Introduction

Originally, mucormycosis was described by Paltauf in 1885, as an infection from nonseptate, broad, branching hyphae typical of molds. However, the first recorded human infection with Mucorales was a case of pulmonary mucormycosis reported by Sluyter in 1847. In 1943, Gregory described mucormycosis as the syndrome of acute orbital mucormycosis characterized by uncontrolled diabetes, unilateral internal and external ophthalmoplegia, proptosis, meningoencephalitis, and rapid death [1].

Mucormycosis previously known as zygomycosis was initially found rarely in the population. It is an angio-invasive disease caused by group of fungi called mucormycetes. It is known to spread by ubiquitous fungi commonly found in soil, fallen leaves, compost, animal dung and air which can be inhaled, causing infection of the lungs, sinuses and extend into brain and eyes or it can also enter the body through a cut or an open wound. Mucormycosis is not a contagious disease, it is known to effect people who are immunocompromised.

According to worldometers 2022 (Jan 14, 2022), SARS-CoV-2 has affected 222 Countries and Territories around the world and has reported a total of 320,959,141 confirmed cases of the coronavirus COVID-19 that originated from Wuhan, China, and a death toll of 5,539,206 deaths around the globe [2]. While the ‘third wave’ of SARS-CoV-2 and its variants-mediated COVID-19 continue to affect the global population, the deadly rise of myriads of manifestations and complications and, specifically, the rise of fatal fungal infection, the mucormycosis, has put the lives of COVID-19 patients further at high risk [3, 4]. Currently, India is having the second largest Covid-19 affected population in the world with more than 36,582,129 cases as on Jan 14, 2022 [2]. It is recorded in various studies that treatment of COVID-19 infection might have led to the sudden surge. In India, more than 45,432 cases and 4252 deaths due to mucormycosis have been reported as on July 15, 2021, either among COVID-19 infected patients or in patients who had recovered from COVID-19 with Rhino-cerebral mucormycosis (77.6%) being the most common variant. Covid-19 associated mucormycosis (CAM) is reported to develop in patients with uncontrolled diabetes mellitus, immunosuppression by steroids, prolonged ICU stay, comorbidities like post-transplant/malignancy, or patients on Voriconazole therapy.

An epidemiological survey conducted about two decades ago suggested that mucormycosis, if left untreated, could be fatal, with mortality rate rising as high as up to 54%. [5] Since there was almost no instance of COVID-19 associated mucormycosis throughout the first wave of SARS-CoV-2, questions arises about the factors and elements that may have instigated or caused this sudden surge of mucormycosis, particularly during the second wave. Types of mucormycosis include Rhino-orbito-cerebral mucormycosis (ROCM), Pulmonary mucormycosis, Gastrointestinal mucormycosis, Cutaneous mucormycosis, Disseminated mucormycosis. In this review, we aim at contemplating the best treatment modality available for the management of facial mucormycosis.

Methods

A systematic literature search was conducted in the electronic database of PubMed, Scopus, web of science, Embase and google scholar from January 2020 until December 2021 using keyword “covid-19 associated mucormycosis”, “rhino-orbital mucormycosis”, “rhinocerebral mucormycosis”, “rhino-orbito-cerebral mucormycosis”, “facial mucormycosis”, “rocm”, “mortality rate”, “treatment”, “covid-19”, “cam”, “pandemic”, “management”, “treatment”, “resection”, “amphotericin”, “maxillectomy”, “exenteration”, “endoscopic surgery”, “fess”, “drug therapy”, “liposomal amphotericin b”, ”mortality”, “death rate”, “outcome”, “quality of life”.

Selection Criteria

Other references cited in the retrieved reports were also reviewed, and if relevant were included in our review. The studies considered relevant to our review were thoroughly examined, and a set of criteria were applied for their selection and inclusion in this systematic review (Fig. 1). The abstracts and full texts were read and classified to select only those that provided the information necessary for our review by two independent authors SS and SC. They were also sorted according to the potential risk of any type of bias.

