Mucormycosis (black fungus/zygomycosis) and COVID-19; Does the coexistence of these two increase mortality?

1Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran 2Clinical Research Development Unit of Imam Khomeini Hospital, Urmia University of Medical Sciences, Urmia, Iran 3Department of Midwifery, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran 4Department of Anesthesiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran 5Student Research Committee, Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran 6Herbert Wertheim College of Medicine, Florida International University, Florida, USA 7American University of Antigua College of Medicine, Antigua and Barbuda 8Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary 9Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Immunopathologia Persa http www.immunopathol.com

M ucormycosis, an angioinvasive infection, is commonly rare and considered as a secondary infection. It occurs in patients with weakened immune system, diabetic ketoacidosis, as well as those patients who are under long-term use of antibiotics and/or steroids (1). The exact prevalence of mucormycosis is unknown but it shows to be increased as studies report. The prevalence of mucormycosis in India (around 140 people/1 000 000 population) is eighty times higher than in developed countries. Some new risk factors such as chronic kidney disease and tuberculosis are reported from developing countries (1). Mucormycosis is rare and usually harmless to healthy people but can be fatal to patients with weakened immune systems as Ercan et al reported (2). In general, a person develops mucormycosis after inhaling fungal spores in the air. Infection can also occur due to skin injuries or after eating contaminated food with fungus (3). Ercan et al revealed that mucormycosis can lead to rapid death without treatment in the presence of an underlying disease and can be treated with surgical debridement combined with intravenous amphotericin B (2). It is difficult to estimate the exact number of patients with mucormycosis as most cases may have been misdiagnosed (1,2). Although mucormycosis is not contagious, it is very difficult to be diagnosed and treated since some mucorales are very resistant to the human immune system. As most of the symptoms that patients experience are during this infection are nonspecific and may be confused with other infections, including other fungal or even viral diseases (3). Mucormycosis manifestations can be presented as sinusitis and then spread to the eyes, optic nerve, and even the brain, and can be accompanied by facial edema, ptosis, and vision loss (4). Most patients with mucormycosis infection caused by mucoraceae family have an underlying disease including diabetes, acquired immunodeficiency syndrome (AIDS), anemia, malnutrition, neoplasm, and immunodeficiency in which their symptoms started with a cold and sinusitis and then were accompanied by pain and swelling in the face (5-7). The diagnosis of mucormycosis is complex and challenging and is based on a direct examination, culture, and histopathological features. One of the main laboratory methods is the internal transcribed spacer region and can be recommended as a first-line method for species identification of mucorales (1,8). During the COVID-19 pandemic, paying attention to symptoms can help for a timely and proper diagnosis. Dexamethasone, as a steroid, is commonly available that can be used to treat severely ill patients and can reduce the mortality rate in COVID-19 patients. However, this treatment reduces the immune system to fight the infection. In addition, steroids raise the blood sugar level in diabetic patients and create a sugar-rich environment in which the fungus can grow (9)(10)(11). We believe that diabetes is associated with a higher mortality rate following getting COVID-19 (12). COVID-19 patients with diabetes are at two times higher risk of developing a severe form of COVID-19 (13). Hence, diabetes is a common risk factor for the severe condition in both COIVD-19 and mucormycosis; therefore, the coexistence of these two diseases can worsen the final status of the patient. About 40 to 50% of patients with mucormycosis have diabetes mellitus, and develop ketoacidosis. The study by Pinto et al showed that 88.2% of patients with mucormycosis have diabetes mellitus and 53.3% of them had diabetic ketoacidosis (14). In addition, in India, by 21 May 2021, diabetes was found in 80% of cases with mucormycosis, and the use of corticosteroids was reported in 76.3% of cases with mucormycosis in patients with COVID-19 (15). The best way to deal with mucormycosis infection is to prevent it by appropriate administration of immunosuppressive drugs and control of underlying diseases such as diabetes (16). The high incidence of COVID-19 patients with mucormycosis in India, which is named COVID-19 associated mucormycosis (CAM), shows a great concern on a new pandemic of mucormycosis (17). It is recommended to avoid indiscriminate use of corticosteroids in COVID-19 patients with diabetes because diabetic patients are much more likely to develop mucormycosis (18). Moreover, the risk of secondary infections increases following glucocorticoid treatment. After getting COVID-19, the immune system is damaged and the use of concurrent immunosuppressant may worsen the status of COVID-19 infection (19,20). According to the Centers for Disease Control and Prevention (CDC), the mortality rate of mucormycosis in patients with COVID-19 has reached 54%, which can be presented in different features based on the patient's status and the infection site (21). In countries like India with the second highest rate of diabetes worldwide, the spread of mucormycosis is lethal (22). The early diagnosis of any type of mucormycosis like rhino-orbital mucormycosis in COVID19 patients is of great importance particularly in those with diabetes or immunodeficiency and receiving systemic corticosteroids. In a case series of COVID-19 patients with mucormycosis, all patients were died despite receiving enough therapy (23)(24)(25). Treating physicians should have a high suspicion for mucormycosis in patients with COVID-19 and diabetes (26,27). In case of mucormycosis infection, histopathological confirmation and fungal culture should be considered for differential diagnosis (28). Therefore, previous medical history is very important in the patients with COVID-19. Additionally, mucormycosis in immunocompromised state facilitates pulmonary mucormycosis (29). Finally, once mucormycosis is diagnosed, a combined method consisting of antifungals administration like amphotericin B, surgical intervention, and the reversal of the underlying condition must be considered as soon as possible (30).

Authors' contribution
Primary draft was prepared by MF, SF, TS and RH. NG, MN, SAM and TS edited the paper. All authors read and signed the final paper.

Conflicts of interest
The authors report no conflict of interests.

Ethical considerations
Ethical issues (including plagiarism, misconduct, data fabrication, falsification, double publication or submission, redundancy) have been completely observed by the authors.

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