[Downloaded free from http://www.jorr.org on Sunday, December 11, 2022, IP: 250.112.173.

92]

Review Article

Mucormycosis: An emerging concern of orofacial

complication in COVID‑19 infection
Anam Mushtaq, Reshi Iram Shafi
Department of Pediatric and Preventive Dentistry, ITS Dental College, Hospital and Research Centre, Greater Noida, Uttar Pradesh, India

Abstract Coronavirus disease (COVID‑19) infection has been seen to be associated with secondary bacterial and fungal
infections. Mucormycosis has been increasingly reported in patients with COVID‑19 infection, especially
those with underlying medical conditions such as diabetes mellitus and on steroid therapy. It is an acute
invasive fungal infection primarily affecting individuals with suppressed immune system. This article presents
the characteristics of mucormycosis infection and its etiological association with COVID‑19. Its diagnosis
and management based on the current guidelines have also been discussed in this literature review.

Keywords: COVID‑19, immunosuppression, mucormycosis

Address for correspondence: Dr. Anam Mushtaq, Department of Pediatric and Preventive Dentistry, ITS Dental College, Hospital and Research Centre,
Greater Noida, Uttar Pradesh, India.
E‑mail: anam_a5@hotmail.com
Submitted: 03‑Nov‑2021 Revised: 29‑Apr‑2022 Accepted: 11‑May‑2022 Published: 01-Jul-2022

INTRODUCTION a large number of cases with mucormycosis have been

Coronavirus disease  (COVID‑19) disease pattern
can range from mild‑to‑severe life‑threatening
conditions of pneumonia which may be associated with
superadded coinfections of bacterial and fungal origin.[1]
Immunocompromised patients that undergo corticosteroid
therapy, artificial ventilation, and those in intensive
care units with prolonged hospitalization are prone to
nosocomial infections. Underlying medical conditions such
as diabetes mellitus further predispose the patients to the
risk of coinfections. The development of opportunistic
infections such as candidiasis, aspergillosis, mucormycosis,
pneumocystis jirovecii, pneumonia, and superinfection by
Acinetobacter baumannii and Staphylococcus aureus has been seen
associated with COVID‑19  patients as well.[2,3] Recently,
reported in patients with active COVID‑19 infection as
well as those postinfection.[1,4,5]
WHAT IS MUCORMYCOSIS?
Mucormycosis is an angioinvasive fungal disease with
characteristic hyphal invasion of tissues leading to infarction
and necrosis.[6] It is caused by fungi of the Mucorales order
underclass zygomycetes.[7] Mucormycosis has a variable
clinical presentation based on anatomic involvement
that may be pulmonary, gastrointestinal, cutaneous,
sinus‑related (pansinusitis, Rhino‑orbital, and rhinocerebral),
or may even be disseminated.[8] The predominant forms
of mucormycosis include rhino‑orbito‑cerebral and
pulmonary mucormycosis and the most common

This is an open access journal, and articles are distributed under the terms of the Creative
Access this article online Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to
remix, tweak, and build upon the work non‑commercially, as long as appropriate credit
Quick Response Code:
Website: is given and the new creations are licensed under the identical terms.

www.jorr.org
For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com

DOI: How to cite this article: Mushtaq A, Shafi RI. Mucormycosis: An emerging
10.4103/jorr.jorr_72_21 concern of orofacial complication in COVID‑19 infection. J  Oral Res Rev
2022;14:161-4.

