Kerala Journal of Ophthalmology

GUEST EDITORIAL
Year
: 2021  |  Volume : 33  |  Issue : 3  |  Page : 242--248

Mucormycosis: An overview


Viji Rangarajan, Anandhalakshmi Subramanian 
 Department of Orbit and Oculoplasty, Aravind Eye Hospital, Coimbatore, Tamil Nadu, India

Correspondence Address:
Dr. Viji Rangarajan
Department of Orbit and Oculoplasty, Aravind Eye Hospital, Coimbatore - 641 014, Tamil Nadu
India

Abstract

Rhino-orbital mucormycosis is a life-threatening opportunistic fungal infection, which affects mainly immunocompromised hosts. It is commonly caused by ubiquitous fungi belonging to the order Mucorales, family Mucoraceae, which is also commonly known as the black fungus among the general population. The prevalence of mucormycosis (approximately 0.14 cases/1000 population) in India is about 80 times higher than in other developed countries. Despite aggressive treatment with surgical debridement and timely antifungal administration, the overall mortality rate is high. COVID 19 pandemic has led to an increase in the incidence of rhino-orbital mucormycosis. A multidisciplinary approach with early diagnosis and timely treatment with good control of glycemic levels, judicious use of steroids, and addressing immune status of patients helps in reducing the mortality and aids in improving survival rates of mucormycosis patients.



How to cite this article:
Rangarajan V, Subramanian A. Mucormycosis: An overview.Kerala J Ophthalmol 2021;33:242-248


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Rangarajan V, Subramanian A. Mucormycosis: An overview. Kerala J Ophthalmol [serial online] 2021 [cited 2022 Jan 23 ];33:242-248
Available from: http://www.kjophthal.com/text.asp?2021/33/3/242/331932


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 Introduction



Rhino-orbital cerebral mucormycosis (ROCM) or phycomycosis is a life-threatening, angioinvasive disease caused by fungi of the order, Mucorales. It occurs mainly in immunocompromised conditions including patients with uncontrolled diabetes mellitus, hematological malignancies, postorgan transplant recipients on immunosuppressive therapy, and patients on iron overload therapy, hemodialysis, and chemotherapy who are at increased risk of acquiring mucormycosis.[1] It may also affect immunocompetent patients following trauma or burns.[2] Clinically classified as rhinocerebral, pulmonary, gastrointestinal, and disseminated. The incidence of mucormycosis has increased markedly in the settings of COVID-19 in India. It has been declared as an epidemic and a notifiable disease in many states.

 Epidemiology



The exact incidence of mucormycosis is unknown. Globally, the prevalence of mucormycosis varied from 0.005 to 1.7/million population. The estimated prevalence of mucormycosis is 70% higher in India than in developed countries.[3] The high prevalence rate may be due to the increased presence of Mucorales in community, hospital environment, and immunocompromised state, especially uncontrolled diabetes. Association of COVID-19 with a recent increase in the incidence of mucormycosis is possibly due to severe acute respiratory syndrome coronavirus-2 causing impaired cell-mediated immunity and lymphopenia leading to a reduction in CD4 and CD8 cells.[4]

 Causative Organisms



Mucorales are saprophytic fungi commonly found in decaying organic matter, soil, and air. Rhizopus, Lichtheimia, Cunninghamella, and Rhizomucor are the common pathogenic species causing mucormycosis in India. Rhizopus arrhizus, a nonseptae filamentous fungi, is the most common cause of mucormycosis in India. Apophysomyces variabilis is the second common isolated agent. Lichtheimia species contributes about 0.5% to 13% of cases from India.[5] Rare pathogens such as Saksenaea erythrospora, Mucor irregularis, and Thamnostylum lucknowense were also reported.[6]

 Risk Factors



Mucormycosis is a rare disease, but several immunocompromised conditions can predispose it. Uncontrolled diabetes is the most common underlying risk factor for contracting mucormycosis and increases the severity of COVID-19. Hyperglycemia causes glycosylation of transferrin and ferritin and reduces iron binding which leads to increase in free iron levels. It enhances the expression of glucose-regulator protein78 of endothelial cells and Mucorales receptor core protein homologs, enabling angioinvasion, hematogenous dissemination, and tissue necrosis.[7] Severe neutropenia, steroid therapy, patients on prolonged ventilatory support, pulmonary tuberculosis, hematological malignancies, solid organ transplantations, malnutrition, autoimmune disease, HIV infection, and usage of immunosuppressant[8] drugs are the other important risk factors to be considered.

 Etiopathogenesis



Saprophytic fungi are rapidly growing fungi, which release a large number of spores in the environment. Inhalation of sporangiospores by the hosts gets colonized in oral mucosa, nose, throat, and paranasal sinuses. In immunocompromised individuals, phagocytosis is impaired, thus fungal spores undergo proliferation with resultant angioinvasion. A rapid progression occurs which leads to pansinus involvement followed by the hematogenous dissemination to bony walls of the nose, palate, orbit, and finally to the brain resulting in extensive necrosis and tissue ischemia [Figure 1].{Figure 1}

 Clinical Presentations



Generalized symptoms

Severe headacheLow-grade feverLocalized facial painMyalgia.

