key: cord-276194-4sfc7hal
authors: Vijayvargiya, Prakhar; Garrigos, Zerelda Esquer; Castillo Almeida, Natalia E.; Gurram, Pooja R.; Stevens, Ryan W.; Razonable, Raymund R.
title: In Reply–The “Perfect Cytokine Storm” of COVID-19
date: 2020-05-29
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.05.016
sha: 
doc_id: 276194
cord_uid: 4sfc7hal

nan

To the Editor:We read with great interest the letter by Testori regarding our Review article "Treatment Considerations for COVID-19: A Critical Review of the Evidence (or Lack Thereof)," 1 Testori pointed out the important association of pro-inflammatory cytokines in the pathogenesis of Coronavirus disease 2019 , which could account for the worse outcome in older individuals. Strategies to combat the pro-inflammatory state, using multiple investigational compounds, are in the pipeline as potential treatment modalities for COVID-19.

In France, the CORIMUNO-19 platform was designed and set up as a series of multicenter randomized controlled trials (RCT) to evaluate the efficacy of immunomodulators and other treatments for COVID-19. As part of this platform, one open-label RCT (CORIMUNO -TOCI) showed that the use of tocilizumab, an interleukin-6 receptor inhibitor, was associated with a significantly 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. 2 As mentioned in our review article, there are several other RCTs that are currently being conducted to assess IL-6 inhibition in COVID-19.

An artificial intelligence platform, BenevolentAI, identified baricitinib, a Janus Kinase (JAK) inhibitor, as another potential option to battle the cytokine storm associated with COVID-19. 3, 4 In addition to its anti-inflammatory properties, baricitinib can have antiviral properties by preventing the adaptor-associated protein kinase 1 (AAK1) and Cyclin G-associated kinase (GAK)-mediated endocytosis of the virus. Baricitinib will be tested as one of the drugs in the National Institute of Allergy and Infectious Diseases (NIAID) 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 in United States Food and Drug Administration based on preliminary data obtained from the ACTT. The press release of this trial stated a 31% faster time to recovery in remdesivir arm compared to placebo (11 days versus 15 days, respectively, P<0.001). 5 The scientific community is eagerly awaiting the release of the clinical trial results. Interestingly, another study, conducted in China, did not demonstrate any significant clinical benefit with remdesivir use. There was no difference in 28-day mortality between the two groups, and the degree of viral decline was similar. However, this study was underpowered to detect significant differences due to low accrual as a result of the decline in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates. 6 The author highlighted the recent reports of prolonged detection of SARS-CoV-2 in some individuals. Howevever, the presence of viral nucleic acid in respiratory samples can be a reflection of nonviable genetic material. The viability of virus material in these patients has not been conclusively demonstrated. 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 RNAi and plasmid DNA based approaches. In the meantime, multicenter trials such as World Health Organization Solidarity Trial, NIAID ACTT, and European CORIMUNO-19 cohort and Discovery trial strive to generate evidence to determine the optimal treatment for COVID-19.

The ongoing climate change, disruption of natural ecosystems, and human migration guarantee that we remain at risk for pandemics in the foreseeable future. Knowledge generated

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

Treatment Considerations for COVID-19: A Critical Review of the Evidence (or Lack Thereof)

Tocilizumab improves significantly clinical outcomes of patients with moderate or severe COVID-19 pneumonia

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

COVID-19: combining antiviral and antiinflammatory treatments. The Lancet Infectious Diseases

NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet

Financial support and conflict of interest disclosure: RRR serves as the principal investigator on clinical trials for tocilizumab and sarilumab. None of the other authors have any conflicts of interest that would influence the manuscript.
