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Mucormycosis: The Black Fungus – An Insidious Killer

Elakshi Garg1, PulinSaluja1*, Aparna Dave1, Charu Khurana1, Manpreet Arora1, Radhika Rai1

1Faculty of Dental Sciences, SGT University, Gurugram, Haryana, India

*PulinSaluja([email protected])

ABSTRACT

The black fungus is not something unknown to the world of medical science but the terrifying face it has acquired in an already shaken up Covid-19 society is a matter of grave concern. The causative organism, Rhizopus oryzae is commonly found in soil and decaying organic matter. It is an opportunistic pathogen and the novel coronavirus has given it the golden opportunity to wreak havoc especially in a developing country like India where the second wave of Covid-19 has left the already distressed country even more vulnerable. The humid climate, unhygienic living conditions and attitude towards systemic health contribute to the pandemic resulting in the black fungus epidemic in India.

The disease is most likely to attack immunocompromised hosts and may manifest in various forms such as rhino- orbital, pulmonary, gastrointestinal, cutaneous and disseminated with the hallmark feature being ischemic tissue necrosis or cell death.

The triggered cytokine storm in the host and steroidal therapy and prolonged hospital stays for treatment have been playing key roles in the high incidence of Mucormycosis in Covid-19 patients. The disease has proven to be fatal or permanently disabling and can be contained only through prevention and early diagnosis.

The article aims to provide all the information currently available about the black fungus and how are Covid-19 and Mucormycosis related.

Keywords: Black Fungus, Coronavirus, India, Mucormycosis, Pandemic

Introduction

Black Fungus, scientifically known as Mucormycosis is an aggressive,angioinvasive infection caused by the filamentous fungi of the Mucorales order of the class of Zygomycetes.

Mucormycosisis the third most common invasive mycosis after candidiasis and aspergillosis.1 These filamentous fungi are typically found in the soil and decaying organic matter. They are opportunistic pathogens regularly cultured from the human nose, throat, and oral cavity of healthy asymptomatic individuals.2These mouldsenter the human body via respiratory tract or skin, and less commonly through the gastrointestinal tract, triggering an acute inflammatory response. In immunocompromised hosts, they invade the blood vessels, causing extensive vessel thrombosis and ischemic tissue necrosis.2

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The principal risk factors in mucormycosis include uncontrolled diabetes and diabetic ketoacidosis, prolonged steroid therapy, persistent neutropenia, desferoxamine therapy, hematological malignancies, illicit use of intravenous drugs, autoimmune disorders, prophylaxis with voriconazole or echinocandins, and the break in skin or mucosa due to trauma, burns and surgical wounds.1This disease is of growing concern in a Covid-19 hit world.

Incidence

An upsurge of mucormycosis is being reported throughout the world over the past two decades, however, the rise in developing countries including India has been worrisome. Three consecutive case series on mucormycosis have been reported from a single tertiary‐care centre in India: 129 cases over 10 years (1990–1999), 178 cases during the subsequent five years (2000–2004) and then 75 cases in an 18 month period during 2006–2007 Many other Indian centres have also subsequently published multiple series of this disease in different risk groups. This increasingly high incidence of mucormycosis in India has been attributed primarily to a continued increase in the patient population with uncontrolled diabetes. In fact, India has the second largest diabetic population globally (65.1 million), with nearly 70% of these cases being those of uncontrolled diabetes. Environmental factors, such as tropical and sub‐tropical humid climate and high temperature in major parts of India, further provide an optimum set‐up for survival of these fungi, and perhaps contribute to the disease prevalence.3

Pathophysiology

Host Defences- Polymorphonuclear phagocytes of normal hosts kill Mucorales by the generation of oxidative metabolites and the cationic peptides defensins. Hyperglycemia and acidosis impair the ability of phagocytes to kill the organisms by both oxidative and nonoxidative mechanisms.

Additionally, corticosteroid treatment affects the ability of bronchoalveolar macrophages to prevent reproduction of the spores in vitro or after in vivo infection induced by intranasal inoculation.4

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Fig 1: Host defenses and pathogenic mechanism of Mucorales in normal and susceptible patients.

