Cumulative Mortality and Factors Associated With Outcomes of Mucormycosis After COVID-19 at a Multispecialty Tertiary Care Center in India

Key Points

Question

What is the mortality rate among patients with COVID-19–associated rhino-orbitocerebral mucormycosis at 1 month?

Findings

In this case-control study of 73 patients, 26 (36%) died within 10 days after admission. The cumulative probability of death was 53% at day 21, and assisted ventilation during prior COVID-19 treatment or visual acuity of no light perception were associated with a higher risk of death.

Meaning

These findings suggest that the mortality rate after rhino-orbitocerebral mucormycosis is high and that a subgroup of patients who have severe COVID-19 or present with severe orbital disease are more likely to die within 10 days of admission.

This case-control study reports outcomes and cumulative mortality rates among patients with COVID-19–associated rhino-orbitocerebral mucormycosis.

Abstract

Importance

An outbreak of COVID-19–associated rhino-orbitocerebral mucormycosis (CAM) has occurred in many parts of the world. Although the clinical profile and risk factors for CAM have been studied, cumulative mortality and its risk factors have not.

Objective

To report the cumulative mortality rates at different times in cases with CAM and identify risk factors for CAM-associated mortality.

Design, Setting, and Participants

This retrospective case-control study was conducted from March 1 to May 30, 2021, in a tertiary care multispecialty hospital in western India. All patients diagnosed with CAM and with a minimum follow-up of 30 days or those who died before 30 days due to CAM were included.

Main Outcomes and Measure

Cumulative mortality in CAM using survival analysis.

Results

A total of 73 consecutive patients with CAM with a mean (SD) age of 53.5 (12.5) years were included in the analysis, of whom 48 (66%) were men. CAM developed at a median of 28 (IQR, 15-45; range, 4-90) days after recovery from COVID-19. Of the 73 patients with CAM, 26 (36%) died; the cumulative probability of death was 26% (95% CI, 16%-41%) at day 7 and doubled to 53% (95% CI, 39%-69%) at day 21. Sinus debridement was performed in 18 of 51 patients (35%), and 5 of 52 (10%) underwent exenteration, whereas intravenous lyophilized amphotericin B was administered to 48 patients (66%). A multivariate Cox proportional hazards regression analysis showed that receiving mechanical ventilation in the past was associated with a nearly 9-fold increased risk of death (hazard ratio [HR], 8.98; 95% CI, 2.13-38.65; P = .003), and patients who had visual acuity of light perception or better had a 46% lower risk of death (HR, 0.56; 95% CI, 0.32-0.98; P = .04). Intravenous amphotericin B administration was associated with a reduced rate of exenteration (0 vs 5 of 25 [20%]; P < .001). On multivariate analysis, those who received intravenous amphotericin B had a 69% reduced risk of death (HR, 0.31; 95% CI, 0.06-1.43; P = .13).

Conclusions and Relevance

These findings suggest that the mortality rate after rhino-orbitocerebral mucormycosis is high and that a subgroup of patients with severe COVID-19 or presenting with severe orbital disease are more likely to die within 10 days of admission.

Introduction

The COVID-19 pandemic has caused devastation globally, with millions affected and hundreds of thousands of deaths. In addition, the immunocompromised state after recovery from COVID-19 has also predisposed patients to opportunistic infections, with fungal infections being common among these.^1,2,3 Recently, the number of cases of COVID-19–associated rhino-orbitocerebral mucormycosis (CAM) has increased,^4,5 with nearly 3000 cases reported in the literature within the last year alone.^1,6,7,8,9,10 The largest series reported recently consisted of 2826 cases from India,⁴ indicating a public health emergency. Many other countries have also reported a sudden surge in cases of CAM during the past few months, suggesting that this condition could soon emerge as a global problem.¹¹

Even before the pandemic, mucormycosis has been known to occur in patients with immunodeficiency, mainly in those with uncontrolled diabetes and ketoacidosis.^12,13 In the largest study on CAM to date, Sen et al⁴ clearly showed that uncontrolled diabetes and use of high-dose systemic corticosteroids were the main risk factors for CAM. However, their study did not report on cumulative survival rates over time. In addition, we believe that data from a large tertiary care multidisciplinary hospital, with uniform practice patterns for managing CAM, can contribute more homogenous data compared with a large aggregation of data from multiple centers where severity of disease and treatment patterns will vary considerably.

