COVID-19 and Mucormycosis: Predisposing Factors and Preventive Strategies
1,2Department of Community Medicine, Shri Sathya Sai Medical College and Research Institute (A Unit of Sri Balaji Vidyapeeth Deemed to be University), Kancheepuram, Tamil Nadu, India
Corresponding Author: Prateek Bobhate, Department of Community Medicine, Shri Sathya Sai Medical College and Research Institute (A Unit of Sri Balaji Vidyapeeth Deemed to be University), Kancheepuram, Tamil Nadu, India, e-mail: email@example.com
How to cite this article: Bobhate P, Shrivastava SR. COVID-19 and Mucormycosis: Predisposing Factors and Preventive Strategies J Basic Clin Appl Health Sci 2021;4(4):92–94.
Source of support: Nil
Conflict of interest: None
Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2. COVID-19 has been associated with a wide range of opportunistic infections, viz. bacterial and fungal. Mucormycosis is one of the most deadly and life-threatening invasive fungal infections which has typically seen a rising trend with the rise in COVID-19 cases. Patients who are at higher risk to develop mucormycosis include those with uncontrolled diabetes mellitus, steroid-induced immunosuppression, acquired immunodeficiency syndrome, immunosuppression due to malignancies or posttransplant, prolonged stay in intensive care units, patients on oxygen therapy and/or mechanical ventilation, etc. Preventive strategies for mucormycosis should aim at addressing the underlying risk factors in COVID-19 patients, airborne infection control at the facility level, as well as personal protective measures at the individual level. Finally, a high index of suspicion, clinically, on the part of the treating physician can go a long way in prompt diagnosis and initiation of aggressive antifungal therapy and extensive surgical management of mucormycosis, leading to an improved outcome.
Keywords: COVID-19, Diabetes mellitus, Mucormycosis, Opportunistic infection.
Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2. Worldwide, it has been estimated that more than 204 million cases of COVID-19 infection have occurred as of August 12, 2021.1 There have been numerous changes in the spectrum of COVID-19 with regard to its diagnosis, management, prevention, complications, and post-COVID sequelae since the emergence of the first case in Wuhan, China, in December 2019.2 Of late, COVID-19 has been associated with a wide range of opportunistic infections, viz. bacterial and fungal. Mucormycosis is one of the most deadly and life-threatening invasive fungal infections which has typically seen a rising trend with the rise in COVID-19 cases.3–5
Mucormycosis is a rare but serious fungal infection caused by a group of molds called Mucormycetes. It most commonly affects the sinuses or the lungs but can also affect the skin post any injury or burn. It usually presents with a blocked nose, facial edema or pain, headache, and proptosis, with a black eschar being seen in the nasal cavity or palate. At times, with intracranial involvement, neurological signs and symptoms may be seen.6–9
Recently, an increasing number of cases of mucormycosis has been reported among COVID-19 cases, especially from India. Higher mortality rates are reported with orbital and intracranial complications with rapid progression if diagnosis and treatment are delayed. Untreated mucormycosis is almost always fatal.10 A high index of suspicion for prompt diagnosis is required. An aggressive treatment strategy combining both medical and surgical management is often needed; however, sometimes, even this does not suffice.11
WHO ARE AT RISK FOR DEVELOPING MUCORMYCOSIS?
Patients who are at higher risk to develop mucormycosis include those with uncontrolled diabetes mellitus, steroid-induced immunosuppression, acquired immunodeficiency syndrome, immunosuppression due to malignancies or posttransplant, prolonged stay in intensive care units, patients on oxygen therapy and/or mechanical ventilation, etc.
DIABETES MELLITUS AND MUCORMYCOSIS
Poorly controlled diabetes mellitus is said to be an important risk factor for mucormycosis.12 It is also found to rise morbidity and mortality in the context of COVID-19.13 It has been reported that COVID-19-associated mucormycosis is classically seen in uncontrolled or poorly controlled diabetics.14 Also, COVID-19 leads to a diabetogenic state by causing damage to the pancreatic islets, and also cytokine storm is associated with higher insulin resistance.15,16 A high index of suspicion is the need of the hour, if any diabetic patient with COVID-19 develops nasal, orbital, or neurological signs and symptoms or presents with these complaints post-COVID-19; it has to be immediately addressed.
