|Year : 2021 | Volume
| 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
|Date of Submission||09-Jun-2021|
|Date of Decision||14-Jun-2021|
|Date of Acceptance||10-Aug-2021|
|Date of Web Publication||27-Sep-2021|
Department of Ophthalmology, ABVIMS and Dr. RML Hospital, Baba Kharak Singh Road, New Delhi - 110 001
Source of Support: None, Conflict of Interest: None
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.
Keywords: COVID-19, epidemic, mucormycosis, orbital mucormycosis, pandemic
|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;9:142-9
|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];9:142-9. Available from: https://www.jcor.in/text.asp?2021/9/3/142/326797
“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. 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. 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. 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. 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.
|Figure 1: (a) Mucormycosis hyphae in potassium hydroxide mount, (b) Mucormycosis hyphae in Hematoxylin and Eosin stain, (c) Mucormycosis hyphae in Lactophenol cotton blue mount (Broad, aseptate hyphae of mucor)|
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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.,, 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., India presently hosts the highest number of cases of mucormycosis. Although only 101 reported cases have been mentioned in a recent meta-analysis, 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. The incidence of diabetes in the meta-analysis mentioned earlier has been reported as 80%.
Several additional risk factors have been postulated to be responsible in COVID-19 disease, viz.,
- Reduction in T-lymphocytes (CD4 and CD8 T-cells)
- Insulin resistance
- Steroids used in the treatment of moderate-to-severe disease causing hyperglycemia and impaired neutrophil function
- Use of Tocilizumab or other immunomodulators
- Cytokine storm leading to increased serum levels of iron and ferritin which support Mucor growth
- Prolonged intensive care unit (ICU) stay and prolonged oxygen therapy
- Of 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:
- Rhino-orbito-cerebral mucormycosis (ROCM)
- Pulmonary mucormycosis
- Cutaneous and soft-tissue mucormycosis
- Gastrointestinal mucormycosis
- Mucormycosis of bones and joints
- Renal mucormycosis and
- Disseminated mucormycosis
The most common type reported in COVID-19 patients, worldwide, is ROCM.
| 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.
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. 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.
| Diagnosis|| |
The diagnosis is based on clinical, radiological, and laboratory features.
- Worsening headache
- Low grade fever
- Nasal stuffiness
- Nasal discharge-mucoid, purulent, blood-tinged or black
- Nasal mucosal erythema, inflammation, purple or blue discoloration, white ulcer or eschar.
Ocular and facial features
- Facial paraesthesia, numbness in the infraorbital region
- Facial palsy
- Regional pain – orbit, paranasal sinus, and facial pain
- Conjunctival congestion and chemosis
- Eyelid, periocular or facial edema
- Eyelid, periocular or facial discoloration
- Fixed pupil
- Decreased corneal sensations
- Sudden ptosis
- Ocular motility restriction-unilateral or bilateral
- Sudden loss of vision.
- Palatal eschar
- Toothache/loosening of teeth
- Loss of sensation/numbness over palatal region.
- Altered mental status
- Focal seizures
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 foramen
- Inferior orbital fissure from pterygopalatine fossa (directly involving the retroglobal structures)
- Lamina papyracea from ethmoid sinuses.,
[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. Direct fungal involvement of the inferior orbital nerve in the pterygopalatine fossa explains the initial facial pain and paraesthesia experienced by some patients. 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. 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: (a) Chemosis with lid edema, (b) lid edema with ptosis, (c) conjunctival eschar with exposure keratitis, (d and e) proptosis with left facial nerve palsy, (f) eschar involving lid with lid edema, ptosis, proptosis, and total ophthalmoplegia|
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|Figure 3: Magnetic resonance imaging (MRI) of a case of mucormycosis sinusitis with orbital involvement. Axial section through bilateral orbits (a) T2-weighted image, (b) T2-fat suppressed image: Axial section– Both orbits.★: Tenting of posterior spherical contour of Right Globe; giving conical appearance, : Straightened and slightly thickened left optic nerve with fuzzy margins and intra-substance altered hyperintense signal, : Soft-tissue fat standing in retro-orbital intraconal as well as extraconal fat, : Hyperintense signal from thickened left medial rectus muscle, : Bilateral ethmoid sinusitis: Heterogeneous hyperintense signal with interspersed hypointense areas, Red ovoid shows soft-tissue thickening at left orbital apex involving left cavernous sinus as well. There is mild luminal attenuation of left ICA as compared to right ICA, Proptosis: Left globe anterior to inter-zygomatic line (dotted yellow line) suggestive of Proptosis, White arrows: Preseptal soft-tissue edema. ICA: Internal carotid artery|
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|Figure 4: Fundus of a patient with COVID-19, mucormycosis, and hypertension. (a) Hypertensive retinopathy, (b) venous dilatation with possible thrombosis|
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The causes of vision loss include:
- Occlusion of CRA or ophthalmic artery by thrombosis
- Direct optic nerve fungal invasion or
- Ischemic optic neuropathy.,
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.
Spread to the brain may occur through the orbital apex, orbital vessels, or the cribriform plate.
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
- Mucosal thickening with irregular patchy enhancement
- Ischemia and nonenhancement of turbinates (black turbinate sign).
- Fluid level in sinuses
- Partial or complete sinus opacification.
- Thickening of medial rectus (early sign) followed by other extraocular muscles with poor enhancement
- Patchy enhancement of orbital fat
- Lesions in the area of superior and inferior orbital fissure and orbital apex
- Stretching of optic nerve, tenting of the posterior pole of eyeball suggest severe inflammatory edema secondary to tissue necrosis
- Bone destruction between sinuses and orbit
- Ophthalmic artery thrombosis.
Magnetic resonance imaging brain and magnetic resonance angiography,
- Invasion of cavernous sinus/cavernous sinus thrombosis
- Internal carotid artery narrowing/thrombosis
- Cerebral infarction/hemorrhage/abscess (later complications).
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 eschar
- Specimens 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 area
- Sample can be collected in a sterile container with normal saline and transported to the laboratory within 2 h
- Avoid sending swabs if pus or sterile body fluid/secretions/scrapings can be aspirated or when tissue can be obtained.,
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.,
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., 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.
Quantitative polymerase chain reaction can be used for the confirmation of diagnosis.
Sample should be collected from active lesions under endoscopy. Debrided tissue should be sent to the laboratory immediately in 10% formalin. 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.,
| 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. Early and aggressive medical and surgical treatment can be sight or life-saving. Nevertheless, the mortality is very high (50%–80%).
| 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]. 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]
|Figure 5: Management approach for possible, probable, or proven ROCM.# #Reproduced with permission. ROCM: Rhino-orbito-cerebral mucormycosis, MRI: Magnetic resonance imaging, CT: Computerized tomography, CNS: Central nervous system ECMM/MSG-ERC: European Confederation of Medical Mycology/ Mycosis Study Group- Education and Research Consortium|
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Protocol for administration of Amphotericin B,
- Liposomal Amphotericin B: 5–10 mg/kg/day
- Amphotericin B deoxycholate: 1.0–1.5 mg/kg/day
- Amphotericin 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).
1 mg in 100 ml of DNS infused over 20 min and observe for any allergic reaction.
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.
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.
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. 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 sanitisation
- Maintenance of personal hygiene
- Clear 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 virus
- Regular disinfection of all ICU gadgets
- Strict control of blood sugar levels in all COVID-19 patients
- Proper management of diabetic ketoacidosis
- Rational and evidence based use of steroids and tocilizumab
- Betadine mouth gargles
- Use of distilled water in oxygen humidifiers
- Use 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
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]