In this study, we present data from a tertiary care multispecialty government hospital in the western Indian state of Maharashtra where we observed an outbreak of CAM from March 1 to May 30, 2021, and report important outcomes in terms of cumulative mortality and its risk factors. Given the large number of patients with CAM, identifying risk factors for mortality may help triage patients with CAM so that those most likely to die undergo emergency lifesaving procedures as early as possible.

Methods

This retrospective case-control study was approved by the institutional ethics committee of BYL Nair Charitable Hospital, Mumbai, India. Informed written consent was obtained from all patients at the time of admission, and all patient data were anonymized for study purposes. Patients were not offered any compensation or incentives for participation in the study. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Case records of all patients with prior confirmation of COVID-19 using results of reverse transcriptase–polymerase chain reaction analysis, treated in house, and with a diagnosis of CAM between March 1 and May 30, 2021, were identified from the medical records department. Those who died after admission or had a minimum follow-up of 30 days were included in the study.

All patients with suspected CAM based on typical clinical features of orbital cellulitis and/or black eschar on the hard palate, face, or nose underwent a deep nasal swabbing from which a potassium hydroxide mount was prepared to identify fungus. In addition to the potassium hydroxide mount, fungal culture was attempted using Sabouraud dextrose agar from all obtained material, including the swab and nasal endoscopy specimen. Presence of pansinusitis as well as orbital and intracranial involvement were confirmed in all patients using either a computed tomography scan or magnetic resonance imaging. Patients also underwent routine blood workup, including complete blood cell count and measurement of fasting blood glucose, C-reactive protein, and serum ferritin levels at the time of admission for CAM. As part of the systemic management, blood glucose level was monitored by endocrinologists at multiple times each day, and all patients were managed with appropriate doses of insulin to maintain adequate glycemic control.

We recorded basic demographic information for all patients as well as other variables such as the presence, duration, and treatment of diabetes; blood glucose level; and ketoacidosis at time of admission for CAM. The interval between COVID-19 recovery (defined as discharge from the hospital) and onset of CAM was recorded in days. Treatment variables for previous cases of COVID-19, including corticosteroid use, requirement of supplemental oxygen, noninvasive ventilation and ventilator support (NIV), and history of use of remdesivir and tocilizumab, were all recorded. We also recorded the history of COVID-19 vaccinations when available.

All patients underwent a comprehensive ophthalmic evaluation, and features of CAM were recorded from the case files, including best-corrected visual acuity (perception of light or not), proptosis, ptosis (complete or partial), extraocular muscle restriction, pupillary reaction, and features specific for CAM, such as black eschar on the face, nostrils, palate, or lids. All patients were advised about functional endoscopic sinus surgery (FESS) with otolaryngology professionals and intravenous amphotericin B administration subject to availability. Duration of intravenous amphotericin B administration was also noted, and the drug treatment was stopped in consultation with otolaryngology professionals when regressing proptosis and visual improvement provided sufficient evidence of disease regression. Retrobulbar amphotericin B was also given to some patients based on the physician’s discretion and availability of the drug. When given, some patients received repeated injections at fixed or variable intervals based on the response to treatment and the physician’s discretion. Orbital exenteration was planned for patients with advanced orbital disease characterized by no perception of light, complete ptosis, and total ophthalmoplegia but was subject to fitness for general anesthesia. Death was the primary outcome measure.

Statistical Analysis

All continuous variables were presented as means (SDs) or medians (IQRs), and group differences were analyzed using the 2-tailed t test or the Wilcoxon rank sum test for nonparametric distributions. Similarly, categorical variables were presented as proportions (percentages), and group differences were analyzed using the χ² or Fisher exact test.