In normal host, defenses such as phagocytes, endothelial cells and iron binding proteins act to prevent the supply of adequate amount of iron for fungal growth whereas in susceptible hosts there may be free serum iron due to certain conditions like acidosis which allow the fungus to scavenge iron, breakdown the defenses and enter the host vasculature.5

Role of Iron- A recently discovered important feature is the increased susceptibility to mucormycosis of patients with elevated available serum iron4. Iron is essential for growth and development, contributing to many vital processes of the cell. Therefore, pathogens use various processes for obtaining iron from the host. Recent data demonstrate that the level of available, unbound iron in serum plays an importantrole in uniquely predisposing patients with DKA to mucormycosis .In mammals, iron is bound to host carrier proteins, such as transferrin, ferritin, and lactoferrin to avoid toxic effects of free iron. This strategy of limiting iron availability is also a major universal host defense mechanism against microbes and against Mucorales in particular, because R. oryzae grows poorly in normal serum.6

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Fig 2: The figure shows the iron uptake mechanism of Mucorales. Heme, DKA and Deferoxamine serve as iron sources directly or indirectly which is taken by the fungi and transported intracellularly with the help of reductase-permease reaction or chelation through the copper oxidase- iron permease complex (FTR1 complex).6

Host-Pathogen Interaction-Mucormycosis infections are characterized by extensive angioinvasion that results in vessel thrombosis leading to tissue necrosis which further can prevent arrival of leukocytes and antifungal agents to the foci of infection. This angioinvasion likely contributes to the capacity of the organism to hematogenouslyspread to other target organs.

Consequently, damage of and penetration through endothelial cells or the extracellular matrix proteins lining blood vessels is likely to be a critical step in the pathogenetic strategy of R.

oryzae.6

Clinical Manifestations

Mucormycosis may present as pulmonary, sinus, rhinocerebral, skin or disseminated infection2. The clinical hallmark of mucormycosis is vascular invasion resulting in thrombosis and tissue infarction/necrosis.1

RHINOCEREBRAL MUCORMYCOSIS- It is the most common form of the disease. The initial symptoms of rhinocerebralmucormycosis are consistent with either sinusitis or periorbital cellulitis and include eye or facial pain and facial numbness, followed by the onset of conjunctival suffusion, blurry vision, and soft tissue swelling. Fever is variable and may be absent in up to half of cases; white blood cell counts are increased, as long as the patient has

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functioning bone marrow. If untreated, infection usually spreads from the ethmoid sinus to the orbit, resulting in loss of extraocular muscle function and proptosis. Marked chemosis may also be seen. The infection may rapidly extend into the neighboring tissues. Onset of signs and symptoms in the contralateral eye, with resulting bilateral proptosis, chemosis, vision loss, and ophthalmoplegia, is an ominous sign that suggests the development of cavernous sinus thrombosis.1

ORAL MANIFESTATIONS- Most commonly the disease presents itself as ulceration of the palate resulting from necrosis due to invasion of a palatal vessel. It is large and deep which may lead to exposure of the underlying bone. Other sites such as gingiva, lips and alveolar ridge may also be involved.

PULMONARY MUCORMYCOSIS- The second most common form of the disease is the Pulmonary form. Most patients with this present with non specific symptoms such as fever, cough, dyspnoea, myalgia and sometimes hemoptysis.7

Radiographic features are somewhat more specific in the case of pulmonary mucormycosis. CT scans at an early stage reveal ground glass apperances in perivascular regions which later developed into nodules or consolidations or both. Another characteristic radiographic feature of the disease is the ―reverse halo sign‖, which can be described as peripheral consolidation with central ground glass.8

Fig 3: ChestCT scan depicting solid nodule surrounded by ground glass opacity also known as the ‗Halo sign‘9

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GASTROINTESTINAL MUCORMYCOSIS- Older literature suggests that gastrointestinal mucormycosis primarily occurs in premature neonates and infants. Other rare cases have been found in immunocompromised patients having AIDS, SLE, etc. Symptoms include abdominal pain and distention, nausea, vomiting, hematochezia. Some patients are found to have intrabdomial abscess and gastric bleeding as well.