Fig. 1
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PRISMA flowchart. Note: *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools. From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71. For more information, visit: http://www.prisma-statement.org/

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This research was approved by the institutional ethics committee and conducted in accordance with preferred reporting items for Systematic Review and Meta-analysis (PRISMA) to answer the following questions:

What are the different treatment modalities available for COVID-19 associated mucormycosis patients? What are the outcomes of each treatment modality in treatment of COVID-19 associated mucormycosis patients? Whether patient has any comorbidities along with COVID-19 infection? What is the mortality rate of COVID-19 associated mucormycosis?

The studies were selected according to the inclusion and exclusion criteria. The inclusion criteria were English-language reports and randomized clinical trials (RCT), reviews of RCTs, case series retrospective study, prospective study and cohort studies. Inclusion criteria were patient with a history of COVID-19 infection who developed mucormycosis of facial bones and paranasal sinus which were then assessed for different treatment modalities used for the management and their outcome. Exclusion criteria selected were non-covid associated mucormycosis patients and patients with mucormycosis involvement other than in head and neck region. Animal studies were excluded.

Details of all the cases that reported mucormycosis in people with COVID-19 so far were retrieved by two authors SC and SS. In addition, the bibliographies of included studies were hand searched to identify potentially eligible studies that were not captured by electronic search. Characteristics of each patient were collected on excel sheet and analyzed on various endpoints and outcomes. Two authors independently checked the veracity of data. In case of any missing or unclear information, the study was excluded from the review.

Data Extraction

Two authors namely SC and SS extracted the data from the full text article and entered in tabular form which contains all descriptive variables namely author and year, number of patients, male, female, demographic site, risk factors, method of diagnosis, treatment, surgical treatment and survival rate (Table 1). The data accumulated from the Excel sheet (Table 1) were analyzed using qualitative data analysis. A narrative synthesis was formed from the extracted data findings and was presented in tabular form and categorized into five major categories:

Table 1 Data extraction sheet
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(i) infection site(s); (ii) predisposing risk factors or underlying conditions; (iii) method(s) of diagnosis;

(iv) details of antifungal therapy (including types of antifungal, dose and treatment duration), endoscopic debridement as well as surgical and/or adjunctive therapy; and (v) patient outcomes, recovery from infection and their mortality. If any of these categories were not fulfilled by an individual chosen study, that study was omitted from further evaluation. Summary of all findings were tabulated in separate tables for data syntheses. The methodological quality of the selected studies was evaluated using the Jonna Briggs Institute (JBI) critical appraisal tool. ROB 2.0 was used to asses risk of bias. Two independent contributors (SC and SS) assessed the quality of included studies and any discrepancies was resolved by discussion with third reviewer PW. Sensitivity analysis was not performed.

Results

On performing a systematic search, records were identified through various databases among which 372 records were identified through PubMed database and a total of 235 records were identified through Additional records involving google scholar (102 records), Embase (48 records), web of science (27 records) and Scopus (58 records). Before screening, 188 duplicate records were omitted as a part of the review. On further screening, 71 studies were removed for not abiding with the chosen inclusion criteria. Selected 31 studies were further screened, out of which 3 of them could not be retrieved. Total of 28 reports were assessed for eligibility, due to lack of complete information 3 studies were further removed.(flowchart 1).

We used the RoB 2.0 tool to assess risk of bias for each of the included studies. A summary of these assessments is provided in (Table 5). In terms of overall risk of bias, there were no concerns about risk of bias for all chosen studies.

