Abstract
Purpose of Review
The current review gives a proper understanding of the various dynamics of COVID-associated mucormycosis (CAM). We provide insight into the agent and recent host-related factors that contributed to CAM. Also, we have discussed various environmental-related factors like fungal spore burden that could have contributed to the pathogenesis of CAM. This review also summarizes the main components of pathogenesis under three primary headings: the immunomodulatory effect of the virus, the involvement of underlying comorbidities conditions in the host, and the numerous treatment-related modalities used during COVID-19 treatment.
Recent Findings
The risk factors for CAM continue to evolve with the development of COVID infection. A sudden rise in CAM cases was observed in countries including India. Along with Rhizopus arrhizus, the rise of other species like Rhizopus homothallicus and Rhizopus microsporus was observed. The virus along with underlying conditions like hyperglycemia, uncontrolled diabetes mellitus, diabetic ketoacidosis, and dysregulated iron metabolism with hyperferritinemia predisposes to CAM. Also, non-judicious and high-dose use of corticosteroids along with interleukins inhibitors (IL-1 and IL-6), and tocilizumab, contributed to a high rise in the cases of CAM. No link was found between the upsurge in CAM cases with the cow dung cake burning in India. Also, the possibility of nosocomial transmission was also raised, which was rejected as the majority of the patients remained at home during COVID-19 infection. Interestingly, in one study, the genetic similarity was observed between the strains isolated from the patient and the environment. Thus, the interplay of various factors like high spore count, uncontrolled diabetes, and the use of inappropriate steroids/IL inhibitors during the management of COVID-19 could have contributed to the alarming rise in cases of CAM.
Summary
Mucorales are found ubiquitously in the environment. Understanding the pathogenesis and environmental factors like spore count and burden can provide insight into the development of CAM which is critical for optimal patient management. Also, COVID-19 management should include strict glycemic control and avoidance of any unnecessary medication.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Singh S, Kanaujia R, Rudramurthy SM. Pathogenesis of COVID-associated mucormycosis’, rhino-orbito-cerebral mucormycosis. In: Gupta, N., Honavar, S.G. (eds) Rhino-orbito-cerebral mucormycosis. Springer, Singapore. pp. 39–49. https://doi.org/10.1007/978-981-16-9729-6_4. This review provides an updated review of COVID-Associated Mucormycosis.
Sharma NC. India reports 40,854 cases of black fungus so far. Mint. 2021:1–9. Available at: https://www.livemint.com/news/india-records-over-40k-cases-of-mucormycosis-11624875874985.html.
Sinha A, Bhaskar SMM. In-hospital prevalence of mucormycosis among coronavirus disease 2019 (COVID-19) patients and COVID-19 in mucormycosis: a systematic review and meta-analysis. Int Forum Allergy Rhinol. 2022;12:313–7.
Patel A, Agarwal R, Rudramurthy SM, Shevkani M, Xess I, Sharma R, et al. Multicenter epidemiologic study of coronavirus disease-associated mucormycosis. India. Emerg Infect Dis. 2021;27:2349–59.
Guzmán-Castro S, Chora-Hernandez LD, Trujillo-Alonso G, Calvo-Villalobos I, Sanchez-Rangel A, Ferrer-Alpuin E, et al. COVID-19–associated mucormycosis, diabetes and steroid therapy: Experience in a single centre in Western Mexico. Mycoses. 2022;65:65–70.
Pal R, Singh B, Bhadada SK, Banerjee M, Bhogal RS, Hage N, et al. COVID-19-associated mucormycosis: An updated systematic review of literature. Mycoses. 2021;64(12):1452–9. https://doi.org/10.1111/myc.13338.
Fungal Diseases and COVID-19 | CDC. [cited 2023 Aug 14]. Available from: https://www.cdc.gov/fungal/covid-fungal.html.
Chander J, Kaur M, Singla N, Punia RPS, Singhal SK, Attri AK, et al. Mucormycosis: Battle with the deadly enemy over a five-year period in India. J Fungi (Basel). 2018;4(2):46.
Prakash H, Chakrabarti A. Global epidemiology of mucormycosis. J Fungi (Basel). 2019;5(1):26.
Hussain S, Riad A, Singh A, Klugarová J, Antony B, Banna H, et al. Global prevalence of COVID-19-associated mucormycosis (CAM): Living systematic review and meta-analysis. J Fungi (Basel). 2021;7(11):985.
Lai CC, Yu WL. Appropriate use of antimicrobial therapy for COVID-19 co-infection. Immunotherapy. 2021;13(13):1067–70.
Muthu V, Rudramurthy SM, Chakrabarti A, Agarwal R. Epidemiology and pathophysiology of COVID-19-associated mucormycosis: India versus the rest of the world. Mycopathologia. 2021;186:739–54. A comprehensive review on the COVID-Associated Mucormycosis.