DRUG THERAPY AND MUCORMYCOSIS
Steroids have been used extensively in COVID-19 management especially in hypoxemic patients and have also been shown to reduce mortality among them. Corticosteroid therapy, short or long term, is a risk factor for opportunistic infections like mucormycosis.17–19 Thus, judicious use of steroids is recommended in COVID-19 infection and it must be avoided in asymptomatic or mild cases without any hypoxemia. The use of immunomodulatory drugs viz. tocilizumab in COVID-19 patients can increase the risk of secondary infections as the viral infection itself leads to immune dysregulation.18,20 Voriconazole therapy is used to prevent opportunistic fungal infections that can sometimes lead to mucormycosis as it is not effective against Mucorales.21 Also, indiscriminate use of broad-spectrum antibiotics can lead to increased rates of mucormycosis and needs to be curbed.
MECHANICAL VENTILATION, INTENSIVE CARE SUPPORT, AND MUCORMYCOSIS
It has been observed that patients with COVID-19 requiring mechanical ventilation, oxygen support, and ICU care have higher rates of development of secondary infections including mucormycosis.22–24 Invasive procedures like tracheostomy have been associated with an increased risk of secondary infections.23 Oxygen humidifiers, especially the reusable ones, can lead to increased aerosol transmission of hospital-acquired pathogens. Disposable oxygen humidifiers are therefore advisable.25 It is also recommended to use clean distilled water in oxygen humidifiers, even for home use.
MANAGEMENT OF MUCORMYCOSIS ASSOCIATED WITH COVID-19
A high index of clinical suspicion is needed to diagnose mucormycosis at an early stage and initiate a prompt and aggressive medical and surgical management protocol.
Warning signs and symptoms in COVID-19 patients which should not be ignored are as follows:26
Mucormycosis of nose/sinus: Headache and nasal obstruction, pain not responding to analgesics, nasal crusting and discharge, loss of sensation or pain in the face, localized puffiness of the face, loosening of teeth or ulceration of the palates, etc.
Mucormycosis of eyes: Redness or eye pain and swelling, double vision, loss of vision, drooping of eyelids, etc.
Mucormycosis of brain: Cranial nerve palsies, altered sensorium, etc.
Basic principles for treatment that need to be followed are as follows:26
Treatment of comorbidities
Continuing treatment of COVID-19 and avoiding immunosuppression
Evaluating the progression of mucormycosis for ocular or intracranial involvement
Confirmation of diagnosis by KOH mount or biopsy; assessing disease progression radiologically
Initiation of antifungal therapy: Liposomal amphotericin B or posaconazole
Aggressive surgical management: Surgical debridement of the necrotic tissue
Liposomal amphotericin B is the drug of choice along with extensive surgical debridement of the infected area and has been shown to improve survival rates. Posaconazole can be used as an alternative antifungal agent.27,28 Delay in the diagnosis or treatment can be detrimental to the outcome and may cause fatalities. Various factors like prompt diagnosis and treatment, type of mucormycosis, immune status of the patient, etc., can determine the prognosis and outcome of the patient.29
PREVENTIVE STRATEGIES FOR MUCORMYCOSIS IN COVID-19
Multidimensional strategies can be implemented for the prevention of mucormycosis in COVID-19. These strategies should aim at addressing the underlying risk factors in COVID-19 patients, airborne infection control at the facility level, as well as personal protective measures at the individual level.