© 2022 Journal of Oral Research and Review | Published by Wolters Kluwer - Medknow 161
[Downloaded free from http://www.jorr.org on Sunday, December 11, 2022, IP: 250.112.173.92]
Mushtaq and Shafi: Mucormycosis in COVID‑19 infection
etiological fungi causing mucormycosis include Rhizopus
spp., Rhizomucor, Mucor spp., and Lichtheimia spp.[9,10]
Mucormycosis infection progresses rapidly over a short
span of time as the Mucorales release large quantity of
airborne spores due to rapid growth and division. It affects
mainly the immunocompromised patients with severe
comorbidities such as uncontrolled diabetes mellitus,
malignancies, patients receiving organ transplantation
and hematopoietic stem cell transplantation, cases of
severe trauma or burn, corticosteroid therapy, and
severe neutropenia.[11] The infection is associated with
high‑mortality rates ranging from 20% to 50% in
localized forms and 70% to 90% in disseminated type of
mucormycosis.[12]
In the Asian continent, diabetes mellitus is the most
common risk factor, whereas in the United States and
European region, malignancies and transplantation pose
the highest risk for mucormycosis.[13‑15]
IMMUNE SUPPRESSION IN COVID‑19
Host immunity and cytokine storm
SARS‑CoV‑2 infection itself causes impairment in the
cell‑mediated immune response leading to reduced
CD4+ T and CD8+ T cell numbers. Clinical deterioration
often occurs rapidly in severe cases which are caused
by a systemic hyperinflammation referred as “cytokine
storm”. There is an overwhelming increase in the plasma
concentrations of pro‑inflammatory cytokines such as
interleukin  (IL)‑6, IL‑10, granulocyte‑colony stimulating
factor  (G‑CSF), monocyte chemoattractant protein 1,
macrophage inflammatory protein 1α, and tumor necrosis
factor‑α.[16] Immunosuppression is deemed the most critical
pathophysiologic phenomenon related to COVID‑19
infection. According to Zhou et al., 50% of COVID‑19
deaths are in patients developing hospital‑acquired
secondary infections. [17] However, according to an
immunoassay study by Remy et al. conducted on
COVID‑19 patients, it is the host immunity dysfunctioning
more than the hypercytokinemia‑induced organ injury
that occurs as an immunologic defect in COVID‑19
eventually reducing the effector immune cells and causing
functional T‑cell and monocyte function defects.[18] All
these immune dysregulating events eventually lead to
an immuncompromised state of patients making them
prone to secondary infections. Another term associated
with this severe immunologic imbalance is “viral sepsis”
in severe COVID‑19 where patients are unable to obtain
viral clearance due to coexisting immunosuppression and
hyperinflammation.[19]
162 Journal of Oral Research and Review | Volume 14 | Issue 2 | July-December 2022
Corticosteroid therapy
Va r i o u s g u i d e l i n e s f o r t h e m a n a g e m e n t o f
COVID‑19  patients suggest the use of corticosteroids
to provide anti‑inflammatory therapy. Although it is
beneficial in reducing disease severity, corticosteroids act as
a double‑edged sword. It has been seen that steroids such
as prednisone, dexamethasone, and methylprednisolone
reduce the need for mechanical ventilation in admitted
patients.[20] Prolonged steroid administration can lead
to adverse effects such as fluid retention, hypertension,
psychological problems, increased body weight, increased
risk of opportunistic infections, osteoporosis, and ocular
problems such as glaucoma and cataract.[21] Delayed viral
clearance and an increase in secondary infections related to
corticosteroid use have also been observed. A multicentric
observational study highlights the significant risk in the
incidence of angioinvasive maxillofacial fungal infections
in patients with diabetes mellitus being treated for
COVID‑19 infection associated with the administration
of corticosteroid.[22]
Medical comorbidities