Seidel D, Simon M, Sprute R, Lubnow M, Evert K, Speer C, et al. Results from a national survey on COVID-19-associated mucormycosis in Germany: 13 patients from six tertiary hospitals. Mycoses. 2022;65:103–9.
Gangneux JP, Dannaoui E, Fekkar A, Luyt CE, Botterel F, De Prost N, et al. Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID study. Lancet Respir Med. 2022;10:180–90.
Hoenigl M, Seidel D, Carvalho A, Rudramurthy SM, Arastehfar A, Gangneux JP, et al. The emergence of COVID-19 associated mucormycosis: Analysis of cases from 18 countries. Lancet Microbe. 2022;3(7):e543–52.
Muthu V, Agarwal R, Rudramurthy SM, Thangaraju D, Shevkani MR, Patel AK, et al. Multicenter case–control study of COVID-19–associated mucormycosis outbreak, India. Emerg Infect Dis. 2023;29(1):8–19. The pioneer Indian study reporting the risk factors in an India.
Prakash H, Skiada A, Paul RA, Chakrabarti A, Rudramurthy SM. Connecting the dots: Interplay of pathogenic mechanisms between Covid-19 disease and mucormycosis. J Fungi (Basel). 2021;7(8):616.
Chandley P, Subba P, Rohatgi S. COVID-19-associated mucormycosis: A matter of concern amid the SARS-CoV-2 pandemic. Vaccines (Basel). 2022;10(8):1266.
Prakash H, Ghosh AK, Rudramurthy SM, Singh P, Xess I, Savio J, et al. A prospective multicenter study on mucormycosis in India: Epidemiology, diagnosis, and treatment. Med Mycol. 2019;57:395–402.
Kaur H, Kanaujia R, Rudramurthy SM. Rhizopus homothallicus: An emerging pathogen in era of COVID-19 associated mucormycosis. Indian J Med Microbiol. 2021;21:04137–2.
Rudramurthy SM, Singh S, Kanaujia R, Chaudhary H, Muthu V, Panda N, et al. Clinical and mycologic characteristics of emerging mucormycosis agent Rhizopus homothallicus - volume 29, number 7—July 2023 - Emerging Infectious Diseases Journal - CDC. Emerg Infect Dis. 2023;29:1313–22.
Pandey M, Singh G, Agarwal R, Dabas Y, Jyotsna VP, Kumar R, et al. Emerging Rhizopus microsporus Infections in India. J Clin Microbiol. 2018;56(6):e00433–18.
Ghosh AK, Singh R, Reddy S, Singh S, Rudramurthy SM, Kaur H, et al. Evaluation of environmental Mucorales contamination in and around the residence of COVID-19-associated mucormycosis patients. Front Cell Infect Microbiol. 2022;2(12):953750.
Arora U, Priyadarshi M, Katiyar V, Soneja M, Garg P, Gupta I, et al. Risk factors for Coronavirus disease-associated mucormycosis. J Infect. 2022;84:383–90.
Richardson M. The ecology of the zygomycetes and its impact on environmental exposure. Clin Microbiol Infect. 2009;15:2–9.
Richardson MD, Rautemaa-Richardson R. Biotic environments supporting the persistence of clinically relevant mucormycetes. J Fungi (Basel). 2019;6(1):4.
Skaria J, John TM, Varkey S, Kontoyiannis DP. Are unique regional factors the missing link in India’s COVID- 19-associated mucormycosis crisis? mBio. 2022;13(2):e0047322.
Kathirvel S, Muthu V, Rudramurthy SM, Kaur H, Chakrabarti A, Agarwal R. Could cattle dung burning have contributed to the epidemic of COVID-19-associated mucormycosis in India? Results of an experimental aero-mycological study. Mycoses. 2022;65:1024–9. An important study describing the results of cattle dung burning in the role of COVID- 19-Associated Mucormycosis.
Muthu V, Agarwal R, Chakrabarti A. COVID-19, mucormycosis, and the cow: Damned lies! Indian J Med Microbiol. 2023;44 100382
Rammaert B, Lanternier F, Zahar JR, Dannaoui E, Bougnoux ME, Lecuit M, et al. Healthcare-associated mucormycosis. Clin Infect Dis. 2012;54:S44–54.
He R, Hu C, Tang Y, Yang H, Cao L, Niu R. Report of 12 cases with tracheobronchial mucormycosis and a review. Clin Respir J. 2018;12:1651–60.
Chakrabarti A, Chatterjee SS, Das A, Panda N, Shivaprakash MR, Kaur A, et al. Invasive zygomycosis in India: Experience in a tertiary care hospital. Postgrad Med J. 2009;85:573–81.
