Mucormycosis in Indian COVID-19 Patients: Insight into Its Patho-Genesis, Clinical Manifestation, and Management Strategies

Abstract

Mucormycosis in patients who have COVID-19 or who are otherwise immunocompromised has become a global problem, causing significant morbidity and mortality. Infection is debilitating and fatal, leading to loss of organs and emotional trauma. Radiographic manifestations are not specific, but diagnosis can be made through microscopic examination of materials collected from necrotic lesions. Treatment requires multidisciplinary expertise, as the fungus enters through the eyes and nose and may even reach the brain. Use of the many antifungal drugs available is limited by considerations of resistance and toxicity, but nanoparticles can overcome such limitations by reducing toxicity and increasing bioavailability. The lipid formulation of amphotericin-B (liposomal Am-B) is the first-line treatment for mucormycosis in COVID-19 patients, but its high cost and low availability have prompted a shift toward surgery, so that surgical debridement to remove all necrotic lesions remains the hallmark of effective treatment of mucormycosis in COVID-19. This review highlights the pathogenesis, clinical manifestation, and management of mucormycosis in patients who have COVID-19.

Keywords: COVID-19; amphotericin-B; mucormycosis; nanoparticles; pathogenesis.

Figure 1

Classification of fungi in the zygomycete order.

Figure 2

Pictorial representation of etiopathogenesis of mucormycosis in COVID-19 patients.

Figure 3

Schematic diagrams of platelets roles; (A) Platelets enhance host immunity, and after invading pathogen/foreign matter it promotes antifungal and antibacterial properties. Thus, various cytokines and chemokines released in granules; (B) The two membrane bound molecules such as TLR and CD154, it allows platelets binding and activates different cells. Thus, adhesion of mucorales hyphae and spores takes place, which causes platelets activation and leads to aggregation and clotting. Furthermore, inhibits hyphal development in presence of fungal destruction, which leads to clot formation and platelets consumption; (C) Prevention of fungi takes place due to the presence of platelet aggregation and therefore, it adheres to fungal wall; (D) COVID-19 patient develops clot in their vital organ and therefore progression of mucormycosis becomes rapid.

Figure 4

Schematic diagrams of natural killer cells roles; (A) Natural killer cells have direct and indirect cytotoxic effects on fungi and produce cytokines and chemokines (includes GM-CSF, TNF-α, IFN-γ. Thus, influences the activity of other immune cells; (B) Damage of mucorales hyphae takes place in presence of natural killer cells, but no effects shown in conidia. Therefore, it leads to no fungal infection; (C) R. oryzae promotes immunosuppressive effects and thus, it inhibits the release of immune regulatory chemokines such as CCL5 and IFN-γ; (D) Human natural killer cells are studied for their ability to minimize exacerbations and enhance event-free periods in hematopoietic transplant patients, and their therapeutic effect may also be helpful in managing and providing therapy for invasive mucormycosis; (E) Natural killer cell counts can be severe to the IgG immunity for COVID-19. The involvement of CD16 on natural killer cells by antibody-coated virus-infected cells results in antibody-dependent cellular cytotoxicity, thus regulates immune response for COVID-19 patient.

Figure 5

Schematic diagrams of Iron uptakes roles; (A) Higher level of Iron (Fe) leads to fungal growth, whereas fungal undergoes apoptosis in iron deficient circumstances; (B) Increase level of iron in animal model cause fungal infection, due to the reduction of phagocyte function and IFN-γ; (C) In the host body the Mucorales obtain iron via three mechanisms: High affinity iron permeases, siderophores and R. oryzae. The R. oryzae promotes the existence of two copies of hemeoxygenases; (D) COVID-19 virus attack haemoglobin and in the presence of higher level of iron it boosted ferritin production, which leads to the increase serum ferritin production and causes hepatic cell death. Therefore, release of iron trigger and leads to higher level of systemic free iron and cause fungal infection. Thus, various drugs show beneficial effects in the management of Mucorales such as deferasirox, deferiprone ferrioxamine and anti-FTR1.

Figure 6

Interaction between Mucorales and endothelial cells during hematogenous proliferation, as well as the influence of host attributes on these relationships and the immune response. (A)—Through glycosylation and protonation, hyperglycemia and ketoacidosis trigger the production of Fe from transferrin.; (B)—Immunological response to disease is harmed by BHB and free Fe, but at the other end, NaHCO3 counteracts this damaging activity by decreasing transferrin iron release and mitigating acidity.; (C)—GRP78 expression on vascular endothelium significantly increased in response to the stressors caused by free Fe, hyperglycemia and ketone substances.; (D)—Free Fe, glucose and BHB increase the production of CotH in fungal cells, resulting in endothelium invasion and increased fungal growth.