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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 9  |  Issue : 1  |  Page : 10-16

Mucormycosis, COVID-19, and immunosuppression – The three sides of similar triangle: Narrative review


Daswani Dental College and Research Centre, Kota, Rajasthan, India

Date of Submission22-Oct-2021
Date of Acceptance24-Jan-2022
Date of Web Publication29-Apr-2022

Correspondence Address:
Dr. Vijayata Jayprakash Singh
Daswani Dental College and Research Centre, Kota - 324 005, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjoralsci.sjoralsci_56_21

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  Abstract 


Introduction: More than two years into the COVID 19 pandemic, medical fraternity each day is facing renewed challenges. Mucormycosis has historically been prevalent in the various parts of world but did not had any diagnostic opportunity before the turn of 20th century. Immunosuppression in any form was always and will forever be the most important ingredients in this disease recipe. Minimally invasive diagnoses with aggressive antimicrobials in addition to the removal of immunosuppression factor are the golden standard of treatment, as oral and maxillofacial surgeons we acknowledge that surgical debridement and various other relatively newer adjunctive therapies have overall reduced the fatal outcomes for such a lethal disease.
Aim: This review article focuses on gathering data in relation to immunosuppression due to whatsoever reason and pathogenesis, management, and chance of positive prognosis for patient suffering from mucormycosis . Including surgical and prosthetic options which ascertain descent quality of life for the patient.
Materials and Methods: Existing data compilation including the latest research and co-relation of various types of immunosuppression as a nidus for mucormycosis, including the role of novel covid-19 from all relevant electronic databases.
Results: Definite co-relation has been stablished for diabetes melitus and covid-19 and speculative co-relation for various types of malignancy and various conditions.
Discussion: A strong immunity is an antagonist for mucormycosis, and new advances in field of medicine and surgery have changed the grim look of past where this disease had a 50% mortality rate.
Conclusion: Existing literature supports immunosuppression in any form as a nidus for mucormycosis, still further, elaborate research and development is required for identifying the particular cocktail for different diseases process.

Keywords: COVID-19, immunosuppression, lipid soluble amphotericin-B, mucormycosis, oral and maxillofacial surgeon


How to cite this article:
Sharma AK, Gupta A, Singh VJ, Gabhane CK, Modi M. Mucormycosis, COVID-19, and immunosuppression – The three sides of similar triangle: Narrative review. Saudi J Oral Sci 2022;9:10-6

How to cite this URL:
Sharma AK, Gupta A, Singh VJ, Gabhane CK, Modi M. Mucormycosis, COVID-19, and immunosuppression – The three sides of similar triangle: Narrative review. Saudi J Oral Sci [serial online] 2022 [cited 2022 Aug 15];9:10-6. Available from: https://www.saudijos.org/text.asp?2022/9/1/10/344406




  Introduction Top


The medical fraternity of the entire world is fighting diligently to salvage the world from the COVID-19 crises but end to the crisis is still not in sight. Immunosuppression which was earlier thought to be the villain causing various microbiological infection has again gained momentum in form of black, white, and yellow fungus and various other hitherto unknown or rare parasite infestations. This review article focuses on the available knowledge in the field of mucormycosis, COVID-19 infections, and state of immunosuppression, as one or the other factor was constantly present in explaining the disease pathogenesis, susceptibility, and prognosis of mucormycosis.


  Epidemiology Top


Clinicians should be highly vigilante in cases of immunocompromised patients and COVID-19 patients, those giving a history of hospital admission and oxygen support, as this category of patients has a combination of various elements.[1] Associated with several opportunistic fungal infection including aspergillosis and mucormycosis, a short course of corticosteroids has recently been reported to link with mucormycosis, especially in people with diabetes mellitus (DM). The hallmark of DM is elevation in blood glucose levels (hyperglycemia) resulting from either a defect in insulin secretion or a change in insulin action which eventually leads to immunosuppression.[2] Surprisingly, 46% of the patients had received corticosteroids within the month and later were then diagnosed with disease of mucormycosis in the European Confederation of Medical Mycology study. Hyperglycemia at the presentation was the single most important risk factor observed in majority of cases (83.3%) of mucormycosis in people with COVID-19, followed by cancer (3.0%). The treatment of COVID-19 has also given a boost to cases of mucormycosis, as the following: corticosteroid − 74.3%, remdesivir − 20.6%, and tocilizumab − 4.1%.

