key: cord-0970216-uq52tcyl
authors: Mahalaxmi, Iyer; Jayaramayya, Kaavya; Venkatesan, Dhivya; Subramaniam, Mohana Devi; Renu, Kaviyarasi; Vijayakumar, Padmavathi; Narayanasamy, Arul; Gopalakrishnan, Abilash Valsala; Kumar, Nachimuthu Senthil; Sivaprakash, Palanisamy; Sambasiva Rao, Krothapalli R.S.; Vellingiri, Balachandar
title: Mucormycosis: An opportunistic pathogen during COVID-19
date: 2021-07-06
journal: Environ Res
DOI: 10.1016/j.envres.2021.111643
sha: 05a43a1be98c30e4404ff7202433f2c5c1bbf5ce
doc_id: 970216
cord_uid: uq52tcyl

The pandemic of coronavirus disease 2019 (COVID-19) still remains on an upsurge trend. The second wave of this disease has led to panic in many countries, including India and some parts of the world suffering from the third wave. As there are no proper treatment options or remedies available for this deadly infection, supportive care equipment's such as oxygen cylinders, ventilators and heavy use of steroids play a vital role in the management of COVID-19. In the midst of this pandemic, the COVID-19 patients are acquiring secondary infections such as mucormycosis also known as black fungus disease. Mucormycosis is a serious, but rare opportunistic fungal infection that spreads rapidly, and hence prompt diagnosis and treatment are necessary to avoid high rate of mortality and morbidity rates. Mucormycosis is caused by the inhalation of its filamentous (hyphal form) fungi especially in the patients who are immunosuppressed. Recent studies have documented alarming number of COVID-19 patients with mucormycosis infection. Most of these patients had diabetes and were administered steroids for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and were consequently more prone to mucormycosis. Hence, the present review emphasizes mucormycosis and its related conditions, its mechanism in normal and COVID-19 affected individuals, influencing factors and challenges to overcome this black mold infection. Early identification and further investigation of this fungus will significantly reduce the severity of the disease and mortality rate in COVID-19 affected patients.

levels to spike, which is challenging for patients with uncontrolled diabetes and the acidic environment due to this condition favors the fungal (Mucorales) growth. Inhalation of filamentous fungi by patients weakens the immune defense pathways. Mucormycosis has also been associated with various underlying conditions that predispose an individual to the infection. Hospitals around the country continue to report a growing trend of mucormycosis cases in COVID-19 patients and this disease has been declared as an epidemic. Hence, the aim of the present review emphasises the history of mucormycosis, its related diseases, its process in normal individuals, immunecompromised and COVID-19 affected subjects, the various risk factors and its effect on multiple organs and challenges to overcome this infection. With increasing pressure on healthcare infrastructure during the COVID-19 pandemic, this review will provide a general evidence base for optimal treatment outcomes and prevention from this fungal infection.