Addressing the risk factors: The underlying factors which can predispose to the development of mucormycosis should be addressed promptly in all COVID-19 patients. These include controlling hyperglycemia, judicious use of corticosteroids, rational use of antibiotics, antifungals, and immunomodulatory drugs, minimizing hospital stay, use of disposable oxygen humidifiers, etc.28,29
Infection prevention and control at the facility level: It is mandatory to have infection prevention and control measures in place at all COVID-19 treatment facilities in order to eliminate the environmental spread of the infection. The following measures can be taken at the hospital level: Regular disinfection and sterilization of hospital equipment like tracheal tubes, oxygen humidifiers, ventilators, etc.; adequate ventilation system; proper wound management; appropriate peripheral and central line management, etc.29,30
Personal protective measures: Cases of mucormycosis have been found to occur among recovered COVID-19 patients as well. Hence, the role of personal protective measures cannot be neglected. These include maintenance of personal hygiene, avoiding construction sites or use of face masks when visiting dusty places, avoidance of contact with soil or use of gloves, shoes, and full-length clothing, avoiding injuries to the skin, etc.30
In conclusion, although various strategies have been outlined for the prevention of mucormycosis among COVID-19 patients, a high index of suspicion, clinically, on the part of the treating physician can go a long way in prompt diagnosis and initiation of aggressive antifungal therapy and extensive surgical management of mucormycosis, leading to an improved outcome.
2. Kubin CJ, McConville TH, Dietz D, Zucker J, May M, Nelson B, et al. Characterization of bacterial and fungal infections in hospitalized patients with coronavirus disease 2019 and factors associated with health care-associated infections. Open Forum Infect Dis 2021;8(6):ofab201. DOI: 10.1093/ofid/ofab201.
3. Song G, Liang G, Liu W. Fungal co-infections associated with global COVID-19 pandemic: a clinical and diagnostic perspective from China. Mycopathologia 2020;31:1–8. DOI: 10.1007/s11046-020-00462-9.
4. Fekkar A, Lampros A, Mayaux J, Poignon C, Demeret S, Constantin JM, et al. Occurrence of invasive pulmonary fungal infections in patients with severe COVID-19 admitted to the ICU. Am J Respir Crit Care Med 2021;203(3):307–317. DOI: 10.1164/rccm.202009-3400OC.
5. Garg D, Muthu V, Sehgal IS, Ramachandran R, Kaur H, Bhalla A, et al. Coronavirus disease (Covid-19) associated mucormycosis (CAM): case report and systematic review of literature. Mycopathologia 2021;5:1–10. DOI: 10.1007/s11046-021-00528-2.
6. Mohindra S, Mohindra S, Gupta R, Bakshi J, Gupta SK. Rhinocerebral mucormycosis: the disease spectrum in 27 patients. Mycoses 2007;50(4):290–296. DOI: 10.1111/j.1439-0507.2007.01364.x.
7. Scheckenbach K, Cornely O, Hoffmann TK, Engers R, Bier H, Chaker A, et al. Emerging therapeutic options in fulminant invasive rhinocerebral mucormycosis. Auris Nasus Larynx 2010;37(3):322–328. DOI: 10.1016/j.anl.2009.09.001.
8. Munir N, Jones NS. Rhinocerebral mucormycosis with orbital and intracranial extension: a case report and review of optimum management. J Laryngol Otol 2007;121(2):192–195. DOI: 10.1017/S0022215106003409.
9. Vairaktaris E, Moschos MM, Vassiliou S, Baltatzis S, Kalimeras E, Avgoustidis D, et al. Orbital cellulitis, orbital subperiosteal and intraorbital abscess. Report of three cases and review of the literature. J Craniomaxillofac Surg 2009;37(3):132–136. DOI: 10.1016/j.jcms.2008.10.007.
10. Gillespie MB, O’Malley BW. An algorithmic approach to the diagnosis and management of invasive fungal rhinosinusitis in the immunocompromised patient. Otolaryngol Clin North Am 2000;33(2):323–334. DOI: 10.1016/s0030-6665(00)80008-0.
11. Ballester DG, González-García R, García CM, Ruiz-Laza L, Gil FM. Mucormycosis of the head and neck: report of five cases with different presentations. J Craniomaxillofac Surg 2012;40(7):584–591. DOI: 10.1016/j.jcms.2011.10.015.
12. Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005;41(5):634–653. DOI: 10.1086/432579.
13. Singh AK, Gupta R, Ghosh A, Misra A. Diabetes in COVID-19: Prevalence, pathophysiology, prognosis and practical considerations. Diabetes Metab Syndr 2020;14(4):303–310. DOI: 10.1016/j.dsx.2020.04.004.
