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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 4  |  Page : 209-214

Mucormycosis in COVID-19


Department of Medicine, MVJMC and RH, Bengaluru, Karnataka, India

Date of Submission16-Jul-2021
Date of Decision25-Aug-2021
Date of Acceptance20-Sep-2021
Date of Web Publication20-Oct-2021

Correspondence Address:
Dr. Vasantha Kamath
Department of Medicine, MVJMC and RH, Hoskote, Bengaluru - 562 114, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ajim.ajim_74_21

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  Abstract 


Mucormycosis has emerged as a disease of immense importance, especially owing to the surge of cases during the second wave of COVID pandemic. Various factors are being attributed to the sudden burst of cases in our country, such as higher fungal spore counts in tropical climate, uncontrolled diabetes mellitus, prolonged steroid therapy, contamination of oxygen facilities, respiratory equipment, reused face mask, and zinc supplements. The need of the hour is to emphasize on awareness of early warning signs, as the benefits appear to be time sensitive.

Keywords: COVID-19, diabetes, mucormycosis, steroids


How to cite this article:
Kamath V, Mathivanan M, Vinay R B, Nivea B. Mucormycosis in COVID-19. APIK J Int Med 2021;9:209-14

How to cite this URL:
Kamath V, Mathivanan M, Vinay R B, Nivea B. Mucormycosis in COVID-19. APIK J Int Med [serial online] 2021 [cited 2021 Nov 29];9:209-14. Available from: https://www.ajim.in/text.asp?2021/9/4/209/328682




  Introduction Top


As India continues to achieve stability over the existing situation, another imminent threat has emerged as a challenge to India in the form of coronavirus disease-associated mucormycosis.[1] Mucormycosis, also known as zygomycosis, is an opportunistic fungal infection caused by the fungi belonging to the Mucorales order. It was first described in 1885 by Paltauf and later coined as mucormycosis in 1957 by Baker. Often referred to as the so-called black fungus, the incidence of mucormycosis has risen rapidly during the second wave of COVID-19 in India.[2] Mucormycosis is an angioinvasive fungal infection with high fatality, and it is the third most common angioinvasive fungal infection after candidiasis and aspergillosis.


  Epidemiology Top


The incidence rate of mucormycosis globally varies from 0.005 to 1.7 per million populations. In India, prevalence of mucormycosis is estimated to be 140 per million populations, which is about 80 times higher than the prevalence in developed countries.[3]

The first case of mucormycosis in COVID-19 in India was detected in Hamirpur district, Shimla, on May 4, 2021, in a 52-year-old women who was diabetic and hypertensive. As many as 28,252 cases of mucormycosis have been reported from 28 states and union territories of India till date. Majority of them are from Maharashtra and Gujarat. The Ministry of Health and Family Welfare declared mucormycosis as a notifiable disease on May 20, 2021, under the Epidemic Diseases Act 1897.

A total of 2281 cases of mucormycosis were reported in Karnataka, of which 156 have succumbed to the disease with a case fatality rate of 6.83%. Under KPME Act Section 7B, mucormycosis was declared as an epidemic on May 18, 2021.

Singh et al. reviewed reports of patients with mucormycosis and COVID-19 worldwide and in India and concluded that majority of them were from India seen predominantly in males. 80% had preexisting diabetes mellitus and 76.3% recorded corticosteroid treatment of COVID-19. 30.7% of patients had succumbed.[4]

Pal et al. in their review retrieved data of 99 patients of COVID-19–associated mucormycosis, of which 72% were from India. Majority of the patients were males and 85% had diabetes mellitus. The median time interval between COVID-19 diagnosis and the first evidence of mucormycosis infection was 15 days. Majority of patients presented with rhino-orbital mucormycosis. Mortality rate was 34%.[5]

In our center, out of 1159 COVID-19 cases, we had three patients who developed mucormycosis.


