Journal of Clinical Ophthalmology and Research

CURRENT OPHTHALMOLOGY
Year
: 2021  |  Volume : 9  |  Issue : 3  |  Page : 142--149

Mucormycosis: An epidemic within a pandemic


Manav Deep Singh1, Shreya Gujral1, Munish Guleria2, Shalini Malhotra3, Taru Dewan1, Anwara Mammel1, Mohandeep Kaur4,  
1 Department of Ophthalmology, ABVIMS and Dr. RML Hospital, New Delhi, India
2 Department of Radio-diagnosis, ABVIMS and Dr. RML Hospital, New Delhi, India
3 Department of Microbiology, ABVIMS and Dr. RML Hospital, New Delhi, India
4 Department of Anesthesiology, ABVIMS and Dr. RML Hospital, New Delhi, India

Correspondence Address:
Shreya Gujral
Department of Ophthalmology, ABVIMS and Dr. RML Hospital, Baba Kharak Singh Road, New Delhi - 110 001
India

Abstract

There has been a steep rise in the incidence of mucormycosis in India during the second wave of COVID-19 infection. This outbreak has principally been attributed to uncontrolled diabetes mellitus and injudicious use of corticosteroids. However, many nondiabetics and those never on steroids have also suffered from this deadly disease recently. Thus, research is under the way to look for other offending factors. Mucormycosis is an opportunistic, potentially fatal, fungal infection caused by a group of saprophytic fungi belonging to family Mucoraceae. Rhino-orbito-cerebral mucormycosis is the most common reported type. The fungi are angioinvasive in nature, leading to thrombosis and rapid tissue necrosis. It also shows neurotropism. We have conducted current literature review using the electronic database of PubMed and recent mycology books, to analyze the possible risk factors, pathogenesis, clinical features, and management protocol of mucormycosis, giving special emphasis on the Indian data. Medline search was supplemented by the personal communication with some researchers, since the problem is of recent origin and publications are still in progress. Our personal experience and current data declared by, or orders issued by union health ministry or state ministries have also been referred to. A high index of suspicion is essential for the early detection as the initial signs and symptoms might go unnoticed as they are nonspecific. The diagnosis requires the sample collection by nasal and sinus endoscopy, direct microscopic examination under potassium hydroxide (KOH), culture, imaging, and molecular tools. Histopathology and KOH mount are the cornerstones for the confirmation of diagnosis. A combination of aggressive medical therapy and surgical debridement can improve the survival. Amphotericin B continues to be the drug of choice.



How to cite this article:
Singh MD, Gujral S, Guleria M, Malhotra S, Dewan T, Mammel A, Kaur M. Mucormycosis: An epidemic within a pandemic.J Clin Ophthalmol Res 2021;9:142-149


How to cite this URL:
Singh MD, Gujral S, Guleria M, Malhotra S, Dewan T, Mammel A, Kaur M. Mucormycosis: An epidemic within a pandemic. J Clin Ophthalmol Res [serial online] 2021 [cited 2022 May 17 ];9:142-149
Available from: https://www.jcor.in/text.asp?2021/9/3/142/326797


Full Text



“Unlike other fungal diseases, even the Acquired Immunodeficiency Syndrome pandemic could not significantly affect the incidence and prevalence of mucormycosis during the last three and half decades. However, upsurge in the number of diabetics has really changed the entire scenario more or less like an epidemic in South-east Asia posing a very serious health threat. Mucormycosis is going to destroy India shortly in a couple of years.” This is a statement given in 2018.[1] Therefore, it is clear that, diabetes has been considered the main risk factor for this disease. The estimated prevalence of mucormycosis in India has been around 70 times higher than the global data even during pre-COVID times.[2] However, this lesser existing disease, mucormycosis, has become a household name during the second wave of COVID-19 pandemic in India. It has now been declared as an epidemic by various states following issuance of advisory from Government of India on May 19, 2021.[3] COVID-19 infection, with or without diabetes, is being considered the major risk factor.