Mucormycosis (also called zygomycosis) is a serious but rare fungal infection caused by a group of molds called mucormycetes. Mucormycosis, or the deadly black fungus, is a lifethreatening fungal infection caused by fungi that belongs to the subphylum Mucoromycotina and order Mucorales (Chegini et al., 2020; Chibucos et al., 2016) . Mucorales fungi are the most common fungi found in haematological malignancies, haematopoietic stem cell transplantation and solid organ transplantation after Aspergillus (Jeong et al., 2019) . Eleven genus and ~27 species under the order Mucorales cause mucormycosis (Gomes et al., 2011) . Among the predominant genera that cause mucormycosis, Rhizopus is the most common followed by Mucor and Lichtheimia. Mucorales are generally found in soil, decaying food, manure and dust (Asghar et al., 2019; Chakrabarti et al., 2009 Chakrabarti et al., , 2006 Chow et al., 2015; Reid et al., 2020) . Mucormycosis was initially described in 1855, as this was the first authentic human case of this condition (Küchenmeister, 1855) . In 1876, pulmonary mucormycosis was discovered by Furbringer in Germany in a cancer patient who presented with a hemorrhagic infarct in the right lung that consisted of fungal hyphae and spores (Furbringer, 1876) . Mucormycosis was first seen in an autopsy in the year 1956 (Baker, 1956) . The main mode of infection of mucormycosis is through the inhalation of spores, consumption of contaminated food and inoculation of the fungi into abrasions or cuts on the skin (Chibucos et al., 2016; Gomes et al., 2011; Jeong et al., 2019; Prakash and Chakrabarti, 2019; Reid et al., 2020) . In addition, outbreaks of mucormycosis have also been linked to contamination of medical devices, ventilation systems and hospital disposables like bandages, hospital linen etc. (Rammaert et al., 2012) . Mucormycosis mostly infects immunocompromised individuals whose immune system lacks the ability to mitigate the fungi. It is mainly diagnosed by laboratory analysis of the biopsy isolated from the site of infection. In addition, other imaging tests like CT are also beneficial for diagnosis (Prakash and Chakrabarti, 2019) . This condition can be classified into six forms namely rhino-orbital cerebral mucormycosis (ROCM), pulmonary, cutaneous, gastrointestinal, disseminated and uncommon sites based on the location of their occurrence. Among them, ROCM is the most commonly occurring one. Among the species that cause mucormycosis, the Rhizopus species was linked with ROCM. At the same time Cunninghamella was found in the pulmonary or disseminated form, while Apophysomyces and Saksenaea were seen in the cutaneous type (Jeong et al., 2019) . The most common sites of infection are sinuses (39%), lungs (24%), disseminated (23%); and skin and soft tissue infection (19%) (Reid et al., 2020) . The fungi begin by invading the blood vessels, which results in thrombosis and infarction of the tissue. When the spores of the fungus, comes in contact with the endothelial cells, angioinvasion occurs. More interaction with the receptors of these cells results in cell damage and fungal spread (Spellberg et al., 2005) . In healthy people, the fungi often get eradicated by the polymorphonuclear phagocytes. Hence fungal growth is usually present in individuals with defects in this mechanism. In addition, Mucorales are sometimes resistant to these mechanisms making them more virulent (Chamilos et al., 2008; Ibrahim and Kontoyiannis, 2013; Kontoyiannis and Lewis, 2006) . Despite the increase in mucormycosis, the prevalence data is not completely compiled due to the lack of population-based studies (Skiada et al., 2020) . In a study comprising of 600 articles, it was found that majority of mucormycosis occurred in Europe (34%), followed by Asia (31%), North or South America (28%), Africa (3%), Australia and New Zealand (3%) (Jeong et al., 2019) . The Leading International Fungal Education (LIFE) estimates 10,000 cases globally, excluding India, and this number increased to 9,10,000 after including the data from India (Prakash and Chakrabarti, 2019) . In India, the prevalence was 0.14 cases per 1000 population, astoundingly higher than in developed countries (Skiada et al., 2020) . The estimation of mucormycosis in countries around the world is illustrated in Figure 1 . In most cases, unless surgery and antifungal therapy are administered promptly, the condition deteriorates rapidly leading to death. The mortality rate was 54% in this condition and vastly depends on the site of infection, underlying comorbidities and type of fungus. The mortality rate was the highest for individuals with disseminated mucormycosis (96%), followed by pulmonary (76%) and sinus (46%) infections (Roden et al., 2005) . The extremely high mortality rate, negative effects of surgery and lack of therapeutic options makes it vital to develop early diagnostic and prevention strategies (Chibucos et al., 2016) .

