Mucormycosis in patients with COVID-19 in Russia: the results of a prospective multi-center study

We present the results of a prospective multicenter study of risk factors, etiology, clinical features, and treatment outcomes for mucormycosis in patients with COVID-19 (COVID-M) in the Russian Federation.

The study included 60 adult patients with COVID-M. To analyze risk factors for COVID-M, we conducted a case-control study. The control group included 60 adult patients with COVID-19 without mucormycosis. To analyze the clinical manifestations of COVID-M, we created a control group of hematological patients with mucormycosis examined in 2011–2020.

In patients with COVID-19, the risk of developing mucormycosis was significantly increased with diabetes mellitus (OR=49) and overweight (OR=4,75), as well as with the use of high (≥100 mg per day for prednisolone) doses of glucocorticosteroids (OR= 4,762), especially ≥10 days (OR=25,4). The main localization of mucormycosis in patients with COVID-19 was the paranasal sinuses (95%) and the orbit (68%). Involvement of ≥2 organs was identified in 70% of patients. The main causative agents of mucormycosis were Rhizopus arrhizus (43%) and unidentified mucormycetes (36%).

90-days overall survival of patients with mucormycosis and COVID-19 – 71%. The stay in the ICU (p=0,01), the use of mechanical ventilation (p=0,0481), the presence of CVC (p=0,049), CNS damage (p=0,016) and ≥ 2 organs (p=0,048) significantly worsened the prognosis of the disease. The best prognosis was in patients who received antifungal therapy (p=0,03875) and surgical treatment (p=0,046).

1. Frias-De-Leon MG, Pinto-Almazan R, Hernandez-Castro R, et al. Epidemiology of systemic mycoses in the COVID-19 pandemic. J Fungi (Basel). 2021;7(7):556.

2. Salmanton-Garcia J, Sprute R, Stemler J, et al. COVID-19-associated pulmonary Aspergillosis, March-August 2020. Emerg Infect Dis. 2021;27(4):1077-1086.

3. Koehler P, Cornely OA, Bottiger BW, et al. COVID-19 associated pulmonary aspergillosis. Mycoses. 2020;63(6):528-534.

4. Hoenigl M, Seidel D, Carvalho A, et al. The emergence of COVID-19 associated mucormycosis: Analysis of cases from 18 countries. The Lancet. 2021;Preprint: 33.

5. Rocha ICN, Hasan MM, Goyal S, et al. COVID-19 and mucormycosis syndemic: double health threat to a collapsing healthcare system in India. Trop Med Int Health. 2021;26(9):1016-1018.

6. Rudramurthy SM, Hoenigl M, Meis JF, et al. ECMM/ ISHAM recommendations for clinical management of COVID-19 associated mucormycosis in low- and middle-income countries. Mycoses. 2021;64(9):1028-1037

7. Salmanton-García J, Koehler P, Kindo A, Falces-Romero I, García-Rodríguez J, Ráčil Z, Chen SC, Klimko N, et al. Needles in a haystack: Extremely rare invasive fungal infections reported in FungiScopeⓇ -Global Registry for Emerging Fungal Infections. J Infect. 2020 Nov;81(5):802-815. doi: 10.1016/j.jinf.2020.08.015. Epub 2020 Aug 13. PMID: 32798532.

8. Klimko N, Kozlova Y, Khostelidi S, Shadrivova O, Borzova Y, Burygina E, Vasilieva N, Denning DW. The burden of serious fungal diseases in Russia. Mycoses. 2015 Oct;58 Suppl 5:58-62. doi: 10.1111/myc.12388. PMID: 26449508.

9. Sen, M., Honavar, S. G., Bansal, R., Sengupta, S., Rao, R., 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 journal of ophthalmology, 69(7), 1670–1692. https://doi.org/10.4103/ijo.IJO_1565_21

10. Prakash H, Chakrabarti A. Epidemiology of Mucormycosis in India. Microorganisms. 2021;9(3):523. Published 2021 Mar 4. doi:10.3390/microorganisms9030523

11. Bellanger AP, Navellou JC, Lepiller Q, et al. Mixed mold infection with Aspergillus fumigatus and Rhizopus microsporus in a severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) patient. Infect Dis now. 2021;51(7):633-635.

12. Seidel D, Simon M, Sprute R, et al. Results from a national survey on COVID-19-associated mucormycosis in Germany: 13 patients from six tertiary hospitals. Mycoses. 2021;00:1–7. https://doi.org/10.1111/myc.1337

13. Buil JB, van Zanten ARH, Bentvelsen RG, et al. Case series of four secondary mucormycosis infections in COVID-19 patients, the Netherlands. Euro Surveill. 2021;26(23):2100510.

14. Evert K, Dienemann T, Brochhausen C, et al. Autopsy findings after long-term treatment of COVID-19 patients with microbiological correlation. Virchows Arch. 2021;479(1):97-108.

15. Hanley B, Naresh KN, Roufosse C, et al. Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a postmortem study. Lancet Microbe. 2020;1(6):e245-e253.