Worsening of glycemic control in diabetic patients can
occur due to COVID‑19 infection itself as well as treatment
such as steroid therapy can cause an exacerbation of
hyperglycemia and eventually lead to fungal infections
such as mucormycosis.[22] Uncontrolled diabetes along with
prolonged high-dose corticosteroid therapy can alter and
reduce the functioning of phagocytes which forms the
main host defense mechanism to ward off mucormycosis
entry and infection in tissues.[23] In severe cases of viral
pneumonia-associated acute respiratory distress syndrome,
blood acidosis along with increased serum ferritin levels
also increase the risk for mucormycosis by enabling
increased uptake of iron by Mucorales species leading to
a rapidly spreading fungal infection.[11]
Severe cases that require mechanical ventilation,
intubation, oxygen therapy, and use of humidifiers during
hospitalization also predispose to secondary infections.[24]
Literature search and evidence‑based review reveal that
mucormycosis reports from India and globally have seen
a sudden upsurge recently and a definite association with
COVID‑19 infection is observed.[1,4,5,22,25‑28]
CLINICAL FEATURES OF MUCORMYCOSIS
Rhino‑orbital‑cerebral mucormycosis is the most prevalent
form in patients with uncontrolled diabetes mellitus.
General nonophthalmic signs and symptoms include
fever, headache, and altered mental status. Orofacial
manifestations can be in the form of facial pain and
[Downloaded free from http://www.jorr.org on Sunday, December 11, 2022, IP: 250.112.173.92]
Mushtaq and Shafi: Mucormycosis in COVID‑19 infection
swelling, nasal discharge or epistaxis, nasal and palatal
ulcerations, and sinusitis. Necrosis of oral tissues can be
observed as a black eschar which indicates local invasion.
It can even manifest as severe forms of bony destruction,
paresthesia, and facial nerve paralysis. Ophthalmic signs
include ophthalmoplegia, corneal edema, decreased vision,
proptosis, or even cavernous sinus thrombosis.[11,29]
DIAGNOSIS TESTS
M u c o r my c o s i s c a n b e d e t e c t e d u s i n g d i r e c t
m i c r o s c o p y w i t h f l u o r e s c e n t s t a i n s s u ch a s
Periodic acid–Schiff stain (PAS)  and  Grocott's Methenamine
Silver Stain (GMS) in sputum and cutaneous lesions which
reveal nonseptate or pauciseptate ribbon‑shaped hyphae
of Mucorales. Culture in a routine media at temperatures
of 30°C and 37°C shows cotton white‑or grayish‑black
colonies of fungal growth to delineate fungus species.
Molecular tests for the diagnosis of mucormycosis include
polymerase chain reaction (PCR) assays, High Resolution
Melt (HRM), and target gene: 18s, 28s, or rDNA analysis.[25]
Lateral flow immunoassay has also been seen to be promising
and more convenient for detecting Mucorales cell wall
fucomannan from point‑of‑care testing of bronchoalveolar
lavage, serum, urine, and tissue samples.[30] Specific breath
profiles of the volatile metabolite sesquiterpene from
different Mucorales species can aid in differentiating
infections from each other.[30]
MANAGEMENT
Improvisation of survival rates can be achieved by a prompt
diagnosis and therapeutic intervention which encompasses
a multidisciplinary approach involving medical, surgical,
radiological, and a sound laboratory facility. Antifungal
therapy and surgical debridement of necrotic lesions along
with the management of underlying medical comorbidities
and immunosuppression are effective in the treatment
of mucormycosis. Amphotericin B (AMB) is considered
the first‑line treatment of mucormycosis. In severe cases,
combination therapy of AMB with isavuconazole or
posaconazole may also be given. Surgical debridement
of lesions should be performed along with antifungal
medication whenever possible.[31] Liposomal AMB is
recommended over conventional AMB deoxycholate due
to lesser toxicity, especially in patients with tolerance and
