Repurposing Immunomodulatory Therapies against Coronavirus Disease 2019 (COVID-19) in the Era of Cardiac Vigilance: A Systematic Review

Abstract

The ongoing coronavirus disease 2019 (COVID-19) pandemic has resulted in efforts to identify therapies to ameliorate adverse clinical outcomes. The recognition of the key role for increased inflammation in COVID-19 has led to a proliferation of clinical trials targeting inflammation. The purpose of this review is to characterize the current state of immunotherapy trials in COVID-19, and focuses on associated cardiotoxicities, given the importance of pharmacovigilance. The search terms related to COVID-19 were queried in ClinicalTrials.gov. A total of 1621 trials were identified and screened for interventional trials directed at inflammation. Trials (n = 226) were fully assessed for the use of a repurposed drug, identifying a total of 141 therapeutic trials using a repurposed drug to target inflammation in COVID-19 infection. Building on the results of the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial demonstrating the benefit of low dose dexamethasone in COVID-19, repurposed drugs targeting inflammation are promising. Repurposed drugs directed at inflammation in COVID-19 primarily have been drawn from cancer therapies and immunomodulatory therapies, specifically targeted anti-inflammatory, anti-complement, and anti-rejection agents. The proposed mechanisms for many cytokine-directed and anti-rejection drugs are focused on evidence of efficacy in cytokine release syndromes in humans or animal models. Anti-complement-based therapies have the potential to decrease both inflammation and microvascular thrombosis. Cancer therapies are hypothesized to decrease vascular permeability and inflammation. Few publications to date describe using these drugs in COVID-19. Early COVID-19 intervention trials have re-emphasized the subtle, but important cardiotoxic sequelae of potential therapies on outcomes. The volume of trials targeting the COVID-19 hyper-inflammatory phase continues to grow rapidly with the evaluation of repurposed drugs and late-stage investigational agents. Leveraging known clinical safety profiles and pharmacodynamics allows swift investigation in clinical trials for a novel indication. Physicians should remain vigilant for cardiotoxicity, often not fully appreciated in small trials or in short time frames.

COVID-19 Vasculopathy: Mounting Evidence for an Indirect Mechanism of Endothelial Injury

“…To that end, in vitro models with cultured human cells or tissue organoids and in vivo animal models have been developed to investigate the mechanisms of SARS-CoV-2 infection and test new therapies [103] , [104] , [105] . Clinical trials are evaluating the safety and efficacy of drugs directed against cytokines and their receptors, cytokine signaling pathways, complement components, and other immune targets implicated in the hyperinflammatory response 106 . As more knowledge is gained on the dysregulated immune response to the SARS-CoV-2 infection and its deleterious effects on the vasculature of the lungs and peripheral organs, clinical outcomes are expected to improve with the introduction of new therapies.…”

Cardiovascular Health and Disease in the Context of COVID-19

“…Numerous drug trials are currently underway to investigate the utility of anti-inflammatory, anti-rejection, anti-complement and anti-neoplastic agents for the treatment of COVID-19 [ 38 ]. In a systematic review of the therapies currently under investigation, Campbell et al note the importance of considering the potential cardiotoxicity of these agents given that adverse effects on the cardiovascular system have significant potential to increase risk of morbidity and mortality [ 38 ].…”

“…Numerous drug trials are currently underway to investigate the utility of anti-inflammatory, anti-rejection, anti-complement and anti-neoplastic agents for the treatment of COVID-19 [ 38 ]. In a systematic review of the therapies currently under investigation, Campbell et al note the importance of considering the potential cardiotoxicity of these agents given that adverse effects on the cardiovascular system have significant potential to increase risk of morbidity and mortality [ 38 ]. Current evidence suggests that anti-inflammatory agents that directly inhibit the IL-1 and JAK pathways as well as complement inhibitors are the least likely of all agents under consideration to result in cardiotoxicity, although there are relatively little data available on the cardiovascular profile of the complement inhibitors under investigation [ 38 ].…”

“…In serious cases, these immunomodulatory agents can alleviate hyperinflammation. For example, the antibody therapy tocilizumab and ulinastatin are drugs that specifically block IL-6 and may be useful for patients with COVID-19 suffering from over-inflammatory processes [ 38 ]. Other antiviral drugs tested in clinical trials for the treatment of COVID-19 have to date proven ineffective and there is some speculation that a combination of immunomodulatory agents and antiviral therapies could yield the best treatment for inflammation in COVID-19 patients [ 94 ].…”

“…In addition, administration of the steroid dexamethasone was shown in a randomized controlled trial to reduce mortality among those with severe respiratory disease requiring mechanical ventilation or oxygen administration [ 95 ]. Until effective treatment strategies are well-defined, treatment providers are urged to maintain awareness of the potential for cardiotoxicity that may not yet be fully appreciated, but could be particularly harmful in the context of COVID-19 [ 38 ]. Driggin et al provide an excellent summary of putative therapies for COVID-19 along with known interactions with existing cardiovascular medications, recommendations for dose adjustments and tips for effective monitoring [ 40 ].…”