Mucormycosis has been associated with various underlying conditions that predispose an individual to the infection. Some of these factors include diabetes, neutropenia, organ or stem cell transplantation, trauma and burns, hematological disorders, steroidal use, metabolic acidosis, intravenous drug usage, renal insufficiency, broad-spectrum antibiotics, increase in iron in the system, malnutrition, usage of voriconazole ( Figure 2 ) (Dantas et al., 2021; Sarvestani et al., 2013; Shariati et al., 2020; Suganya et al., 2019) . A previous study from Europe (Skiada et al., 2011) showed that, the most significant underlying causes were hematological malignancies, while it was diabetes mellitus in India (Chakrabarti et al., 2009) , Iran (Dolatabadi et al., 2018) , Middle East, North Africa (Stemler et al., 2020) and Mexico (Corzo-León et al., 2018) . Among the different forms of mucormycosis, ROCM has been concomitant with the presence of diabetes. The cutaneous form was more prominent in individuals with trauma, and organ transplant was related to the pulmonary, gastrointestinal and disseminated type. In addition, underlying hematological malignancies were present in disseminated type and neutropenia in the pulmonary form (Jeong et al., 2019) . Mucormycosis occurs mainly in individuals with uncontrolled diabetes, and this is because the innate immunity in these individuals, impacts the polymorphonuclear phagocytes to destroy the fungi. In patients with diabetes, the sinus was the most affected area followed by the pulmonary areas (Rammaert et al., 2012) . Individuals with hematological malignancies were also predisposed to mucormycosis during the neutropenia phase of the ailment. The presence of mucormycosis in hematological malignancies can be attributed to chemotherapy and the usage of voriconazole used in the treatment of aspergillosis (Shadrivova et al., 2019) . Mucormycosis was also more common in patients with acute leukemia than other types of malignancies. The main modes of prevention of mucormycosis in patients with hematological malignancies include avoidance of environmental exposures and the treatment strategies were surgery, antifungal treatment and reversal of neutropenia (Pagano et al., 1997) . Transplantation therapies have also been diagnosed as risk factors for mucormycosis. However, the incidence of the condition varies based on the type of organs that are being transplanted. Since recipients of transplantation therapies are administered immunosuppressants and high doses of steroids, it makes them more vulnerable to mucormycosis (Almyroudis et al., 2006) . In addition, corticosteroids also suppress macrophages and neutrophils inhibiting the ability of the body to fight the infection (Mcnulty, 1982) . Steroid administered individuals also fall under the high-risk category. Stem cell therapy patients are also treated with voriconazole which influences the occurrence of mucormycosis when used prophylactically (Lionakis et al., 2018) . Another factor contributing to mucormycosis is iron overload and deferoxamine therapy, which is being used to treat patients with diabetic ketoacidosis, haemodialysis and renal failure. However, this deferoxamine therapy makes the patients more likely to develop mucormycosis. The iron that is removed by the drug is used by the fungi to grow making a favorable condition for its development (Boelaert et al., 1991) . Interestingly, mucormycosis is not just observed in patients with comorbid conditions, and it can also be seen in individuals after surgery, probably after using contaminated products (Jeong et al., 2019) . A detailed explanation regarding various studies related to mucormycosis and its clinical studies is provided in Table 1 . Since invasive mucormycosis is also predominant in clinical settings, it is imperative to maintain a sterile environment that is safe for patients. In addition, care should be taken while assisting patients with chronic conditions in clinical settings to prevent the onset of mucormycosis.

