Clinical Edge Journal Scan

Clinical Edge Journal Scan Commentary: COVID-19 October 2021

Dr. Bhadelia scans the journals, so you don’t have to!

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Nahid Bhadelia, MD, MALD

The pathophysiology of acute COVID-19 appears to be a combination of damage due to direct viral invasion and cytotoxicity, endothelial damage, coagulopathy, and an overactive and hyperinflammatory immune response. Over the course of the pandemic, the role of and optimal timing of treatment with several immunomodulatory agents (in addition to antivirals) has been explored in averting the secondary maladaptive immune response often seen in severe disease. The largest benefit has been seen with corticosteroids which helped decrease mortality among hospitalized patients on oxygen in RECOVER trial. However, numerous more selective immunomodulatory agents have also been evaluated in clinical trials, considered more favorable due to narrower immunosuppressive effect, including IL-6 inhibitors, IL-1 inhibitors, TNF-alpha inhibitors and janus kinase inhibitors.

Marconi et al report out the results of the COV-Barrier study, a phase 3 randomized placebo controlled (RCT) trial with baricitinib, a JAK-STAT pathway inhibitor generally used to suppress proinflammatory cytokine production and systemic inflammation in rheumatoid arthritis, in hospitalized COVID-19 patients. The 1525 participants equally divided between placebo and baricitinib in an intention to treat analysis, were recruited from 12 countries, and most were on systemic corticosteroids (79.3%) and about one fifth received the antiviral, remdesivir. The study did not show a difference in the primary outcome (a composite of progression to more severe disease including need for high flow oxygen, non-invasive or invasive mechanical ventilation or death by 28 days), but did note a 5% absolute reduction in mortality at 28 days. Based on this results, Baricitinib may have a role similar role in the care of COVID-19 patients as tocilizumab (an IL-6 inhibitor) when given in combination with steroids, but may be used in the care of patients earlier in their disease including those on high flow or noninvasive oxygen as well as those requiring invasive mechanical ventilation, compared to tocilizumab, which is currently preferred by many clinicians in those on more intensive respiratory support and within 24-48 hours of ICU admission. Like other immunomodulators, there is a concern for increased secondary infections with the use of this therapy, but JAK inhibitors also carry a risk for increase in venous thromboembolic events. Interestingly, in this trial, there was no difference in the incidence of either of these adverse effects between the placebo and treatment groups.

The results of a phase 3 RCT with Canakinumab, an anti-interleukin-1B monoclonal antibody, on the other hand, did not show a benefit in primary outcome of survival without need for mechanical ventilation day 3 to day 29, or recovery time, in hospitalized patients who had elevated C-reactive protein and ferritin but were not yet intubated. Canakinumab was evaluated because IL-1B has been identified as one of the signature elevated cytokines in a maladaptive immune response to SARS-CoV-2 infection and because had shown some promise in small and retrospective studies.

Lastly, on the prevention side, a study of Regeneron’s anti-SARS-CoV-2 monoclonal antibody cocktail (casirivimab and imdevimab) was evaluated in a double blind placebo controlled RCT in prevention of development of symptomatic SARS-CoV-2 infection within 28 days among household contacts who did not have prior immunity. In the study, 1.5% of those who received the monoclonal therapy subcutaneously versus 7.8% of those who received placebo met the primary endpoint. Additionally, those who received the therapy and were symptomatic, resolved their symptoms two weeks earlier. The real-world utility of the results, however, maybe limited to specific groups, given that need for early identification of contacts, the need to access medical facility for administration, as well as the cost of the drug. There may be a role in high risk and immunocompromised contacts who do not develop adequate immune response to vaccination.

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