renal dysfunction.[31,32] An initial dose of 5 mg/kg body
weight or double dosage in patients with  Central Nervous
system (CNS) involvement is advised till an appropriate
and favorable response to the treatment is manifested.
This may be followed by prescribing sustained release
Journal of Oral Research and Review | Volume 14 | Issue 2 | July-December 2022 163
of 300 mg posaconazole twice a day for the 1st day and
later 300 mg every day. Posaconazole is advised as salvage
therapy in cases with AMB tolerance. Alternatively, 200 mg
isavuconazole thrice a day for 2  days can also be given
instead of posaconazole followed by 200 mg daily.[33] The
Indian Council of Medical Research (ICMR) has recently
issued guidelines on the management of mucormycosis in
COVID‑19 patients. ICMR advises monitoring of diabetic
patients carefully to avoid progression to ketoacidosis,
judicious use of corticosteroids, and antimicrobials. The
use of sterile water in humidifiers for oxygen therapy is
also advised. Definitive medical management involves the
installation of peripherally inserted central catheter line
and systemic hydration with infusion of normal saline
intravenously before AMB administration. Antifungal
therapy is advised for at least 4–6  weeks till signs and
symptoms subside. A  strict clinical and radiographic
monitoring of patients is advised to assess treatment
response and progression of infection.[34]
CONCLUSION
COVID‑19‑associated mucormycosis is a significant
secondary infection that is being frequently reported in
COVID‑19 patients. Diabetes mellitus and corticosteroid
therapy‑induced immunosuppression have been seen to be
closely associated with the development of mucormycosis
as an opportunistic infection. It is advised that steroids be
used judiciously in hospitalized patients to avoid severe
immune suppression. Dental practitioners must also be
vigilant in diagnosis and detecting early signs and symptoms
of common forms of orofacial mucormycosis to initiate a
prompt treatment for better outcomes.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Mehta  S, Pandey  A. Rhino-orbital mucormycosis associated with
COVID-19. Cureus 2020;12:e10726.
2. Sharifipour E, Shams S, Esmkhani M, Khodadadi J, Fotouhi-Ardakani R,
Koohpaei  A, et al. Evaluation of bacterial co-infections of the
respiratory tract in COVID-19 patients admitted to ICU. BMC Infect
Dis 2020;20:646.
3. Gangneux  JP, Bougnoux  ME, Dannaoui  E, Cornet  M, Zahar  JR.
Invasive fungal diseases during COVID-19: We should be prepared.
J Mycol Med 2020;30:100971.
4. Werthman-Ehrenreich  A. Mucormycosis with orbital compartment
syndrome in a patient with COVID-19. Am J Emerg Med
2021;42:264.e5-8.
5. Garg D, Muthu V, Sehgal IS, Ramachandran  R, Kaur H, Bhalla A,
et al. Coronavirus disease (Covid-19) associated mucormycosis (CAM):
[Downloaded free from http://www.jorr.org on Sunday, December 11, 2022, IP: 250.112.173.92]
Mushtaq and Shafi: Mucormycosis in COVID‑19 infection
Case report and systematic review of literature. Mycopathologia
2021;186:289-98.
6. Frater JL, Hall GS, Procop GW. Histologic features of zygomycosis:
Emphasis on perineural invasion and fungal morphology. Arch Pathol
Lab Med 2001;125:375-8.
7. 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.
8. Jeong W, Keighley C, Wolfe R, Lee WL, Slavin MA, Kong DC, et al.
The epidemiology and clinical manifestations of mucormycosis:
A systematic review and meta-analysis of case reports. Clin Microbiol
Infect 2019;25:26-34.
9. Serris A, Danion F, Lanternier F. Disease entities in mucormycosis.
J Fungi (Basel) 2019;5:23.
10. Gomes MZ, Lewis RE, Kontoyiannis DP. Mucormycosis caused by
unusual mucormycetes, non-Rhizopus, -Mucor, and -Lichtheimia species.
Clin Microbiol Rev 2011;24:411-45.
11. Prakash H, Chakrabarti A. Global epidemiology of mucormycosis.
J Fungi (Basel) 2019;5:26.