Mucormycosis is a life-threatening opportunistic fungal infection caused by fungi of family Mucoraceae of order Mucorales. These fungi include species of Mucor, Rhizopus, Rhizomucor, Lichtheimia, Saksenea, and Apophysomyces.[1] These are aseptate or pauci-septate, branched, broad filamentous fungi [[Figure 1]a (KOH mount) and b (H and E stain)], which are ubiquitous in nature and grow in soil and decaying organic matter. These rarely cause infection in an immunocompetent host.[4]{Figure 1}

The predisposing factors include uncontrolled hyperglycemia, ketoacidosis, corticosteroids/immunosuppressive drugs, solid organ or hematological malignancies, and organ transplantation. Voriconazole prophylaxis in transplant recipients, severe burns, open wound following trauma, neutropenia, hemochromatosis, deferoxamine or desferrioxamine iron chelation therapy, malnutrition, etc., are additional reported risk factors.[4],[5],[6] The outbreak of mucormycosis in India, in the setting of the second wave of COVID-19, is mainly attributed to uncontrolled diabetes mellitus (preexisting or COVID-19 induced) and irrational and indiscriminate use of corticosteroids.[6],[7] India presently hosts the highest number of cases of mucormycosis.[6] Although only 101 reported cases have been mentioned in a recent meta-analysis,[6] more and more cases are being observed in all the parts of the country every day. This number has been reported as 28,252 on June 07, 2021 in India alone, with 86% having a history of COVID-19 and 62.3% diabetes.[8] The incidence of diabetes in the meta-analysis mentioned earlier has been reported as 80%.[6]

Several additional risk factors have been postulated to be responsible in COVID-19 disease, viz.[6],[9]

Reduction in T-lymphocytes (CD4 and CD8 T-cells)Insulin resistanceSteroids used in the treatment of moderate-to-severe disease causing hyperglycemia and impaired neutrophil functionUse of Tocilizumab or other immunomodulatorsCytokine storm leading to increased serum levels of iron and ferritin which support Mucor growthProlonged intensive care unit (ICU) stay and prolonged oxygen therapyOf late, antibiotic abuse, excess use of zinc supplementation, use of industrial oxygen for medical purposes, use of tap water in oxygen humidifiers, lack of hygiene, etc., have also been implicated as possible risk factors for the development of mucormycosis. However, concrete evidence is lacking.

The clinical varieties

The clinical types, depending on the site of involvement, are as follows:[1]

Rhino-orbito-cerebral mucormycosis (ROCM)Pulmonary mucormycosisCutaneous and soft-tissue mucormycosisGastrointestinal mucormycosisMucormycosis of bones and jointsRenal mucormycosis andDisseminated mucormycosis

The most common type reported in COVID-19 patients, worldwide, is ROCM.[6]

 Pathogenesis



The portal of entry is predominantly through inhalation of fungal spores through nose or mouth. The fungus, from there, invades the paranasal sinuses, orbit and brain.[5]

Mucormycosis has predilection for internal elastic lamina of blood vessels. It damages the endothelium causing thrombosis, further leading to ischemia and necrosis of the involved tissue.[5] It has been popularised, among masses, as “Black fungus” because of the rapid necrosis and eschar formation which is black in color. In fact, the term “Black fungus” is a misnomer because these fungi are grayish white in color. Black fungi, also known as black yeasts, are actually dematiceous fungi which have melanin pigment in their cell wall. The examples are Exophiala and Alternaria species.[10]

 Diagnosis



The diagnosis is based on clinical, radiological, and laboratory features.

Clinical features

Generalised symptoms

Worsening headacheLow grade feverMalaise.

Nasal features

Nasal stuffinessEpistaxisNasal discharge-mucoid, purulent, blood-tinged or blackNasal mucosal erythema, inflammation, purple or blue discoloration, white ulcer or eschar.

