In our systematic review, we finalized 25 studies/case reports/case series which included population majorly from Indian origin. There were few studies noted from Egypt, Iran, Kanseri city, etc. We looked upon cases of Covid associated rhino-orbito-cerebral mucormycosis. Our main intention was to evaluate the efficacy of various treatment modalities whether in combination or alone in reducing mortality rate of patients with rhino-orbito-cerebral mucormycosis associated with COVID-19 infection.

Total number of patients evaluated in this review were 544 patients out of which 380 were male and 164 were female. Majority of patients had history of immunosuppressed disease, majorly being associated with Diabetes mellitus, which was observed within 410 patients. There were also reported cases of newly developed diabetes mellitus post-COVID-19 infection. Other associated immunocompromised diseases involved hypertension (32 patients), chronic kidney diseases (6 patients), cardiovascular diseases (18 patients), hypothyroidism (9 patients), nephropathy, pneumonitis, etc.(Fig. 2).

Out of the chosen twenty five such studies, Gupta et al [6] reported 8 patients with hypertension, three with no medical history. Riad et al [7] reported 3 patients with cardiovascular diseases which included angina, Hypertension along with 6 patients suffering from Diabetes Mellitus. Kumari Abha [8] et al. mentioned 3 patients of chronic kidney disease and 1 suffering from liver diseases rest 16 patients suffering from Diabetes Mellitus. Bayram et al. [9] reported 3 patients suffering from chronic kidney disease, 1 with myelodysplastic syndrome. Barman et al [10] reported patients with hypertension 1 hyperthyroidism 1, diabetes mellitus 8 patients. Nehra et al [11] reported 4 patients with hypertension and 6 with diabetes mellitus .

According to study conducted by pippal et al [12] out of 80 rhino-orbito-cerebral mucormycosis infected patients 72 patients were known diabetic, 60 patients had diabetes mellitus along with hypertension. In their study at the end of four-month follow-up period, there were no deaths reported. 72.5% patients involved were treated with antifungal drugs along with FESS and surgical debridement.

Meher et al [13] in their study evaluated 131 COVID-19 associated out of which 85 patients were known case of diabetes mellitus. They reported use of antifungal drug therapy in 106 patients, voriconazole was used in 5 patients, maxillectomy in 32 patients, orbital exenteration in 20 patients and FESS surgical debridement was done in 99 patients. They reported 7 deaths in their study.

The number of days between COVID-19 infection and development of mucormycosis were not clearly mentioned in the chosen articles. It is said that oxygen therapy, corticosteroid abuse for the treatment of COVID-19 infection acts as a causative factor in development of mucormycosis. In a data of 465 cases of mucormycosis without COVID-19 infection in India, Patel et al. has shown that rhino-orbital presentation was the most common (67.7%), followed by pulmonary (13.3%) and cutaneous type (10.5%) [14]. Diagnosis of mucormycosis was clinically dependent on the basis of common symptoms according to the 1950 Smith and Krichner criteria for the clinical diagnosis of mucormycosis is still considered to be gold standard and includes. [15]:

(i)

Black, necrotic turbinate’s easily mistaken for dried, crusted blood,

(ii)

Blood-tinged nasal discharge and facial pain, both on the same side,

(iii)

Soft peri-orbital or peri-nasal swelling with discoloration and induration,

(iv)

Ptosis of the eyelid, proptosis of the eyeball and complete ophthalmoplegia and,

(v)

Multiple cranial nerve palsies unrelated to documented lesions.

Clinical examination was followed by KOH stain, Lactophenol cotton blue (LCB) mount, and Diagnostic Nasal Endoscopy. Radiological support was taken from CECT and MRI. It was observed that majority of mucormycosis infected patients were treated using combination therapy of antifungal drugs. Oral Posaconazole was majorly prescribed as discharge medication or as a second line of drug if patient is allergic to amphotericin B or has developed acute kidney infection on having amphotericin-B. Oral Posaconazole as a discharge medication was given to 274 patients. Patients were treated by either using one antifungal drug or as a combined antifungal drug therapy approach. Various combinations followed were Amphotericin B with caspofungin in 1 patient, Amphotericin B with Posaconazole in 3 patients, Amphotericin B with Posaconazole and caspofungin in 2 patients, meropenem with vancomycin in 2 patients, liposomal amphotericin B infusion with Posaconazole in 8 patients. Majority of patients were treated with either liposomal amphotericin B at 5–10 mg/kg/bw observed in 345 patients or were given Amphotericin B only observed in 179 patients. Other antifungal drugs used were voriconazole in 6 patients, itraconazole in 3 patients.

Surgical management included Functional endoscopic sinus surgery which was done in majority of the cases (486 patients). The approach used for treatment of mucormycosis was to go as invasive as possible in first attempt depending on the extent of the lesion. This approach seemed to be the most effective and hence decreasing the mortality rate, but quality of life was questioned upon. There were procedures like maxillectomy (77 patients), orbital exenteration (87 patients) and orbital decompression (11 patients) done as a form of surgical management. Even though these procedures add to decreased quality of life but surely gives reasons to believe that early antifungal drug therapy along with invasive surgical management has reduced mortality rate in such patients.

It was found that infected rhino-orbito-cerebral COVID-19 associated mucormycosis population who were treated with only antifungal drug therapy out of which only 25 patients recovered whereas 14 were reported dead. In patients who were treated with both antifungal drug therapy along with surgical debridement, there was evident increase in chances of survival observed with alive patients being 428 and 76 patients could not be saved. (Fig. 4)

Limitations of this review were limited follow-up period of the patients and limited data of interval between diagnosis, surgical intervention and its outcome. There was no clear mention of the mortality rate in the chosen studies; hence, it could not be determined.