Abstract

The second wave of COVID-19 in early 2021 has caused havoc across the globe and despite a bit flattening curve of SARS-CoV-2 cases in India, another fatal complication known as CAM created chaos in the whole country. An alarmingly high increase in the number of cases led to the healthcare infrastructure inadequacy due to excessive demand for hospital beds, drugs, oxygen, and vaccines. The rhino-orbital-cerebral form is the most common clinical presentation observed. A complex interplay between uncontrolled blood glucose, unjudicial use of corticosteroids and SARS-CoV-2 infection has to an upsurge in CAM cases. The majority of these cases had diabetes as predisposing comorbidity and corticosteroids were administered to treat COVID-19. Probable pathologic mechanisms may involve immunological and inflammatory processes. Diabetes, together with COVID-19 induces systemic immunological alterations, leading to decreased immunity and an augmented risk of secondary infections. Prolonged use of high-dose corticosteroids acts as another risk factor for CAM. The hypoxic conditions in COVID-19, uncontrolled diabetes, steroid-induced hyperglycemia, DKA, and increased ferritin levels due to SARS-CoV-2 mediated immunosuppression provide a perfect environment for the Mucorales spores germination in these patients. The recommended treatment strategies mainly include surgical debridement and antifungal therapy using Amphotericin B and selected azoles. Several clinical guidelines focusing on Indian patients have been proposed for accurate diagnosis of infection, identifying clinical presentation, understanding the pathogenesis mechanisms, and tracking the disease course for rapid management of the disease.