The most common organ involved with mucormycosis was nose and sinus (88.9%), followed by rhino-orbital (56.7%) and rhino-orbital cerebral mucormycosis (ROCM) type (22.2%).[3] In patients with systemic autoimmune diseases who are already immunocompromised due to immunosuppressive drugs, prolonged high-dose corticosteroid treatment led to the state of transient hyperglycemia which favored mucormycosis.[4] Statistically, the occurrence of mucormycosis varies from 0.01 to 0.2/1 lakh population in Europe and the United States of America and is much higher in India (14/1 lakh population).[5] The higher prevalence of mucormycosis in India can be related to climatic and socioeconomic conditions and also to large diabetic population.[6] Although mucormycosis is very rare in healthy individuals, we are able to see such cases once in a while. The only documented evidence for the majority of mucormycosis in trauma cases has been done by military for the casualties of the war.[7] One patient had telluric trauma 367 days before mucormycosis diagnosis and was infected by Saksenaea vasiformis.[8] It has been difficult to establish a cause and effect the relationship between COVID-19 and mucormycosis in conjunction to corticosteroids. There has been a number of triggers that may precipitate mucormycosis in people with COVID-19 in relation to corticosteroids.[9]


  Etiopathogenesis Top


COVID-19 is an infective inflammatory disease with multisystem involvement caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The major factors involved in the pathophysiology of SARS-CoV-2 disease are as follows:

  1. Markedly raised proinflammatory CD4 T-cells and CD8 toxic granules
  2. Cytokine surge
  3. Hemoglobinopathy
  4. Hypercoagulable state
  5. Altered iron metabolism and increased iron overload resulting in hypoxia and multisystem failure in severe cases.[9]


High glucose, low pH, free iron, and decreased phagocytic activity of white blood cell in addition to ketones. It amplified the expression of glucose-regulator protein 78 of endothelium cells and fungal ligand spore coating homolog protein, enabling angioinvasion, hematogenous dissemination, and tissue necrosis.[5],[10] Zinc is an essential micronutrient for all eukaryotes and is an important factor contributing to the growth and virulence of pathogenic fungi.[11] We found that half of the Rhizopus arrhizus isolates obtained from COVID-associated mucormycosis patients showed a significant increase in growth in zinc-enriched fungal culture medium. In addition to the increased colony count, we also observed that the colonies were larger and had higher fungal biomass in zinc-supplemented media.[11]