Survival analysis was performed using death as the censoring variable, and Kaplan-Meier curves were plotted to depict cumulative probability of survival at various times. Time to death was defined as the interval between admission for CAM and death. The survival probability was assessed using the Cox proportional hazards regression models and displayed using hazard ratios (HRs) with 95% CIs. Potential covariates used for adjusting HRs were those with a P < .05 in univariate models and those that have been shown to influence treatment failure rates in previous studies. A best-fit multivariate model was identified using sensitivity analysis and the Akaike information criteria after eliminating variance inflation and significant interaction between covariates.

All data were entered in Excel, version 2019 (Microsoft Corporation) and analyzed using STATA, version 12.1 I/c (StataCorp LLC). All P values were 2 sided, with P < .05 indicating statistical significance; there were no adjustments for multiple analyses.

Results

We included 73 consecutive patients with CAM during the study period. The mean age of patients was 53.5 (12.5 [range, 32-86]) years; 48 patients (66%) were men and 25 (34%) were women. Because all participating patients were from India with the same race and ethnicity, these data were not collected separately but implied. Vaccination status was available for 47 patients, of whom 42 (89%) had not taken the available COVID-19 vaccine, 5 (11%) had taken the first dose of the vaccine, and none had taken both doses of the vaccine. Regular steam inhalation after COVID-19 was taken by 15 of the 40 patients (38%) who responded to this question.

The sinus involvement with CAM was bilateral in 17 patients (23%) and unilateral in 56 (77%). Orbital involvement was bilateral in 6 patients (8%) and unilateral in 62 (85%), whereas 5 (7%) did not have orbital involvement. Involvement of the central nervous system was seen in 6 patients (8%) on radiographic imaging, of whom 4 had involvement limited to the cavernous sinus and 2 had more diffuse involvement; both patients with diffuse involvement died. The severity of COVID-19 before CAM was classified as follows: home care and ambulatory (2 [3%]), hospitalized but no supplemental oxygen (7 [10%]), hospitalized and needed supplemental oxygen (43 [59%]), hospitalized and needed NIV (14 [19%]), and mechanical ventilation (3 [4%]), whereas COVID-19 severity was not available for 4 patients.

Table 1 shows a summary of all baseline characteristics, underlying predisposing factors, details of prior COVID-19 treatment, and characteristics of their ophthalmic presentation. Most patients had received corticosteroids (58 of 59 [98%]) intravenously, and 48 of 65 patients (74%) had diabetes. Among patients with diabetes, more than half had uncontrolled glucose levels at time of presentation with CAM. In addition, 7 patients (10%) who were not known to have diabetes were detected with uncontrolled glucose levels at time of admission for CAM. Development of CAM occurred a mean of 31.1 (19.7) days after COVID-19 recovery (median, 28 [IQR, 15-45] days; range, 4-90 days). Of the 58 patients who had received intravenous corticosteroids for COVID-19 management, 54 (93%) received intravenous methylprednisolone and 5 (9%) received intravenous dexamethasone. Prolonged oxygen supplementation was needed in 42 of 58 patients (72%) during COVID-19 management, and 17 of 73 patients (23%) needed NIV or mechanical ventilatory support. All patients had underlying risk factors for CAM.

Table 1. Comparison of Demographic and Clinical Characteristics Between Patients Who Died vs Patients Who Survived.