Mucormycosis is caused by the inhalation of its filamentous (hyphal form) fungi, especially in patients who have undergone weakness in the arsenal of immune defense. The characteristic phenotype of this disease is the growth of hyphae in and around the blood vessels, leading to lifethreatening scenarios in severely immunocompromised patients. Once the fungal spores invade the human system, the hyphae intrude on the blood vessels, resulting in tissue infarction, necrosis and thrombosis. Mucormycosis occurs in the host by two steps: 1) by evading the immune system and surviving inside the host cell, 2) perturbation of the immune system further damaging the host cell (Brunke et al., 2016) . In immunocompromised patients, iron is abundantly released via sequestering proteins which creates a favorable environment for the growth of fungi inside the human body. Also, Mucorales fungi consume iron using high-affinity iron permease and transport iron to development inside the host cell (Artis et al., 1982) . The virulence factors of the pathogen play a key role to accomplish the damage. Spore coat (CotH) protein which is present on the spore surface of the Mucorales is responsible for penetrating, disrupting and damaging the immune cells (Gebremariam et al., 2014) . The epithelial cells are the first line of contact to fungal pathogens, especially the mucoralean fungi damaging the epithelial cell via increased signaling of plateletderived growth factor receptor B (PDGFRB) provides the proper growth factors to the fungi. The neutrophils are the first line of defense against these fungi, as these are an important part of the innate immune system and regulate the adaptive immune system (Jaillon et al., 2013) . In diabetic or steroid use patients due to ketoacidosis or hyperglycemic conditions, the chemotactic factors released by neutrophils decrease thereby increasing the fungal hyphae in human hosts (Roilides et al., 2012) . The Mucorales, after entering the host cell produces Mucorales-specific T-cells which generates interleukins (IL-4, IL-10 and IL-17) and IFN-γ. These pro-inflammatory cytokines further stimulate CD4+ T cells and damage the host cell (Castillo et al., 2018; Potenza et al., 2011) . Also, the fungal hyphae reduce the release of various immunomodulatory molecules such as RANTES (regulated upon activation, normal T-cell expressed and secreted) and IFN-γ, which are secreted by NK cells which appears in the early stage of infection (Schmidt et al., 2016 (Schmidt et al., , 2013 . These key findings explain the susceptibility of immunocompromised patients to mucormycosis and its possible mechanism of action inside the host cell ( Figure 3A ).

The advent of COVID-19 has sprung upon the world myriad of conditions and complications (Balachandar et al., 2020a; Iyer et al., 2020; Mahalaxmi et al., 2021) . Mucormycosis is an another milestone added in COVID-19, that has emerged as a deadly complication associated with COVID-19. In March 2021, 41 cases of COVID-19 associated mucormycosis has been reported worldwide and 70% were from India. There is a surge in these cases amidst the second wave in India (Monica Slavin and Karin Thursky, 2021) . There have been 2,245 cases and 120 deaths from the infection in Maharashtra state (Barnagarwala, 2021). As of June 5, 2021, Rajasthan reported 2,651 cases and 85 deaths (Mukherjee, 2021) and Telangana reports around 50 cases daily (Ali, 2021) . In Tamil Nadu, till June 9, 2021, total mucormycosis reported being to be 1,196 (Josephine, 2021) . The mucormycosis stemming from COVID-19 patients has been more commonly observed in patients with a history of diabetes mellitus and 95% of individuals with severe or critical COVID-19 (Alekseyev et al., 2021; John et al., 2021) . In addition to this, a two month old heart transplant patient developed mucormycosis three months after the COVID-19 diagnosis. This was of the cutaneous type as the old intravascular device location and despite aggressive treatment, the patient had died (Khatri et al., 2021) . This evidence indicates that transplant patients need more vigilant care in the clinical setting while managing COVID-19 as these patients are already predisposed to mucormycosis ( Figure 4 ). Similarly, a patient with acute myeloid leukemia (AML) also suffered mucormycosis after the COVID-19 infection (Zurl et al., 2021) . Although these factors such as diabetes, organ transplantation and hematological factors are commonly linked to mucormycosis, it is evident that COVID-19 infection also acts as a trigger in these situations. In addition, it has also been observed that people with no history of any underlying condition can also be diagnosed with mucormycosis post-COVID-19 infection (Maini et al., 2021) . There are many plausible explanations for the occurrence of mucormycosis post-COVID-19 infection. COVID-19 patients exhibit a wide array of pulmonary changes Vishnupriya et al., 2021) which may be a focal point for fungal initiation. Moreover, COVID-19 is also associated with immune dysfunction (Renu et al., 2020) preventing the polymorphonuclear phagocytes from attacking the fungal spores upon entry . Patients with severe COVID-19 also require a prolonged hospital stay and mechanical ventilation (Balachandar et al., 2020b) ; the occurrence of fungal spores in this equipment could also contribute to mucormycosis in these individuals (Khatri et al., 2021) . The immunosuppressants and corticosteroid medications that are warranted in COVID-19 can contribute significantly to the occurrence of mucormycosis (Khatri et al., 2021) . Further, in addition to hyperglycemia, COVID-19 also contributes to changes in iron metabolism. High ferritin levels have been observed in COVID-19, the high iron concentrations release reactive oxygen species while damaging the nearby tissue. The cytokines released during COVID-19 further increases intracellular iron and leakage of iron into the circulation, posing as a risk factor for the development of mucormycosis (John et al., 2021) . Although the diagnosis of mucormycosis is mainly made by observing fungus in biopsies and culturing the tissue (Johnson et al., 2021) , waiting for the cultures in the dire COVID-19 situation may be impractical as the progression of mucormycosis is speedy (Dallalzadeh et al., 2021) . Also, other therapeutic options besides reversal of underlying cause must be implemented as the reversal of these conditions may not be possible while treatment is ongoing for COVID-19. This is especially true due to the need to use high doses of steroids for the treatment of COVID-19 (Moorthy et al., 2021; Sharma et al., 2021) . In this condition, it is evident that the use of antibiotics and steroids may be dangerous for some patients as they may trigger the onset of these life-threatening fungal infections. It is extremely important for the doctors treating patients with COVID-19 to be mindful of patients with underlying illnesses and prescribed steroids or immunosuppressants (Sarkar et al., 2021) . Despite the tremendous burden on the healthcare system due to the overwhelming increase in cases, more vigilance is required in utilizing preventive measures for this condition (Kanwar et al., 2021) . Also, it is important to periodically check the air in the hospital wards and the oxygen therapy machinery for spores (Suryanarayanan and Shaanker, 2021 ). In addition, recovered patients should also be advised to stay indoors for few weeks to build up their immunity and follow-up studies to prevent any adverse complications. Since it's important that care should be taken in disposal of solid waste of COVID-19 patients, similar measures must be undertaken for individuals with the infection (Iyer et al., 2021) . Moreover, there is an urgent need to develop prompt diagnostic measures to manage mucormycosis in time (Veisi et al., 2021) . The proper management of mucormycosis must be prioritized to prevent more COVID-19 related deaths.