In all, there were 25 studies abiding with preformed inclusion and exclusion criteria among which a total of 544 rhino-orbito-cerebral mucormycosis patients with a history of COVID-19 infection were taken in reference. There were 380 men and 164 women included. Population included in this review were majorly from Indian cities (19 studies) followed by Egypt (3 studies), Iran (1 study), kanseri city (1 study) and Honduras city (1 study). The diagnosis of mucormycosis was reached by performing either of the following tests; KOH staining, diagnostic nasal endoscopy, histopathology, lactophenol cotton blue stain. Often, CT, CECT, MRI radiological diagnosis were done along with the biopsy to understand the extent of the lesion. On evaluation COVID-19 associated mucormycosis patients, it was observed that maximum number of patients were suffering from Diabetes Mellitus which was seen in 410 patients, along with other diseases like hypertension in 32 patients, chronic kidney diseases in 3 patients, renal diseases in 10 patients, cardiovascular diseases in 18 patients, hypothyroidism in 9 patient, respiratory diseases in 6 patients, hypertension along with diabetes mellitus were reported in 72 patients. (Table 2)(Fig. 2).

Table 2 Medical history of patients with COVID-19 associated facial mucormycosis
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Fig. 2
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Associated Medical History

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Various treatment modalities were used for the management of COVID-19 associated rhino-orbito-cerebral mucormycosis patients among which a few of them were treated by using only antifungal drugs either alone or in combination with other antifungal drugs. The common antifungal drugs used were Amphotericin B (Amph-b), Liposomal Amphotericin B (LAMB), Posaconazole (POS), Itraconazole (ITC), Voriconazole, Caspofungin, vancomycin, meropenem, etc. Majority of patients were treated with Liposomal Amphotericin B (345 patients) followed by Amphotericin B in (79 patients), voriconazole (6 patients), itraconazole (3 patients). Combined antifungal drug therapy included treatment with liposomal amphotericin B with Posaconazole in 8 patients, Amphotericin B with Posaconazole in 3 patients, amphotericin B with Posaconazole and caspofungin in 2 patients, amphotericin B with caspofungin in 2 patients and meropenem with vancomycin were used in 2 patients. As part of surgical debridement, majority of patients underwent Functional endoscopic sinus surgery (FESS) done in 486 patients as form of primary intervention. Along with FESS patient with extensive lesion underwent maxillectomy (77 patients), orbital exenteration (87 patients), orbital decompression (11 patients) depending on the extent of the infection. It was found that combination therapy of antifungal drug along with surgical debridement helped saving many lives (Table 3) (Fig. 3). Out of 544 patients, there were 90 deaths reported and 1 patient was lost to follow-up. In patients who were only on drug therapy it was found that 14 of them could not be saved, whereas 25 patients only on antifungal drug therapy recovered. In the chosen publications for this review article, 428 patients recovered who underwent surgical debridement along with antifungal drugs whereas 76 patients were deceased. (Table 4) (Fig. 4).

Table 3 Treatment modalities
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Fig. 3
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Outcome of various treatment modalities

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Table 4 Outcome of various treatment modalities
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Fig. 4
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Treatment modalities

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Discussion

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 .

Table 5 Risk of bias
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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]:

  1. (i)

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

  2. (ii)

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

  3. (iii)

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

  4. (iv)

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

  5. (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.

Conclusion

Our review concluded that surgical debridement should be performed whenever feasible in parallel to antifungal treatment. The drug of choice is liposomal amphotericin B (5–10 mg/kg/bw qDay infuse IV at rate of 2.5 mg/kg/hr). In case of renal failure, posaconazole or Isavuconazole was shown to be effective as well as for maintenance therapy. If a patient is intolerant to liposomal amphotericin B, its dose can be reduced, but should stay ≥ 5 mg/kg bodyweight. In case of extensive disease, rapid progression, or poor general condition, the addition of Isavuconazole or posaconazole can be considered. Treatment should be continued until resolution of initially indicative findings on imaging and reconstitution of host immune system. Hence, early surgical debridement along with antifungal drugs is proven to be beneficial and gives a better outcome in management of rhino-orbital mucormycosis patients.

Differences between protocol and review: in our protocol, duration of hospital stays in days was one of the detrimental category which was not evident in all the studies hence that category was omitted as one of the factors.