Characteristic	Patient groupa			Difference (95% CI)	P value
	Overall (73 [100%])	Survived CAM (47 [64%])	Death due to CAM (26 [36%])
Age, mean (SD), y	53.5 (12.6)	53.2 (11.8)	54.2 (14.1)	0.01 (−1.3 to 4.2)	.97
Men	48/73 (66)	32/46 (68)	16/26 (62)	7 (16 to 30)	.57
COVID-19 vaccine not taken	42/47 (89)	25/28 (89)	17/19 (89)	0	.98
Regular steam inhalation	15/40 (38)	11/26 (42)	4/14 (29)	13 (9 to 35)	.39
Diabetes	48/65 (74)	32/41 (78)	16/24 (67)	11 (7 to 32)	.31
Using insulin	32/52 (62)	20/35 (57)	12/17 (71)	14 (8 to 36)	.01
Uncontrolled diabetes	27/47 (57)	14/33 (42)	13/14 (93)	51 (33 to 68)	.001
HRCT score during COVID-19, mean (SD)b	7.8 (4.8)	6.9 (4.8)	10.1 (4.1)	3.21 (2.01 to 7.02)	.01
Time since COVID-19, mean (SD), dc	31.1 (19.7)	35.5 (21.2)	22.2 (12.8)	−13.3 (−24.5 to −2.2)	.03
COVID-19 treatment
Corticosteroids	58/59 (98)	36/37 (97)	22/22 (100)	3 (1 to 8)	.43
Duration of intravenous corticosteroids, mean (SD), d	8.7 (5.8)	8.3 (5.9)	9.5 (5.7)	1.13 (−2.23 to 4.51)	.56
Intravenous remdesivir	34/73 (47)	24/47 (51)	10/26 (38)	13 (10 to 36)	.20
Tocilizumab	6/73 (8)	5/47 (11)	1/26 (4)	7 (5 to 19)	.51
NIV and/or mechanical ventilation	17/73 (23)	6/47 (13)	11/26 (42)	34 (8 to 51)	.02
Prolonged oxygen supplementation	42/58 (72)	24/37 (65)	18/21 (86)	21 (2 to 40)	.08
Duration of supplemental oxygen, mean (SD), d	7.5 (8.5)	4.1 (5.6)	15.3 (9.1)	11.13 (5.17 to 17.10)	.003
Time to outcome, mean (SD), d	14.6 (11.3)	19.7 (12.5)	9.5 (6.9)	−10.26 (−15.89 to −4.64)	.001
Ophthalmic presentationd
Visual acuity of no light perception	12/73 (16)	3/47 (6)	9/26 (35)	29 (9 to 48)	.02
Complete ptosis	13/73 (18)	7/47 (15)	6/26 (23)	8 (8 to 27)	.29
Proptosis	48/73 (66)	25/47 (53)	23/26 (88)	27 (8 to 45)	.02
Total ophthalmoplegia	28/73 (38)	19/47 (40)	9/26 (35)	5 (2 to 28)	.50
Treatment of mucormycosis
Diagnostic nasal endoscopy	22/49 (45)	18/32 (56)	4/17 (24)	32 (10 to 54)	.03
Intravenous antifungal administered	49/73 (67)	32/47 (68)	17/26 (65)	3 (1 to 25)	.81
Duration of intravenous antifungal given, mean (SD), d	14.8 (12.5)	19.2 (13.1)	6.8 (6.0)	−12.3 (−20.1 to −4.5)	.001
Retrobulbar amphotericin B	18/45 (40)	11/29 (38)	3/16 (19)	19 (1 to 34)	.18
FESS	18/51 (35)	14/36 (39)	4/15 (27)	12 (10 to 34)	.40
Exenteration	5/52 (10)	3/35 (9)	2/16 (13)	4 (1 to 17)	.77

Abbreviations: CAM, COVID-19–associated rhino-orbitocerebral mucormycosis; FESS, functional endoscopic sinus surgery; HRCT, high-resolution computed tomography; NIV, noninvasive ventilation and ventilator support.

^a Unless otherwise indicated, data are expressed as number/total number of patients with available data (%).

^b Scores range from 0 to 25, with higher scores indicating worse disease.

^c Calculated for those who developed CAM after COVID-19 recovery.

^d The most common symptoms at ophthalmic presentation were facial pain in 26 of 73 patients (36%) overall and 9 of 26 patients (34%) who died due to CAM and nasal discharge in 20 of 47 patients (43%) who survived (P = .06).