Hepatic mucormycosis is an extremely rare and fatal form which is usually diagnosed only during post-mortem.10

CUTANEOUS MUCORYCOSIS- The third most common form of the disease is cutaneous mucormycosis which spreads primarily through direct inoculation because of traumas like needle stick injury, animal stings and bites, motorvehicle injuries and burn injuries. The disease can locally invade through muscle,fat, fascia and underlying bone or secondarily by dissemination from other sites . Classical feature of cutaneous mucormycosis is the formation of a necrotic eschar. Most commonly involved sites include arms and legs. Other locations include the scalp, face, thorax, back, abdomen, perineum, breast, neck and gluteal area. Initial lesions are reddish to purple indurated plaques which may become necrotic with an erythematous halo which may develop into an eschar. In some cases target lesions and ulcerations are also seen.11,12

Fig 4: Necrotic eschar involving right eyelid12 Diagnosis

Despite of several advancements in medical sciences and diagnostic modalities, mucormycosis continues to be a disease whose 4 - <90% cases remain undiagnosed until post mortem because

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of a variety of factors including non specific clinical presentation and obvious similarities to Aspergillosis and unavailability of biomarkers.The inability of Beta-D-Glucan and galactomannan to identify the antigen is another reason for its difficult diagnosis.13,22,31

Clinical Diagnosis:History of uncontrolled diabetes or prolonged treatment with steroids and drugs like voriconazole make the host susceptible. Tissue necrosis is the hallmark sign of mucormycosis. Certain symptoms such as cranial nerve palsy, diplopia, sinus pain, proptosis, periorbital swelling, orbital apex syndrome, and ulcers of the palate should be considered as ‗red flags‘ and adequate imaging modalities should be used if a patient presents with the above mentioned symptoms.14

Radiography: CT scans are able to detect the disease in early stages whereas conventional radiographs are unsuccessful to do so. CT scans show lesions such as nodules, cavities, halo signs, reverse halo signs, wedge shaped infiltrates with pleuritic pain which are usually charachteristic of angioinvasive fungal diseases.15

Histopathology: Histopathological examination remains the most important and accurate diagnostic tool in not only identifying mucormycosis but also differentiating pathogenic strains and confirm blood vessel invasion. Mucorales produce typical ribbon like pauciseptate hyphae which are wide (9-20 micrometer), non pigmented, thin walled with right angled branching (Figure 5). Stains which highlight the fungal wall are Periodic Acid Schiff(PAS) and Grocott methenamine-silver (GMS) stain.16

Fig 5: Microscopic appearance of Mucorales on lactophenol cotton blue stained slides.17

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Fungal Cultures:Yet another effective diagnostic procedure is mycotic culture. Mucorales can be observed on both selective and non-selective media. They show an extremely rapid growth rate and can cover the whole plate in a few days hence they are termed as ‗lid lifters‘. The growth can be described as ‗cotton candy like‘. Most species show a yellow to tan discolouration on the reverse side of the plate and even grey to black on the sporulating surface on malt 2% medium.

17,18

Fig 6: Macroscopic Appearance of Positive CultureforMucorales17

Serology: Serologic testing is a minimally invasive procedure hence it is easily acceptable to the patient and moreover if positive they reduce the need for cultures. These tests identify the presence of Immunodiffusion (ID), complement fixation (CF) and enzyme immunoassay (EIA).19

Molecular Methods:Various molecular methods have been implied in the diagnosis of fungal infections. Diagnosis in tissue samples can be done with the help of either panfungal primer targeting ITS region followed by sequencing or by Mucorales specific primer for semi nested PCR.

In blood samples, a real time qPCR is an effective method for early detection.20

Management

Establishing constructive strategies for the treatment of mucormycosis has been difficult since studies have been conducted on a small group of people presenting a variety of symptoms.