  Etiology Top


Mucorales commonly called as bread or pin molds are saprophytic fungi that reproduce asexually by nonmotile sporangiospores in the environment that become hyphae forms in the tissue. These organisms are ubiquitous in nature and usually found in decaying organic matter and in the soil. Among the Mucorales, Rhizopus oryzae is the most common cause of infection. Less commonly isolated species are Rhizopus microsporus, Rhizomucor pusillus, Lichtheimia corymbifera, and Apophysomyces elegans. Mucor species, which despite its name, rarely causes mucormycosis [Table 1].
Table 1: Classification of Fungi

Click here to view



  Risk Factors Top


  1. COVID-19
  2. Diabetes mellitus
  3. Neutropenia
  4. Steroids
  5. Primary immune deficiency
  6. Hematological malignancy
  7. Iron overload state
  8. Desferrioxamine therapy
  9. Transplant recipients
  10. Severe burns
  11. Acquired immunodeficiency syndrome
  12. Intravenous (i.v.) drug abusers
  13. Malnutrition
  14. Open wound following trauma.



  Triad of COVID-19 Predisposing to Mucormycosis Top


  1. COVID-19 (cytokine storm, hyperferritinemia, lymphopenia, endothelial damage)
  2. Diabetes (high prevalence genetically)
  3. Rampant use of corticosteroid (increases blood glucose).



  Pathogenesis Top


Inhalation of sporangiospores from environmental sources deposit in nasal turbinates, paranasal sinuses, thus invading the innate immune system and germinate, leading to angioinvasion and tissue destruction. Recent studies have found that Mucorales are able to downregulate several host defense mechanisms and have identified specific receptors through which Mucorales attach to the endothelium, facilitating their endocytosis and subsequent angioinvasion.[6] Macrophages are the main immune effector cells in controlling these fungi by rapid and efficient phagocytosis of the spores. However, Mucorales have evolved mechanisms to block phagosomal maturation and species-specific mechanisms to either survive as dormant spores inside the macrophage such as Rhizopus species or germinate and escape as Mucor species.[7]


  Mucormycosis in COVID-19 Top


Endotheliitis, endothelial damage, thrombosis, lymphopenia, reduction in the CD4+ and CD8+ T-cell level predispose to secondary or opportunistic fungal infections.

Increase in cytokines in patients with COVID-19, especially interleukin-6 (IL-6), increases free iron by increasing ferritin levels due to increased synthesis and decreased iron transport.

Steroids reduce the phagocytic activity of white blood cells, which are both the first-line and second-line defense mechanism, leading to impairment of bronchoalveolar macrophages migration, ingestion, and phagolysosome fusion. Uncontrolled hyperglycemia and precipitation of diabetic ketoacidosis (DKA) are often observed due to corticosteroid intake, thus making a diabetic patient exceptionally vulnerable to mucormycosis.

Hyperglycemia causes glycosylation of transferrin and ferritin and reduces iron binding, thereby increasing the availability of free iron. Freely available iron is an ideal resource for mucormycosis.

Patients with DKA are uniquely predisposed to mucormycosis. In a study conducted by Gebremariam et al., mice which were given beta hydroxy butyrate developed clinical acidosis and became extremely susceptible to mucormycosis, thus reinforcing the importance of careful metabolic control to prevent and manage mucormycosis.[8]

Freely available iron is an ideal resource for mucormycosis. Clinical hallmarks of mucormycosis infections include the unique susceptibility of patients with increased available serum iron, propensity of the organism to invade blood vessels, and defective phagocytic function.[9] The Deferasirox-Ambisome Therapy for Mucormycosis study showed that the combination of LAMB with deferasirox was associated with increased mortality.[10]

Fungal cells must acquire zinc for proper development during their life cycle, even when they are saprophytes or during the infection process. To hamper pathogen growth, mammalian hosts typically reduce the levels of free zinc and other metals by secreting a zinc-binding protein that is able to scavenge zinc from tissues invaded by the fungus.[11],[12]


  Clinical Presentations Top


Rhino-orbital-cerebral mucormycosis

This is the most common presentation of mucormycosis. The infection starts in paranasal sinuses and thereafter invades orbit and brain. It is frequently observed in association with uncontrolled diabetes and diabetic ketoacidosis. The usual presentation is with unilateral facial pain, swelling, numbness, chemosis, proptosis, orbital cellulitis, seizures, delirium, and coma. On examination:

  • Facial findings: Facial swelling, paresthesia over the sinus tract on face, discoloration of skin (necrosis), infection in dangerous area of face
  • Nasal findings: Foul smelling nasal discharge, nasal congestion, sinusitis, erythematous to violaceous to black necrotic eschar in the nasal cavity
  • Orbital findings: Loss of vision, periorbital cellulitis, chemosis, proptosis, ophthalmoplegia
  • Intraoral findings: Halitosis, intraoral pus discharge, ulceration, blackening of mucosa, exposed palatal bone/sinus tract, loosening of teeth/unhealed tooth socket, mobility of the maxilla
  • Cerebral involvement: Abnormal mentation and internal carotid thrombosis resulting in contralateral hemiplegia.


