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An event is serious (based on the ICH definition) when the patient outcome is:

• * death

• * life-threatening

• * hospitalisation

• * disability

• * congenital anomaly

• * other medically important event

In a case series of 7 patients treated at an institute in India, six men aged 48−69 years were described, who developed mucormycosis following off-label treatment with dexamethasone, prednisone, tocilizumab or methylprednisolone for COVID-19 infection. Additionally, two of these patients developed hypokalaemia or elevated serum creatinine during treatment with amphotericin-B or amphotericin-B liposomal for mucormycosis [not all routes, dosages and outcomes stated; duration of treatments to reaction onsets not stated].

Case 1: A 52-year-old man presented with discharge from the left eye along with pain and difficulty while eating for a month. His pain was persistent and had dispersed over the temporal area. It showed worsening with head movements and eventually resolved on its own. He had a 7-year history of type-2 diabetes mellitus (DM) under unspecified hypoglycaemic drugs treatment. Two months ago, he had also tested positive for SARS-CoV-2 and was receiving remdesivir, multivitamins along with a tapering dose of off-label IV dexamethasone 6mg and tocilizumab. An intraoral examination revealed tenderness of the alveolar mucosa along with black barebone and loss of mucoperiosteum over the midline of his palate, gingival necrosis and an ulcerative lesion on the left alveolar process of his maxilla. A cottony greyish-white colony was also detected on Sabouraud dextrose agar (SDA) and a lactophenol cotton blue (LCB) revealed aseptate hyphae, nodal rhizoids and short sporangiophores, indicating Rhizopus microsporus. A CT scan showed mucosal thickening along with gross destruction of the floor, anterior and lateral walls and roof of the left and right maxillary sinus. A brain MRI indicated sinusitis in the maxillary and ethmoid sinuses along with an abscess in the left orbit. Biopsy revealed granulation tissue with fungal elements. Thus, a diagnosis of Rhizopus microsporus mucormycosis secondary to dexamethasone and tocilizumab was confirmed and he received treatment with IV amphotericin-B 2 mg/kg daily for 8 days. However, he developed hypokalaemia and elevated serum creatinine secondary to amphotericin-B. Thus, amphotericin-B was substituted with posaconazole and he underwent a functional endoscopic sinus surgery (FESS). Left eye enucleation and total maxillectomy were also performed. Subsequently, an obturator was provided and he continued therapy with posaconazole. After 2 weeks, he was discharged without any recurrence and satisfactory wound healing. At the most recent follow-up, he was disease-free for the past 7 months under physician supervision for diet alteration and DM control.

Case 2: A 58-year-old man presented with palate ulcer for 15 days along with swelling and pain in the right back tooth region for a month. A month ago, he had undergone extraction for upper right canine and oedema around his right eye. His medical history was significant of type-2 diabetes mellitus for 12 years, ischaemic cardiomyopathy, end stage renal disease under haemodialysis and hypertension. He was diagnosed with COVID-19 one month earlier and had received treatment with remdesivir and tapering dose of off-label prednisone 40mg for 7 days. Upon analysis, a widespread sensitive swelling was detected on the right side of his face. An intraoral analysis showed ulcerative lesion in the right half of the hard palate, covered with yellowish slough and everted borders. Nasal endoscopy indicated pus in the inferior and middle meatus along with a granular mass in the right nasal cavity extending the septum to the opposite side and partly eroding it. Based on these findings, a provisional diagnosis of mucormycosis or osteomyelitis was made. Further findings indicated bony erosion and diffuse radiopacity in the right nasal cavity and maxillary sinus along with invasion to brain vessels. He underwent right eye enucleation and subtotal maxillectomy of the right side. Microscopic evaluation of multiple yellowish black soft tissue bits revealed several viable and necrotic bony, mucosal and soft tissue focally covered with acute inflammatory exudates. Additionally, foci of angioinvasion and extensive fungal outgrowth including brownish spores with slender hyphae and multiple broad aseptate hyphae were observed. Several dilated vascular channels with haemorrhage were also detected. Thus, a diagnosis of mucormycosis secondary to prednisone was confirmed. He was initiated on a treatment with IV amphotericin-B liposomal [liposomal amphotericin-B] 2 mg/kg daily and ciprofloxacin. However, he developed hypokalaemia secondary to amphotericin-B liposomal. He also developed moderate acute renal failure. Post-surgery, inter-hemispheric cerebral haematoma was detected, which was later complicated by coma and respiratory distress and resulted in his demise.