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Principles of treatment:

 Assessment of severity

 Early diagnosis

 Antifungal therapy

 Surgical debridement of necrotic tissues

 Reversal of immunosuppression

 Control of underlying diseases21

Antifungal Therapy:The first line drugs such as Liposomal Amphotericin B in the dosage of 5- 10 mg/kg and Triazole Posaconazole should be started as soon as possible. Treatment should not be delayed for more than 6 days. Other drugs including Echinocandins and B-caspofungins can be co-administered for combination therapy. High doses of liposomal amphotericin B can cause nephrotoxicity.Isavuconazole is a relatively newer drug which has proven to be helpful in patients with renal and hepatic compromise.22,23,24

Stepdown therapy from Amphotericin B to Posaconazole or Isavuconazole should be started3 weeks later but the actual duration shall depend on the suppression of symptoms. The stepdown therapy should be started by overlapping Posaconazole with amphotericin B for about 1-2 weeks.24

Surgery: Surgical removal of the necrotic tissue and resection of the involved organ has to be done in more severe cases where the fungus has invaded the vessels.

PMNs should be checked after each therapy to see the neutrophil count to determine body‘s responses and if the above therapies are successful then the host‘s underlying medical condition should be treated.

Hyperbaric Oxygen:Hyperbaric oxygen is an adjunctive treatment modality with minimal adverse effects. It acts by neutralizing the acidosis in the host thus suppressing fungal growth as well as reducing tissue hypoxemia.25

Covid-19 And Mucormycosis

Currently, the world is hit with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) pandemic which may manifest as a mild to a life threatening disease. Covid 19 also brings

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along the adequate circumstances for a plethora of opportunistic pathogens to attack the already compromised host. One of those is Rhizopus oryzaeof the family Mucorales which causes Mucormycosis (black fungus).26

Etiopathogenesis

Covid 19 itself alters the host immunity to a great extent and the prolonged steroid therapy or hospital stay only invites the deadly fungus. Most cases of mucormycosis reported in Covid 19 patients were seen in those patients who were already suffering from an underlying disease, most often being uncontrolled diabetes and diabetic ketoacidosis. The hyperglycemic and acidemic environment makes the perfect habitat for Mucorales spores to proliferate and adhere to the endothelium. Patients having a history of hematological malignancies and organ transplants are also at an even higher risk of death due to mucormycosis post covid.27,28

It has been found that Covid 19 infection triggers overexpression of inflammatory cytokines such as (IL-2,IL-6,TNF-alpha), decreased count of CD4+T cells and CD8+T cells which leave the host more vulnerable to fungal infections.29

Glucocorticoids can be referred to as a ‗double edged sword‘ as on one hand they have proven to be one of the very few effective treatment modalities by suppressing the cytokine storm but on the other hand they compromise the host immunity which pave the way for various opportunistic infections. Hence use of steroids in mild cases and high doses of should be averted. Usage of other drugs like Tocilizumab which hamper the pathways of immune system should also be avoided if there is no clear benefit.30

Another factor which complements the spread of the black fungus is hygiene. A probable pathway of fungal entry in hospitalized covid patients could be contaminated catheters, drains, ambulatory bags, adhesive tapes, intravascular devices etc., hence health care facilities need to be more cautious than ever in terms of sanitation.31

Moreover India provides the fungus with adequately humid climate to reproduce 31 and poor sanitation facilities make the fungus ubiquitous. Intake of contaminated food and water, contact

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with cow dung may give the fungi a free pass to enter the human body thus making mucormycosis an epidemic here.

