Advertisement
Mayo Clinic Proceedings Home

In reply—The “Perfect Cytokine Storm” of COVID-19

      We read with great interest the letter by Testori regarding our review article.
      • Vijayvargiya P.
      • Garrigos Z.E.
      • Castillo Almeida N.E.
      • Gurram P.R.
      • Stevens R.W.
      • Razonable R.R.
      Treatment considerations for COVID-19: a critical review of the evidence (or lack thereof).
      Testori pointed out the important association of proinflammatory cytokines in the pathogenesis of coronavirus disease 2019 (COVID-19), which could account for the worse outcome in older individuals. Strategies to combat the proinflammatory state, using multiple investigational compounds, are in the pipeline as potential treatment modalities for COVID-19.
      In France, the Cohort Multiple Randomized Controlled Trials Open-label of Immune Modulatory Drugs and Other Treatments in COVID-19 Patients (CORIMUNO-19) platform was designed and set up as a series of multicenter randomized controlled trials (RCTs) to evaluate the efficacy of immunomodulators and other treatments of COVID-19. As part of this platform, one open-label RCT, CORIMUNO-TOCI, found that the use of tocilizumab, an interleukin-6 receptor inhibitor, was associated with a lower ventilation requirement (invasive or noninvasive) or death at day 14. However, the final report of this RCT has not yet been released for peer review.
      Tocilizumab improves significantly clinical outcomes of patients with moderate or severe COVID-19 pneumonia. APHP website.
      As mentioned in our review article, there are several other RCTs that are currently being conducted to assess interleukin-6 inhibition in COVID-19.
      An artificial intelligence platform, BenevolentAI, identified baricitinib, a Janus kinase inhibitor, as another potential option to battle the cytokine storm associated with COVID-19.
      • Richardson P.
      • Griffin I.
      • Tucker C.
      • et al.
      Baricitinib as potential treatment for 2019-nCoV acute respiratory disease.
      ,
      • Stebbing J.
      • Phelan A.
      • Griffin I.
      • et al.
      COVID-19: combining antiviral and anti-inflammatory treatments.
      In addition to its anti-inflammatory properties, baricitinib can have antiviral properties by preventing the adaptor-associated protein kinase 1 and cyclin G-associated kinase–mediated endocytosis of the virus. Baricitinib will be tested as one of the drugs in the National Institute of Allergy and Infectious Diseases Adaptive COVID-19 Treatment Trial (ACTT). As we emphasized in our review article, the appropriate timing for the use of these anti-inflammatory agents will be critical. It is important to reiterate that the host inflammatory response plays a vital role in the immune defense against the infection, and curbing the inflammatory state may decrease the response mounted by the host’s immune system.
      Since the online publication of our review, the investigational RNA-dependent RNA inhibitor remdesivir has been granted emergency use authorization by US Food and Drug Administration on the basis of preliminary data obtained from the ACTT. The press release of this trial stated a 31% faster time to recovery in the remdesivir arm compared with placebo (11 days vs 15 days, respectively; P<.001).
      NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19. National Institute of Allergy and Infectious Diseases website.
      The scientific community is eagerly awaiting the release of the clinical trial results. Interestingly, another study, conducted in China, did not find any clinical benefit with remdesivir use. There was no difference in 28-day mortality between the 2 groups, and the degree of viral decline was similar. However, this study was underpowered to detect significant differences because of low accrual as a result of the decline in severe acute respiratory syndrome coronavirus 2 infection rates.
      • Wang Y.
      • Zhang D.
      • Du G.
      • et al.
      Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.
      The author highlighted the recent reports of prolonged detection of severe acute respiratory syndrome coronavirus 2 in some individuals. However, the presence of viral nucleic acid in respiratory samples can be a reflection of nonviable genetic material. The viability of the virus material in these patients has not been conclusively established. Nonetheless, we agree with his comment that there is an urgent need for the development of antiviral therapies and vaccines. Indeed, there are many parallel and collaborative efforts to advance this goal, at an extraordinary pace, and some using novel RNA interference- and plasmid DNA–based approaches. In the meantime, multicenter trials such as World Health Organization’s Solidarity Trial, National Institute of Allergy and Infectious Diseases ACTT, and European CORIMUNO-19 cohort as well as DISCOVERY trial strive to generate evidence to determine the optimal treatment of COVID-19.
      The ongoing climate change, disruption of natural ecosystems, and human migration guarantee that we remain at risk of pandemics in the foreseeable future. Knowledge generated now will not only help us fight the current pandemic, but our lessons will also prepare us to prevent and maybe better coordinate our response for the future pandemics. Our reliance on evidence-based medicine generated through RCTs is critical to ensure that we are prepared for what comes next.

      References

        • Vijayvargiya P.
        • Garrigos Z.E.
        • Castillo Almeida N.E.
        • Gurram P.R.
        • Stevens R.W.
        • Razonable R.R.
        Treatment considerations for COVID-19: a critical review of the evidence (or lack thereof).
        Mayo Clin Proc. 2020; 95: 2037-2038
      1. Tocilizumab improves significantly clinical outcomes of patients with moderate or severe COVID-19 pneumonia. APHP website.
        • Richardson P.
        • Griffin I.
        • Tucker C.
        • et al.
        Baricitinib as potential treatment for 2019-nCoV acute respiratory disease.
        Lancet. 2020; 395: e30-e31
        • Stebbing J.
        • Phelan A.
        • Griffin I.
        • et al.
        COVID-19: combining antiviral and anti-inflammatory treatments.
        Lancet Infect Dis. 2020; 20: 400-402
      2. NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19. National Institute of Allergy and Infectious Diseases website.
        • Wang Y.
        • Zhang D.
        • Du G.
        • et al.
        Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.
        Lancet. 2020; 395: P1569-P1578