Case 3: A 60-year-old man presented with a 1-week history mild swelling and pain in the right back teeth region and had undergone extraction in the same area. His medical history was significant for diabetes mellitus for 6 years. He had also tested positive for COVID-19 5 months ago and received treatment with remdesivir, unspecified steroids and off-label tocilizumab. A CT scan showed sinus lining thickening extending towards the maxillary alveolar ridge and erosion if the anterior wall of the right maxillary antrum. Culture and histopathological findings confirmed a diagnosis of mucormycosis secondary to tocilizumab. He was initiated on amphotericin-B and a functional endoscopic sinus surgery (FESS) was carried out with limited maxillectomy on the right side. He was discharged 2 weeks post-treatment and after 2 months, no recurrence was recorded.

Case 5: A 48-year-old man presented with swelling and pain in the midface region. He experienced numbness and excruciating pain in the left and right midface areas. His medical history was significant for diabetes mellitus for 3 years under unspecified medication. He was also diagnosed with COVID-19 8 months ago with ICU admission and had received treatment with remdesivir, off-label IV methylprednisolone 80 mg/day for 18 days and off-label dexamethasone 4mg twice daily injection for 12 days. An intraoral analysis indicated yellowish discolouration of mucosa with necrotic bone and bad breath. A provisional diagnosis of COVID fungal infection was made. CT scan showed mucosal thickening in ethmoid and sphenoid sinuses and bilateral maxillary, thinning of right maxillary sinus wall, partial obliteration of the fronto-ethmoidal recess on the right side and an ill-defined soft tissue thickening in the pre-maxillary area. He underwent extraction of the loosened tooth, subtotal maxillectomy of both sides and debridement of bilateral maxillary sinus along with a functional endoscopic sinus surgery (FESS). Further findings of broad and non-septate hyphae confirmed a diagnosis of mucormycosis secondary to methylprednisolone and dexamethasone. He received treatment with amphotericin-B and diffuse opacification of the affected areas was reduced. He was discharged 14 days later with satisfactory wound healing and a follow-up post-discharge for 3 months indicated uneventful healing.

Case 6: A 65-year-old man presented with acute toothache in the upper right molar region and swelling and severe discomfort in the right side of his face that has extended to his eye. His medical history was significant for uncontrollable non-insulin dependent diabetes mellitus for 15 years and hypertension for 13 years under unspecified medication. Two weeks prior to presentation, he had experienced partial blockage of his right nostril along with fever. He had tested positive for COVID-19 4 months ago under ICU admission and had received treatment with tapering doses of off-label IV prednisone 40mg injection for 11 days. He was later discharged when tested negative. Upon clinical examination, he appeared febrile and exhibited paraesthesia of the right infraorbital nerve and mild right orbital swelling. Additionally, orbital oedema and severe ptosis was observed in the right eye region. An intraoral analysis revealed necrotic bone regions extending from the extraction site to the adjoining teeth along with a tender swelling and black necrotic gingival tissue in the upper right buccal mucosa. Gingival mucosa was also detected. A CT scan revealed clear obliteration of the left and right maxillary sinus. Histopathology findings confirmed a diagnosis of mucormycosis secondary to prednisone. He was initiated on a treatment with amphotericin-B liposomal [liposomal amphotericin-B] and subsequently he underwent functional endoscopic sinus surgery (FESS), surgical debridement and partial maxillectomy. Along with exenteration, his right eye was also sutured with nylon sutures. In the next few days, he remained stable and additionally received chlorhexidine, hydrogen peroxide and ceftriaxone [Monocef]. He was discharged with uneventful healing of the wound. Later, he developed extensive pneumonia and respiratory distress which led to his demise after 1 month of treatment.

Case 7: A 69-year-old man presented with pain and swelling on the left side of his face and 2-week of foul mouth odour. His medical history was significant for hypertension for 10 years and diabetes for 12 years, both under unspecified medication. He had tested positive for COVID-19 4 months ago and was placed on ventilation due to severe hypoxia. For COVID-19, he had received off-label treatment with prednisone and tocilizumab. Upon general examination, he appeared febrile with left eye ptosis and orbital oedema. An intraoral analysis showed pus discharge and soft tissue necrosis in the right and left maxillary alveolus. An incisional biopsy revealed foreign material, necrotic fibrous connective tissue, non-vital bone, flattened, wide-angle and broad hyphae. Thus, a diagnosis of mucormycosis secondary to prednisone and tocilizumab. A brain and facial MRI showed destructive and mucolytic foci in the left nasal bone region and left and right maxilla. The facial CT also showed obliterated left maxillary sinus and swollen midface region. These findings further suggested a diagnosis of rhino-orbito-cerebral mucormycosis. He was hospitalised and a functional endoscopic sinus surgery (FESS), total maxillectomy and left eye exenteration were performed. He also received treatment with amphotericin-B and glucose [dextrose]. One month post-surgery, he was discharged with satisfactory wound healing. A 6-month follow-up indicated an asymptomatic status.