Of the 73 patients with CAM, 26 (36%) died, and 5 of 52 (10%) underwent orbital exenteration. Of those who survived, 7 had regressed CAM, 36 were alive with stable disease but were receiving treatment, 2 were alive but had disease progression, and 2 had taken discharge against medical advice. A total of 18 of 51 patients (35%) underwent FESS. Using survival estimates, the cumulative probability of death (Figure 1) occurring was 26% (95% CI, 16%-41%) at day 7 and increased to 42% at day 14 (95% CI, 30%-58%) and 53% at day 21 (95% CI, 39%-69%). Patients who died had more severe COVID-19 disease before CAM as evidenced by increased mean high-resolution computed tomography scores (10.1 [4.1] vs 6.9 [4.8]; scores range from 0-25, with higher scores indicating worse disease), more need for assisted ventilation (11 of 26 [42%] vs 6 of 47 [13%]), and longer mean duration of supplemental oxygen (15.3 [9.1] vs 4.1 [5.6] days) (Table 1). This group also had a higher proportion of patients with uncontrolled diabetes (13 of 14 [93%] vs 14 of 33 [42%]), with significantly more requiring insulin for diabetes control (12 of 17 [71%] vs 20 of 35 [57%]), and they presented earlier after COVID-19 recovery than those who survived (mean, 22.2 [12.8] vs 35.5 [21.2] days) (Table 1). Last, this group presented with worse disease (Table 1) in the form of worse visual acuity, including no perception of light (9 of 26 [35%] vs 3 of 47 [6%]), ptosis (6 of 26 [23%] vs 7 of 47 [15%]), proptosis (23 of 26 [88%] vs 25 of 47 [53%]), or total ophthalmoplegia (9 of 26 [35%] vs 19 of 47 [40%]).

Figure 1. Kaplan-Meier Survival Estimates of Cumulative Survival .

Data are given during the first 40 days after onset of COVID-19–associated rhino-orbitocerebral mucormycosis (CAM).

Table 2 shows a comparison between groups of patients who did and did not receive intravenous amphotericin B. None of the patients who received intravenous amphotericin B required orbital exenteration compared with 5 of 25 (20%) in the group that did not receive the drug. There were no other major differences between groups, including absolute and cumulative mortality rates (Figure 2) (eg, cumulative mortality of 50% in patients receiving amphotericin B vs 55% with no amphotericin B at day 21; P = .41, log-rank test). A total of 18 patients (25%) underwent retrobulbar amphotericin B injections as a single dose (7 [39%]), 2 doses on alternate days (4 [22%]), 3 doses on alternate days (4 [22%]), or 2 to 3 doses with variable frequency (3 [17%]). Of these, 5 patients died (28%) compared with 12 of 29 (41%) who did not receive retrobulbar amphotericin (P = .63). Of the remaining 13 patients, 3 underwent exenteration, whereas 8 were stable and 2 improved. The most common adverse effect seen after retrobulbar amphotericin B treatment was worsening of lid edema (8 of 18 [44%]) and chemosis (6 of 18 [33%]), whereas 4 patients (22%) had extraocular movement restriction and 2 (11%) developed worsening of ptosis. All these adverse effects were seen in patients with repeated injections. Overall, we could not determine whether retrobulbar amphotericin B led to any improvement in morbidity or mortality rates when given concomitantly with intravenous amphotericin B.

Table 2. Comparison of Demographic and Clinical Characteristics Between Patients Who Did and Did Not Receive Intravenous Amphotericin B.

Characteristic	Amphotericin B receiveda		Difference (95% CI)	P value
	No (25 [34%])	Yes (48 [66%])
Age, mean (SD), y	53.2 (11.7)	54.2 (14.1)	−1.1 (−7.4 to 5.3)	.65
Men	17/25 (68)	31/48 (65)	3 (1 to 8)	.77
Diabetes	13/18 (72)	35/47 (74)	3 (1 to 6)	.85
Using insulin	4/15 (27)	28/37 (76)	49 (27 to 70)	.002
Uncontrolled diabetes	6/12 (50)	21/35 (60)	10 (4 to 14)	.55
Time since COVID-19, mean (SD), db	25.5 (11.2)	31.9 (20.5)	6.1 (−11.0 to 23.3)	.63
Visual acuity of no light perception	2/18 (11)	10/34 (29)	18 (2 to 35)	.42
Complete ptosis	6/16 (37)	7/33 (21)	16 (5 to 39)	.34
Proptosis	5/5 (100)	8/9 (89)	11 (2 to 19)	.44
Total ophthalmoplegia	6/25 (24)	22/48 (46)	21 (10 to 43)	.01
Diagnostic nasal endoscopy	2/6 (33)	20/43 (47)	14 (9 to 37)	.54
Retrobulbar amphotericin B	4/10 (40)	14/37 (38)	2 (1 to 21)	.90
FESS	6/7 (86)	12/44 (27)	59 (40 to 77)	.03
Exenteration	5/25 (20)	0	20 (NC)	<.001
Death	10/25 (40)	16/48 (33)	7 (3 to 30)	.57

Abbreviations: FESS, functional endoscopic sinus surgery; NC, not calculated.

