The “Black Fungus” in India: The Emerging Syndemic of COVID-19–Associated Mucormycosis
Authors: Sumanth Gandra, Sanjay Ram, Stuart M. Levitz
Journal: Annals of Internal Medicine (2021)

Ideas and Opinions8 June 2021The “Black Fungus” in India: The Emerging Syndemic of COVID-19–Associated MucormycosisFREESumanth Gandra, MD, MPH, Sanjay Ram, MBBS,andStuart M. Levitz, MDSumanth Gandra, MD, MPHWashington University School of Medicine, Saint Louis, Missouri (S.G.)Search for more papers by this author, Sanjay Ram, MBBSUniversity of Massachusetts Medical School, Worcester, Massachusetts (S.R., S.M.L.).Search for more papers by this author,andStuart M. Levitz, MDUniversity of Massachusetts Medical School, Worcester, Massachusetts (S.R., S.M.L.).Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M21-2354 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Mucormycosis is a rare disease caused by fungi of the order Mucorales (1). The agents of mucormycosis are ubiquitous environmental molds found in soil and decaying organic matter; exposure to airborne spores is commonplace, yet disease is very rare. In a susceptible person, spores germinate into hyphae, which then invade surrounding tissue, including blood vessels, resulting in hemorrhagic infarction. The name “black fungus” given to mucormycosis in news reports refers to the dark, necrotic tissue seen in people afflicted by this disease. Major risk factors for mucormycosis include poorly controlled diabetes mellitus and immunosuppression due to hematologic cancer or receipt of immunosuppressive chemotherapy including corticosteroids. The 2 most common clinical syndromes are rhino-orbito-cerebral and pulmonary mucormycosis. The rhino-orbito-cerebral form generally begins in the sinuses and progresses over several days to involve contiguous structures, which can result in facial disfigurement, cranial nerve palsies, blindness, and brain invasion. Treatment requires aggressive surgical debridement and antifungal agents. The drug of choice for initial treatment is amphotericin B, preferably as a lipid formulation. Fluconazole and voriconazole have no activity against the causative fungi. Mortality is high, especially if diagnosis and prompt initiation of medical and surgical therapy are delayed.India has more than 65 million adults with diabetes (2). A survey of 13 055 blood samples in 4 states in India revealed a weighted prevalence of diabetes and prediabetes that ranged from 5.3% to 13.6% and from 8.1% to 14.6%, respectively (3). The prevalence of diabetes was higher in urban than in rural areas. In all 4 states surveyed, rates of diabetes were highest among urban men in the 55- to 64-year-old age group (range, 25% to 45%). Rapid urbanization and an increasingly sedentary lifestyle are believed to contribute to the high prevalence of diabetes in India.India is experiencing a second wave of COVID-19, with 28.2 million cases reported as of this writing, although this is likely an underestimate; the true toll is estimated at more than 500 million cases (4). The unprecedented increase in COVID-19 cases during this second wave exposed the crippled health care system. Oxygen supplies have dwindled, hospitals have turned away patients because of a lack of beds, and shortages of critical medicines have occurred. In the midst of this crisis, a “syndemic” of rhino-orbito-cerebral mucormycosis infections has arisen, with nearly 9000 cases reported so far from several states in India (5). A syndemic recognizes the interactions between social and biological factors that result in more adverse disease outcomes (6). Compounding the crises are reported shortages of amphotericin B, the main drug used to treat mucormycosis. Although COVID-19–associated mucormycosis is not unique to India, emerging data indicate that the extraordinarily high prevalence is multifactorial, with contributions from poorly controlled diabetes, excessive use of corticosteroids and possibly antibiotics, and environmental exposure (7). The hot and humid environment in India likely promotes growth of Mucorales species.Based on the RECOVERY trial, dexamethasone at a dosage of 6 mg once a day for up to 10 days is recommended for hospitalized patients with COVID-19 who are receiving supplemental oxygen or mechanical ventilation (8). However, glucocorticoids have no benefit in patients who do not require respiratory support. Despite this, many patients with mild COVID-19 not requiring supplemental oxygen have been treated with glucocorticoids, sometimes with higher doses and longer durations than recommended in the RECOVERY trial. Corticosteroids predispose to mucormycosis by suppressing the immune system and by increasing blood glucose levels in persons with prediabetes and diabetes. More than 80% of patients with COVID-19–associated mucormycosis are