Clinical Manifestations

Rhino-orbital/cerebral and pulmonary mucormycosis are the two forms most commonly being reported in Covid patients. The infection can directly spread through the nasal cavity to the sinuses, orbits and intracranial spaces or via bloodstreams. In rare cases the it can spread to the kidneys, lining of heart chambers causing endocarditis and bone causing osteomyelitis. Marked trauma to the pulmonary vascular linings and angiogenesis have also been reported in the autopsy reports of Covid 19 patients which are suggestive of mucormycosis. The diseases is difficult to treat and has proven to be fatal.28,33,34

In covid patients, Rhino orbital mucormycosis may initially manifest as facial swelling, lid swelling,paresthesia, headache, sinusitis, ulcerations in the oral cavity which may gradually result into necrotic eschars on the palate, nasal turbinates or orbital region. Lymphadenopathy may also be seen.27,35

Most of the Indian population is very ignorant and irregular with periodic check-ups and turn upto clinics only if they are facing pain or swelling. What they do not understand is while a lot of systemic diseases may not have any exhibiting symptoms but they keep on affecting organs insidiously and Diabetes Mellitus is one of those diseases and thus extremely prevalent in the country.

How to Avoid Mucormycosis Post Covid:

 First and foremost measure should be limited usage of steroids. Physicians should keep in mind the possibility of secondary fungal infections while prescribing drugs.

 If the host has a systemic disease, it should be regularly checked and measures to keep itunder control should be taken.

 A diet rich in proteins and plenty of fluids should be taken by the patient.

 High risk patients should be made aware of the disease and should seek medical help if they suspect the slightest of symptoms.

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 Broad spectrum antibiotics should also be used in the lowest possible dose for the shortest duration.35

 Maintenance of proper hygiene in health care facilities.

 Avoid food and beverages from dirty contaminated places.

 Proper usage and disposal of masks.

Current Treatment Regime:The treatment plan more or less remains the same in covid patients and includes antifungal chemotherapy followed by debridement of necrotic tissue if required.

Antifungal drug Amphotericin B remains the drug of choice in the dose of 5mg/kg along with adjuvant drugs such as posaconazole followed by step down therapy.35

Conclusion

Mucormycosis or the black fungus pathogen has always been present in the environment but it is a disease of emerging concern in a Covid-19 hit, developing country like India where this fatal disease is being the cause of numerous deaths on a daily basis. It has grabbed India by its neck due to India‘s lack of responsiveness towards sanitation and healthcare. It is a disease in which the slightest of negligence can have the most severe consequences. The need of the hour is todiagnose the disease in its earliest stage so that effective treatment can be provided to the patients and the mortality rate is contained.

References

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[2] Michaell A Huber, Spencer W. Redding, Vidya Shankar, Sook—Bin Woo. Burket‘s Oral Medicine 12th Edition, Infectious diseases.

[3] Chakrabarti A,Singh R. Mucormycosis in India: unique features. Mycoses 2014: 57; 85-90.

[4] Spellberg B, Edwards J, IbrahimA. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clinical microbiology reviews 2005: 18(3); 556-569.

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[5] Nidhi M, Sadia K, Khatri A, Arnab G, Khan NA. Gastrointestinal Mucormycosis in a two- year-old child: A clinical and radiological enigma. Medical mycology case reports. 2019 Dec 1;26:5-9.

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[7] Lee FY, Mossad SB, AdalKA. Pulmonary mucormycosis: the last 30 years. Archives of Internal Medicine 1999: 159(12); 1301-1309.

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[12] Castrejón-Pérez AD, WelshEC, MirandaI, Ocampo-Candiani J, WelshO. (2017). Cutaneous mucormycosisAnaisbrasileiros de dermatologia 2017: 92(3); 304-311.

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[14] SkiadaA, Lass-Floerl C, Klimko N, Ibrahim A, Roilides E, Petrikkos G. Challenges in the diagnosis and treatment of mucormycosis. Medical mycology 2018: 56; S93-S101.

[15] Walsh TJ, Gamaletsou MN, McGinnis MR, Hayden RT, KontoyiannisDP. Early clinical and laboratory diagnosis of invasive pulmonary, extrapulmonary, and disseminated mucormycosis (zygomycosis). Clinical Infectious Diseases 2012: 54; S55-S60.

