Current Understanding in the Pathophysiology of SARS-CoV-2-Associated Rhino-Orbito-Cerebral Mucormycosis: A Comprehensive Review

Abstract

Aim Recently, with the second wave of COVID-19, the Indian subcontinent has witnessed a dramatic rise in mucormycosis infection in patients recovered from COVID-19. This association has been documented in various case reports/case series and institutional experiences, and the mortality associated with this fungal infection is emerging as a cause of concern. The aim of the present paper is to provide a scientific overview on the pathogenesis of mucormycosis in COVID-19 beyond the conventional understanding of the disease process, which may not otherwise explain the increased incidence of mucormycosis in SARS-CoV-2. Methodology This paper is structured as a narrative review of the published literature on the pathogenesis of COVID-19 which contributes to the development of mucormycosis. Apart from the acknowledged role of ketoacidosis, high blood sugar, and iron metabolism in the pathogenesis of mucormycosis, other factors involved in pathophysiology of COVID-19 which might alter or enhance the mucormycosis infection such as (1) the role of ferritin, (2) high serum iron, (3) free radical-induced endothelitis, (4) hepcidin activation, (5) upregulation of glucose receptor protein (GRP78) are discussed in the pathophysiology of COVID-19-associated mucormycosis. Conclusion A new proposal for the pathogenesis based on the ferritin, viral mimicry of hepcidin and GRP78–CotH3 interaction, which clearly explains the surge in mucormycosis in SARS-CoV-2 infection, has been explained.

Role of COVID 19 Inflammatory Markers in Rhino-Orbito-Cerebral Mucormycosis: A Case Study in Predisposed Patients at a Designated Nodal Centre

“…White PL et al [ 15 ] stated that corticosteroid therapy during COVID 19, was associated with higher risk of invasive fungal sinusitis. The propensity of corticosteroids to impair migration, ingestion and phagolysosome fusion in macrophages may explain suppressed immunity in such patients [ 16 ]. However, a sizeable number of patients with history of short course of low dose corticosteroids, diabetes with controlled blood sugars and with a history of home isolation were also seen to have developed mucormycosis in our study.…”

COVID-19–associated mucormycosis: Evidence-based critical review of an emerging infection burden during the pandemic’s second wave in India

“…COVID-19–associated rhino-orbital-cerebral mucormycosis (CAROCM) is the most common type observed during the current epidemic, followed by the pulmonary form [ 16 , 17 ]. Prior to the COVID-19 pandemic, the mucormycosis mortality was 50%.…”

“…This, in turn, causes endothelial destruction and inflammation called endothelitis. In addition, the hepcidin mimetic action of the virus further induces ferritin independent of the inflammatory reaction [ 17 ]. Thus, COVID-19–induced immunosuppression increases the risk of opportunistic infection, damages the endothelium and alveoles, easing the port of fungal invasion, and increases the glucose level due to the acute diabetes-like state caused by pancreatic damage; increased ferritin level supports fungal growth, and increased body temperature is optimal for thermotolerant fungi.…”

“…Up-regulation of 78-kDa glucose-regulated protein (GRP78), a heat shock protein, in patients with COVID-19 (5 times more than controls) due to increased glucose and iron content caused by diabetic ketoacidosis (DKA) or induced by dexamethasone use also facilitates fungal entry. Besides, it promotes Mucorales’ pathogenicity and virulence [ 17 , 50 ].…”

COVID Induced Functional Exhaustion and Persistently Reduced Lymphocytes as Vital Contributing Factors for Post-COVID Rhino-orbital and Cerebral Mucormycosis in Patients with Diabetes: Report from the Indian Sub-continent

“…Through the observation of this study and previously reported data by various authors, the reduction and the functional exhaustion of lymphocytes (including CD4 + T and other subsets) should be considered as the vital contributing factor for the surge in cases of rhino-orbital and cerebral mucormycosis post SARS-CoV-2 infections, apart from the established predisposing factors that include: ketoacidosis, high blood sugar, iron metabolism related aberrancy, role of ferritin, high serum iron, free radical-induced endothelitis, hepcidin activation, and upregulation of glucose receptor protein (GRP78) [ 15 ].…”