If untreated, infection usually spreads from the ethmoid sinus to the orbit leading to proptosis and resulting in compromise of extraocular muscle function. Onset of symptoms in contralateral eye, with resulting bilateral proptosis, chemosis, vision loss, and ophthalmoplegia, is suggestive of development of cavernous sinus thrombosis.


  Clinical Pointers of Mucormycosis Suspicion Top


  1. High dose and early initiation of steroids
  2. Uncontrolled diabetes mellitus
  3. Neutropenia
  4. Lymphopenia
  5. High levels of IL-6 and serum ferritin
  6. Tocilizumab usage.


Smith and Kirchner Clinical Diagnostic Criteria

  1. Blood-tinged nasal discharge and facial pain
  2. Black, necrotic turbinates (easily mistaken for dried, crusted blood)
  3. Soft periorbital or perinasal swelling with discoloration and induration
  4. Ptosis of the eyelid, proptosis of the eyeball, and complete ophthalmoplegia
  5. Multiple cranial nerve palsies unrelated to documented lesions.



  Diagnosis and Staging Top
[Table 2] [13]
Table 2: Proposed Staging of Rhino-Orbital-Cerebral Mucormycosis (ROCM)[13]

Click here to view


  1. Microscopy


  2. It is the most rapid diagnostic method. Broad, 10–15 μm wide, infrequently septate, thin-walled hyphae, focal bulbous dilatations and irregular branching are usually seen [Figure 1].
    Figure 1: Hyphae of Mucor under light microscope (Gomori-Gomori's methenamine silver stain, ×40)

    Click here to view


  3. Histopathology


  4. To confirm a histopathological infection, nonpigmented hyphae showing tissue invasion must be shown in tissue sections stained with hematoxylin and eosin, periodic acid–Schiff stain, or Grocott-Gomori's methenamine silver [Figure 2].
    Figure 2: Histopathology of nasal tissue showing Mucor hyphae (H and E stain, ×10)

    Click here to view


  5. Needle aspirate, a tissue biopsy specimen
  6. Culture


  7. Culture is recommended for genus and species identification and for antifungal susceptibility testing. Sensitivity of culture is not optimal, as only approximately one-third of all microscopically positive specimens reveal positive cultures. All Mucorales grow rapidly (3–5 days) on most fungal culture media, such as Sabouraud's dextrose agar and potato dextrose agar incubated at 25°C–30°C

  8. Computed tomography scan – Erosion of bones and obliteration of sinuses can be seen
  9. Magnetic resonance imaging (MRI) – Infarction of nasal mucosa is seen as nonenhancement of nasal turbinates in a contrast-enhanced MRI referring to as “black turbinate sign”
  10. Polymerase chain reaction (PCR) – PCR-based approaches have shown promising potential in rapidly diagnosing mucormycosis. The spore coating protein homolog encoding CotH genes are uniquely and universally present among Mucorales. CotH is detected in the plasma, urine, and bronchoalveolar lavage.


Differential diagnosis of rhino-orbital-cerebral mucormycosis

  1. Bacterial orbital cellulitis
  2. Cavernous sinus thrombosis
  3. Rapidly growing orbital tumor
  4. Aspergillosis.


Treatment of mucormycosis

Treatment has to be started as soon as possible; delay in amphotericin B treatment is associated with increased mortality and delay in treatment beyond 5 days of onset of symptoms doubles the mortality.[14] Amphotericin B has to be started preoperatively when the patient is waiting for surgery.

Injection liposomal amphotericin B (i.v.) 5–10 mg/kg/day to be diluted in 200 mL of 5% dextrose over 2–3 h for 14–21 days.

