Following the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the incidence of mucormycosis has increased. This, in conjunction with the pandemic has caused devastating human health issues globally, particularly among South Asian and other Asian countries, particularly in individuals with major predisposing conditions, such as uncontrolled diabetes mellitus, comorbidity effects from steroid therapy with elevated iron levels (1). Mucormycosis can be defined as an angio-invasive fungal infection with relatively high morbidity and mortality rates. Broadly the species of the phylum Zygomycota cause mucormycosis, particularly Mucorales and Entomophthorales. In Mucorales, four genera that are most closely associated are Cunninghamella, Rhizopus, Mucor, Absidia, etc. Conidiobolus and Basidiobolus are the two key genera belonging to the Entomophthorales order and tend to cause infections in human beings (2). The etiologic agents of mucormycosis are cosmopolitan in distribution. The mucormycosis condition is a classical opportunistic invasion and typically affects immunocompromised individuals, particularly those with conditions, such as ketoacidosis, burn or trauma, or those under iron chelation treatment and some individuals who are severely immunocompromised due to malignancy or even chemotherapy (3). The case incidence of mucormycosis is underrated possibly due to laborious diagnostic procedures and mostly depends on histopathalogical analysis or the culturing process and remains under-reported (4).

Among all mucormycetes, Rhizopus oryzae is the most widespread strain and contributes for 60% of human cases and is also responsible for 90% of rhinocerebral mucormycosis cases (5). With a devastating and multifaceted clinical symptomatology, mucormycosis has emerged as an infectious disease worldwide. Mucor moulds are generally found in soil, plants, manure or even in fruit and vegetable compost, and are rarely found in air as a transient existence. Depending on the site of infection, mucormycosis differentiates into a rhinocerebral, pulmonary, cutaneous and gastrointestinal infection (6). The pathogenicity of infection ranges from mild to fatal, depending on the incubation period of the moulds. The incubation period of this fungus is 5 to 6 days; individuals can become infected by inhaling spores of moulds. Mucormycosis is generally non-contagious, and due to potential innate immunity, the majority of individuals exposed to the spores do not develop infection (7).

Once affected by Mucorales, the disease progresses rapidly. Moreover, opportunistic fungi, such as Mucor irregularis or Rhizomucor variabilis reported from China, tend to cause diverse epidemiological and clinical manifestations (8).

In India, ~31 million individuals were affected by the COVID-19 pandemic, and the number of COVID-19-related mucormycosis cases also simultaneously increased, particularly during the second wave, which occurred in June, 2021. During 2021, mucormycosis was observed to be prevalent in India, and its estimated incidence was 14 in every 100,000 individuals compared to other cases (9). A sudden emergence of mucormycosis cases along with COVID-19 was observed; although rare, mucormycosis was a serious and rapid complication associated with COVID-19(9). The major cause of this condition was Mucorales spore inhalation by patients with COVID-19 with a low oxygen (hypoxia), hyperglycemic index or even steroid-induced hyperglycaemia, acidic conditions such as metabolic acidosis, diabetic ketoacidosis and high iron levels (increased ferritins), with a decreased phagocytic activity of white blood cells (WBCs) due to immunosuppression (SARS-CoV-2-mediated or other comorbidities). This was coupled with prolonged hospitalization with or without COVID-19 infection or sometimes after a few weeks of recovery (5-9). However, during the COVID-19 pandemic, the number of mucormycosis cases increase in India perhaps due to improper hygienic maintenance in hospital linens, medications and packaged foods. This increase may also be due to the following reasons: Following infection with COVID-19 patients have a low immune status due to a decrease in WBCs. In addition, during the viral infection, patients are medicated with corticosteroids and tocilizumab to reduce lung inflammation, which often worsens the immune status, hence leading patients to become prone to fungal infection (9). The extent of acute Mucor infection is dependent upon the overall immunological status and overall health status of an individual. As COVID-19 can damage respiratory tissues and blood vessels, this increases the susceptibility to fungal infection; black fungus invades (angioinvasive mycosis) rapidly and multiplies in blood vessel walls where it effectively reduces and tears blood vessels and tissues, thereby resulting in tissue damage (10). The infection can have adverse affects in oxygen-dependent patients with poor sanitary or aseptic practices.

Depending on the site of infection, mucormycosis may be categorised into the following types (Table I).