The symptoms of COVID-19 includes a rise in body temperature, osmolarity, hypoxia and breathlessness (Balachandar et al., 2020a) . The COVID-19 recovered patients of late have been distressed with a new infection called mucormycosis disease. This fungal disease could easily invade the sinus and lungs, making its way to intra-orbital and intracranial regions of the body (Sundaram et al., 2014) . The main symptoms of COVID-19 create a perfect environment for the growth and development of Mucorales inside the human body. Hosts susceptible to mucormycosis include diabetics, those on systemic corticosteroid use, patients with neutropenia and hematologic malignancies, stem cell transplant patients and immunocompromised individuals (Binder et al., 2014) . Reports suggest that diabetic patients are more prone to acquire COVID-19 accompanied by mucormycosis infection (Mehta and Pandey., 2020; Mekonnen et al., 2021; Ahmadikia et al., 2021; Alekseyev et al., 2021; Ravani et al., 2021; Garg et al., 2021) . The potential mechanism by which diabetes increases COVID-19 morbidity, and mortality is a) reduced viral clearance, b) decrease in T-cell function, c) high cytokine storm, d) immune-suppression (Balachandar et al., 2020b) . Hyperglycemia worsens the cytokine storm by disrupting endothelial cells leading to multi-organ damage in COVID-19 patients. During diabetic ketoacidosis, the acidic environment and increase in the levels of free ferric ions support the growth of Mucorales. These circumstances support the invasion and successful attachment of the hyphae from the Mucorales inside the body. Individuals with chronic diabetes accompanied with foot ulcers are prone to this infection as any injured skin tissue is an easy entry route for this fungus. Further, treatment for COVID-19 is still preliminary (Kar et al., 2020; Kinoshita et al., 2021) , and to combat the effect of SARS-CoV-2 infection, patients are given heavy doses of steroids (corticosteroids), as it reduces the inflammation in the lungs and might also curb the damages that had happened in the body due to the cytokine storm. Meanwhile patients affected with this new strain of COVID-19 are mostly treated with heavy steroids, extreme use of oxygen masks and ventilators which makes these patients more susceptible to mucormycosis. Steroids reduce both inflammation and the activity of the immune system, where the production of white blood cells (WBCs) and T-helper cells are decreased, making it easy for any foreign substances to invade and completely corrode the immune system in the host cell. Also, these steroids could trigger the uncontrolled release of sugar, which also enables the Mucorales to grow, multiply and invade at a rapid rate ("What patients with diabetes, cancer and kidney disorders need to know about black fungus," 2021). Only a few case reports have been published regarding the impact of mucormycosis on COVID-19 affected patients (Table 2) . Hence, these possible mechanisms have been listed based on the points and suggestions provided by various doctors and researchers ( Figure 3B ), where the above-explained reasons may be potential factors for the occurrence of mucormycosis among COVID-19 recovered or infected patients.

