LAUSR

The pandemic of Corona Virus Disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is continuing to cause substantial loss of life and economic damage globally. Epidemiological studies have indicated that majority cases are mild and self-limiting. However, the mortality rate ranges between 2 and 20% depending upon patient’s age, demographic factors, and comorbidities (1–4)1. Thus, far, the largest study of 72,314 patients fromChina reported that 81% of cases were mild with a case fatality rate of 2.3%. The study further showed that a subgroup of 5% of cases had a more severe illness—respiratory failure, septic shock, coagulopathy, and multiorgan dysfunction—and among those mortality was nearly 50%. The epidemiological studies of COVID-19 patients available thus far underscore the heterogeneity of clinical presentation as well as the unpredictable nature of its progression to cytokine storm and acute respiratory distress syndrome (ARDS)–terminal events that lead to mortality associated with COVID-19 (1–3). Most patients who succumb to COVID-19 develop severe illness and are reported to have other comorbidities, immunosenescence, or are immunosuppressed (3–7)1. In a desperate attempt to curb mortality in severe COVID-19, several immuneand nonimmune-based therapeutic strategies, both investigational and repurposed, are being utilized including convalescent plasma, anti-microbial, anti-inflammatory, and immunomodulatory agents (8–14). However, no evidence exists related to the safety and efficacy of these agents and current measures are akin to “shooting in the dark” with a hope that “something will work.” For instance, the most favored and commonly used drug worldwide in the initial phase of the outbreak is now shown to be non-efficacious and, potentially, more toxic. In an open-label, randomized controlled trial of 199 PCR-confirmed COVID-19 patients, HIV-1 protease inhibitor, lopinavir-ritonavir (that showed in vitro activity against SARS-CoV-1), did not demonstrate any impact on clinical improvement, mortality or viremia, in comparison to supportive medical management (9). The other repurposed drugs that were expected to change the course of illness have also not demonstrated a clear signal thus far. In the particular cases of hydroxychloroquine (HCQ) and remdesivir, no clear clinical benefit has been demonstrated in several studies reported thus far. Studies have also suffered from uninterpretable or flawed trial designs (heterogeneous comparator arms), small sample size, either having a clinically oriented outcome or not demonstrating clinical benefit, or did not have sufficient data to demonstrate safety (e.g., baseline and serial electrocardiograms in the case of studies conducted to evaluate HCQ). In an open-label, non-randomized