The number of COVID-19 pandemic-associated black fungus infection cases has increased globally and a similar situation was observed in India. Furthermore, In India, The National COVID-19 task force has issued an advisory notice and the Union Health Ministry has instructed the states/UTs to declare black fungus as an epidemic. Infection with Mucorales, particularly in immunocompromised individuals can be quite rampant and progressive with the etiological agent being the opportunistic fungus, Mucor irregularis (22). Generally, the infection is chronic, occurring in immunocompetent patients, involving the skin and subcutaneous tissues, leading to severe complications. In India, the state of Rajasthan first declared a mucormycosis epidemic, while the city of Surat noted that 8 out of 40 COVID-19 survivors developed this infection in the eyes and lost their vision (information obtained from the India Today web desk during the second lockdown in 2021) (22).

Mucormycosis symptoms generally begin with sinusitis, nasal blockage, congestion with blackish or bloody nasal discharge, pain in the cheek bone or one-sided facial pain, numbness, swelling, blackish discoloration on nose palate, loosening of the teeth, blurred or double vision with pain, thrombosis, necrosis, chest pain, pleural effusion with difficulty in respiratory functions (21-41) (Fig. 1).

The word mycosis stands for the lethal fungal disease caused by infection and direct interaction of fungal spores with the body tissues. Mucormycosis, dermatophytoses, yeast infections, systemic mycoses and mycetoma are the pathogenic fungi involved in mycosis disease (42). Prakash et al (43) documented the pathogenic Mucorales fungi, Rhizopus, Lichtheimia, Cunninghamella, Rhizomucor and Apophysomyces as the causitive agents of mucormycosis, which were isolated from Indian soils and similarly from air samples. Among the Rhizopus species, Rhizopus arrhizus and Rhizopus homothallicus are the most common agents causing ROCM. Apophysomyces variabilis is the second highest causative agent and accounts for 60% of the total cases of mucormycosis in the population (44). During the COVID-19 pandemic, the main factors responsible for the development of COVID-19-associated mucormycosis included the high rate of diabetes mellitus, unsanitary/poor hygienic conditions and high ferritin levels in the body (45). The disease sets with the entry of Mucor or other strain spores via the air tract either through the nose, mouth or skin lacerations (46). Upon the entry of the spores, individuals who are compromised with cellular and humoral immunity are unable to provide a defence against the pathogen (47). Thus, the fungus can then spread to the paranasal sinuses, and later to the orbit, meninges or brain. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS-2) are the two receptors through which COVID-19 enters the cell. ACE2 is the receptor for the majority of cells in the body and has a higher rate of expression in the respiratory and renal tract, and gastrointestinal epithelium. TMPRSS receptors are similar to ACE2, but are present only in respiratory and gastrointestinal epithelial cells. TMPRSS-2 along with ACE2 receptors has a tendency to attack lymphocytes, thus reducing CD4⁺ and CD8⁺ T-cell counts, resulting in a weaker immunity, also inducing lymphopenia. The reduction in the T-cell number consequently increases interleukin levels and effectively achieves the state of the cytokine storm (48). The cytokine storm weakens the defence system reserve pool, causes the atrophy of lymphoid tissue, and prevents the further production, differentiation and proliferation of protective lymphocytes. The weakened immune system paves the way for the entry of Mucorales into the body. Another key condition which fuels the fungal growth is lactic acidosis; this eventually destroys type II alveolar cells, leading to excessive respiratory disabilities that intensify acid-base levels. The resulting hypoperfusion and hypoxemia worsens the condition of the body by increasing acidic conditions. The coupled reaction of the cytokine storm and lacto/keto acidosis aggravates the state of the patient; in this case, there is an urgent need for treatment through immunosuppressive steroids. These criteria promote an ideal environment for the fungus to grow (49). In addition to this, increased ferritin level due haemolysis and an increased body temperature promote the growth and development of the fungus in immunosuppressed individuals (50). The ACE2 receptor nourishes the growth of Mucorales by damaging pancreatic β-cells, which results in elevated plasma glucose levels, and the consequent increase in glucose levels feeds the fungus. This explains the increased rate of mucormycosis in diabetic patients (6,47,48). These irreversible consequences eventually deteriorate the overall health status of the patient, often leading to fatal results (51).

It has been reported that during 2013-2015, in four major tertiary care hospital in India, there were 388 incidents of mucormycosis, and 56% of these cases had unregulated diabetes, which demonstrates that the existence of underlying conditions predisposes the proliferation of the fungus. In addition, trauma was reported in 10% of these cases, which signifies the linkage of this fungal infection to diabetes (39,41,52). India has a prevalence of diabetes of 9% in the adult population (44). Conversely, coronavirus infects the pancreas and can disrupt blood sugar levels perhaps due to the infection or due to clinical treatment. In this context, host immunity appears to be compromised; consequently, elevated sugar levels provide an ideal pabulum for mucormycosis development and in individuals with uncontrolled diabetes, this enables the highest replication of SARS CoV-2, which produces mitochondrial reactive oxygen species and activates hypoxia-inducible factor 1α (18,19). In fact, the uncontrolled diabetes condition enhances acidic media, which is an ideal condition for the proliferation of the fungus. Thus, mycelial invasion and proliferation are promoted by the hyperglycaemic index and acidosis (53) followed by the enhanced release of iron from ferritin (due to acidosis). Therefore, it is critical to maintain blood sugar levels under control during the course of antifungal treatment.