  Pathogenesis Top


Host resistance impairment is the prerogative for the initiation and progression of pathogenic conditions through local colonization (infiltration) in the oral cavity. The frequency of oral mycosis has tremendously increased globally with surge in the use of immunosuppressive drugs and immunodeficiency viral infection.[1] Mucorales or fungal spores can enter into a susceptible host through inhalation, ingestion of contaminated food, or abraded skin. These routes can cause rhino-orbito-cerebral, pulmonary, gastrointestinal, or cutaneous/wound infections in patients. Most distinguished characteristics of mucormycosis is its angioinvasive property, resulting in vascular thromboses that may lead to severe tissue necrosis.[12] A recently identified clinical feature is the escalating susceptibility to mucormycosis is elevated available serum iron. It has been known for 20 years now that patients treated with the iron chelator deferoxamine have a markedly increased incidence of invasive mucormycosis. Even though deferoxamine is an iron chelator from the perspective of the human host, Rhizopus spp. actually utilize deferoxamine as a siderophore to supply previously unavailable iron present in the blood but now available to the fungus.[13] Patients with diabetic ketoacidosis are at colossal risk of developing rhino-cerebral mucormycosis, as there has been substantial correlation between elevated iron in blood and metabolic acidosis.[14] A recent immunophenotyping study of young and old individuals diagnosed or not diagnosed with COVID-19 substantiated that COVID-19 fosters age-induced immune cell polarization and gene expression related to inflammation and cellular senescence, and conversely, aging-associated dysregulated immune responses may somewhat account for culpability (trigger) to COVID-19.[15] Moreover, then, victims of natural disaster are at risk owing to wounds contaminated with water, soil, or debris.[5] Prednisone, greater than 600 mg/a day, total methylprednisolone dose of 2–7 g given during a month before the onset of mucormycosis, predisposes immunocompromised people to this disease. A very short course (5–14 days) of steroid therapy has caused mycormycosis in some cases [Table 1].[3]
Table 1: Corelation of various factors for pathogenesis

Click here to view



  Etiology Top


Mucormycosis is caused by sap Rhizopus, Mucor, Cunninghamella, saprophytic fungi such as Rhizomucor, Saksenaea, Apophysomyces or Lichtheimia, S. vasiformis.[1] The pandemic SARS-CoV-2 infection since March 2020[1] and become one of the reason for this triad.


  Clinical Presentation Top


The 1950 Smith and Krichner criteria for the clinical diagnosis of mucormycosis are still considered to be gold standard and included in [Table 2].
Table 2: Smith and Krichner criteria

Click here to view


The point of entry determines the clinical representation of mucormycosis and the organ systems involved. The rhinocerebral mucormycosis, first mentioned by Paltauf in1885, affected several organs involving the nose, paranasal sinuses, orbits, and central nervous system. The clinical representation of rhinocerebral mucormycosis is not very accurate. It is associated with varying degrees of headache, fever, rhinorrhea, orbital-facial cellulitis, and ocular and neurological damage.[8],[16],[17] When the fungal hyphae enters the blood stream, they can disseminate into other organs. Mucorhyphae form thrombi within the blood vessels which reduce vascularity to the tissues and cause necrosis. The diagnosis of mucormycosis is due to high degree of suspicion, recognition of host factors, and prompt assessment of clinical manifestations. When there is substantial central nervous system (CNS) involvement, the angioinvasive nature of the fungus results in cavernous sinus thrombosis and internal carotid artery encasement and thrombosis, which can result in capacious cerebral infarctions.[14] Diplopia in a patient with diabetes or pleuritic pain in a neutropenic host is a sign of this infection and testing very crucial.[12] Necrotizing fasciitis is a bacterial invasive disease which spreads in a subcutaneous plane[18] in opposition of mucormycosis which may show bony involvement, but both gives of quite a similar clinical picture other than above given criteria.


  Diagnostic Investigation Top


Radiographic study

Plain radiographs of the paranasal sinuses and orbits may demonstrate thickening of the sinus mucosa, with or without air-fluid levels, but this is not specific. Soft-tissue swelling, proptosis, and extraocular muscle swelling can also be seen.[5],[16] Computed tomography (CT) scan with contrast or magnetic resonance imaging (MRI) may demonstrate erosion or destruction of bone or sinuses and help delineate the extent of the disease.[19]

Computed tomography scan

The most common radiographic pattern of pulmonary mucormycosis on initial CT is a halo sign and then a nodule or mass. However, when it was studied very early and in a serial follow-up, sequential morphological changes such as (i) reversed halo sign followed by (ii) consolidation or nodule or mass with halo sign and, finally, (iii) central necrosis and air-crescent sign.[5] CT of the maxilla and orbit shows membrane thickening or periosteal and bone rupture in such cases[8] However, patients with early rhinocereberal orbital form of mucormycosis may have normal MRI and CT scans, and surgical exploration with biopsy of suspected areas of infection should always be performed in patients who are considered at greater risk due to other comorbid conditions. Given the constraints associated with imaging studies, the diagnosis of mucormycosis confirmatory only on the histopathological evidence of fungal invasion of the tissues.[14] Investigation as in plain orbit or sinus radiography may be necessary when CT is not reliable.[5]

