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

Abstract

Purpose of Review 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. Recent Findings 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. Summary 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.

Invasive mixed fungal disease after covid-19: A series of seven cases

“…The culture correlation (though less sensitive, but diagnostic) was confirmatory for the diagnosis of invasive fungal disease. 11 The tissue diagnosis of fungal disease was even more challenging, particularly in conventional H&E stains. In suspected cases, additional histochemical stains like GMS or PAS need to be applied for better visualization of fungi admixed with a gamut of tissue reaction patterns and can augment and aid pathologist for its early diagnosis.…”

“…8 Radotra and Challa in their review quoted that hyperglycemia, acidosis, availability of free iron, lowered host defenses, and fungal virulence were the factors that promoted the growth of Mucorales. 11 The COVID-19 treatment modality might have resulted in dysregulation of the glycemic control and predisposition to secondary fungal infections, especially in the setting of comorbid factors like DM. Amalanathan et al reported a case of Mucormycosis that presented as orbital cellulitis in a patient of COVID-19 pneumonia with steroid dependence and uncontrolled DM.…”

An extensive review on antifungal approaches in the treatment of mucormycosis

“…It is also believed that natural killer (NK) cells play a significant fungi and because of this NK cells act effectively in the initial phase of infection. [19] The experimental and clinical studies showed that individuals with phagocytic dysfunctions are more prone to the risk of mucormycosis. It has been revealed that the oxidative metabolites of cationic peptides and defensins generated by both mononuclear and polymorphonuclear phagocytic systems of normal individuals kill the Mucorales (Figure 2).…”

“…Regulated upon activation, normal T‐cell expressed, and presumably secreted (RANTES) and IFN are the vital chemicals, secreted less frequently in direct contact between fungal hyphae and NK cells that enhance the fungicidal activity of macrophages and the host defense against fungi and because of this NK cells act effectively in the initial phase of infection. [ 19 ]…”

Rapid Cytological Diagnosis With Evaluation of Pre- and Post-Therapeutic Fungal Morphological Characteristics in Mucormycosis

“…It is an angioinvasive disease caused by fungi belonging to the order mucorales of class zygomycetes [ 2 ]. The most common mode of infection is through inhalation of sporangiospores and could also occur through direct inoculation from disrupted skin or mucosal surfaces [ 3 ]. The fungus is highly vasotropic in nature causing tissue infarctions and becomes rapidly disseminated specially in immuno-compromised patients (diabetics, glucocorticoid therapy, patients with malignancy receiving chemotherapy, allogenic stem cell transplant recipients) [ 4 ].…”