FEATURE Hopes High for Anti-inflammatories to Combat COVID-19 Immune System Storms How the immune response tips so radically off-balance is unclear, but research, some drawing on recent CVD trials, ploughs on. By Caitlin E. Cox April 23, 2020 The body’s potent immune response to COVID-19 poses unique risks to the heart, but as accumulating data suggest, this opens the door to a host of anti-inflammatory agents as potential therapies, many of them having already been tested in the prevention of cardiovascular events. Researchers around the world are hoping that this link, especially as it relates to interleukin-6 (IL-6) and its precursor interleukin-1 (IL-1), will provide new ways to temper symptoms and reduce complications in patients suffering a severe course of this deadly disease. “Whereas COVID-19 is primarily a respiratory infection, it has important systemic effects including on the cardiovascular and immune systems. Patients with preexisting cardiovascular conditions represent large proportions of patients with symptomatic infection, and experience disproportionately worse outcomes at between five- to tenfold increase in mortality,” Peter P. Liu, MD (University of Ottawa, Canada), and colleagues note in a review of the topic recently published in Circulation. Systemic inflammation has long been posited as a trigger for cardiovascular events. Here, in the setting of COVID-19, many believe anti-inflammatory agents have an important role to play in bringing the virus to heel. “We believe that, in part, one of the relevant pathways involved in the inflammatory storm, the so-called cytokine storm, associated with COVID-19 is the IL-1/IL-6 pathway, . . . which is also very relevant in cardiovascular disease,” Jean-Claude Tardif, MD (Montreal Heart Institute, Canada), told TCTMD. Tardif led last year’s COLCOT trial showing that colchicine can reduce ischemic events post-MI. Just solving the problem in one part of the world will not be the key.JEAN-CLAUDE TARDIF“” In today’s COVID-19 era, Tardif and others are taking a fresh look at colchicine, which is the focus of six studies currently listed on ClinicalTrials.gov. Among them is the randomized, double-blind, placebo-controlled COLCORONA trial with Tardif at the helm, set to enroll 6,000 patients in the US and Canada; its primary endpoint is the composite of death or the need for hospitalization due to COVID-19 infection within 30 days. But colchicine is far from the only anti-inflammatory being investigated. Anti-COVID-19 candidates Numerous studies are examining their effects on IL-6 and/or IL-1, key actors in the body’s response to SARS-CoV-2 that can alter heart rhythm and drug absorption. “At the moment, the potential of COVID-19 to affect the cardiovascular system is probably underestimated, at least in comparison to the respiratory system involvement,” stressed Pietro Enea Lazzerini, MD (University of Sienna, Italy). What’s key here, he commented to TCTMD, is for clinicians to be vigilant for arrhythmias in their patients and recognize the “potential pro-arrhythmic role of the high-grade systemic inflammatory state characterizing COVID-19.” It’s also clear that COVID-19 can be prothrombotic, said Binita Shah, MD (NYU Langone Health, New York, NY), co-investigator of the COLCORONA trial at her center. She told TCTMD she’s seeing a “fair number” of MIs among COVID-19 patients. In their review, Liu and colleagues also make the observation that inflammation’s consequences extend beyond arrhythmia. In the vascular system, they note, it can cause diffuse microangiopathy with thrombosis as well as result in myocarditis, heart failure, acute coronary syndrome, rapid deterioration, and sudden death. Shah pointed out that there’s already evidence to back IL-6 as a target in the cardiovascular setting—in the groundbreaking CANTOS trial, researchers found the lower the IL-6 level, the better the outcomes for prior MI patients with elevated high-sensitivity C-reactive protein.