Magnetic resonance imaging

MRI is useful to identify intradural and intracranial extension of the disease, cavernous sinus thrombosis or thrombosis of the cavernous portion of the internal carotid artery. Perineural spread of the disease can also be demonstrated with contrast enhanced MRIs. MRI is more sensitive when representing soft tissue lesions in contrast to CT scans.[14]

T2-weighted MRI can demonstrate intracerebral extension, whereas contrast-enhanced MRI can demonstrate perineural spread of the disease.[20]

Angiography or surgical exploration

Used in areas of anatomic complexity, like orbit, where reactive inflammation maybe difficult to distinguish from true invasion with CT or MRI.[21]

Diagnosis

There is much to be done regarding the early detection of oral cancer to reduce the professional delay[22] but when this happens with mucormycosis results are immediately fatal. As sometimes, some individuals may correlate the characteristics of mucormycosis with malignancy in ignorance.

Direct microscopy

Aseptate hyphae with wide angle branching (45°sub to 90° sub) is characteristic of mucor species.[19] For direct microscopy, Calcofluor white staining solution was used. The key features with mucoromycetes were thick-walled, refractile hyphae 6–15 μm in diameter, swollen cells (≤50 μm) and sometimes, distorted hyphae.[23] Histopathology tests are always confirmatory.

Culture

Low cost culture medium is required but yet not diagnostically available.

Biopsy

Specimen from surgical exploratory site is the only (invasive) option for confirmation.[5]

Differential diagnosis

Circulating antigen such as galactomannan and β-D-1,3-glucan is positive for invasive aspergillosis and so differentiates it from mucormycosis. Therefore, samples from the infection site are required to diagnose mucormycosis based on the microscopic detection of typical hyphae or on a positive culture.[5]

For Candida albicans, although Periodic acid-schiff (PAS) unquestionably remains the mainstay of identification of fungus in routine cytological preparations, AO fluorescence preparations offer several advantages in routine cytological smears and for distinguishing it from mucormycosis.[24]


  Management of mucormycosis Top


The successful treatment of mucormycosis is based on the four principles:

  1. Early diagnosis
  2. Reversal of the underlying predisposing factors, if possible (for example, corticosteroids should be administered at reduced dosages or stopped if at all possible and hyperglycemia and acidemia should be corrected in diabetic ketoacidosis)
  3. Urgent surgical debridement of infected and necrotic tissue;[25],[14] appropriate antifungal therapy.[4]



  Pharmacologic Management Top


Amphotericin B (liposomal)

Amphotericin B (AmB) (liposomal) is the most commonly used for mucormycosis. Combination management of liposomal AmB and posaconazole showed synergistic effects.[1] Most of the negative side effects can be avoided by using lipid preparations of AmB. This lipid-based formulation of AmB increases circulation and alters the biodistribution of associated AmB. Because drugs that complex with lipid vehicles stay longer in the vasculature, they localize and reach higher concentrations in tissues with increased capillary permeability (i.e., tissues in which infection and inflammation are present) compared to regions of normal tissue, which are essentially impassable to lipid-complexed drugs, This is “passive targeting,” the method of increasing drug targeting to diseased sites. In mucor sites, drug is released due to the action of lipases secreted from surrounding inflammatory cells. Therefore, lipid formulations allow for better CNS solubility. Conventional AmB does not cross the brain–blood barrier efficiently, but the concentration of lipid-based AmB in brain tissue still remains unknown. The lethal dose (LD50) of lipid-based AmB is 10–15 times higher than that of conventional AmB and has causes less toxicity to the kidneys. Renal monitoring serum creatinine, potassium, magnesium levels, and blood urea nitrogen are very important.[19] Thus, the lipid formulations are ideally suitable for therapy against infections such as rhino-orbital cerebral zygomycosis (ROCZ), which require large doses of drug administered over long periods of time. The recommended dose of liposomal AmB is 5 mg/kg/day prepared as a 1 mg/mL infusion and delivered at a rate of 2.5 mg/kg/h.

