Combining immunomodulators and antivirals for COVID-19 – Authors' reply

We 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".1Bermejo-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)00084-7Summary Full Text Full Text PDF Scopus (7) Google Scholar 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. Our Comment is not to diminish the role of immunopathology or that of immunomodulators in this disease. Our intention was to balance the participation of the virus and that of inflammation in the pathogenesis of severe COVID-19, stressing the direct association between those signatures of increased viral replication and those of increased inflammation, immunosuppression, endothelial dysfunction, coagulation activation, and tissue damage, which support the role of uncontrolled viral replication as a major driver of severe disease. We agree with Chen and Quach that the two phases (viral replication and inflammation) model has actually become quite obsolete. However, the effect of this model in research and social networks has been, and still is, very important—eg, one of the founding articles proposing this model has received 464 citations and 2171 tweets in less than 1 year.2Siddiqi 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 (1133) Google Scholar Our Comment highlighted the necessity of developing effective antivirals for this disease. As outlined by Chen and Quach with their example of Epstein-Barr virus and cytomegalovirus infections, the future of COVID-19 treatment is likely to involve administering effective antivirals combined with anti-inflammatory or even immune-stimulatory therapies3Remy KE Brakenridge SC Francois B et al.Immunotherapies for COVID-19: lessons learned from sepsis.Lancet Respir Med. 2020; 8: 946-949Summary Full Text Full Text PDF PubMed Scopus (87) Google Scholar in those patients with biomarker signatures predicting successful response to each one of these approaches. We strongly advocate a personalised medicine approach for COVID-19 disease, as we have proposed for sepsis.4Bermejo-Martin JF Andaluz-Ojeda D Almansa R et al.Defining immunological dysfunction in sepsis: a requisite tool for precision medicine.J Infect. 2016; 72: 525-536Summary Full Text Full Text PDF PubMed Scopus (65) Google Scholar Alternative antivirals to those already tested in multidomain clinical trials (such as remdesivir or ritonavir–lopinavir) could be helpful to prevent progression from mild to severe disease or to improve outcome of patients with COVID-19 once severe disease is already evident.5White KM Rosales R Yildiz S et al.Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A.Science. 2021; 371: 926-931Crossref PubMed Scopus (190) Google Scholar New trials should be implemented to test this notion. Additionally, combined therapies with immunomodulators and antivirals could have much to say in preventing complications of COVID-19 in the long-term. 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. Combining 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 AccessMounting evidence of impaired viral control in severe COVID-19Substantial 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.1,2 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. Full-Text PDF Open Access

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