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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 3  |  Page : 86-89

The nexus between mucormycosis and COVID-19: A review


1 Department of Oral & Maxillofacial Surgery, Vyas Dental College and Hospital, Jodhpur, Rajasthan, India
2 Department of Oral Medicine Diagnosis and Radiology, Vyas Dental College and Hospital, Jodhpur, Rajasthan, India

Date of Submission18-Jun-2021
Date of Acceptance21-Jul-2021
Date of Web Publication27-Sep-2021

Correspondence Address:
Dr. Sugandha Arya
Department of Oral Medicine Diagnosis and Radiology, Vyas Dental College and Hospital, Jodhpur, Rajasthan.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/INJO.INJO_22_21

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  Abstract 

Mucormycosis is a disease of the diseased. Infection arises through inhalation of spores, contamination of the traumatized tissue, ingestion, and direct inoculation. High incidence of mucormycosis is seen in uncontrolled diabetic or immuno-compromised patients. Recently, its appearance has been linked with the COVID-19-affected individuals who are being treated by excess steroids or on other immunosuppressants and those with history of systemic disease. Therefore, for successful management, excessive steroids and immunosuppressive drugs should be avoided in mild cases of COVID-19.

Keywords: COVID-19, immunosuppressants, mucormycosis, rhinocerebral, rhinomaxillary, rhinoorbital


How to cite this article:
Raju SK, Kurdekar RS, Prakash V J, Vyas A, Arya S. The nexus between mucormycosis and COVID-19: A review. Int J Oral Care Res 2021;9:86-9

How to cite this URL:
Raju SK, Kurdekar RS, Prakash V J, Vyas A, Arya S. The nexus between mucormycosis and COVID-19: A review. Int J Oral Care Res [serial online] 2021 [cited 2021 Nov 29];9:86-9. Available from: https://www.ijocr.org/text.asp?2021/9/3/86/326822




  Introduction Top


Mucormycosis (black fungus) is an emerging angioinvasive infection caused by the ubiquitous filamentous fungi belonging to the class of Zygomycetes.[1],[2] It is a life-threatening, opportunistic, and fulminant fungal infection.[3],[4],[5] Baker, an American pathologist, coined the term mucormycosis. Paltauf, the German pathologist, reported the first case of mucormycosis in 1885 and described it as Mycosis Mucorina.[6]


  Epidemiology Top


The prevalence of mucormycosis in India is reported to be approximately 0.14 cases per 1000 population, which is about 80 times the prevalence reported in other developed countries.[7]


  Pathophysiology Top


Mucor is a saprophytic aerobic fungus; its spores exist widely in nature and are spread in soil, air, food, and decaying organic material.[8] Because of its associated low virulence potential, it may occur in the nasal mucosa of healthy people as a commensal. It can survive in vitro for 2–5 days.[8] If the patient becomes immunosuppressed, this fungus may germinate within the par nasal sinuses and spread intracranially or to other nearby structures such as the orbit. Infection arises by inhalation of spores that get deposited in pulmonary alveoli.[9] Their germination is favored by low oxygen, high glucose, acidic medium, and high iron levels. It also spreads via ingestion or contamination of traumatized mucosa like ulcer or extraction socket by fungal spores. The hallmarks of disease caused by these organisms are angioinvasion, thrombosis, ischemia, and necrosis of involved hard and soft tissue.[10],[11]


  Risk Factors Top


Risk factors include uncontrolled diabetes mellitus (DM), especially ketoacidosis, steroid use, extremes of age, blood dyscrasias, neutropenia, especially with hematological malignancy, HIV and AIDS, renal insufficiency, organ or stem cell transplantation, irradiation, iron overload, skin trauma, broad-spectrum antibiotics, hepatitis, tuberculosis, malignant disease, intravenous drug abuse, by the administration of corticosteroids and immunosuppressive drugs, prophylactic voriconazole for aspergillosis, malnutrition, penetrating trauma/burns, concurrent hemodialysis (especially when using the chelating agent desferrioxamine), use of occlusive dressings/boards, tongue blades, blast injury, malt/lumbar industrial workers, construction workers, and poor wound care.[11],[12]

DM is observed to be a major predisposing factor in 36–88% of all mucormycosis cases. Mucormycosis can occur in both non-diabetic and metabolically controlled diabetic patients as well but when the disease becomes uncontrolled, it leads to the impairment of neutrophil function, phagocytosis, and oxidative reactions along with causing an increase in free iron level which acts as a substrate and thereby enhances the growth of mucormycosis.[13],[14]