^a Unless otherwise indicated, data are expressed as number/total number of patients with available data (%).

^b Calculated for those who developed COVID-19–associated rhino-orbitocerebral mucormycosis after COVID-19 recovery.

Figure 2. Comparison of Survival Estimates in Patients Who Received Intravenous Amphotericin B vs Those Who Did Not .

CAM indicates COVID-19–associated rhino-orbitocerebral mucormycosis.

A multivariate Cox proportional hazards regression analysis (Table 3) with a best-fit model showed that a history of receiving either NIV or mechanical ventilation was associated with a nearly 9-fold increased risk of death (HR, 8.98 [95% CI, 2.13-38.65]; P = .003) due to CAM. In the same model, patients who had visual acuity of light perception or better had a 46% lower risk of death (HR, 0.56 [95% CI, 0.32-0.98]; P = .04), whereas those who received intravenous amphotericin B had a 69% reduced risk of death (HR, 0.31 [95% CI, 0.06-1.43]; P = .13).

Table 3. Factors Associated With Mortality.

Variable	Univariate analysis, HR (95% CI)	Multivariate analysis
		HR (95% CI)	P value
Age (in 1-y increments)	0.99 (0.97-1.03)	NA	NA
Sex (vs men)	1.86 (0.83-4.17)	NA	NA
Time since COVID-19 recovery (in 1-d increments)	0.95 (0.92-0.98)a	0.98 (0.94-1.02)	.51
Need for oxygen as NIV (vs no NIV)	2.45 (1.12-5.38)a	8.98 (2.13-38.65)a	.003
Corticosteroid use (vs none)	2.01 (0.11-10.70)	NA	NA
Antifungal use (vs none)	0.72 (0.32-1.58)	0.31 (0.06-1.43)	.13
Visual acuity of light perception (vs no light perception)	0.55 (0.38-0.79)a	0.56 (0.32-0.98)b	.04
Total ophthalmoplegia (vs partial plegia)c	0.96 (0.42-2.25)	NA	NA

Abbreviations: HR, hazard ratio; NA, not applicable; NIV, noninvasive ventilation and ventilator support.

^a P < .001.

^b P < .05.

^c Not taken to multivariate models in view of variance inflation and high interaction with visual acuity.

Discussion

In this retrospective study of 73 patients with various grades of rhino-orbitocerebral mucormycosis, we found a relatively high cumulative mortality rate of 53% at 3 weeks after admission. All patients had at least 1 underlying risk factor for development of CAM, including administration of high-dose systemic corticosteroids or uncontrolled diabetes. Intravenous amphotericin B was associated with a reduced risk of orbital exenteration; however, it was not associated with a decreased mortality rate. Retrobulbar amphotericin B also did not alter disease progression, although it was given to only 18 patients. Patients who died had more severe COVID-19 before developing CAM, and those who received NIV or mechanical ventilation were at a much higher risk of death within 10 days of admission, as were those who had no light perception in the involved eye.