Ocular manifestations

Ocular painPeriorbital edemaProptosis [Figure 2]Ptosis [Figure 3]DiplopiaOphthalmoplegia [Figure 4]Discoloration of skin in the periocular region.Numbness in the infraorbital regionDefective color visionSudden blindness due to CRAO, thrombosis of posterior ciliary arteries, infarction of the intraorbital part of the optic nerve, or direct fungal invasion of intracranial part of the optic nerve or optic chiasma[9] [Figure 5].{Figure 2}{Figure 3}{Figure 4}{Figure 5}

Nasal symptoms

Nasal blockNasal bleedingBlackish or blood-tinged nasal dischargePost nasal drip.

Oral manifestations

Toothache, loosening of teethLoss of sensation or numbness over the hard palatal regionBlackish discoloration of buccal mucosa – Eschar formation [Figure 6]Perforation over the palatal region.{Figure 6}

Pulmonary manifestations

FeverCough with progressive dyspneaPleuritic chest pain.

Cutaneous and soft tissue manifestations

Erythema with indurationBlack eschar at trauma/puncture siteMuscle pain.

Gastrointestinal manifestations

FeverBleeding per anusAbdominal massIntestinal perforation.

Cerebral involvement

Altered sensoriumHemiparesisSeizures.

 Investigations



Laboratory investigations include

Complete blood countBlood sugar levels including fasting blood sugar, postprandial blood sugar, and HBA1CRenal function testLiver function testSerum electrolytesSerology–HIV, hepatitis B surface antigen, HCVSerum ferritin.

 Histopathology and Direct Microscopy



Definitive diagnosis is achieved by the histopathological examination of the specimen collected by a high nasal swab or diagnostic endoscopy during the endoscopic sinus debridement of the involved tissue. The fungal invasion may be patchy, so multiple biopsies from the active areas of infection may be required. Microscopical analysis of the specimen using 10% potassium hydroxide mount shows nonseptate branched fungal hyphae branching at right angles[9] which provides presumptive diagnosis. Calcofluor white, Grocott-Gomori's methenamine silver, and periodic acid–Schiff are the special stains helpful in illustrating the presence and morphology of the fungus [Figure 7] and [Figure 8].[10]{Figure 7}{Figure 8}

 Culture



Surgically debrided or biopsied specimen should be cultured for the identification of the fungus to genus and species level and for antifungal susceptibility.

Specimens should be collected aseptically in sterile containers and transported to the laboratory within 2 h. Samples are cultured on Sabouraud dextrose agar without cycloheximide, brain–heart infusion agar, or potato dextrose agar. Fungal cultures should be examined twice weekly for 4 weeks before reporting it as negative. It usually takes 2–3 days for the colonies to appear. Identification is based on macroscopic dirty white, fluffy, cotton-like colonies and microscopic morphology and growth temperature which is usually 30°C and 37°C [Figure 9].{Figure 9}

 Imaging



Computed tomography (CT) and magnetic resonance imagining (MRI) help in the early diagnosis of ROCM. Imaging shows the changes proportional to the extent of the fungus invasion of the affected tissue.[11] CT scans demonstrate mucosal thickening and a lack of air–fluid level in the infected sinus in the early stages. In later stage, it demonstrates the destruction of the medial orbital wall and the rectus muscles invasion, orbital apex, and involvement of ipsilateral cavernous sinus.[12],[13] Compared to CT scans, MRI allows for better visibility of orbital soft tissue invasion, infratemporal fossa involvement, intracranial structures, perineural invasion, and vascular obstruction.[14],[15] Fungal elements in MRI cause low intensity due to mucosal involvement and lack of enhancement of the mucosa is caused by its angioinvasive nature. MRI variables such as T1- and T2-weighted images show devitalized mucosa appearing as contiguous foci of infection causing non-enhancing tissue, which appears as “Black turbinate sign.”[16] In case of progressive ROCM disease, MRI shows hyperintense sinus wall, T2-W hyperintense lesion extending from paranasal sinus along orbital apex into intracranial structures, and narrowing or slow flow in the ipsilateral internal carotid artery [Figure 10].{Figure 10}

 Diagnosis



Possible rhino-orbital cerebral mucormycosis

Patients with typical signs and symptoms with a history of COVID treatment, DM, on steroid therapy, supplemental oxygen, and ventilator support.

Probable rhino-orbital cerebral mucormycosis

Signs and symptoms along with diagnostic nasal endoscopy findings (or) contrast-enhanced MRI or CT.

Proven rhino-orbital cerebral mucormycosis

Clinicoradiological features along with microbiological confirmation (on direct microscopy) or culture/HPE/molecular diagnostics.[17]

 Staging



Stage 1: Involvement of nasal mucosaStage 2: Involvement of PNSStage 3: Involvement of orbitStage 4: Involvement of central nervous system (CNS).