reported to have had elevated blood glucose levels at presentation with fungal infection (7). Indeed, misuse of glucocorticoids and failure to adequately control elevated glucose levels appear to be the major contributing factors.Other possible contributing factors include shortages of oxygen and overuse of antibiotics. Although these effects are not proven, hypoxia may exacerbate damage of tissue partially infarcted by angioinvasion, and antibiotics may suppress normal bacterial flora, allowing fungi to become established in the sinuses. In India, antibiotics have been extensively used for mild and moderate COVID-19 cases despite their ineffectiveness. During the first wave of COVID-19, an estimated 216 million excess doses of all antibiotics and 6.2 million azithromycin treatment courses were attributed to COVID-19 (9).What can be done to curtail the ongoing syndemic of COVID-19–associated mucormycosis in India? First, nonpharmacologic measures, such as masking policies and social distancing, should be taken to reduce risk for transmission of SARS-CoV-2. Several states in India have imposed lockdowns, which is helping to reduce the spread of COVID-19. These nonpharmacologic measures have short-term benefits; the long-term solution involves vaccination. International efforts are under way and are much needed to replenish critical health care supplies and materials needed for vaccine manufacturing. Second, implementation of mitigation strategies is urgently needed to decrease the risk for mucormycosis in persons infected with SARS-CoV-2. The Indian Health Ministry recently issued evidence-based guidelines for appropriate mucormycosis management (10). Corticosteroids should be used only in situations in which there is evidence of their effectiveness, and then only at recommended doses and durations (8). Blood glucose levels must be closely monitored and controlled, particularly in patients who are known to be diabetic or are receiving corticosteroids. Antibiotics should be reserved for situations in which bacterial superinfections are suspected. People should avoid environments where exposure to Mucorales is likely to occur. Third, efforts must be undertaken to educate health care providers and the public about the signs and symptoms of mucormycosis because early aggressive surgical treatment and antifungal therapy improve outcomes. Regarding antifungal therapy, hospitals need to have adequate supplies of amphotericin B. The COVID-19 crisis has unmasked inequities and strained health care systems globally, particularly in low- and middle-income countries. The overuse of corticosteroids and antibiotics may have been an attempt to avoid hospitalizations because of the shortage of hospital beds and oxygen. Stronger restrictions on over-the-counter sales of systemic corticosteroids and antibiotics should be considered. Restrictions were issued for hydroxychloroquine in March 2020, which contributed to reduced hydroxychloroquine sales during the first wave of the pandemic (9). Finally, strengthening infrastructure and improving health care delivery systems are high priorities to forestall such crises.References1. Jeong W, Keighley C, Wolfe R, et al. The epidemiology and clinical manifestations of mucormycosis: a systematic review and meta-analysis of case reports. Clin Microbiol Infect. 2019;25:26-34.[PMID: 30036666] doi:10.1016/j.cmi.2018.07.011 CrossrefMedlineGoogle Scholar2. Nanditha A, Ma RC, Ramachandran A, et al. Diabetes in Asia and the Pacific: implications for the global epidemic. Diabetes Care. 2016;39:472-85. [PMID: 26908931] doi:10.2337/dc15-1536 CrossrefMedlineGoogle Scholar3. Anjana RM, Pradeepa R, Deepa M, et al; ICMR–INDIAB Collaborative Study Group. Prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in urban and rural India: phase I results of the Indian Council of Medical Research-INdia DIABetes (ICMR-INDIAB) study. Diabetologia. 2011;54:3022-7. [PMID: 21959957] doi:10.1007/s00125-011-2291-5 CrossrefMedlineGoogle Scholar4. Gamio L, Glanz J. Just how big could India's true Covid toll be? New York Times. 25 May 2021. Accessed at www.nytimes.com/interactive/2021/05/25/world/asia/india-covid-death-estimates.html on 25 May 2021. Google Scholar5. Biswas S. Black fungus: India reports nearly 9,000 cases of rare infection. BBC News. 23 May 2021. Accessed at www.bbc.com/news/world-asia-india-57217246 on 25 May 2021. Google Scholar6. Singer M, Bulled N, Ostrach B, et al. Syndemics and the biosocial conception of health. Lancet. 2017;389:941-950. [PMID: 28271845] doi:10.1016/S0140-6736(17)30003-X CrossrefMedlineGoogle Scholar7. Singh AK, Singh R, Joshi SR, et al. Mucormycosis in COVID-19: a systematic review of cases reported worldwide and in India. Diabetes Metab Syndr. 