Liposomal AmB is well tolerated in children even in higher doses.[26] In poor countries, when operating facilities and availability of blood products may be limited, repeated small-volume, bedside debridement and local amphotericin may be effective adjuncts to systemic antifungal therapy. Large defects require reconstructive procedures. These proposes surgical algorithm for therapy of soft-tissue mucormycosis in children.[26] With conventional Amphotericin (the drug of choice) is nephrotoxic, the safer liposomal amphotericin quite a costly endeavor for such population.[1]


  Posaconazole Top


Compassionate-use posaconazole is currently available, and its potential for combination therapy with a polyene, caspofungin, or both, is worthy of the study.[4] Posaconazole is a promise in vitro and in vivo activity against mucorales, but there are no data for the utilization of first-line posaconazole therapy. Posaconazole, therefore, finds its place within the therapeutic armamentarium for prophylaxis or consolidation after induction treatment with L-Amb.[27],[28] No study has been conducted on the efficacy of posaconazole intravenous or tablet formulations as the single line of treatment in mucormycosis treatment. Finally, mucormycosis cases have been reported in patients undergoing posaconazole prophylaxis despite satisfactory serum concentrations.[5] Posaconazole penetrates the cerebrospinal fluid (CSF) relatively poorly, but CSF concentration is improved in meningeal inflammation.[29] In patients with adequate renal function, at least 3 weeks of parenteral AmB followed by de-escalation to oral posaconazole has been suggested.[29]

Patients who are stabilized after surgery and commencement of parenteral antifungal therapy, step-down to oral posaconazole can be considered.[30],[6] It is also cost-effective compared with AmB.[6] Posaconazole is also a suitable alternative to AmB (in the absence of CNS involvement) if renal toxicity develops.[29] Another option for salvage treatment, proposed by ECIL-6 is the combination of lipid AmB and caspofungin or posaconazole.[12]

Isavuconazole is a novel triazole with a wide spectrum of activity against yeasts and moulds such as Mucorales and Aspergillus species.[29]


  Echinocandins Top


Caspofungin and micafungin. The combination of LAmB and micafungin at 1 mg/kg/day synergistically improved survival compared to either monotherapy arm. Monotherapy with micafungin at 3 mg/kg/day resulted in more surviving animals than monotherapy with micafungin at 1 mg/kg/day.[31]

Surgical management

The person with the greatest knowledge to manage traumatic dental injury is generally the last person to see the patient.[32] Similarly, oral and maxillofacial surgeons who are well acquainted with the rapid progression of mucor invasion are not the first responders here.

Aggressive early surgical debridement of the infected craniofacial tissues is the foundation of successful treatment of ROCZ mucormycoses. This includes resection of involved tissues of the face, including skin and muscle, any skin of the nose that's involved, maxillary and ethmoid sinuses, necrotic tissue of the temporal area and infratemporal fossa, and orbital exenteration.

Surgical technique of endoscopic Modified Denker is generally required if mucor is progressive. The steps are as follows:

  • Step 1: Mucosal cuts
  • Step 2: Soft-tissue dissection over the maxilla
  • Step 3: Bony cuts to the maxilla.[33]


Patients who had palatal erosion and required palatal resection, surgical approach of choice was open maxillectomy through weber ferguson incision followed by closure of palatal defect using temporalis muscle flap.[33]

An aggressive surgical approach is the key to survival. The keys to successful therapy include suspicion of the diagnosis with early perception of the signs and symptoms, correction of underlying medical disorders such as ketoacidosis and aggressive medical and surgical intervention. The use of all available therapeutic modalities within the treatment of this fatal infection, including intravenous liposomal AmB and hyperbaric oxygen additionally to the aggressive surgical debridement, is mandatory.