14. John TM, Jacob CN, Kontoyiannis DP. When uncontrolled diabetes mellitus and severe COVID-19 converge: the perfect storm for mucormycosis. J Fungi 2021;7(4):298. DOI: 10.3390/jof7040298.
15. Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol 2010;47(3):193–199. DOI: 10.1007/s00592-009-0109-4.
16. Kothandaraman N, Rengaraj A, Xue B, Yew WS, Velan SS, Karnani N, et al. COVID-19 endocrinopathy with hindsight from SARS. Am J Physiol Endocrinol Metab 2021;320(1):E139–E150. DOI: 10.1152/ajpendo.00480.2020.
17. Group WHOREAfC-TW, Sterne JAC, Murthy S, Diaz JV, Slutsky AS, Villar J, et al. Association between administration of systemic corticosteroids and mortality among critically Ill patients with COVID-19 a meta-analysis. JAMA 2020;324(13):1330–1341. DOI: 10.1001/jama.2020.17023.
18. Koushiappi E, Porfyridis I, Karagiannis C, Adamide T, Georgiou A. Pulmonary mucormycosis (zygomycosis) presenting as an infective exacerbation of chronic obstructive pulmonary disease. Eur J Case Rep Intern Med 2018;5(12). DOI: 10.12890/2018_000995.
19. Sharma S, Grover M, Bhargava S, Samdani S, Kataria T. Post coronavirus disease mucormycosis: a deadly addition to the pandemic spectrum. J Laryngol Otol 2021;135(5):442–447. DOI: 10.1017/S0022215121000992.
20. Mehta S, Pandey A. Rhino-orbital mucormycosis associated with COVID-19? Cureus 2020;12(9):e10726. DOI: 10.7759/cureus.10726.
21. Ibrahim A, Spellberg B, Edwards Jr J. Iron acquisition: a novel prospective on mucormycosis pathogenesis and treatment. Curr Opin Infect Dis 2008;21(6):620. DOI: 10.1097/QCO.0b013e3283165fd1.
22. Rawson TM, Moore LS, Zhu N, Ranganathan N, Skolimowska K, Gilchrist M, et al. Bacterial and fungal coinfection in individuals with coronavirus: a rapid review to support COVID-19 antimicrobial prescribing. Clin Infect Dis 2020;71(9):2459–2468. DOI: 10.1093/cid/ciaa530.
23. Zhang H, Zhang Y, Wu J, Li Y, Zhou X, Li X, et al. Risks and features of secondary infections in severe and critical ill COVID-19 patients. Emerg Microbes Infect 2020;9(1):1958–1964. DOI: 10.1080/22221751.2020.1812437.
24. Yang X, Yu Y, Xu J, Shu H, Liu H, Wu Y, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020;8(5):475–481. DOI: 10.1016/S2213-2600(20)30079-5.
25. Banerjee M, Pal R, Bhadada SK. Intercepting the deadly trinity of mucormycosis, diabetes and COVID-19 in India. Postgrad Med J 2021. DOI: 10.1136/postgradmedj-2021-140537.
27. Elinav H, Zimhony O, Cohen MJ, Marcovich AL, Benenson S. Rhinocerebral mucormycosis in patients without predisposing medical conditions: a review of the literature. Clin Microbiol Infect 2009;15(7):693–697. DOI: 10.1111/j.1469-0691.2009.02884.x.
28. Goldstein EJ, Spellberg B, Walsh TJ, Kontoyiannis DP, Edwards J Jr, Ibrahim AS. Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 2009;48(12):1743–1751. DOI: 10.1086/599105.
29. Mucormycosis key facts. India: World Health Organization; 2021. Available from: https://www.who.int/india/emergencies/coronavirus-disease-(covid-19)/mucormycosis [Last Accessed on July 6, 2021].
30. Mucormycosis–people at risk and prevention. Center for Disease Control and Prevention; 2021. Available from: https://www.cdc.gov/fungal/diseases/mucormycosis/risk-prevention.html [Last Accessed on July 7, 2021].
© The Author(s). 2021 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.