Mucormycosis is an invasive infection caused by naturally occurring fungus in the soil and human beings get infected by inhaling the spores floating in the air. These spores get lodged in the nasal passages and sinuses and cause the disease. Black Fungus is a rare fungal infection and is primarily contracted in the Intensive Care Unit (ICU) of a hospital and can be fatal, causing loss of vision and even death. Earlier symptoms include greyish-black pigmentation in the nose or oral cavity and blockage of the nasal cavity. Spores of fungus near the eyes leads to ocular swelling, and a few patients may get lesions over the cheeks. At a later stage, this fungus can make its way to the brain. It is quite severe, and the fatality rate can go up to 50%. Treatments include antifungal drugs like amphotericin-B that are given intravenously and supportive therapy.

Healthcare workers and ICU technicians should be educated to change flow meters frequently and to sterilize oxygen tubing. Besides alveolar damage with severe inflammatory exudation, COVID-19 patients always have immunosuppression with decreased CD4 + T and CD8 + T cells . Critically ill patients, especially the patients admitted to the ICU with mechanical ventilation or who had a longer duration of hospital stay, are more likely to develop fungal coinfections . The symptoms of mucormycosis includes infection that can vary from person to person, these symptoms include headache, fever, facial, nasal pain, blackish nasal discharge, loss of vision, toothache (Loss of teeth, swelling in the upper jaw) and paralysis. Unless treated, this infection can cross the central nervous system (CNS) and become a lifethreatening disease. Early diagnosis can be lifesaving, but the infections can be extremely challenging to treat, even at an early stage. These patients are treated with amphotericin-B injections, but these drugs can induce substantial side effects, including kidney damage. In less severe cases, endoscopy has been inserted into the nasal cavity to remove the fungus. In the severe spread of infections, the surgeon will remove the infected part. Earlier identifications of fungal co-infections can significantly reduce the mortality rate.

Mucormycosis can frequently infect the sinuses, brain or lungs but it has been said that it can also the impact on oral cavity, gastrointestinal tract, skin and other organs. The infection of mucormycosis could result in the following outcomes in different organs 1) when infected in the sinusitis, it blocks the nasal cavity leading to blackish or bloody discharge; 2) Face-local pain on cheekbone, one-sided facial pain or numbness; 3) Oral cavity-loosening of teeth or jaw; 4) Eyeblurred/double vision, vision loss; 5) Skin-thrombosis or necrotic skin lesion; 6) Lungs-chest pain, worsening of respiratory symptoms. However, in COVID-19 affected patients, mostly it affects the eye, oral region and brain.

The mucormycosis infection classically starts its journey inside the human body in the nasal or maxillary sinus and spreads to sphenoid or ethmoid sinus. After which it intrudes the orbit via ethmoid foramina or nasolacrimal duct or by splitting lamina papyracea (Sundaram et al., 2014; Teixeira et al., 2013) . The lesion in the eye occurs due to the angioinvasion of the germinated hyphae resulting in dry gangrene. Whereas when the angioinvasion occurs via cavernous sinus thrombosis/ internal carotid artery results in cerebral infarction, mycotic abscesses or aneurysms and haematogenous dissemination (Ochiai et al., 1993; Sundaram et al., 2014) . When the blood vessel necrosis occurs in the ophthalmic artery it might lead to blindness, cranial nerve palsies and other motor and sensory deficits.

