Discussion

Coronavirus disease 2019 infection is a global public health disease emergency,^{Reference Zhou, Yang, Wang, Hu, Zhang and Zhang16} and it is giving rise to another life-threatening emergency of rhino-orbital-cerebral mucormycosis. Although the incidence is 0.005–1.7 per million,^{Reference Wang, Wang, Chen and Qin17} cases are increasing at present. If an immunocompromised patient suffers from Covid-19, the propensity for co-infection with mucormycosis is high. In addition, if an immunocompetent patient suffers from Covid-19, the resultant immunosuppression due to the disease and its management per se can lead to rhino-orbital-cerebral mucormycosis.

During the severe acute respiratory syndrome outbreak in 2003 caused by SARS-CoV-1, the incidence of co-infection with the fungus was 14.8–27 per cent, which was an eye-opener.^{Reference Sharma, Grover, Bhargava, Samdani and Kataria18,Reference Zhang, Li, Huang, Cao and Hao19} There exists a similarity between SARS-CoV-2 and the previous SARS-CoV-1.^{Reference Peeri, Shrestha, Rahman, Zaki, Tan and Bibi20} The proteomic similarity analyses of both the strains showed highly homologous behaviour (95–100 per cent), and they share 76 per cent sequence similarity in their S proteins.^{Reference Kaur, Singh, Dar, Bijarnia, Dhingra and Kaur21}

The lethal triad of Covid-19, uncontrolled diabetes mellitus and corticosteroid therapy carries the highest risk for rhino-orbital-cerebral mucormycosis and ultimately results in exhausted immunity. Other risk factors include organ or bone marrow transplantation, neutropenia, other forms of metabolic acidosis, increased serum iron levels, malignant haematological disorders, deferoxamine, and iron chelation therapy in patients receiving haemodialysis.^{Reference Waizel-Haiat, Guerrero-Paz, Sanchez-Hurtado, Calleja-Alarcon and Romero-Gutierrez22,Reference Serris, Danion and Lanternier23} Coronavirus disease 2019 infection results in lymphopenia, reduced cluster of differentiation 4 and 8 counts, and an inflammatory cytokine surge.^{Reference Liu, Li, Liu, Liang, Wang and Wang24} It induces a prothrombotic and diabetogenic state by direct viral infection of endothelial cells and diffuse endothelial inflammation.^{Reference Liu, Li, Liu, Liang, Wang and Wang24–Reference Mehta and Pandey26} In our series, 14.6 per cent of patients were positive for Covid-19 on reverse transcription polymerase chain reaction testing at the time of presentation.

Uncontrolled diabetes mellitus results in impaired neutrophil function, leading to defective chemotaxis, transmembrane migration and reduced superoxide production. It causes reduced binding of transferrin to iron in acidotic conditions and favours Mucor growth. By increasing 78-kDa glucose-regulated protein GRP78, it mediates invasion of and damage to human endothelial cells. Through structural and functional modifications of platelets, it results in a defect in membrane properties and alterations of nitric oxide metabolism. The active ketone reductase system in uncontrolled diabetes favours Mucor growth in the acidic and glucose-rich environment.^{Reference Lim, Bae, Kwon and Nauck27} Those with diabetes are at a higher risk for complications and mortality than non-diabetics.^{Reference Kumar, Arora, Sharma, Anikhindi, Bansal and Singla9,Reference de Almeida-Pititto, Dualib, Zajdenverg, Dantas, de Souza and Rodacki10,Reference Apicella, Campopiano, Mantuano, Mazoni, Coppelli and Del Prato28} In our series, 29.2 per cent of patients had long-standing diabetes mellitus, while 68.2 per cent had been diagnosed with recent-onset diabetes mellitus.

Corticosteroid therapy results in hyperglycaemia and causes impaired neutrophil migration and phagolysosome fusion.^{Reference White, Dhillon, Cordey, Hughes, Faggian and Soni29} As we have no definitive management for Covid-19, only systemic corticosteroids have been shown to improve survival in patients with immunomodulation-related lung damage.^{Reference Müller, Groß, Conzelmann, Krüger, Merle and Steinhart30,Reference Sterne, Murthy, Diaz, Slutsky and Villar31} In our series, 87.8 per cent of patients had a history of corticosteroid usage. Cases of rhino-orbital-cerebral mucormycosis can be reduced by the cautious use of steroids with careful titration and strict sugar monitoring.