Injection amphotericin B (i.v.) 1–1.5 mg/kg/day mixed with 200 mL 5% dextrose over 2–3 h for 14–21 days in hospital [Table 3].
Table 3: Amphotericin B Versus Liposomal Amphotericin B

Click here to view


After 3–6 weeks of amphotericin B therapy, consolidation therapy with posaconazole/isavuconazole for 3–6 months should be instituted. Patients who are intolerant to amphotericin B can be given alternative agents such as posaconazole (injectables or tablet) 300 mg twice a day on day 1, followed by 300 mg once a day for 3–6 months, and tablet isavuconazole 200 mg three times a day for 2 days followed by 200 mg once a day 3–6 months.

In general, 4 weeks to months of therapy is given. Therapy can be continued until the resolution of signs and symptoms.

Adverse effects

  1. Acute reaction - Chills, fever, aches, and pain associated with nausea and vomiting lasting for 2–5 h, due to release of cytokines
  2. Long-term toxicity - Nephrotoxicity is the most important long-term complication and it occurs uniformly and is dose related and manifests as azotemia, reduced GFR, acidosis, hypokalemia, and hypomagnesaemia. Most patients develop slowly progressive anemia which is due to bone marrow suppression.


Premedication

Premedication is given to prevent the infusion-related side effects. The most common regimens include diphenhydramine, a corticosteroid (usually avoided in mucormycosis), acetaminophen, and heparin, administered alone or in combination with these drugs.[15] 500 ml normal saline to be administered over one hour before Amphotericin B infusion to prevent nephrotoxicity.

Administration

Reconstitution is done by adding 12 mL sterile water for injection to 50 mg-vial (resulting concentration 4mg/mL); do not use fluids containing sodium chloride or bacteriostatic agent (saline makes the suspension coarse and should be avoided). Vial is to be vigorously shaken for 30 seconds and further dilution is done by withdrawing appropriate amount of reconstituted solution and adding 5% dextrose to provide a final concentration of 1-2mg/ml. It can be administered through existing IV line, preferably peripheral. Flush line with 5% dextrose prior to infusion, or else use separate line over at least two hours using controlled infusion device.

Postmedication and monitoring

500 ml normal saline is given over one hour after Amphotericin B infusion to prevent nephrotoxicity. Creatinine, magnesium, and potassium levels have to be monitored every 2 days over the course of treatment with Amphotericin B.

When to stop the treatment

The duration of antifungal therapy should be individualized. Indications for stopping treatment are:

  1. Near normalization of radiological images
  2. Negative follow-up biopsy specimen and culture from the affected site
  3. Recovery from immune suppression.


Role of hyperbaric oxygen

Hyperbaric oxygen suppresses fungal growth in vitro and has theoretical value in treating mucormycosis as it reduces the tissue hypoxia and acidosis.[16],[17]

Role of ophthalmologist

Medial wall of the orbit is involved if infection spreads from ethmoid sinus and inferior wall is involved if infection spreads from maxillary sinus. Surgical debridement of necrosed and osteomyelitic bone is advised to reduce the further spread of mucormycosis. Rarely, mucormycosis can present with loss of vision, which is mainly due to angioinvasion of Mucor into the central retinal artery leading to thrombosis and ischemia leading to central retinal artery occlusion and loss of vision. Edema of the rectus muscles can present as isolated ophthalmoplegia in such cases MRI is preferred and managed conservatively with serial MRI scan every 48–72 h until there is no progression of disease and bone involvement.

Role of ENT Surgeon

Surgical debridement in mucormycosis aims in:

  1. Debulking of infected tissue and removal of revitalized tissue ensuring faster action of antifungal therapy
  2. Getting histopathological and microbiological evidence.


Pulmonary mucormycosis

It is the second most common presentation of mucormycosis. Pulmonary mucormycosis was first described by Fürbinger in 1876 in Germany, in a patient who died of cancer and in whom the right lung showed a hemorrhagic infarct with fungal hyphae and a few sporangia. Pulmonary involvement is often observed in patients having neutropenia, bone marrow and organ transplant, and hematological malignancies. It usually manifests as dyspnea, cough, and chest pain. Hemoptysis is seen when there is angioinvasion.

Cutaneous/subcutaneous mucormycosis

In immunologically normal individuals, it is due to the traumatic implantation of soil or vegetation or via direct access through i.v. catheters, subcutaneous infection, and maceration of skin by moist dressing.

Gastrointestinal mucormycosis

In malnourished individuals, a greater incidence of gastrointestinal involvement is noted. Further, premature infants fed with a wooden spatula are at increased risk of gastrointestinal disease.