16. Zurl C, Hoenigl M, Schulz E, et al. Autopsy proven pulmonary Mucormycosis due to Rhizopus microsporus in a critically Ill COVID-19 patient with underlying hematological malignancy. J Fungi (Basel). 2021;7(2):88. 17. Pasero D, Sanna S, Liperi C, et al. A challenging complication following SARS-CoV-2 infection: a case of pulmonary mucormycosis. Infection. 2020;49(5):1055-1060

17. Placik DA, Taylor WL, Wnuk NM. Bronchopleural fistula development in the setting of novel therapies for acute respiratory distress syndrome in SARS-CoV-2 pneumonia. Radiol Case Rep. 2020;15(11):2378–2381. doi: 10.1016/j.radcr.2020.09.026. [PMC free article] [PubMed] [Cross-Ref] [Google Scholar]

18. Mehta S, Pandey A. Rhino-orbital mucormycosis associated with COVID-19. Cureus. 2020;12(9):e10726. [PMC free article] [PubMed] [Google Scholar]

19. Monte Junior ESD, Santos M, Ribeiro IB et al. Rare and fatal gastrointestinal mucormycosis (Zygomycosis) in a COVID-19 patient: a case report. Clin Endosc. 2020;53(6):746–749. doi: 10.5946/ce.2020.180. [PMC free article] [PubMed] [Cross-Ref] [Google Scholar]

20. Pasero D, Sanna S, Liperi C, et al. challenging complication following SARS-CoV-2 infection: a case of pulmonary mucormycosis. Infection. 2020 Dec 17:1–6. doi: 10.1007/s15010-020-01561-x. Epub ahead of print. PMID: 33331988; PMCID: PMC7745708.

21. Mekonnen ZK, Ashraf DC, Jankowski T, et al. Acute Invasive Rhino-Orbital Mucormycosis in a Patient With COVID-19-Associated Acute Respiratory Distress Syndrome. Ophthalmic Plast Reconstr Surg. 2020. doi:10.1097/IOP.0000000000001889. [PMC free article] [PubMed]

22. Zurl C, Hoenigl M, Schulz E, Hatzl S, Gorkiewicz G, Krause R, et al. Autopsy Proven Pulmonary Mucormycosis Due to Rhizopus microsporus in a Critically Ill COVID-19 Patient with Underlying Hematological Malignancy. J Fungi (Basel). 2021 Jan 27;7(2):88. doi: 10.3390/jof7020088. PMID: 33513875; PMCID: PMC7912223.

23. Hostelidi S.N., Zajcev V.A., Pelih E.V., YAshina E.YU., Rodionova O.N., Bogomolova T.S. Mukormikoz na fone COVID-19: opisanie klinicheskogo sluchaya i obzor literatury. Klinicheskaya mikrobiologiya i antimikrobnaya himioterapiya. – 2021. T.23, №3. – C.255-262.

24. Donnelly J.P., Chen SC, Kauffman CA. at al. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clinical Infectious Diseases, Volume 71, Issue 6, 15 September 2020, p.1367–1376, https://doi.org/10.1093/cid/ciz1008

25. Vremennye metodicheskie rekomendacii «Profilaktika, diagnostika i lechenie novoj koronavirusnoj infekcii (COVID-19)». Versiya 10, 08.02.2021. https://static-0.minzdrav.gov.ru

26. 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. Published 2021 Jul 29. doi:10.3390/jof7080616

27. Prakash H, Singh S, Rudramurthy S, 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(1):118–23. https://doi.org/10.1093/Mmy/Myz031

28. Hostelidi S.N., SHadrivova O.V., Borzova YU.V., Desyatik E.A., Nikolaeva N.G., Bogomolova T.S. i drugie. Klinikolaboratornye osobennosti mukormikoza u vzroslyh. Problemy medicinskoj mikologii. – 2020. – T.22, №2. – C.22-28.

29. Moorthy A, Gaikwad R, Krishna S, Hegde R, Tripathi KK, Kale PG, Rao PS, Haldipur D, Bonanthaya K. SARS-CoV-2, Uncontrolled Diabetes and Corticosteroids-An Unholy Trinity in Invasive Fungal Infections of the Maxillofacial Region? A Retrospective, Multi-centric Analysis. J Maxillofac Oral Surg. 2021 Mar 6:1-8. doi: 10.1007/s12663-021-01532-1. Epub ahead of print. PMID: 33716414; PMCID: PMC7936599.

30. Sarkar S, Gokhale T, Choudhury SS, Deb AK. COVID-19 and orbital mucormycosis. Indian J Ophthalmol. 2021 Apr;69(4):1002-1004. doi: 10.4103/ijo.IJO_3763_20. PMID: 33727483; PMCID: PMC8012924.

31. Kumar M, Sarma DK, Shubham S, et al. Mucormycosis in COVID-19 pandemic: Risk factors and linkages. Curr Res Microb Sci. 2021;2:100057. doi:10.1016/j.crmicr.2021.100057.

32. Cornely OA, Alastruey-Izquierdo A, Arenz D, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019;19(12):e405-e421. doi:10.1016/S1473-3099(19)30312-3.