Mucormycosis occurs in the oral cavity mainly due to spread of spores through inhalation, open oral wounds, ulceration or an extraction socket in the mouth, particularly in the patients who are immune-compromised (Rajashri et al., 2020) . Diagnosis can be made based on the appearance of necrotic lesions in the form of pressure sores in the orbital-nasal region, the palate or the floor of the mouth. The infection of mucormycosis especially in the maxillofacial regions spreads to regions such as the oral cavity, maxilla, palate, nose, paranasal sinuses and finally into CNS (Bakathir, 2006) . Angioinvasion of Mucorales and its spores into the blood vessels leads to the thrombus formation, which causes progressive necrosis of associated hard and soft tissues.

The manifestation of mucormycosis in the CNS mainly questions the survival rate and proper functioning of the organs in the infected individual. After the entry of the fungus, the invasion occurs either via hematogenous spread or by direct cranial dispersion from the paranasal sinuses. Patients who have diabetes mellitus as a major co-morbidity for mucormycosis, the CNS becomes the third most common site of infection (Bannykh et al., 2018; Higo et al., 2015) . The fungal hypha develops in the internal elastic lamina and spreads to the arterial lumen, eradicating intravascular thrombosis. Vascular occlusion leading to cerebral infarction and hemorrhagic necrosis, even before hyphal invasion in brain tissue (Economides et al., 2017) . Hyphal invasion of the necrotic brain parenchyma occurs in advanced CNS mucormycosis and might lead to death (Malik et al., 2014) . Hence, the growing piece of evidence shows that it is important to have options open to diagnose this disease in different dimensions. It has several sites of infection mainly attacking the immune system and causing infection in individuals.

Mucormycosis is a fungal infection with a high mortality rate of 50 percent. An increasing number of COVID-19 patients have been developing this infection while still at the hospital or after discharge. Patients hospitalized for COVID-19 and particularly those who require oxygen therapy during COVID-19 illness are at a much higher risk of mucormycosis. Inhalation of Mucor spores by patients with a compromised immune system will lead to colonization of the fungus, invasion of the host and development of mucormycosis. Individuals with uncontrolled diabetes are at a higher risk of mucormycosis because the high blood sugar levels make it easier for the fungi to grow and survive. Their weaker immune systems offers less protection against the infection. Hot and humid conditions, oxygen, humidifiers and oxygen delivery masks may contribute to the spread of infection. Delay in diagnosis and treatment can make the impact of this fungal infection deadlier.

COVID-19 has put the entire world in turmoil situation, and an exact cure for this deadly infection has not been found yet. Its an infection, the consequential immunosuppression, former co-morbidities and its medications have made the patients susceptible to secondary fungal infections such as Mucormycosis. This is an opportunistic fungal infection that is caused due to mucor hyphae that are commonly available in soil, plants, dungs, rotting fruits and vegetables. The COVID-19 affected patients who are more susceptible to these infections are immunocompromised, have diabetes, and are prescribed heavy steroids. As mucormycosis is angioinvasive, once inhaled, its spores begin to grow, and the fungal hyphae invade the blood vessels, further contributing to tissue infarction, necrosis and thrombosis. This fungal infection is life-threatening as it occurs among those who have immunosuppression accompanied with diabetic ketoacidosis, neutropenia, increased serum levels of iron, excess release of sugar due to overtake of steroids which finally results in a decrease in levels of WBCs, T-cells and other immunomodulatory cells and triggers the cytokine storm that damages the cellular organs. Therefore, researchers and healthcare professionals should promptly control this mucormycosis infection by understanding its influence and range of severity, especially on COVID-19 patients. A multidisciplinary approach should include prompt diagnosis, treatment with antifungals, any appropriate surgical consultation and treatment, which may reverse the underlying condition. Additional research in this area is recommended to investigate the mucormycosis in COVID-19 infected and recovered patients. Hence vigorous investigations to emphasize the root cause of mucormycosis, specifically in COVID-19, should be under the scope of research. A diagnostic study for this opportunistic pathogen should not be ignored in case the patient is COVID-19 positive and immunosuppressed.

