. However, three concepts in their Comment regarding host inflammatory responses and immunomodulatory therapy require clarification or rebuttal. Full-Text PDF Open AccessCombining immunomodulators and antivirals for COVID-19 – Authors' replyWe thank Luke Chen and Tien Quach for their interest on our Comment. We could not agree more with the title of their reply letter, combining immunomodulators and antivirals for COVID-19, which is consistent with the conclusion of our Comment: "the available evidence would support combined strategies to simultaneously control viral replication and deleterious inflammation, based on specific indicators or biomarkers of both pathophysiological processes".1 Our conclusion already proposed using biological indicators to guide anti-inflammatory and antiviral therapies in COVID-19, which converges with the so-called threshold concept of pathological immune activation raised by Chen and Quach. Full-Text PDF Open Access

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