According to Indian guidelines, moderate cases should receive systemic methylprednisolone 0.5–1 mg/kg/day or dexamethasone 0.1–0.2 mg/kg for 3 days within 48 hours of admission if inflammatory markers are raised or the need for mechanical ventilation is present. Severe cases should receive systemic methylprednisolone 1–2 mg/kg/day or dexamethasone 0.2–0.4 mg/kg for 5–7 days.^{Reference Sen, Lahane, Lahane, Parekh and Honavar7} A European Confederation of Medical Mycology study reported a 46 per cent incidence of corticosteroid therapy administration one month before Mucor, and 44 per cent of patients had a history of immunosuppressant drugs.^{Reference Skiada, Pagano, Groll, Zimmerli, Dupont and Lagrou32}

The incidence of superadded co-infections with fungi and bacteria in hospitalised Covid-19 patients is documented as 8 per cent. Broad-spectrum antibiotics were used in 72 per cent of patients.^{Reference Rawson, Moore, Zhu, Ranganathan, Skolimowska and Gilchrist33} Song et al. reported that these opportunistic infections are more common in the middle and later phases of infection.^{Reference Song, Liang and Liu34} White et al. stated that the mortality rate among Covid-19 patients with mucormycosis is 53 per cent, while those without mucormycosis have a reduced mortality rate of 31 per cent.^{Reference White, Dhillon, Cordey, Hughes, Faggian and Soni29} In our series, one death was observed among active Covid-19 patients. The remaining three deaths occurred in patients who were negative for Covid-19 at that time.

Extensive examination of patients suffering and recovered from Covid-19, and awareness of the warning signs, allow detection of the dreaded complication at an early stage. The goals of mucormycosis management include reversal of the underlying immunosuppression; in addition, systemic antifungals reduce fungal load and aggressive debridement can enhance penetration of antifungal therapy.^{Reference Liu, Li, Liu, Liang, Wang and Wang24} Topical therapy with amphotericin B increases the local penetration of the drug and enhances outcomes. A delay of even 6 days in commencing treatment increases the mortality from 35 per cent to 66 per cent.^{Reference Sen, Lahane, Lahane, Parekh and Honavar7} The prognosis is poor even after all efforts, with 33.3–80 per cent mortality, and even more than 80 per cent mortality in poorly managed cases.^{Reference Jung, Kim, Park, Song, Cho and Lee35}

First-line therapy is liposomal amphotericin B, amphotericin B lipid complex and oral posaconazole suspension. Isavuconazole is used as salvage therapy.^{Reference Cornely, Alastruey-Izquierdo, Arenz, Chen, Dannaoui and Hochhegger15} The ideal duration of amphotericin B treatment is unclear, and there are no guidelines. We should monitor the individual's response by assessing inflammatory markers, serum electrolytes and renal function test results during the clinical response. The cost of amphotericin B carries a financial burden and can be back-breaking for a poor healthcare system. In one Indian study, 24.3 per cent of patients left hospital because of the high anticipated costs associated with mucormycosis management.^{Reference Patel, Kaur, Xess, Michael, Savio and Rudramurthy36} Treatment for Covid-19 is already a financial burden, and liposomal amphotericin B is adding to it.

We performed endoscopic endonasal debridement with Denker's approach in 21 patients and found the maxillary sinus to be the most commonly involved, implicated in 19 patients (90 per cent), followed by the ethmoid sinuses in 78 per cent, sphenoid sinus in 58 per cent and frontal sinus in 20 per cent of cases. On the contrary, Sharma et al. stated that the ethmoids were the most commonly affected sinuses in their study of 23 patients with coronavirus-associated mucormycosis.^{Reference Sharma, Grover, Bhargava, Samdani and Kataria18} It has been stated that disease limited to sinonasal areas can be managed by endoscopic debridement, and up to 94.4 per cent success can be achieved.^{Reference Sen, Lahane, Lahane, Parekh and Honavar7} Total maxillectomy was performed in six patients because of palatal and cheek involvement. Orbital exenteration with eyelid sparing was performed in four patients in our series because function and cosmesis could not be salvaged in the presence of extensive orbital involvement. There are no guidelines for orbital exenteration.^{Reference Sen, Lahane, Lahane, Parekh and Honavar7} At the last follow up, 37 patients were alive and on antifungal therapy.