In a case study conducted among 95 patients with COVID-19-associated mucormycosis (CAM) who were admitted to the Bowring and Lady Curzon Hospital from June to September, 2021 (70 males and 25 females), 69% of the patients had type 2 diabetes mellitus with mean serum ferritin levels of 537.38±468.88 ng/ml. The patients were positive for Mucorales and the KOH test, while serum ferritin levels were markedly elevated and identified as Aspergillus, Mucor, Rhizopus and Candida spp. (54).

Since the mortality, morbidity and haematological defects are prominent features, the diagnosis of mucormycosis poses a tough challenge. Rapid diagnosis from invasive aspergillosis is of top priority as antifungal treatment would differ, while the underlying clinical conidtions are almost similar (6,55). Basically, direct microscopy was the gold standard for diagnosis until recently; however, the process was cumbersome. In the case of invasive aspergillosis, the assay for circulating antigens, such as galactomannan/β-D-1,3-glucan is ideal, although it provides no evidence of Mucormycosis (56). Hence, for mucormycosis, direct microscopy, histopathology for hyphal detection and invasion along with the analysis of cultural characteristics on Sabouraud dextrose agar or potato dextrose agar are optimal diagnostic tools. With the advent of molecular biology tools and applications, the rapid detection of fungal infection has become a reality. A quantitative multiplex polymerase chain reaction (qPCR)-based 18S rRNA targeting Mucor/Rhizopus, Lichtheimia and Rhizomucor has recently become a hallmark of detection, particularly during the early stages and even within 3 days of the disease onset using blood or serum with 90% authenticity (52). In the case of post-burn infection, this can be detected 11 days before standard diagnosis. RT-PCR analysis of Mucorales in tissue/biopsy for haematological malignancies can detect probable mucormycosis infection (57).

The effective treatment of mucormycosis is generally based on a multifaceted strategy, which may include early medication at the optimal dosage, the complete evacuation of the fungus and use of diverse adjunctive therapies (58). The majority of Mucorales exhibit resistance to most antifungal agents in vitro (voriconazole). Amphotericin B is an effective drug, with the exception of some species of Cunninghamella and Apophysomyces (6). In addition, posaconazole and isavuconazole are also effective, and itraconazole and terbinafine exhibit some activity against certain species.

Mucormycosis may result in the loss of the upper jaw or even sometimes the eyes. Due to this loss of the jaw, patients may have difficulty with chewing, swallowing, facial aesthetics and can suffer a disrupted self-confidence (73).

The early, effective and rapid diagnosis/administration of suitable effective drugs, the application of hyperbaric oxygen, recombinant cytokines, the transfusion of granulocytes, surgical intervention, prosthetic obturator are the typical and crucial methods in successful management (16,74). Patients with uncontrolled diabetes require rapid corrective measures for metabolic abnormalities; the use of sodium bicarbonate (with insulin) is mandatory to reverse ketoacidosis, as it reduces the ability of Mucorales invasion (74). However, the use of immunosuppressive drugs/corticosteroids need to be reduced to the lowest possible level with epidemiological knowledge (75).

The COVID-19 pandemic has increased the risk of infections worldwide due to the lack of specific treatments available for the most devastating viral infections. During the second wave of the pandemic, the number of deaths rapidly increased and reached uncontrollable levels. The management of COVID-19 led to the continuous use of steroids, antibiotics and breath supportive sources, such as oxygen carriers and ventilators; these worsened the conditions of patients by increasing comorbidities. Co-morbidities, such as diabetes and cardiovascular diseases intensified during the management of COVID-19, which led to the development of secondary infections, such as mucormycosis. Mucormycosis is an invasive fungal infection accompanied by ketoacidosis, high glucose and high ferritin levels, neutropenia and a lower immunity. All these parameters make patients immunocompromised, with decreased levels of WBCs, T-cells and other immune cells, leading to a cytokine storm in the body and the impairment of cellular organs. As the management of the disease is critical, novel diagnostic and treatment strategies are required for mucormycosis in order to prevent higher morbidity and mortality rates. Hence, additional extensive research and investigations to elucidate the root cause of mucormycosis are warranted in order to provide clinicians with the tools to combat infection in association with the pandemic.