More recently, mucormycosis is commonly seen to be associated with corona virus as its predisposing factor. Coronavirus disease 2019 (COVID-19) is an infection that is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 disease has a propensity to cause extensive pulmonary involvement and subsequent alveolo-interstitial pathology that may predispose to invasive fungal infections of the airways including the sinuses and the lungs.[1],[15]


  Clinical Manifestations Top


Clinically, mucormycosis is not associated with any specific age group and both the sexes are equally affected. It occurs in one of the six forms: rhino cerebral, pulmonary, cutaneous, gastrointestinal, disseminated, and miscellaneous. The rhinocerebral form is observed to be the most common form which accounts for 30–50% of all cases of mucormycosis, with Rhizopus being the predominant pathogen involved in its occurrence.[8],[16],[17] This form has been concomitantly associated with poorly controlled DM and diabetic ketoacidosis. The rhinocerebral form is further subdivided into two subtypes: a highly fatal rhino-orbito-cerebral form which is invasive and may involve the ophthalmic and internal carotid arteries and a less fatal rhinomaxillary form which involves the sphenopalatine and greater palatine arteries, thereby resulting in thrombosis of the turbinate and necrosis of the palate.[8],[16],[17]

Site of invasion: Nose, paranasal sinuses, lungs, kidneys, etc.

Mode of spread: Either through direct extension or through blood vessels/lymph vessels.

Sites involved: Palate being the most common site followed by buccal mucosa, maxillary and mandibular lip, and mandible.[8],[16],[17]

Oral considerations: Symptoms involving the oral, cranial, and facial structures account for about 60% of all cases. Intraorally, ulcer with raised erythematous borders with surface of the ulcer appearing black and necrotic with areas of denudation is seen. Other associated signs and symptoms include nasal obstruction, bloody nasal discharge, facial pain and headache, visual disturbances, and facial paralysis.[17]


  Diagnosis Top


It can be done by various methods such as culture, potassium hydroxide smears, and histopathological examination of biopsied specimen by routine hematoxylin and eosin stains as well as by special stains and can confirm the clinical diagnosis with the appearance of right-branching aseptate hyphae, which are considered typical of mucor species, along with evidence of angioinvasion and tissue necrosis. Other laboratory diagnostic modalities include molecular detection of zygomycetes. However, the results so far have been observed to be less than promising. Cerebrospinal fluid analysis has also been reported as helpful in the diagnosis.[8],[18],[19]


  Differential Diagnosis Top


Wegener’s granulomatosis, tuberculosis, squamous cell carcinoma, malignant salivary gland tumor, and tertiary syphilis, because of these pathologies, commonly show involvement of palate in the form of a solitary ulcer like that of mucormycosis.[12]


  Imaging Modalities Top


A clinical suspicion of mucormycosis requires confirmation by radiological examination. Radiographically, opacification of sinuses in conjunction with patchy effacement of bony walls of sinuses may be observed. A computed tomography scan with contrast shows membrane or periosteal thickening and bony disruption. Magnetic resonance imaging scan can demonstrate erosion or destruction of bone and help to delineate the extent of disease.[8],[12],[20]


  Treatment For Mucormycosis Top


It is based on three main principles: reversal of underlying predisposing conditions, prompt initiation of antifungal therapy, and surgical intervention when appropriate.[21]

The role of surgery[22]: Extensive surgical debridement to remove necrotic tissue and establish sinus drainage is essential in the treatment as the involved blood vessels are ischemic and the antifungal drugs would not reach their target tissues. Surgical intervention has been associated with favorable outcome but the guidelines related to the timing and extent of appropriate surgical management have not been clear. Although orbital exenteration has been considered in the context of intracranial spread due to lack of evidence-based studies, surgical intervention is considered. Irrigation of the surgical site with amphotericin B solution has also been proposed based on the vaso-occlusive nature of the infection, leading to reduced delivery of antibiotics to infected areas.

