key: cord-0975419-kx7vdu4s authors: Ravindra, Khaiwal; Ahlawat, Ajit title: Five probable factors responsible for COVID-associated mucormycosis outbreak in India date: 2021-09-27 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.09.057 sha: 7f071b7d6723e073722df073a53d9fbcb22eaad0 doc_id: 975419 cord_uid: kx7vdu4s The second wave of COVID-19 due to Delta (B.1.617.2) variant led to the rapid rise of total coronavirus and COVID-associated mucormycosis cases reported from India. Hence, the current perspective explores the possible causes of rapid upsurge in COVID-associated mucormycosis cases, which was accounted for over 70% of global cases. The five most probable factors associated with the increase of mucormycosis in COVID-19 patients include diabetes mellitus, steroids overdose, high iron levels, immuno-suppression, combined with other possible factors such as unhygienic conditions, prolonged hospitalization, use of ventilators and leaky humidifiers in oxygen cylinders, creates an ideal environment for contracting mucormycosis. However, these cases could be brought down by disseminating simple preventive measures and creating awareness among the medical society and general public on this rare and deadly contagion of COVID-associated mucormycosis. The identification of the early symptoms will help to restrict the spread of lethal fungal diseases. Further, a collaborative team of surgeons, ophthalmologists, physicians, otolaryngologists specialists would be required in the hospital wards to proceed with quick surgeries on severely impacted patients. Abstract: The second wave of COVID-19 due to Delta (B.1.617.2) variant led to the rapid rise of total coronavirus and COVID-associated mucormycosis cases reported from India. Hence, the current perspective explores the possible causes of rapid upsurge in COVID-associated mucormycosis cases, which was accounted for over 70% of global cases. The five most probable factors associated with the increase of mucormycosis in COVID-19 patients include diabetes mellitus, steroids overdose, high iron levels, immuno-suppression, combined with other possible factors such as unhygienic conditions, prolonged hospitalization, use of ventilators and leaky humidifiers in oxygen cylinders, creates an ideal environment for contracting mucormycosis. However, these cases could be brought down by disseminating simple preventive measures and creating awareness among the medical society and general public on this rare and deadly contagion of COVID-associated mucormycosis. The identification of the early symptoms will help to restrict the spread of lethal fungal diseases. Further, a collaborative team of surgeons, ophthalmologists, physicians, otolaryngologists specialists would be required in the hospital wards to proceed with quick surgeries on severely impacted patients. Keywords: COVID-19, COVID-associated mucormycosis, diabetes mellitus, steroids overdose, awareness Perspective: India has faced a catastrophic COVID-19 second wave due to Delta (B.1.617.2) variant known to have a higher viral load. As of 1 st June 2021, the total reported cases in India contributed to the majority of worldwide cases, with a peak of over 0.4 million patients on 7 th May 2021. Since then, the daily new coronavirus cases are dropping in India, but the rapid rise in COVIDassociated mucormycosis (CAMCR) cases posed another challenge to the country's already burdened healthcare system (Raut and Huy, 2021 ) Mucormycosis (MCR), a.k.a black fungus, an invasive fungal infection generally caused by a group of opportunistic molds called mucormycetes, is a sporadic but life-threatening infection if handled ineffectively. As per previously published literature, the overall all-cause mortality rate in mucormycosis cases was found to be 54% (Roden et al., 2005) . The variation in mortality rate depends upon the patient's existing condition, type of fungus, and affected body parts (e.g., the death rate was found to be 46% among sinus infected patients, 76% contribution was for pulmonary-related infections, and a whopping 96% for disseminated mucormycosis) (Roden et al., 2005) . Within the ongoing COVID-19 second wave in India, a rapid upsurge in COVID-associated 4 mucormycosis cases was observed when compared to the first wave. The reasons behind the substantial rise during the second wave need proper investigation. India has reported approximately 14872 cases of mucormycosis as of 28 th May 2021 (Raut and Huy, 2021) . The Indian states, Maharashtra and Gujarat, contributed the most to mucormycosis cases in active and recovered coronavirus patients (Raut and Huy, 2021) . Within Maharashtra state, cities like Nagpur and Pune account for almost 33% of Maharashtra's mucormycosis cases. Multiple Indian states have already declared it as an epidemic after a surge in COVID-associated mucormycosis cases and deaths, such as Telangana, Karnataka, Bihar, Chhattisgarh, Madhya Pradesh, Rajasthan, Uttarakhand, Haryana and Delhi (Raut and Huy, 2021) . According to a new study, a total contribution of approx. 71% of worldwide mucormycosis cases in COVID-19 patients from December 2019 to April 2021 were from India (John et al., 2021) . The Indian Council of Medical Research (ICMR) has recently provided some important guidelines related to COVID-associated mucormycosis (ICMR, 2021) . However, there are a few missing points in the guidelines that should be included as soon as possible to protect against the deadly mucormycosis. For creating more awareness among the medical society and general public on this rare and fatal infection, we have provided details on probable factors causing COVIDassociated mucormycosis. The five most probable factors associated with the increase of mucormycosis in COVID-19 patients are described here. First, diabetes mellitus is the most common risk factor linked to an increase in mucormycosis in India (Singh et al., 2021) . Diabetes mellitus being the most common risk factor for mucormycosis worldwide, accounting for a 46% mortality rate (Jeong et al., 2019) . In 2018, a 5 meta-analysis consisting of 851 cases of mucormycosis was conducted. The