21 May 2021. [Epub ahead of print]. doi:10.1016/j.dsx.2021.05.019 Google Scholar8. Horby P, Lim WS, Emberson JR, et al; RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384:693-704. [PMID: 32678530] doi:10.1056/NEJMoa2021436 CrossrefMedlineGoogle Scholar9. Sulis G, Batomen B, Kotwani A, et al. Sales of antibiotics and hydroxychloroquine in India during the COVID-19 epidemic: an interrupted time series analysis. PLoS Med. 2021. [Forthcoming]. Google Scholar10. Ministry of Health and Family Welfare; Government of India. Evidence based advisory in the time of COVID-19: screening, diagnosis & management of mucormycosis. Accessed at www.icmr.gov.in/pdf/covid/techdoc/Mucormycosis_ADVISORY_FROM_ICMR_In_COVID19_time.pdf on 25 May 2021. Google Scholar Comments 0 Comments Sign In to Submit A Comment Shubhang Mazumdar MDEmory Hospital In Atlanta Ga7 June 2021 Follow Up on the article on Mucormycosis Excellent Narrative Of the etiology of Mucormycosis with Covid 19 cases in India. I agree steoids and antibiotics are randomly used in India without any scientific basis. Prasanta Raghab Mohapatra, Baijayantimala MishraAll India Institute of Medical Sciences, Bhubaneswar, India8 June 2021 Role of zinc to the Syndemic of COVID-19-Associated Mucormycosis (CAM) in India There has been an alarming rise of mucormycosis in patient with COVID-19 during second wave in India1. During the first wave, the rise of mucormycosis prevalence was nearly 2.1-fold when compared to pre-covid previous year in India2. Uncontrolled diabetes and use of prolonged and high doses corticosteroid are two well-known causes of mucormycosis in covid 19 patients2. However, but the reason of such huge number of Covid associated mucormycosis(CAM) cases during this second wave in India1 warrants further exploration of etiologies in order to tackle the threat from every possible aspect. Since COVID pandemic started during early 2020, zinc supplements have been commonly prescribed as an antiviral agent in a broader perspective, as already being used for such viral diseases like influenza and rhinovirus. In absence of any definitive anti-COVID drug, the zinc is widely used as a component of therapeutic or prophylactic regimen along with other vitamins popularly known as ‘immunity boosters’ for months together by thousands of COVID patients particularly in India.3,4 On the other hand, it is scientifically proven that zinc starvation inhibits microbial growth in tissues and zinc acts as key nutrition for fungal growth. Zinc deficiency induces biological stress in fungal cells and hinders the fungal growth by restricting the activity of zinc-binding proteins, which are mainly transcription factors involved in numerous biological processes.5. In vitro study, it has been seen that zinc chelator (zinc antidote) like clioquinol or phenanthroline or other zinc chelator inhibit the growth of this fungus. It means zinc deprivation inhibit the fungal growth. Not only this, it is difficult to grow this fungus in zinc deficient tissue.6 As we know the COVID-19 suppresses the body immune system of the host. In the background of diabetes and steroid use, causes further hyperglycemia and acidosis condition that have been attributed to impair the phagocytic function is a classic setting of ‘triple immune suppression’. We never thought zinc supplements might have severed as supportive fuel for the growth of fungus in the environment of multilevel immune suppressions. Therefore, excessive use of Zinc in almost all COVID patients might have played a significant contributing factor for rising CAM cases in India. Prasanta R Mohapatra, MD, FACP(USA), FRCP(London), FRCP (Glasg), FCCP(USA), Baijayantimala Mishra,. MD, FRCP(London), FRCP (Glasg), FIDSA AII India Institute of Medical Sciences, Bhubaneswar-751019, India References 1. Gandra S, Ram S, Levitz SM. The "Black Fungus" in India: The Emerging Syndemic of COVID-19-Associated Mucormycosis. Ann Intern Med. 2021 Jun 8. doi: 10.7326/M21-2354. Epub ahead of print. PMID: 34097436. 2. Patel A, Agarwal R, Rudramurthy SM, Shevkani M, Xess I, Sharma R, Savio J, Sethuraman N, Madan S, Shastri P, Thangaraju D, Marak R, Tadepalli K, Savaj P, Sunavala A, Gupta N, Singhal T, Muthu V, Chakrabarti A; MucoCovi Network3. Multicenter Epidemiologic Study of Coronavirus Disease-Associated Mucormycosis, India. Emerg Infect Dis. 2021 Jun 4;27(9). doi: 10.3201/eid2709.210934. Epub ahead of print. PMID: 34087089. 3. Oyagbemi AA, Ajibade TO, Aboua YG, et al. Potential health benefits of zinc supplementation for the management of COVID-19 pandemic. J Food Biochem. 2021 Feb;45(2):e13604. doi: 10.1111/jfbc.13604. Epub 2021 Jan 17. PMID: 33458853; PMCID: PMC7995057. 4. Bhaumik S, John O, Jha V. Low-value medical care in the pandemic-is this what the doctor ordered? Lancet Glob Health. 2021 Jun 2:S2214-109X(21)00252-7. doi: 10.1016/S2214-109X(21)00252-7. Epub ahead of print. PMID: 34089644. 