Antifungal therapy: Treatment of the underlying systemic disease, especially control of the glycemic state or modification/cessation of immunosuppressive drugs, helps in decreasing the morbidity and mortality associated with mucormycosis. Amphotericin B deoxycholate when administered intravenously (1–1.5 mg/kg daily) is proven to be the primary therapy for mucormycosis.[12],[20],[23]

Amphotericin B is the polyene antifungal drug which after binding to ergosterol alters the permeability in the fungal cell membrane. Due to its toxicity, the patient has to be monitored for renal damage and anaphylaxis. Liposomal amphotericin B in the initial dose of 5 mg/kg body weight (10 mg/kg body wt. in case of CNS involvement) is the treatment of choice. Each vial contains 50 mg. It should be diluted in 5% or 10% dextrose; it is incompatible with normal saline/Ringer’s lactate. It has to be continued till a favorable response is achieved and disease is stabilized which may take several weeks. Conventional amphotericin B (deoxycholate) in the dose 1–1.5 mg/kg may be used if liposomal form is not available and renal functions and serum electrolytes are within normal limits. Liposomal amphotericin B is less nephrotoxic than conventional amphotericin B.[12],[20],[23]

Iron chelation therapy: Deferasirox and Deferiprone are new iron chelators, which in contrast to Deferoxamine cannot be utilized by the fungi as siderophores. Deferasirox has also been used successfully as salvage therapy in a case of rhinocerebral mucormycosis opening up new areas of clinical research.[12],[20],[24]

Adjunctive therapies: Hyperbaric oxygen therapy has been used as an adjunct to aggressive surgical debridement. Granulocyte colony-stimulating factor may also be administered to improve host defenses and also to enhance leukocyte count to promote immunity.[12],[20],[25],[26],[27]

Prognosis: Prognosis rate has been reported to be 90% or more with mucormycosis, before the administration of amphotericin B and radical surgery. The overall survival rate of diabetic patients with mucormycosis who undergo treatment is approximately 60%.[27]


  Management of Mucormycosis in Covid-19-Affected Top


Since COVID-19 leads to immunosuppression, all physicians should therefore be mindful of the probability of mucormycosis in patients with COVID-19 illness, especially those with comorbidities and patients on immunosuppressive agents or on extensive steroids and broad-spectrum antibiotics which will be leading to the development or exacerbation of a pre-existing fungal disease in the coming future. Control of hyperglycemia, early treatment with liposomal amphotericin B, and surgery are therefore essential for the successful management of mucormycosis. Furthermore, the use of glucocorticoids in mild COVID-19 cases (without hypoxemia) or the utilization of higher dosages should be avoided. Drugs targeting immune pathways such as tocilizumab should be discouraged in the absence of a clear benefit. A delay of even 6 days in initiating treatment doubles the 30-day mortality from 35% to 66%.[1],[15],[16],[17],[28]


  Conclusion Top


Mucormycosis warrants emergency treatment. Despite improvements in imaging modalities leading to earlier diagnoses and increasing therapeutic options, it is still difficult to treat. Recently, it has been considered a concomitant factor in Covid-19 patients because of immunosuppression. Control of hyperglycemia, early treatment with liposomal amphotericin B, and surgery are essential for the successful management of mucormycosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Revannavar SM, Supriya PS, Samaga L, Vineeth VK. COVID-19 triggering mucormycosis in a susceptible patient: A new phenomenon in the developing world? BMJ Case Rep2021;14:e241663.  Back to cited text no. 1
    
2.
Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh TJ, Kontoyiannis DP . Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis 2012:54(Suppl. 1):s25-38.  Back to cited text no. 2
    
3.
Eucker J, Sezer O, Graf B, Possinger K. Mucormycoses. Mycoses 2001;44:253-60.  Back to cited text no. 3
    
4.
de Almeid OP, Scully C. Fungal infections of the mouth. Braz J Oral Sci 2002;1:19-25.  Back to cited text no. 4
    
5.
Suganya R, Malathi N, Vyshnavi Devi J. Mucormycosis: A brief review. J Pure Appl Microbiol 2019;13:161-5.  Back to cited text no. 5
    
6.
Paultauf A. Mycosis mucorina. Virchows Arch Path Anat 1885;102:543-64.  Back to cited text no. 6
    
7.
Skiada A, Pavleas I, Drogari-Apiranthitou M. Epidemiology and diagnosis of mucormycosis: An update. J Fungi (Basel) 2020;6:265.  Back to cited text no. 7
    
8.
Wadhawan R, Luthra K, Redd Y. Mucormycosis; deadlier infection: An overview. Acta Biomed Sci 2015;2:11-5.  Back to cited text no. 8
    
9.
Auluck A. Maxillary necrosis by mucormycosis. A case report and literature review. Med Oral Patol Oral Cir Bucal 2007;12:E360-4.  Back to cited text no. 9
    