presence of diabetes mellitus was indicated as an independent risk factor in the study (Statistics: odds ratio=2.69; 95% CI=1.77-3.54; P <0.001) (Jeong et al., 2019) . India ranked as second in overall contribution towards the world's total population with diabetes mellitus. In fact, in over 50% of mucormycosis cases in India, diabetes mellitus was significantly reported. In India's recently published study on mucormycosis, 57% of patients had uncontrolled diabetes mellitus and 18% had diabetic ketoacidosis (Prakash et al., 2019) . Second, the excessive intake of steroids. Since the recovery trial revealed that steroids reduced mortality in COVID-19 patients on oxygen or who required mechanical respiration, steroids have become widely used. Even patients who did not have hypoxia (low blood oxygen) or who did not require hospitalization were frequently given heavy doses of steroids. In most cases, people with black fungus had self-medicated themselves on unauthorized steroids after their oxygen concentration levels had dropped. The deadly combination of steroids and failed immune system due to COVID-19 had increased immune defense breach. Endothelialitis, which is seen during severe COVID-19, is another plausible description of the relationship between COVID-19 and mucormycosis (Ackermann et al., 2020) . Third, the unsanitary conditions could have increased the risk of developing mucormycosis infections. Patients received additional oxygen via an oxygen concentrator in their homes due to the unavailability of hospital beds during the mammoth COVID-19 second wave. In most oxygen concentrators, frequent use of distilled water for supplemental humidification is needed as the moisture source when using a refillable humidifier bottle. The distilled water may serve as 6 a potential source for pathogenic organisms such as bacteria and mold. Apart from that, there could be a lot of contamination in the pipes used for oxygen cylinders. The immuno-suppressed patient had a long-term stay in the intensive care unit on these pipes and oxygen cylinders, which could have increased the infection. Fourth, high ferritin levels could be associated with a rise in mucormycosis cases in India. The change in iron metabolism was found to occur in severe COVID-19 (Perricone et al., 2020) . Higher ferritin levels may lead to an increase in intracellular iron. This will result in the production of reactive oxygen species, which will cause tissue damage. In cases with strong infection, cytokines excite the synthesis of ferritin and downregulate the iron export, leading to the overloading of intracellular iron, thus aggravating the whole process (Edeas et al., 2020) . Excess-free iron is released as a result of tissue damage (Edeas et al., 2020) . The overloading of intracellular and excess free iron could be the unique risk factors for mucormycosis (Ibrahim et al., 2012) . In addition, for a rapid rise in mucormycosis, wide-scale shortages of Amphotericin B, the mainstay therapy for mucormycosis, are being reported. Fifth, poor indoor ventilation supports the prolonged airborne spread of fungal spores present in the air or around the surrounding environment.. A recent study validates mucormycosis infection from linens from a company supplying hospital linen with poor indoor ventilation, high humidity, and dusty conditions (Cheng et al., 2016) In a nutshell, diabetes mellitus, steroids overdose, high iron levels, immuno-suppression, combined with other possible factors such as unhygienic conditions, prolonged hospitalization, 7 use of ventilators and leaky humidifiers in oxygen cylinders, creates an ideal environment for contracting mucormycosis. Not to forget that patients infected with delta variant got severe immune suppression compromising the host response and increased the risk of developing further opportunistic infections, including those caused by molds, leading to a higher risk of adverse outcomes in the case of delayed diagnosis and inadequate treatment. To prevent mucormycosis transmission, it is suggested to use the treatment routines such as antifungal remedies and surgical debridement (Bala et al., 2015) . In a previously published study, it was found that surgery with medical treatment with amphotericin B appeared to be superior (odds ratio = 0.2, p < 0.04) than amphotericin B alone (61.5% vs. 10.3% patient survival) (Bala et al., 2015) . In addition, the focus should be to identify possible sources of mold indoors and mitigate them immediately. For such, the indoor air temperature and humidity checks should be performed regularly, specifically those days when humidity exceeds 60%, where there are increased chances of mold growth. The indoor temperature and humidity should be maintained at 24 o C and 40-60%, respectively, to minimize both the risk of mucormycosis as well as coronavirus infection (Ahlawat et al., 2020 a,b; Moriyama et al., 2020; Dabisch et al., 2021) . The air filters present in the air-conditioning systems should be changed in a timely manner (Hartnett et al., 2019) . In response to control the mucormycosis spread, the Indian government, along with the state government support, have quickly commenced actions to take over the situation. This was done by dispensing guidelines, making arrangements for separate rooms in hospitals to manage mucormycosis cases, and acquiring the essential drugs, i.e., amphotericin B (Raut and Huy, 8 2021). The Indian government and ICMR also need to consider the additional solutions provided in this letter for curbing the deadly mucormycosis on an immediate basis. Furthermore, disseminating information and providing key materials to the general public will supplement preventing an upsurge in mucormycosis cases in COVID-19 patients and mortality. Lastly, there is a need to create awareness about fungal diseases amongst clinicians and the public to identify the early symptoms and restrict the spread of lethal fungal diseases (Ravindra and Mor, 2021). 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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.Funding Source: None.Ethical Approval: Not required.