COVID-19 associated Mucormycosis (CAM): A Battle within the War

The recent spurt of mucormycosis cases during the second wave of COVID-19 pandemic in India has drawn global attention. Mucormycosis is a serious infection typically seen in immunocompromised individuals and uncontrolled diabetics caused by fungi in the order Mucorales.¹ Mucorales has 55 genera and 126 species of which 38 are human pathogens.¹ Rhizopus arrhizus has emerged as predominant organism causing COVID-19 associated Mucormycosis (CAM) in India.² Other common species include Rhizomucor spp., Mucor spp., Cunninghamela spp., Apophysomyceses spp. and Leichtheimia spp.² Mucorales are ubiquitous in hot and humid climatic regions.² Mucormycosis in humans presents as rhino-orbital-cerebral mucormycosis (ROCM-most common type), pulmonary, cutaneous and disseminated mucormycosis.²

The second wave of COVID-19 pandemic witnessed an unprecedented explosion of CAM with 28,252 cases reported in the national registry and the Indian government reacted by including CAM in the list of notifiable diseases.⁴

Major Risk Factors – Diabetes and Corticosteroids

Researchers who have pondered over the reasons of CAM attribute this predominantly to uncontrolled blood sugar levels in diabetics.^1,2,5 A nationwide OPAI-IJO collaborative study on mucormycosis in COVID-19 (COSMIC) reported on 2826 cases of CAM.⁵ They found diabetes mellitus (DM) in 78% and about half (44%) had poor control or diabetic ketoacidosis.⁵ The relative higher prevalence of DM and pre-diabetes at 7.3% and 10.6% respectively, among adults in India, correlates well with the CAM epidemic.⁶ COVID-19 itself has been reported to precipitate diabetes by direct damage to pancreatic islets and indirectly by damaging small blood vessels and inducing insulin resistance.^7,8 Evidence seems to be emerging that injudicious use of corticosteroids in the treatment of COVID-19 is likely to have played a role in the CAM epidemic.⁶ In the COSMIC report, 28% (789 cases) of rhino-orbital-cerebral mucormycosis (ROCM) who had COVID-19 did not need hospital admission.⁵ Assuming these individuals had oxygen saturation levels precluding hospitalization, it is interesting to note that 73% received corticosteroids in some form pointing towards an injudicious use of corticosteroids.⁵

Health Care services

Coming as surprise within the COVID-19 pandemic, the surge of CAM needed health care systems within both the public and private sector, to get their act together and rise to the challenge. Many centers formed ‘mucor-team’ drawing from multiple disciplines and formulated guidelines through consensus and evidence in the literature. Large campaigns both in print and audio-visual media, helped raise awareness in the general public. Digital technology through telemedicine and dedicated ‘mucor-helplines’ allowed home consults to suspects across the country. In the midst of this battle, an acute shortage of liposomal Amphotericin-B, the drug of choice for mucormycosis, was rather unfortunate. Second line medications – posaconazole and isavuconazole were used in the interim before the government intervened to resolve the supply-demand mismatch for Amphotericin-B.

Research on Mucormycosis

The collaborative COSMIC report showed that the geographic distribution of CAM matched to some degree the distribution of COVID-19 cases in India.⁶ While some regions were overrepresented (Gujarat) and others (Tamil Nadu and West Bengal) had fewer ROCM compared to COVID-19 cases.⁶ Multiple new staging systems of ROCM were proposed to facilitate management and prognosticate the outcome.^6,9 Deep understanding of imaging especially magnetic resonance imaging, in the management of ROCM evolved.¹⁰ Finally validation of the staging systems with recruitment of a large sample of ROCM patients will help us understand the pathogenesis of ROCM and its outcome in the future. Time will decide the outcome of this battle and the war.

Please visit the IAPB Mucormycosis Research Round Up for all the articles about CAM that were published in June and July.

References:

1. Walther G, Wagner L, Kurzai O. Updates on the taxonomy of mucorales with an emphasis on clinically important taxa. J Fungi. 2019; 5(4).
2. Patel A, Agarwal R, Rudramurthy SM, et al. Multicenter Epidemiologic Study of Coronavirus Disease–Associated Mucormycosis, India. Emerg Infect Dis. 2021; 27(9).
3. Richardson M. The ecology of the zygomycetes and its impact on environmental exposure. Clin Microbiol Infect. 2009;15 (Suppl 5):S2–S9.
4. Statement from Health Minister, Government of India to press. https://www.tribuneindia.com/news/nation/28-252-black-fungus-cases-in-india-265262 (last accessed, 8 May 2021)
5. Sen M, Honavar SG, Bansal R, Sengupta S, Rao R, Kim U, et al. 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;69:1670-92.
6. Prevalence of diabetes and prediabetes in 15 states of India: results from the ICMR–INDIAB population-based cross-sectional study.
7. Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabeto 2010;47(3):193–199.
8. Müller JA, Groß R, Conzelmann C, et al. SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nat Metab. 2021;3(2):149–165.
9. Naik MN, Rath S. The ROC Staging System for COVID-related Rhino-Orbital-Cerebral Mucormycosis. Semin Ophthalmol. 2021 Jul 14:1-5
10. Sreshta K, Dave TV, Varma DR, Nair AG, Bothra N, Naik MN, Sistla SK. Magnetic resonance imaging in rhino-orbital-cerebral mucormycosis. Indian J Ophthalmol. 2021 Jul;69(7):1915-1927.

Photo credit: Shamim Khan