10.
Sammassimo S, Mazzotta S, Tozzi M, Gentili S, Lenoci M, Santopietro R, et al. Disseminated mucormycosis in a patient with acute myeloblastic leukemia misdiagnosed as infection by Enterococcus faecium. J Clin Microbiol 2004;42:487-9.  Back to cited text no. 10
    
11.
Dai Y, Walker J, Ruba A, Faisal A. Mucormycosis in two community hospitals and the role of infectious disease consultation: A case series. Int J Gen Med 2013;6:833-8.  Back to cited text no. 11
    
12.
Arya S, Sharanamma B, Patil N. Rhino-maxillary form of mucormycosis causing sinusitis: A rare case report with review of literature. J Oral Med Oral Sur Oral Pathol Oral Radiol 2015;1:42-7.  Back to cited text no. 12
    
13.
Petrikkos G, Drogari-Apiranthitou M. Zygomycosis in immunocompromised non-haematological patients. Mediterr J Hematol Infect Dis 2011;3:e2011012.  Back to cited text no. 13
    
14.
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;41:634-53.  Back to cited text no. 14
    
15.
Sarkar S, Gokhale T, Choudhury SS, Deb AK. COVID-19 and orbital mucormycosis. Indian J Ophthalmol 2021;69:1002-4.  Back to cited text no. 15
[PUBMED]  [Full text]  
16.
Napoli JA, Donegan JO. Aspergillosis and necrosis of the maxilla: A case report. J Oral Maxillofac Surg 1991;49:532-4.  Back to cited text no. 16
    
17.
Burket LW, Greenberg MS, Glick M. Burkett’s Textbook of Oral Medicine. 10th ed. Philadelphia, PA: Lippincott. p. 496-7.  Back to cited text no. 17
    
18.
Chayakulkeeree M, Ghannoum MA, Perfect JR. Zygomycosis: The re-emerging fungal infection. Eur J Clin Microbiol Infect Dis 2006;25:215-29.  Back to cited text no. 18
    
19.
Cottrell DA, Mehra P, Malloy JC, Ghali GE. Midline palatal perforation. J Oral Maxillofac Surg 1999;57:990-5.  Back to cited text no. 19
    
20.
Sreenath G, Prakash AR, Kanth MR, Reddy PS, Vidhyadhari P. Rhinomaxillary mucormycosis with palatal perforation: A case report. J Clin Diagn Res 2014;8:ZD01-3.  Back to cited text no. 20
    
21.
Spellberg B, Edwards J, Ibrahim A. Novel perspectives on mucormycosis: Pathophysiology, presentation, and management. Clin Microbiol Rev 2005;18:556-69.  Back to cited text no. 21
    
22.
Mallis A, Mastronikolis SN, Naxakis SS, Papadas AT. Rhinocerebral mucormycosis: An update. Eur Rev Med Pharmacol Sci 2010;14:987-92.  Back to cited text no. 22
    
23.
Greenberg RN, Mullane K, van Burik JA, Raad I, Abzug MJ, Anstead G, et al. Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother 2006;50:126-33.  Back to cited text no. 23
    
24.
Ibrahim AS, Spellberg B, Edwards J. Iron acquisition: A novel perspective on mucormycosis pathogenesis and treatment. Curr Opin Infect Dis 2008;21:620-5.  Back to cited text no. 24
    
25.
Torres-Narbona M, Guinea J, Muñoz P, Bouza E. [Zygomycetes and zygomycosis in the new era of antifungal therapies]. Rev Esp Quimioter 2007;20:375-86.  Back to cited text no. 25
    
26.
Couch L, Theilen F, Mader JT. Rhinocerebral mucormycosis with cerebral extension successfully treated with adjuvant hyperbaric oxygen therapy. J Otolaryngol Head Neck Surg 1988;114:79194.  Back to cited text no. 26
    
27.
Liles WC, Huang JE, van Burik JA, Bowden RA, Dale DC. Granulocyte colony-stimulating factor administered in vivo augments neutrophil-mediated activity against opportunistic fungal pathogens. J Infect Dis 1997;175:1012-5.  Back to cited text no. 27
    
28.
Sen M, Lahane S, Lahane TP, Parekh R, Honavar SG. Mucor in a viral land: A tale of two pathogens. Indian J Ophthalmol 2021;69:244-52.  Back to cited text no. 28
[PUBMED]  [Full text]  




 

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   Abstract
  Introduction
  Epidemiology
  Pathophysiology
  Risk Factors
   Clinical Manifes...
  Diagnosis
   Differential Dia...
  Imaging Modalities
   Treatment For Mu...
   Management of Mu...
  Conclusion
   References

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