The systematic evaluation of treatment response through nasofibroscopic evaluation and biopsies of great utility in prognostic assessment.[34],[35]


  Alternative Treatment Top


Neutropenia is another significant risk factor. The correction of neutropenia with granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor is important to improve the outcome. Initiation of early and appropriate antifungal administration and, if required, discontinuation of steroids or deferoxamine is advisable.[14]


  Hyperbaric Oxygen Top


Hyperbaric oxygen has been used as an adjunct to the current therapeutic approach of aggressive surgical debridement, AmB therapy and control of underlying predisposing conditions. Studies have shown that hyperbaric oxygen exerts a fungistatic effect, assists neovascularization with subsequent healing in poorly perfused acidotic and hypoxic but viable tissue. Treatment regime consists of exposure to 100% oxygen for 90 min to 2 h at pressures of 2.0–2.5 atmospheres with one or two exposures daily for a total of 40 treatments.


  Immunostimulant Drugs Top


The checkpoint inhibitor nivolumab and interferon should be a drug for consideration for an immunocompetent patient as it has shown results in an extensive abdominal mucormycosis patient unresponsive to conventional therapy.[5]


  Discussion Top


COVID-19, immunosuppression and mucormycosis is a very important triad and hence, should never missed with a vigilant eye. One and the most important antagonist to mucormycosis is a good immunity. In the mid 20th century mucormycosis was considered to be a side effect of improved antibiotics and steroids use. Hence, COVID-19 let to mucormycosis per se is an understatement. But immunosuppressive conditions due to any possible reason predisposes us to be a victim of both these disease i.e., a very severe COVID infection and/or Mucormycosis or both. Clinical presentation of Mucormycosis is very vivid and varied. As people fail to recognize the real pathological associations involved along with other clinical complication assuming that dental doctors are not enough competent to treat or say, diagnose mucormycosis, this misconception cause them to lose their life or permanent tissue mutilation.[35] Surgical debridement with or without the various modalities ranging from partial maxillectomy to total maxillectomy with orbital exenteration when required in combination to aggressive anti-fungal therapy of lipid soluble amphotericin-B has dramatically improved prognosis. However, nephrotoxicity of amB is quite prominent, so combination therapy is preferable. The exact duration and dose of AmB needed for cure of rhinocerebral mucormycosis have not been accurately established.[36] Some newer drugs such as deferasirox and deferiprone show quite promise in against to deferoxamine. However, more studies are intended. Hyperbaric oxygen stays on its promise of innovation, but long-term studies will determine its long haul as these facilities are quite limited in third world countries. Once again a suppressed immune for whatsoever reasons, is a railway station for all microbial disease named trains. Hence, the need of the hour is to determine the accurate treatment needs of the patients to salvage them from mucormycosis and also having an Eagles vision determining the early diagnoses of mucormycoses. It is shown that prognosis and quality of life is the main stay of concern of a patient rather than the immediate disease implication. Multidisciplinary approach from various specialists right from a neurologist, ophthalmologist, ENT, oral and maxillofacial surgeon to a prosthodontist for rehabilitation are very much desirable for a patient.[20]


  Conclusion Top


Immunosuppression as a repressed immune due to existing comorbidities or due to severe acute infection (COVID-19) is a precursor for mucormycosis, and recent advances in treatment modalities have enhanced survival and rehabilitation outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Epidemiology
Etiopathogenesis
Pathogenesis
Etiology
Clinical Present...
Diagnostic Inves...
Management of mu...
Pharmacologic Ma...
Posaconazole
Echinocandins
Alternative Trea...
Hyperbaric Oxygen
Immunostimulant ...
Discussion
Conclusion
References
Article Tables

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