Pathogenesis and Pathology of COVID-Associated Mucormycosis: What Is New and Why

There is global increase in the incidence of mucormycosis. However, a sudden increase in the COVID-associated mucormycosis (CAM) was noted, particularly in India, during the second wave of the COVID-19 pandemic. The interplay of factors involved in the pathogenesis is complex. In this review, the influence of pre-existing disease, exaggerated risk factors, altered milieu due to COVID-19 itself and the consequences of its treatment on the host pathogen interactions leading to the disease and morphology of the fungus will be highlighted.

Hyperglycemia, acidosis, available free iron, lowered host defenses, and the fungal virulence factors promote the growth of Mucorales. There is a high background prevalence of diabetes mellitus (DM) in India. Uncontrolled or undiagnosed DM, COVID-19 itself, and inappropriate administration of corticosteroids in high doses and for prolonged periods result in hyperglycemia. Diabetic ketoacidosis (DKA) and metabolic acidosis due to hypoxia or renal failure contribute to acidic pH and dissociate bound iron from serum proteins. The host defenses are lowered due to COVID-19-induced immune dysregulation, hyperglycemia itself, and administration of corticosteroids and immune suppressants for the treatment of COVID-19. The altered metabolic milieu in the local microenvironment of nose and paranasal sinuses (PNS) promotes specific interaction of glucose-regulated protein-78 (GRP-78) on host cells with spore coat protein homologue (CotH 3) on Mucorales resulting in rhino-orbito-cerebral mucormycosis (ROCM) as the predominant clinical form in CAM. The pathology is extensive soft tissue involvement with angioinvasion and perineural invasion. Melanized hyphae and sporangia were seen on histopathology, which is unique to CAM. While many factors favor the growth of Mucorales in CAM, hyperglycemia, hyperferritinemia, and administration of hyperbaric oxygen result in reactive oxygen species (ROS) and inadequate humidification results in dehydration. Melanization is possibly the adaptive and protective mechanism of Mucorales to escape the unfavorable conditions due to the treatment of COVID-19.

High background prevalence of DM, inappropriate administration of corticosteroids and immune dysregulation due to COVID-19 favor the growth of Mucorales in CAM. Melanization of Mucorales hyphae and sporangia on histopathology probably represent adaptive and protective mechanism due to the treatment with hyperbaric oxygen with inadequate humidification as well as the metabolic alterations.