  Prevention Top


All efforts should be made to maintain optimal glycemic control. Only judicious evidence-based use of corticosteroids in patients with COVID-19 is recommended to reduce the burden of fatal mucormycosis.


  Conclusion Top


COVID-19 pandemic has resulted in widespread mortality, morbidity, and social and economic upheavals of an unprecedented magnitude. The high mortality rate among mucormycosis patients calls for an increased index of suspicion and aggressive attempts to diagnose and treat the disease at an early stage.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kwon-Chung KJ. Taxonomy of fungi causing mucormycosis and entomophthoramycosis (zygomycosis) and nomenclature of the disease: Molecular mycologic perspectives. Clin Infect Dis 2012;54 Suppl 1:S8-15.  Back to cited text no. 1
    
2.
Fürbringer P. Observations on pulmonary mycosis in humans. Virchows Arch. 1876;66:330-65.  Back to cited text no. 2
    
3.
Available from: https://www.who.int/india/emergencies/coronavirus-disease-(covid-19)/mucormycosis. [Last accessed on 2021 Jul 15].  Back to cited text no. 3
    
4.
Singh AK, Singh R, Joshi SR, Misra A. Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India. Diabetes Metab Syndr 2021;15:102146.  Back to cited text no. 4
    
5.
Pal R, Singh B, Bhadada SK, Banerjee M, Bhogal RS, Hage N, et al. COVID-19-associated mucormycosis: An updated systematic review of literature. Mycoses. 2021 Jun 16:10.1111/myc.13338.  Back to cited text no. 5
    
6.
Petrikkos G, Tsioutis C. Recent advances in the pathogenesis of mucormycoses. Clin Ther 2018;40:894-902.  Back to cited text no. 6
    
7.
Nicolás FE, Murcia L, Navarro E, Navarro-Mendoza MI, Pérez-Arques C, Garre V. Mucorales species and macrophages. J Fungi (Basel) 2020;6:E94.  Back to cited text no. 7
    
8.
Gebremariam T, Lin L, Liu M, Kontoyiannis DP, French S, Edwards JE Jr., et al. Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis. J Clin Invest 2016;126:2280-94.  Back to cited text no. 8
    
9.
Ibrahim AS. Host cell invasion in mucormycosis: Role of iron. Curr Opin Microbiol 2011;14:406-11.  Back to cited text no. 9
    
10.
Spellberg B, Ibrahim AS, Chin-Hong PV, Kontoyiannis DP, Morris MI, Perfect JR, et al. The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: A randomized, double-blinded, placebo-controlled trial. J Antimicrob Chemother 2012;67:715-22.  Back to cited text no. 10
    
11.
Lulloff SJ, Hahn BL, Sohnle PG. Fungal susceptibility to zinc deprivation. J Lab Clin Med 2004;144:208-14.  Back to cited text no. 11
    
12.
Goyette J, Geczy CL. Inflammation-associated S100 proteins: New mechanisms that regulate function. Amino Acids 2011;41:821-42.  Back to cited text no. 12
    
13.
Honavar, Santosh G Code Mucor, Indian Journal of Ophthalmology: 2021;69:1361-5.  Back to cited text no. 13
    
14.
Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin.Infect. Dis. 2008;47;503-9.  Back to cited text no. 14
    
15.
Goodwin SD, Cleary JD, Walawander CA, Taylor JW, Grasela TH Jr. Pretreatment regimens for adverse events related to infusion of amphotericin B. Clin Infect Dis. 1995;20:755-61.  Back to cited text no. 15
    
16.
Ferguson BJ, Mitchell TG, Moon R, Camporesi EM, Farmer J. Adjunctive hyperbaric oxygen for treatment of rhinocerebral mucormycosis. Rev Infect Dis. 1988;10:551-9.  Back to cited text no. 16
    
17.
Couch L, Theilen F, Mader JT. Rhinocerebralmucormycosis with cerebral extension successfully treated with adjunctive hyperbaric oxygen therapy. Arch Otolaryngol Head Neck Surg. 1988;114:791-4.  Back to cited text no. 17
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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  In this article
Abstract
Introduction
Epidemiology
Etiology
Risk Factors
Triad of COVID-1...
Pathogenesis
Mucormycosis in ...
Clinical Present...
Clinical Pointer...
Prevention
Conclusion
Diagnosis and St...
References
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