12. Sipsas NV, Gamaletsou MN, Anastasopoulou A, Kontoyiannis DP.
Therapy of mucormycosis. J Fungi (Basel) 2018;4:90.
13. Chakrabarti A, Das A, Sharma A, Panda N, Das S, Gupta KL, et al.
Ten years’ experience in zygomycosis at a tertiary care centre in India.
J Infect 2001;42:261-6.
14. Skiada A, Pagano L, Groll A, Zimmerli S, Dupont B, Lagrou K, et al.
Zygomycosis in Europe: Analysis of 230 cases accrued by the registry
of the European Confederation of Medical Mycology  (ECMM)
Working Group on Zygomycosis between 2005 and 2007. Clin
Microbiol Infect 2011;17:1859-67.
15. Kontoyiannis DP, Yang H, Song J, Kelkar SS, Yang X, Azie N, et al.
Prevalence, clinical and economic burden of mucormycosis-related
hospitalizations in the United States: A retrospective study. BMC Infect
Dis 2016;16:730.
16. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology:
A review. Clin Immunol 2020;215:108427.
17. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk
factors for mortality of adult inpatients with COVID-19 in Wuhan,
China: A retrospective cohort study. Lancet 2020;395:1054-62.
18. Remy KE, Mazer M, Striker DA, Ellebedy AH, Walton AH, Unsinger J,
et al. Severe immunosuppression and not a cytokine storm characterizes
COVID-19 infections. JCI Insight 2020;5:140329.
19. Riva  G, Nasillo  V, Tagliafico  E, Trenti  T, Comoli  P, Luppi  M.
COVID-19: More than a cytokine storm. Crit Care 2020;24:549.
20. van Paassen  J, Vos  JS, Hoekstra  EM, Neumann  KM, Boot  PC,
Arbous SM. Corticosteroid use in COVID-19 patients: A systematic
review and meta-analysis on clinical outcomes. Crit Care 2020;24:696.
21. Mattos-Silva P, Felix NS, Silva PL, Robba C, Battaglini D, Pelosi P,
164 Journal of Oral Research and Review | Volume 14 | Issue 2 | July-December 2022
et al. Pros and cons of corticosteroid therapy for COVID-19 patients.
Respir Physiol Neurobiol 2020;280:103492.
22. Moorthy A, Gaikwad R, Krishna S, Hegde R, Tripathi KK, Kale PG,
et al. 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;20:418-25.
23. Spellberg  B, Edwards J Jr., Ibrahim  A. Novel perspectives on
mucormycosis: Pathophysiology, presentation, and management. Clin
Microbiol Rev 2005;18:556-69.
24. Clancy CJ, Nguyen MH. Coronavirus disease 2019, Superinfections,
and antimicrobial development: What can we expect? Clin Infect Dis
2020;71:2736-43.
25. Song G, Liang G, Liu W. Fungal co-infections associated with global
COVID-19 pandemic: A  clinical and diagnostic perspective from
China. Mycopathologia 2020;185:599-606.
26. 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 Rep 2021;14:e241663.
27. Mekonnen  ZK, Ashraf   DC, Jankowski  T, Grob  SR, Vagefi  MR,
Kersten  RC, et al. Acute invasive rhino-orbital mucormycosis in a
patient with COVID-19-associated acute respiratory distress syndrome.
Ophthalmic Plast Reconstr Surg 2021;37:e40-80.
28. 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;135:442-7.
29. Vaughan  C, Bartolo  A, Vallabh  N, Leong  SC. A  meta-analysis of
survival factors in rhino-orbital-cerebral mucormycosis-has anything
changed in the past 20 years? Clin Otolaryngol 2018;43:1454-64.
30. Skiada  A, Pavleas  I, Drogari-Apiranthitou  M. Epidemiology and
diagnosis of mucormycosis: An update. J Fungi (Basel) 2020;6:265.
31. Cornely OA, Alastruey-Izquierdo A, Arenz D, Chen SC, Dannaoui E,
Hochhegger B, 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:e405-21.
32. Hiemenz  JW, Walsh  TJ. Lipid formulations of amphotericin
B: Recent progress and future directions. Clin Infect Dis
1996;22 Suppl 2:S133-44.
33. Available from: https://www.dghs.gov.in/WriteReadData/News/20
2106090337278932402DteGHSComprehensiveGuidelinesforMana
gementofCOVID-19inCHILDREN_9June2021.pdf.  [Last accessed
on 2022 Feb 12].
34. Available from: https://www.icmr.gov.in/pdf/covid/techdoc/
Mucormycosis_ADVISORY_FROM_ICMR_In_COVID19_time.
pdf. [Last accessed on 2021 Apr 17].