5. Eide DJ. The oxidative stress of zinc deficiency. Metallomics. 2011 Nov;3(11):1124-9. doi: 10.1039/c1mt00064k. Epub 2011 Jul 26. PMID: 21789324. 6. Staats CC, Kmetzsch L, Schrank A, Vainstein MH. Fungal zinc metabolism and its connections to virulence. Front Cell Infect Microbiol. 2013 Oct 14;3:65. doi: 10.3389/fcimb.2013.00065. PMID: 24133658; PMCID: PMC3796257. Jay MehtaDistingushed professor, UAMS9 June 2021 Mucormycosis in CCOVID-19 patients The article by et al highlights the evolution and dangers of mucormycosis in patients with COVID-19. The authors state “Major risk factors for mucormycosis include poorly controlled diabetes mellitus and immunosuppression due to hematologic cancer or receipt of immunosuppressive chemotherapy including corticosteroids.” However, recent reports from Kerala in India suggest that these risk factors may not be the core risk factors, and many non-diabetics without immunosuppression may also be victims of this deadly disease. Regardless of the etiology, the physicians taking care of COVID-19 patients shole remain cognizant of this disease entity, and investigators should continue to identify most appropriate treatment/s. Sumanth Gandra, MD, MPH, Sanjay Ram, MBBS, Stuart M. Levitz, MDWashington University School of Medicine, University of Massachusetts Medical School29 October 2021 Authors' Response to Mehta We would like to thank Dr. Mehta for the comment. We are not aware of any published reports from State of Kerala in India or other publications from India indicating that there are other unique risk factors for mucormycosis in COVID-19 patients. We came across two published studies from State of Kerala reporting on 50 mucormycosis patients during second COVID-19 wave1, 2. In Thayyil et al. study1 which included 40 patients, 79% (31 patients) had diabetes mellitus and 65% (26 patients) received corticosteroids. In the second study by Arjun et al.2 which included 10 patients, all of them had diabetes mellitus and eight patients received corticosteroids. These findings indicate that the core risk factors for mucormycosis remain the same to date. A small minority of patients lack core risk factors and thus we need to remain vigilant as this is an emerging syndemic. References: Thayyil, Jayakrishnan, Amrutha Divakaran, and Navya Anikkady. "COVID-19 associated mucormycosis during the second wave of pandemic in South India. “International Journal of Research in Medical Sciences” 9.9 (2021): 1. Arjun, R., et al. "COVID-19-associated rhino-orbital mucormycosis: a single-centre experience of 10 cases." QJM: An International Journal of Medicine 1 (2021): 4. Author, Article, and Disclosure InformationAuthors: Sumanth Gandra, MD, MPH; Sanjay Ram, MBBS; Stuart M. Levitz, MDAffiliations: Washington University School of Medicine, Saint Louis, Missouri (S.G.)University of Massachusetts Medical School, Worcester, Massachusetts (S.R., S.M.L.).Disclosures: Authors have reported no disclosures of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M21-2354.Corresponding Author: Stuart M. Levitz, MD, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Room LRB317, Worcester, MA 01605; e-mail, stuart.levitz@umassmed.edu.Current Author Addresses: Dr. Gandra: 4523 Clayton Avenue, Campus Box 8051, Saint Louis, MO 63110.Dr. Ram: University of Massachusetts Medical School, Lazare Research Building, 3rd Floor, Room 322, 364 Plantation Street, Worcester, MA 01605.Dr. Levitz: Department of Medicine, 364 Plantation Street, Room LRB317, Worcester, MA 01605.Author Contributions: Administrative, technical, or logistic support: S.M. Levitz.Analysis and interpretation of the data: S. Gandra, S.M. Levitz, S. Ram.Collection and assembly of data: S. Gandra, S.M. Levitz, S. Ram.Conception and design: S. Gandra, S.M. Levitz, S. Ram.Critical revision for important intellectual content: S. Gandra, S.M. Levitz, S. Ram.Drafting of the article: S. Gandra, S.M. Levitz, S. Ram.Final approval of the article: S. Gandra, S.M. Levitz, S. Ram.This article was published at Annals.org on 8 June 2021. 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New Insights into Black Fungal Diversity Using the Long Cold Incubation MethodMucormycosis in Indian COVID-19 Patients: Insight into Its Patho-Genesis, Clinical Manifestation, and Management StrategiesEditorial: Immunity to Fungal Infections: Insights From the Innate Immune Recognition and Antifungal Effector MechanismsEmergence of a medley of invasive fungal infections amidst the coronavirus disease 2019 (COVID-19) pandemic in India September 2021Volume 174, Issue 9 Page: 1301-1302 Keywords Amphotericin Antibiotics Antifungals Blood COVID-19 Glucose Health care Health systems strengthening Oxygen Patients ePublished: 8 June 2021 Issue Published: September 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...