Ocular and facial features

Facial paraesthesia, numbness in the infraorbital regionFacial palsyRegional pain – orbit, paranasal sinus, and facial painConjunctival congestion and chemosisEyelid, periocular or facial edemaEyelid, periocular or facial discolorationFixed pupilDecreased corneal sensationsSudden ptosisDiplopiaOcular motility restriction-unilateral or bilateralProptosisSudden loss of vision.

Oral features

Palatal escharToothache/loosening of teethLoss of sensation/numbness over palatal region.

Cerebral features

Altered mental statusFocal seizuresParalysis

Ophthalmology and Mucor

The spread of infection to the orbit occurs through:

Erosion of floor of the orbit through maxillary sinus or through inferior orbital foramenInferior orbital fissure from pterygopalatine fossa (directly involving the retroglobal structures)Lamina papyracea from ethmoid sinuses.[4],[11]

[Figure 2] shows the spectrum of findings in mucormycosis. Mucor, being an angio-invasive group of fungi, leads to increased incidence of thrombosis causing infarcts in respective areas. Apart from angioinvasion, perineural spread also occurs.[12] Direct fungal involvement of the inferior orbital nerve in the pterygopalatine fossa explains the initial facial pain and paraesthesia experienced by some patients.[11] Central retinal artery (CRA) thrombosis may lead to its occlusion leading to blindness. On magnetic resonance imaging (MRI), it shows as straightening of the optic nerve and tenting of the globe making it conical in shape with apex at the insertion of the optic nerve [Figure 3]a and [Figure 3]b. Fundus examination may reveal generalized retinal oedema, arteriolar attenuation, and cherry red spot.[13] We have observed venous dilatation along with obstruction in a hypertensive patient with COVID-19 and mucormycosis [Figure 4]a and [Figure 4]b.{Figure 2}{Figure 3}{Figure 4}

The causes of vision loss include:

Occlusion of CRA or ophthalmic artery by thrombosisDirect optic nerve fungal invasion orIschemic optic neuropathy.[11],[14]

Not all patients presenting with ptosis/ophthalmoplegia have orbital involvement. Sometimes, the clinical manifestations mimic orbital apex syndrome due to sphenoiditis which leads to oedema of the orbital apex. In such cases, vision remains unaffected.[15]

Spread to the brain may occur through the orbital apex, orbital vessels, or the cribriform plate.[16]

Radiological findings

Contrast-enhanced MRI of the brain, orbit, and paranasal sinuses is the imaging modality of choice. Because of increased soft-tissue resolution, MRI provides a better visualization of invasion/involvement of orbital soft tissue, infratemporal fossa, intracranial structures and perineural invasion, and vascular obstruction than computerized tomography (CT).

Nose and paranasal sinuses

Early signs:[17]

Mucosal thickening with irregular patchy enhancementIschemia and nonenhancement of turbinates (black turbinate sign).

Late signs:[17]

Fluid level in sinusesPartial or complete sinus opacification.

Orbits[17]

Thickening of medial rectus (early sign) followed by other extraocular muscles with poor enhancementPatchy enhancement of orbital fatLesions in the area of superior and inferior orbital fissure and orbital apexStretching of optic nerve, tenting of the posterior pole of eyeball suggest severe inflammatory edema secondary to tissue necrosisBone destruction between sinuses and orbitOphthalmic artery thrombosis.

Magnetic resonance imaging brain and magnetic resonance angiography[5],[17]

Invasion of cavernous sinus/cavernous sinus thrombosisInternal carotid artery narrowing/thrombosisCerebral infarction/hemorrhage/abscess (later complications).