 Medical Management



Rhino-orbital mucormycosis should be treated as an emergency without delay in initiation of therapy. Prompt antifungal administration, correction of underlying risk factor such as hyperglycemia, acidemia and aggressive surgical intervention is essential for good prognosis.[18]

 Induction Therapy



Drug of choice: Liposomal amphotericin B – Intravenous (IV) administrationDose for sino-orbital involvement – 5 mg/kg/dayDose for cerebral involvement – 10 mg/kg/day.

 Injection Mode and Monitoring



Test dose: Injection liposomal amphotericin B 1 vial (50 mg) to be diluted in 12 ml of the diluent and 0.25 ml (1 mg) of solution made, to be mixed in 100 ml dextrose and to be infused in 30 min. Assessment for fever and allergic reactions is mandatoryPrehydration: Five hundred milliliter normal saline administered over 30 min with 1 ampule (20 mmol) potassium chlorideTherapy: 5 mg–10 mg/kg/day amphotericin B in 500 ml DS with 10 units of human insulin regular over 3 hPost hydration: Five hundred milliliter normal saline administered over 30 min.

After every dose of amphotericin B, renal function test with serum electrolytes has to be monitored.

If liposomal amphotericin B is unavailable, amphotericin B deoxycholate or amphotericin B lipid complex, which is less expensive can be used, but found to cause systemic toxicity.

In conditions where amphotericin is contraindicated

Isavuconazole IV 200 mg thrice daily for 2 days ->200 mg once from day 3 for 4–6 weeks (or)Posaconazole IV 300 mg twice daily on day 1 – >300 mg once from day 2 for 4–6 weeks.

 Retrobulbar Transcutaneous Amphotericin



Transcutaneous retrobulbar injection of amphotericin B

Injection into the retrobulbar space has been described as a minimally invasive, globe-sparing treatment for orbital mucormycosis.[19] Since lidocaine or bupivacaine is inflammatory, amphotericin B must be reconstituted with sterile water. Patients are anesthetized with a retrobulbar injection of 2–3 ml to avoid medication-induced pain. After 5 min, a 24-gauge retrobulbar needle was used to deliver 1 ml of liposomal amphotericin B to the retrobulbar space.[20]

Indications

The indications for retrobulbar injection are mild orbital involvement, patients presenting with ROCM with good vision acuity, without apical/CNS spread. It can also be administered along with IV amphotericin.

Dose

One milliliter of 3.5 mg/ml

Follow-up therapy

IV liposomal amphotericin B-5–10 mg/kg/day for a minimum of 4 weeks.

Step down therapy

IV isavuconazole 200 mg thrice daily for 2 days followed by 200 mg once from day 3 or IV posaconazole 300 mg twice daily on day 1 followed by 300 mg once from day 2 administered for 3–6 months (or) for a minimum of 6 weeks till evidence of clinical or radiological regression is noted.

 Surgical Management



In case of predominant sinonasal with no (or) limited orbit involvement/vision preserved

Functional endoscopic sinus surgery is indicated to reduce the fungal load from the sinuses with irrigation with amphotericin B 1 mg/ml ± turbinectomy ± palatal resection ± medial orbital wall resection depending on the extension of the disease.

In case of disease progression, worsening of orbital component in <72 h

Orbital exenteration is indicated.

In limited central nervous system involvement

Orbital exenteration with aggressive debridement of paranasal sinuses ± turbinectomy ± palatal Resection ± orbital wall resection with clean margins is indicated.

In case of extensive central nervous system involvement

If systemic condition of the patient permits, orbital exenteration with aggressive debridement of paranasal sinuses ± turbinectomy ± palatal resection ± orbital wall resection with clean margins should be done.

 Preventive Measures



Judicious and supervised use of systemic corticosteroids/tocilizumabAggressive monitoring and control of diabetes mellitusStrict aseptic precautions while administering oxygenPersonal and environmental hygieneUsage of clean distilled water for humidifiers during oxygen therapyAdministration of antibiotics/antifungals only when indicatedDo not neglect all cases with a blocked nose as cases of bacterial sinusitis, particularly immunocompromised patients and COVID-19 patients on immunomodulatorsClinical tests such as pupillary reaction, ocular motility, sinus tenderness, and palatal examination should be a part of routine physical evaluation of a COVID-19 patient.

 Conclusion



ROCM is estimated to be high in India than in developed countries. In India, a large number of susceptible hosts are diabetics, a considerable number of patients are ignorant of their diabetic status and neglect regular health checkup.[1] Mortality associated with mucormycosis is noticeably high due to delays in diagnosing the disease and the challenges in managing the advanced stage of infection.

In COVID-19 pandemic outbreak, it is possible to decrease the incidence of morbidity and mortality due to mucormycosis by high index of suspicion and detailed evaluation, early diagnosis, reversal of underlying predisposing risk factors, aggressive surgical debridement,[8] and prompt antifungal therapy with effective multidisciplinary approach.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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