Rhino-orbital-cerebral mucormycosis in COVID-19 patients - Taming the black evil with pharmacological weapons.

Sir,

The global pandemic caused by COVID-19 virus has infected over 130 million across the globe, resulting in more than 2.8 million deaths on the day of writing this letter. At present, India is fighting against the second wave of COVID-19, which has proven to be more dangerous, spreading faster, and claiming more lives. A wide spectrum of secondary fungal and bacterial co-infections are being reported.[1] These may be associated with preexisting morbidities such as uncontrolled diabetes, lung pathologies, or may result from hospital-induced ventilator-associated pneumonia. There is another fungal pandemic in the form of fatal mucormycosis building up in our country. There is an urgent need to combat this deadly infection to prevent disastrous sequelae. This letter is aimed at giving useful insights into stages of mucormycosis, clinical profile, and various pharmacological options available to combat this emergency during the pandemic.

India is the diabetic capital of the world having 77 million diabetic patients (8.9% adults) constituting a major risk factor for mucormycosis. The health experts have already raised concerns about the possibility of 2500 mucormycosis cases per day in India. The major predisposing factors include diabetes mellitus, corticosteroids overuse, immunodeficiency diseases, malignancies or immunosuppressive drugs, COVID-19 infection, patients on remdesivir, tocilizumab, and iron overload in the body. Rawson et al.[2] in their review found that 8% (62/806) of the patients during the hospital stay had developed secondary fungal or bacterial infections.[2] The patients with secondary fungal infections are at increased risk of developing widespread pulmonary pathology and alveoli-interstitial lung disease. These fatal and invasive fungal infections are probably due to specific pathophysiological manifestations of the COVID-19 virus. Moreover, the immune dysregulation induced by COVID-19 virus reduces the T-lymphocytes number including CD4+ T cells and CD8+ T cells significantly. This results in altered innate immunity. A recent study highlighted 26.7% incidence of invasive fungal infections and 53% mortality of COVID-19-admitted patients.

Mucormycosis can be categorized into four stages. Stage 1 (nasal mucosa involvement) is characterized by nasal discharge, stuffiness, epistaxis, and foul smell. Stage 2 (paranasal sinuses involvement) manifestations include dental and facial pain, edema, and sinus tenderness. Stage 3 (orbital and ocular involvement) manifestations include ptosis, proptosis, diplopia, and cranial nerve involvement. Stage 4 (neurological involvement) is characterized by higher mental function involvement, seizures, paralysis, and cavernous sinus thrombosis. The laboratory diagnosis is based on smearing on 10% KOH mount, fluorescence on calcofluor white, and culture of mucor hyphae on sabouraud dextrose agar, potato dextrose agar, and brain hear infusion broth. Imaging options are vital to rule out central nervous system involvement which includes contrast enhance magnetic resonance imaging and computed tomography scan in which magnetic resonance imaging takes an upper hand owing to its high sensitivity and specificity for soft tissue delineation. The management is dependent on prompt clinical and laboratory diagnosis, meticulous risk stratification, and targeted and appropriate drug therapy with multiple aggressive interventions to safeguard life. The various pharmacological drugs available for the treatment can be categorized as liposomal amphotericin B (LAMB) (lipid formulation), posaconazole, and isavuconzole. Recently, novel pharmacotherapeutic drugs have shown promise in the management of mucormycosis with other comorbidities. These include combination therapy in the form of amphotericin B (AMB) + echinocandins, AMB + triazole, polyene and posaconazole, anti-retroviral therapy + AMB (HIV), AMB + hematopoietic growth factors, white cell transfusion graft-versus-host-disease, AMB + deferasirox (synergistic action), AMB + hyperbaric oxygen (synergistic action), and AMB + interferon-γ + Nivolumab (inhibit mucormycosis) [Table 1]. In uncontrolled mucormycosis, i.e., usually Stage 3 and above, the management rests on amphotericin-assisted sinus irrigation, surgical debridement, and orbital exenteration. If the patient is systemically unfit to undergo surgical intervention, LAMB is the gold standard with aggressive metabolic control.

Table 1

Various pharmacological management options for mucormycosis[3]

Approved pharmacotherapy
Broad category	Drug	Dosage	Adverse effects	Remarks
Antifungal	LAMB	5 mg/kg/day from day 1 of infection	NephrotoxicityElectrolyte derangements	Less effective alternative amphotericin lipid complex and deoxycholate formulation
Antifungal-newer triazoles	Posaconazole	2×200 mg BD for 2 days IV, 1×200 mg IV from day 3	Anemia, epistaxis, muscle pain	Posaconazole requires cyclodextrin vehicle for solubility
	Isavuconazole	2×300mg day 1 IV1×2 300 mg IV from day 2	Headache, rash, pedal edema	Once the patient stabilizes switch to oral formulation with the same dose
Experimental pharmacotherapy
Broad category	Drug	Remarks
Combination therapy	AMB + echinocandinsAMB + triazole,polyene and posaconazole	Experimental, no beneficial effectsAvoid in hematological malignancies, cost plays a big factor
Adjunctive therapy	AMB + hematopoietic growth factors, white cell transfusions	GVHD with mucormycosis patients
Adjunctive therapy	AMB + anti-retroviral therapy	HIV with mucormycosis patients
Adjunctive therapy	AMB + iron chelator – deferasirox	Inhibit mucormycosis growth
Adjunctive therapy	AMB + HBO	HBO enhance the AMB action by reversing acidosis and thus, helpful in treating mucormycosis
Combination therapy	AMB + interferon-γ + nivolumab	Interferon-γ prevent life-threatening fungal infections by restoring monocyte functionNivolumab inhibits T-cell proliferation and cytokine production

AMB=Amphotericin B, LAMB=Liposomal AMB, GVHD=Graft-versus-host disease, HBO=Hyperbaric oxygen, IV=Intravenous

Hirabayashi et al.[4] also reported that AMB deoxycholate retrobulbar injections, systemic intravenous (IV) antifungals, and debridement of the sinuses endoscopically act as a very good treatment option for orbital mucormycosis. Joos and Patel[5] in their case report proved that when the orbital cavity was irrigated daily with AMB, it resulted in effective infection control and also avoided the need for orbital exenteration in cases with extensive nasal and orbital involvement. COVID-19-induced immunosuppression, corticosteroids use, and mechanical ventilation along with uncontrolled DM have ignited another flame of the mucor pandemic. This had added to not only mortality but also to the economic burden for poor socioeconomic strata in India. IV LAMB is a costly drug and a single treatment may cost around an average of 4–8 lakhs. Ophthalmologists, ear, nose, and throat specialists, neurologists, and even pharmacologists play a huge role in the early diagnosis of mucormycosis associated with COVID-19. We have to search for cost-effective drug alternatives if the mucormycosis pandemic continues in the near future. We believe that pharmacological research and multidisciplinary collaboration have a huge role to play in combating this deadly infection of mucor in a viral land.

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Conflicts of interest

There are no conflicts of interest.