Laboratory diagnosis

Microbiological findings

Procedure of sample collection and transportation:

Sample collection should be done by endoscopy and material should be collected from relatively healthy area with advancing edge and not from escharSpecimens may include debrided tissue/biopsy, crust, debris, scab, granulation tissue, discoloured mucosa, secretions, scraping or exudate from nares, hard palatal lesions, sinus material or biopsy from extracted tooth socket areaSample can be collected in a sterile container with normal saline and transported to the laboratory within 2 hAvoid sending swabs if pus or sterile body fluid/secretions/scrapings can be aspirated or when tissue can be obtained.[17],[18]

Samples collected with swabs give low diagnostic yield. Direct microscopy using potassium hydroxide mount shows aseptate or pauci-septate, broad, branched (≥45°–90°) ribbon like filamentous fungal hyphae [Figure 1]a. It is useful for rapid diagnosis and has 90% sensitivity.[1],[17]

Culture using Sabouraud dextrose agar at 30°C and 37°C yields rapid growth of cotton white or grayish brown colonies. However, its positivity is low.[1],[17] Other media such as potato dextrose agar and brain–heart infusion agar can also be used. Lactophenol cotton blue mount on a slide is useful for the identification of different genera of mucormycosis [Figure 1]c.[19]

Molecular diagnostics

Quantitative polymerase chain reaction can be used for the confirmation of diagnosis.[17]

Histopathology

Sample should be collected from active lesions under endoscopy. Debrided tissue should be sent to the laboratory immediately in 10% formalin.[18] Staining with H and E, periodic acid-Schiff and Grocott-Gomori's methenamine silver special stains demonstrate the pathognomonic broad, irregular, nonseptate and branched hyphae [Figure 1]b. Hyphae showing tissue invasion is confirmatory of invasive ROCM. Evidence of tissue necrosis may also be present.[4],[17]

 Management



The prevention of hyperglycemia, judicious use of steroids, and hygienic practices are probably the most important for its prevention. A high index of suspicion is required as the disease is highly aggressive and may begin with nonspecific signs and symptoms. Addressing early symptoms such as facial paraesthesia, pain or numbness in the infra-orbital region, nasal blockage, palatal discoloration, conjunctival congestion or chemosis in the clinical setting of COVID-19 (of any severity, with or without diabetes or steroid usage) should arouse suspicion of mucormycosis and early treatment should be started. The mainstay of treatment is antifungals with sinus debridement. Liposomal Amphotericin B is the drug of choice. Isavuconazole and posaconazole are other first-line alternatives in case of contraindication to Amphotericin B. Orbital cellulitis, ptosis, proptosis, and cavernous sinus thrombosis are relatively late signs. Whereas early orbital involvement may be treated by retrobulbar injections of Amphotericin B, later stages may require extensive surgery like exenteration. In advanced disease, a multidisciplinary team consisting of intensivist, internal medicine specialist, ophthalmologist, otorhinolaryngologist, oral and maxillofacial surgeon, dentist, radiologist, microbiologist, histopathologist, neurologist, and neurosurgeon is needed.[17] Early and aggressive medical and surgical treatment can be sight or life-saving. Nevertheless, the mortality is very high (50%–80%).[6]

 Staging the Disease



A number of clinicians and researchers are in the process of developing staging systems as well as the management protocols for ROCM. One such system has recently been proposed by Honavar [Table 1].[17] Although this system is reasonably comprehensive, progression of disease may not strictly follow this course and we may see more systems and classifications in near future. A management protocol based on this staging has also been proposed [Figure 5][17]{Table 1}{Figure 5}

Protocol for administration of Amphotericin B[18],[19]

Recommended dose

Liposomal Amphotericin B: 5–10 mg/kg/dayAmphotericin B deoxycholate: 1.0–1.5 mg/kg/dayAmphotericin B lipid complex: 5 mg/kg/day

Pre- and post-hydration

Five hundred millilitres of normal saline over 30 min, 2 h before and after infusion of Amphotericin B. To reduce the risk of renal toxicity and hypokalaemia, 500 ml of normal saline + one ampoule (20 mmol) of potassium chloride can be given.