The authors declare that they have no known competing interests or personal relationships that could have appeared to influence the work reported in this paper

The author Dr. VB would like to thank Bharathiar University and Mizoram University (DBT-Advanced State Biotech Hub)for providing the necessary infrastructure facility and the RUSA 2.0 BEICH Project (Bharathiar University) for providing necessary help in carrying out this review process of the manuscript.

This work was supported by the Project funded by MHRD-RUSA 2.0 -BEICH (Dr.VB).

Abdolalizadeh, P., Kashkouli, M.B., Khademi, B., Karimi, N., Hamami, P., Es' haghi, A., 2020. Diabetic versus non-diabetic rhino-orbito-cerebral mucormycosis. Mycoses 63, 573-578. Abela, L., Toelle, S.P., Hackenberg, A., Scheer, I., Güngör, T., Plecko, B., 2013. Fatal outcome of rhino-orbital-cerebral mucormycosis due to bilateral internal carotid occlusion in a child after hematopoietic stem cell transplantation. The Pediatric infectious disease journal 32, 1149-1150. Medications like voriconazole, broad-spectrum antibiotics and steroids are also known to predispose an individual to mucormycosis. In addition, an increase in iron levels in the circulation, neutropenia and immunosuppressant treatments like stem cell therapy and organ transplant make individuals more vulnerable to the condition. Exposure to spores through cuts and burns on the skin and intravenous drug usage are also risk factors for mucormycosis.

When the Mucorales enters an immune-compromised patient through inhalation , or through wounds, it is initially gets attached to the epithelial cells receptor using its CotH receptors. Further, the PDGFRB signalling pathways provides essentials for the proper development and growth of the fungal hyphae. Also, if the patients have diabetes, ketoacidosis and hyperglycaemia damage the neutrophils, making it easy for the fungi spread. Once the fungi are developed it starts to produce Mucorales-specific T cells which has various pro-inflammatory cells such as IL-4, IL-10, IL-17, IFN-γ, which triggers the cytokine storm resulting into cellular damages.

Mucormycosis is becoming common among COVID-19 patients, especially due to physiological stressors such as high body temperature osmolarity, hypoxia which are common conditions when affected with SARS-CoV-2. Also, these patients undergo heavy intake of steroids, use oxygen masks and ventilators to combat SARS-CoV-2 infection, which turns as an entry pass to the body for the Mucorales fungus. Further, this fungal infection could impact the COVID-19 in two-way scenario: 1) when the COVID-19 patients who have diabetes as comorbidity, create an acidic environment that enables a unique environment for these fungi to grow. Also, due to hyperglycaemia, there is a decrease production of T-cells and immunosuppression, resulting in a cytokine storms. 2) heavy intake of steroids also release a huge amount of sugar which helps in the rapid multiplication and growth of fungal hyphae. Also, steroids tend to inflammation the immune cells leading to cytokine storm and damage to cellular organs.

A COVID-19 infected patient may be more susceptible to mucormycosis because, of a dysregulated immune system and may receive immune suppressant drugs that prevent the phagocytic cells in the body from attacking the fungus at an optimum level. COVID-19 also increases iron in the circulation and the fungus uses this iron to grow and proliferate and making the individual more vulnerable to infection. COVID-19 infected individuals are often given oxygen therapy. Contamination in these devices can serve as points of mucormycosis infection. The steroid therapy offered to COVID-19 patients places them at further risk for this condition.  Partial opacification of the right sphenoid sinus and erosions of the lamina papyracea was observed.  Clinical and radiographic findings noticed with fungal rhinosinusitis. The right eye had mild proptosis with erythema and edema of the eyelids and conjunctival chemosis  Co-infection COVID-19 and Rhizopus. These diseases share risk factors, have high mortality rates, but presently have contradictory management principles.

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The authors declare they have no conflict of interest.J o u r n a l P r e -p r o o f

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:J o u r n a l P r e -p r o o f