Biswal M, Gupta P, Kanaujia R, Kaur K, Kaur H, Vyas A, et al. Evaluation of hospital environment for presence of Mucorales during COVID-19 associated mucormycosis outbreak in India – A multi-centre study. J Hosp Infect. 2022;122:173–9. A landmark study describing the presence of Mucorales in the environment.
Prakash H, Singh S, Rudramurthy SM, Singh P, Mehta N, Shaw D, et al. An aero mycological analysis of Mucormycetes in indoor and outdoor environments of northern India. Med Mycol. 2020;58:118–23.
Ghosh AK, Singh R, Reddy S, Singh S, Rudramurthy SM, Kaur H, et al. Evaluation of environmental Mucorales contamination in and around the residence of COVID-19-associated mucormycosis patients. Front Cell Infect Microbiol. 2022;12:1–9.
Salazar F, Bignell E, Brown GD, Cook PC, Warris A. Pathogenesis of respiratory viral and fungal coinfections. Clin Microbiol Rev. 2022;35(1):e0009421.
Shah VK, Firmal P, Alam A, Ganguly D, Chattopadhyay S. Overview of immune response during SARS-CoV-2 infection: lessons from the past. Front Immunol. 2020;11:553450.
Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh TJ, Kontoyiannis DP. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis. 2012;54:S23–34.
Smith SM, Boppana A, Traupman JA, Unson E, Maddock DA, Chao K, et al. Impaired glucose metabolism in patients with diabetes, prediabetes, and obesity is associated with severe COVID-19. J Med Virol. 2021;93:409–15.
Montefusco L, Ben Nasr M, D’Addio F, Loretelli C, Rossi A, Pastore I, et al. Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection. Nature Metabolism. 2021;3:774–85.
Muthu V, Dhaliwal M, Sharma A, Nair D, Kumar HM, Rudramurthy SM, et al. Serum glucose-regulated protein 78 (GRP78) levels in COVID-19-associated mucormycosis: results of a case–control study. Mycopathologia. 2022;187:355.
Jose A, Singh S, Roychoudhury A, Kholakiya Y, Arya S, Roychoudhury S. Current understanding in the pathophysiology of SARS-CoV-2-associated rhino-orbito-cerebral mucormycosis: A comprehensive review. J Maxillofac Oral Surg. 2021;20:373–80.
Majeed A, Ashraf Shajar M, St Z, Maather A, Maazer A. Is hemoglobin the missing link in the pathogenesis of COVID-19? Anaesthesia, Pain & Intensive Care. 2020;24:9–12.
Vlahakos VD, Marathias KP, Arkadopoulos N, Vlahakos DV. Hyperferritinemia in patients with COVID-19: An opportunity for iron chelation? Artif Organs. 2021;45:163–7.
Kumar HM, Sharma P, Rudramurthy SM, Sehgal IS, Prasad KT, Pannu AK, et al. Serum iron indices in COVID-19-associated mucormycosis: A case–control study. Mycoses. 2022;65:120.
RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693–704.
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.
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.
Bhogireddy R, Krishnamurthy V, Jabaris SSL, Pullaiah CP, Manohar S. Is Mucormycosis an inevitable complication of Covid-19 in India? Braz J Infect Dis. 2021;25:101597.
Zirpe K, Pote P, Deshmukh A, Gurav SK, Tiwari AM, Suryawanshi P. a retrospective analysis of risk factors of Covid-19 associated mucormycosis and mortality predictors: A single-center study. Cureus. 2021;13(10):e18718.
Özbek L, Topçu U, Manay M, Esen BH, Bektas SN, Aydın S, et al. COVID-19–associated mucormycosis: a systematic review and meta-analysis of 958 cases. Clin Microbiol Infect. 2023;29(6):722–31.
Ravindra K, Ahlawat A. Five probable factors responsible for the COVID-associated mucormycosis outbreak in India. Int J Infect Dis. 2021;112:278–80.
Author information
Authors and Affiliations
Contributions
R.K. prepared the draft; P.S. prepared the figure and edited the draft; S.M.R. was responsible for the conceptualization and finalization of the manuscript. All authors reviewed the manuscript.
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare no competing interests.
Human and Animal Rights and Informed Consent
This is a review article and does not involve any human or animal studies; hence, consent and ethical clearance are not required.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Kanaujia, R., Sreenivasan, P. & Rudramurthy, S.M. Pathogenesis of COVID-19-Associated Mucormycosis: An Updated Evidence-Based Review. Curr Fungal Infect Rep 18, 69–75 (2024). https://doi.org/10.1007/s12281-024-00484-6
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12281-024-00484-6