[16] Skiada A, Pavleas I, Drogari-Apiranthitou M. Epidemiology and Diagnosis of Mucormycosis: An Update. Journal of Fungi 2020; 6(4):265.

[17] BouzaE, MunozP,Guinea J. Mucormycosis: an emerging disease?. Clinical Microbiology and Infection 2006:12; 7-23.

[18] Pilmis B, Alanio A, LortholaryO, LanternierF. Recent advances in the understanding and management of mucormycosis.Research 2018; 7.

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[19] RichardsonM,Page I. Role of serological tests in the diagnosis of mold infections. Current fungal infection reports 2018: 12(3); 127-136.

[20] MillonL, SchererE, Rocchi S, Bellanger AP. Molecular strategies to diagnose mucormycosis. Journal of Fungi 2019: 5(1); 24.

[21] Sipsas NV, Gamaletsou MN, AnastasopoulouA, Kontoyiannis DP. Therapy of mucormycosis. Journal of Fungi 2018: 4(3); 90.

[22] KontoyiannisDP, Lewis RE. How I treat mucormycosis. Blood, The Journal of the American Society of Hematology 2011: 118(5): 1216-1224.

[23] Chakrabarti A, Singh S.Management of Mucormycosis.Current Fungal Infection Reports 2020: 1-13.

[24] GuideID. The Terrifying Threat of Mucormycosis. 2021

[25] Berrylin J. Ferguson, Thomas G. Mitchell, Richard Moon, Enrico M. Camporesi, Joseph Farmer, Adjunctive Hyperbaric Oxygen for Treatment of RhinocerebralMucormycosis, Reviews of Infectious Diseases, Volume 10, Issue 3, May 1988, 551–559.

[26] Laturiya R, Badal S,DoiphodeA,Nagargoje G, BhaleS,Sonare M. Rising incidence of mucormycosis during covid 19: a review. 2019 MIDSR Journal of Dental Research 2020: 2 (2 );

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[27] Tabarsi P, Khalili N, Pourabdollah M, Sharifynia S, NaeiniAS, Ghorbani J, AskariE. (2021).

COVID-19 associated rhinosinusitis mucormycosis due to Rhizopus oryzae: A rare but potentially fatal infection occurring after treatment with corticosteroids.

[28] John TM, Jacob CN,Kontoyiannis DP. When Uncontrolled Diabetes Mellitus and Severe COVID-19 Converge: The Perfect Storm for Mucormycosis. Journal of Fungi 2021: 7(4); 298.

[29] SharmaS, GroverM, Bhargava S, SamdaniS,KatariaT. Post coronavirus disease mucormycosis: A deadly addition to the pandemic spectrum. The Journal of Laryngology &

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[30] Garg D, Muthu V, Sehgal IS. Coronavirus Disease (Covid-19) Associated Mucormycosis (CAM): Case Report and Systematic Review of Literature. Mycopathologia 2021: 186: 289–298.

[31] Rammaert B, Lanternier F, Zahar JR, Dannaoui E, Bougnoux ME, LecuitM, Lortholary O, Healthcare-Associated Mucormycosis. Clinical Infectious Diseases 2012: 54 (1);, Pages S44–S54

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[32] ChkhotuaA, Yussim A, Sobolev V, Bar‐Nathan N, Shaharabani E, Shapir Z, Weinberger M.

Mucormycosis of the renal allograft: case report and review of the literature. Transplant International 2001: 14(6); 438-441.

[33] Veisi A, BagheriA, Eshaghi M, RikhtehgarMH, RezaeiKanavi M, FarjadR. Rhino-orbital mucormycosis during steroid therapy in COVID-19 patients: A case report. European Journal of Ophthalmology 2021.

[34] Patil S, Sarate D, Chopade S, Khade M, Dhage S, and SwaradaKangate. "Emerging Challenge of Mucormycosis in postCOVID Patients." IAR Journal of Medical Case Reports 2021: 2 (3).

[35] Mehta S, Pandey A. Rhino-orbital mucormycosis associated with COVID-19. Cureus 2020: 12(9).

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