Method of dilution

For an average adult of 60 kg body weight, 300 mg (5 mg/kg) of liposomal Amphotericin B is needed i.e., 6 vials. Each 50 mg vial of liposomal Amphotericin B is reconstituted with 10 ml of distilled water i.e., 60 ml (normal saline should NOT be used for reconstitution as it can cause precipitation).

Test dose

1 mg in 100 ml of DNS infused over 20 min and observe for any allergic reaction.

Infusion

The 60 ml of reconstituted solution is added to 300 ml of 5% dextrose which is infused intravenously over a period of 2 h. If there is risk of fluid overload, use 250 ml pre/post hydration or skip posthydration. Alternatively, Amphotericin B may be mixed with lesser quantity of 5% dextrose and infused over 2 h using infusion pump.

Protect from light during administration.

Monitoring

Serum creatinine, electrolytes and C-reactive protein to be monitored every alternate day throughout the course of treatment with Amphotericin B.

Some other opportunistic infections have also been reported in COVID-19 patients. These include Mycoplasma pneumonia, Pseudomonas aeruginosa, Haemophilus influenzae, Klebsiella pneumoniae, Acinetobacter baumannii, Candida, Aspergillus, respiratory syncytial virus, influenza A, influenza B, rhino/enteroviruses, parainfluenzae etc.[20]

Role of iron in mucormycosis

There may be a role of iron chelation with lactoferrin and other chelating agents in COVID-19 with diabetes or deranged blood sugar and high ferritin levels.[21] Mucor grows selectively in an iron rich environment. Desferrioxamine in particular has been tried as a salvage therapy. But by itself it has a siderophilic site which may promote growth of Mucor. So it may be used only after debulking surgery. Now we have other agents such as deferasirox which actually have been shown to be fungicidal in ROCM cases. As ferritin levels go up, cellular iron rises (serum iron carrying capacity reduces). Corona virus spike protein has a hepcidin mimetic effect. This transports iron within cells which causes release of ferritin. Intracellular iron damages cells by activation of free radicals by iron catalysed Fenton reaction as well as the Haber-Weiss reaction. Also ferritin causes complement activation and thrombotic tendency and activation of fibrinolytic pathway. Haem breakdown by corona virus also contributes to releasing more iron and complement activation. In terms of therapy, we may use a mild iron chelator like Lactoferrin (100 mg capsules available) for high risk cases. Lactoferrin is both mildly antiviral and also immunomodulatory and may support sugar control in the patients with COVID who have deranged blood sugar, known diabetic or otherwise. For diagnosed cases, before debulking, deferasirox or defriprone may be used as they do not supply iron to fungus. Deferasirox is oral single day therapy 20–30 mg/kg body weight. Deferapronecan be given as 75 mg/kg body weight oral 2–3 times a day.

 Prevention



As we have, recently, become aware of many risk factors, prevention of occurrence of this disease can go a long way in preventing loss of life or sight. The preventive measures include:

Environmental sanitisationMaintenance of personal hygieneClear explanation of early symptoms and signs of mucormycosis to patients at the time of discharge as most COVID-19 patients develop mucormycosis a few weeks after discharge and when they have already become negative for corona virusRegular disinfection of all ICU gadgetsStrict control of blood sugar levels in all COVID-19 patientsProper management of diabetic ketoacidosisRational and evidence based use of steroids and tocilizumabBetadine mouth garglesUse of distilled water in oxygen humidifiersUse of antibiotics and antifungals only when indicated.

 Summary



Thus to summarise, mucormycosis is an uncommon life threatening fungal infection which has reached epidemic proportions during COVID-19 pandemic. Diabetes and steroids usage being the most important, many more risk factors have been implicated. Prevention by avoiding/controlling these factors, maintaining hygiene and early aggressive treatment can go a long way in reducing morbidity and mortality from this disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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