Systematic review of COVID-19 autopsies: 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

Abstract

Background To date, more than 161,000 people have died from the coronavirus disease 2019 (COVID-19) yet the fundamental drivers of the morbidity and mortality 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 with COVID-19 need to be discovered and addressed with urgency. Despite a marked drop in frequency, 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. Traditionally, the intact organs are carefully removed, inspected, and weighed. Because lung weight is often affected by the cause of death and the last breath occurs very near if not at the moments of death, the evaluation of the lungs is one of the starting points of any COD investigation[3]. Method A comprehensive search was performed to systematically review all reported autopsy findings in COVID-19 patients in order to better understand the underlying disease mechanisms resulting in death. We then compared these findings with the results of a targeted literature review of hyaluronan in relationship to acute respiratory distress syndrome (ARDS). Results In total, data from 181 autopsies were identified. From this group, 6 autopsies of COVID-19 patients were selected for a 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 2196g-approximately 2.5x normal lung weight. Hyaline membranes were consistently identified on histologic sections. A review of the literature reveals that hyaluronan has been associated with the pathophysiology of ARDS since 1967. However, its key role in driving the morbidity and mortality of the condition has heretofore not been fully recognized. Conclusions We propose that the induced hyaluronan storm syndrome or IHS, is the model that best addresses the heretofore perplexing respiratory failure that is the proximal cause of death in a minority, but ever rising number, of patients. In addition to treating and preventing IHS in currently infected individuals now; an aggressive research effort should be undertaken to discover why the majority of individuals who are exposed to the virus are either minimally or asymptomatic, while a minority of high-risk individuals rapidly progress to respiratory failure and death. Keywords Systematic review; COVID-19; SARS-CoV-2; Hyaline Membrane; Hyaluronan; Acute Respiratory Distress Syndrome; ARDS; Autopsy; IHS; Induced Hyaluronan Storm Syndrome; COD; Cause of Death

A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm

“…Furthermore, in another autopsy study of a COVID-19 patient, histological analysis found extensive hyaline membranes, which the authors interpreted as indicative of ARDS ( Xu et al, 2020 ). Finally, a meta-analysis showed that there was a statistically significant 4.6 fold difference in lung weight of COVID-19 patients versus controls, which they conclude is consistent with the HA-hydrogel formation known to occur in ARDS ( Mong et al, 2020 ).…”

“…Reports from blood studies include leukopenia, eosinopenia, neutrophilia, elevated liver enzymes, C-reactive protein, and ferritin ( Fan et al, 2020 ; Huang et al, 2020 ; Goyal et al, 2020 ). Furthermore, autopsies have reported extensive hyaline membrane formation in the lungs of COVID-19 patients ( Barton et al, 2020 ; Xu et al, 2020 ; Adachi et al, 2020 ; Mong et al, 2020 ). Specifically, histological analysis of the lungs of a deceased COVID-19 patient showed organizing hyaline membranes in the early stages of alveolar lesions and prominent hyaline membranes in the exudative phase of diffuse alveolar damage ( Adachi et al, 2020 ).…”

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“…Fourth, as detailed below, STAT3 indirectly activates TGF-β in the extracellular matrix (ECM), and TGF-β upregulates PAI-1 production [93]. Fifth, severe ARDS cases of COVID-19 result in diffuse alveolar damage (DAD) and the formation of hyaline membranes [94]. Hyaluronan (HA) is essential for many biological functions, but it is a causative agent in ARDS when it becomes a low-molecular-weight HA (LMW-HA) [95].…”

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“…24 The alveolar cavity is often filled with serum, fibrin exudate and extensive transparent hyaline membrane formations, as observed in autopsies. 22,[25][26][27] White blood cells that infiltrate the alveoli are mainly monocytes and macrophages. Type II lung alveolar cell proliferation and focal lung cell shedding can be observed.…”