Accelerated hyaluronan concentration as the primary driver of morbidity and mortality in high-risk COVID-19 patients: with therapeutic introduction of an oral hyaluronan inhibitor in the prevention of Induced Hyaluronan Storm Syndrome

To date, the fundamental drivers of the morbidity and mortality in COVID-19 remain uncertain. Clinicians worldwide appear to be at a loss to know how to prevent and treat the severe respiratory distress in these patients effectively. Consequently, the fundamental mechanisms leading to death in high-risk patients need to be discovered and addressed with urgency. The post-mortem autopsy remains an essential part of both discovering the cause of death in a particular individual, but also in advancing the science and treatment of disease, especially in the case of novel pathogens such as SARS-CoV-2[2]. The goal of an autopsy is to discover the cause of death (COD) using a macro/microscopic investigation. Because lung weight is often affected by the cause of death and the last breath occurs very near if not at death, the evaluation of the lungs is one of the starting points of any COD investigation[3]. A comprehensive search was performed to systematically review all reported autopsy findings in COVID-19 patients with respect to lung weights and histologic findings. We then compared these findings with the results of a targeted literature review of hyaluronan in relationship to acute respiratory distress syndrome (ARDS). In total, data from 38 autopsies were identified. From this group, 36 autopsies of COVID-19 patients were selected for detailed review and statistical analysis. The average lung weight of those who were determined to have died as a result of SARS-CoV-2 was 1683g approximately 3.2 times the normal lung weight. Hyaline membranes were consistently identified on histologic sections. A review of the literature reveals that markedly elevated lung weights and hyaline membranes and have been associated with the pathophysiology of ARDS since 1967. However, the key role key of hyaluronan in driving the morbidity and mortality of the condition has heretofore not been fully recognized. We propose that the induced hyaluronan storm syndrome or IHS, is a model that addresses the heretofore perplexing respiratory failure that is the proximal cause of death. An aggressive research effort should be undertaken to discover why the majority of individuals who are exposed to the virus are minimally symptomatic, while a minority of high-risk individuals rapidly progress to respiratory failure and death. "You may take notes for 20 years, from morning to night at the bedside of the sick, upon the diseases of the viscera, and all will be to you only a confusion of symptoms...a train of incoherent phenomena. Open a few bodies and this obscurity will disappear." - Marie-Francois-Xavier Bichat (1771-1802), "The Father of Histology"[1].