The mortality rate we observed is higher than the 14% reported by Sen et al⁴ from a nationwide collaborative study on CAM with more than 2800 patients. There are several reasons for this difference. First, our institution is a tertiary care referral center; therefore, our cohort may have included patients with more advanced disease, as evidenced by most patients having orbital involvement and many having cerebral involvement. Second, lyophilized amphotericin B was administered to only 66% of our patients, and although we saw benefit in preventing exenteration, mortality was not affected. Third, FESS that can debride the nidus of fungal infection in the sinuses was performed in only 35% of our patients, which may have contributed to higher mortality rates. However, given the sudden surge of daily cases and limited availability of equipment and personnel, we believe that the best possible care was given to patients. Fourth, our cohort may be a more homogenous group of patients managed by the same set of physicians using similar treatment protocols for most patients as opposed to a national registry with heterogeneity in treatment patterns and disease severity. We believe that the actual mortality may be somewhere between the 14% reported by Sen et al⁴ from the large Indian series and the 53% that we report at 3 weeks. It is also important to note that Sen et al⁴ did not report on final visual, morbidity, or mortality outcomes from their large series because of ongoing treatments in most of their patients. We suspect that at the end of 3 to 4 weeks of treatment, the cumulative mortality rate might be significantly higher in their cohort as well, although this claim is speculative given that their results are not published. Last, we observed much higher CAM-related mortality in patients who had more severe COVID-19 in the past. Because our institution is a designated COVID-19 hospital, we manage a high number of patients with severe COVID-19, and many patients who survive return for management of CAM. Therefore, the patients in our cohort may have been predisposed to death owing to more severe COVID-19 in the past, which may mean that our mortality rate is an overestimation.

Mortality due to rhino-orbitocerebral mucormycosis as well as systemic disease has been studied in the past. Jeong et al,¹² in a meta-analysis published before the COVID-19 pandemic, reported an all-cause mortality of 41% due to mucormycosis. They also reported that combined surgical and antifungal therapy was associated with a 77% lower risk of mortality compared with treatment with antifungals alone. Lanternier et al¹³ also reported a much higher cumulative mortality rate of more than 50% at 24 weeks after diagnosis despite high-dose (10 mg/kg/d) liposomal amphotericin B, although most of the cases were associated with underlying malignant disease. Our mortality rates are similar to rates of these reports and clearly demonstrate need for urgent FESS in all cases of CAM involving the sinuses.

Because amphotericin B was in short supply owing to heightened demand, we had the opportunity to compare patients who did and did not receive the drug for CAM. The major difference we found was that amphotericin B reduced the number of exenterations. Mortality was 7% lower in this group, although this finding did not attain statistical significance. Lanternier et al¹³ also did not find a significant effect of liposomal amphotericin B on mortality, although they enrolled only 40 patients. To the best of our knowledge, our study is the first to compare mortality rates in patients who did and did not receive amphotericin B for CAM. In view of our results, we believe that antifungal monotherapy may not be sufficient without performing concomitant FESS at the earliest opportunity, although prospective studies with better designs are required to confirm this hypothesis. We also had the opportunity to evaluate the outcomes of retrobulbar administration of amphotericin B in 18 patients. We did not observe any benefit of this route of administration compared with intravenous administration; therefore, despite our limited sample as well as some prior case reports of successful outcomes,¹⁴ we do not recommend this mode of therapy, especially when amphotericin B is in short supply. To the best of our knowledge, this is the largest series reporting outcomes associated with administration of retrobulbar amphotericin B.

Limitations

The limitations of our study are its retrospective nature and relatively smaller sample size compared with recently published data, making it difficult to generalize our results and comment on efficacy of our treatment protocols. Regardless, because mucormycosis is a sufficiently rare disease, our study presents a good sample from a tertiary referral center and has homogeneity with regard to patient treatment methods. To the best of our knowledge, this is the first study presenting survival analysis, cumulative mortality, and HRs for factors associated with death from a cohort of cases with CAM. The mortality indicators we observed, such as assisted ventilation and presence of severe orbital manifestations, can help physicians triage patients for emergency procedures such as FESS and administer systemic antifungal agents when in short supply.

Conclusions

In this case-control study, we present outcomes from a clinical practice setting during an outbreak of CAM with an overwhelming number of cases such that ideal treatments could not be administered to all patients. The cumulative mortality from CAM crossed 50% at 3 weeks after admission; therefore, this infection requires urgent treatment with a combination of FESS and intravenous antifungal agents to salvage life. We also found that patients who require assisted ventilation for COVID-19 and those with more severe disease evidenced by no perception of light and proptosis are at a higher risk of death. Uncontrolled diabetes and systemic corticosteroid use are the predominant risk factors for CAM. Further study is needed to document cumulative mortality rates from centers across the world so that meaningful comparisons can be made and mortality indicators can be studied thoroughly. Further research is also needed to understand whether CAM differs in any of its characteristics from prepandemic cases.