• 1.   WHO. COVID-19 Weekly Epidemiological Update. May 25, 2021. https://www.who.int/ docs/defaultsource/coronaviruse/situation-reports/20210525_weekly_epi_update_41.pdf ?sfvrsn=d602902c_6&download=true (Accessed May 28, 2021).
• 2.   Hagen A.COVID-19-Associated Mucormycosis: Triple Threat of the Pandemic. American Society for Microbiology. July 15, 2021. https://asm.org/Articles/2021/July/COVID-19-AssociatedMucormycosis-Triple-Threat-of
• 3.   Werthman-Ehrenreich A. Mucormycosis with orbital compartment syndrome in a patient with COVID-19. Am J Emerg Med.2021 42: 264.e5–264. e8.https://doi.org/10.1016/j.ajem.2020.09.032.
• 4.   Cox G. Mucormycosis. Uptodate- July 2020. [Google Scholar]).
• 5.   John TM, Jacob CN, Kontoyiannis DP. When Uncontrolled Diabetes Mellitus and Severe COVID-19 Converge: The Perfect Storm for Mucormycosis. J Fungi (Basel). 2021 ; 7(4):298. doi: 10.3390/jof7040298.
• 6.   Singh P. Black fungus: here is a list of states with highest number of mucormycosis cases. Hindustan Times. May 21, 2021. https://www.hindustantimes.com/india-news/black-fungusstates-with-highest-number-of-mucormycosiscases-101621559394002.html (Accessed May 28, 2021).
• 7.   Fouad YA, Abdelaziz TT, Askoura A, Saleh MI, Mahmoud MS, Ashour DM and, Ashour MM. Spike in Rhino-Orbital-Cerebral, Mucormycosis Cases Presenting to a Tertiary Care Center During the COVID-19 Pandemic. Front. Med. 2021;8:645270. doi: 10.3389/fmed.2021.645270.
• 8.   Pal R, Singh B, Bhadada SK, et al. COVID-19- associated mucormycosis: An updated systematic review of literature. Mycoses. 2021;00:1–8. https://doi.org/10.1111/myc.13338.
• 9.   Sahu RK, Salem-Bekhit MM, Bhattacharjee B, et al. Mucormycosis in Indian COVID-19 Patients: Insight into Its Patho-Genesis, Clinical Manifestation, and Management Strategies. Antibiotics (Basel). 2021; 10 (9):1079.
• 10.   Muniangi-Muhitu H, Akalestou E, Salem V, Misra S, Oliver NS and Rutter GA. Covid-19 and Diabetes: A Complex Bidirectional Relationship. Front. Endocrinol. 2020; 11:582936. doi: 10.3389/fendo.2020.582936.
• 11.   Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV- 2 infection. Eur J Intern Med. 2020; 76:14-20. doi:10.1016/j.ejim.2020.04.037.
• 12.   Ravani SA, Agrawal GA, Leuva PA, Modi PH, Amin KD. Rise of the phoenix: Mucormycosis in COVID-19 times. Indian J Ophthalmol. 2021; 69:1563-8.
• 13.   Singh AK, Singh R, Joshi SR, Misra A. Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India. Diabetes & Metabolic Syndrome: Clinical Research & Reviews.2021; doi:https://doi.org/10.1016/j.dsx.2021.05.019.
• 14.   Sen M, Honavar SG, Bansal R, Sengupta S, Rao R, Kim U etal. Members of the Collaborative OPAI-IJO Study on Mucormycosis in COVID-19 (COSMIC) Study Group. Epidemiology, clinical profile, management, and outcome of COVID-19-associated rhino-orbital-cerebral mucormycosis in 2826 patients in India - Collaborative OPAI-IJO Study on Mucormycosis in COVID-19 (COSMIC), Report 1. Indian J Ophthalmol. 2021; 69(7):1670-1692. doi: 10.4103/ijo.IJO_1565_21.
• 15.   Post COVID Tsunami of Black Fungus (Mucorrmycosis) Available at URL: https://cmeindia.in/post-covid- tsunami-of-black-fungusmucormycosis/ CME India Repository. May 10 2021. (Accessed on August 8, 2021).
• 16.   Mulakavalupil B, Vaity C, Joshi S, Misra A, Pandit RA. Absence of Case of Mucormycosis (March 2020-May 2021) under strict protocol driven management care in a COVID-19 specific tertiary care intensive care unit. Diabetes Metab Syndr. 2021;15(4):102169. doi: 10.1016/j.dsx.2021.06.006.
• 17.   Cavezzi A, Troiani E, Corrao S. COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract. 2020;10(2):1271. doi:10.4081/cp.2020.1271.
• 18.   Aranjani JM, Manuel A, Abdul Razack HI, Mathew ST. COVID-19-associated mucormycosis: Evidencebased critical review of an emerging infection burden during the pandemic's second wave in India. PLoS Negl Trop Dis. 2021;15(11):e0009921. Published 2021 Nov 18. doi:10.1371/journal.pntd.0009921.
• 19.   Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395 (10234):1417-1418. doi:10.1016/S0140-6736(20)30937-5.
• 20.   Ehsani S. COVID-19 and iron dysregulation: distant sequence similarity between hepcidin and the novel coronavirus spike glycoprotein. Biol Direct. 2020; 15: 19. doi.org/10.1186/s13062-020-00275-2.
• 21.   AIIMS. COVID-19 infection and rhino-orbitocerebral mucromycosis: Treatment organisation & guidance. 2021 May 18. All India Institute of Medical Sciences, New Delhi. Available from: https://covid.aiims.edu/mucormycosis-in-covid-19/ (Accessed on January 3, 2022).
• 22.   CIDS. Diagnosis and management of COVID-19 associated mucormycosis (CAM): Fact sheet from CIDS. Clinical Infectious Disease Society. Available from: http://www.cidsindia.org/pdf/covid-19/Mucormycosis-Fact-Sheet.pdf (Accessed on January 3, 2022).
• 23.   DGHS. Guideline for management of mucormycosis in COVID-19 patients. Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India. Available from: https://dghs.gov.in/WriteReadData/News/.20210517111 9301555988MucormycosismanagementinCovid-19. pdf (Accessed on January 3, 2022).
• 24.   FISF. COVID-19 associated mucormycosis (CAM). 2021 May 20. Fungal Infection Study Forum. Available from: http://www.fisftrust.org/covid-19/Asscoiated-Mucormycosis/ (Accessed on January 3, 2022).
• 25.   ICMR. Screening, diagnosis & management of mucormycosis: Evidence based advisory in the time of COVID-19. 2021 May 9. Advisory Experts and National Task Force for COVID-19, Indian Council of Medical Research, Department of Health Research, Ministry of Health and Family Welfare, Government of India. Available from: https://www.icmr.gov.in/pdf/covid/techdoc/Mucormycosis_Advisory_from_ICMR_In_COVID19_time.pdf (Accessed on January 3, 2022).
• 26.   IMA. Mucormycosis: guidelines for the diagnosis and management. Indian Medical Association Head Quarters. Available from: https://www.ima-india.org/ima/pdfdata/Mucormycosis%20 Guidelines%20for%20the%20diagnosis%20and%20 Management.pdf. (Accessed on January 3, 2022).
• 27.   WHO. Key facts: Mucormycosis. World Health Organization, South-East Asia:India [Internet]. Available from: https://www.who.int/india/emergencies/coronavirus-disease-(covid-19)/mucormycosis (Accessed on January 3, 2022).
• 28.   Honavar SG. Code Mucor: Guidelines for the diagnosis, staging and management of rhinoorbitocerebral mucormycosis in the setting of COVID-19. Indian J Ophthalmol. 2021; 69(6):1361–5. https://doi.org/10.4103/ijo.IJO_1165_21
• 29.   Directorate General of Health Services, MoHFW, GOI Comprehensive Guidelines for Management of COVID-19 patients. COVID-19 Management: Managing Mucormycosis guide box. May, 2021. https://www.dghs.gov.in/WriteReadData/News/202105270436027770348ComprehensiveGuidelinesforManagementofCOVID-1927May2021DteGHS.

Data Sharing Statement

Funding