The collaborative study of COVID-19 Associated Rhino-Orbital-Cerebral Mucormycosis in Iran (CA-ROCM-IR) involved 274 patients from eight tertiary referral ophthalmology centers in the period of 4 months through the pandemic, which confirmed the outbreak of this opportunistic fungal infection in Iran like other reported outbreaks among several countries.
On average, CA-ROCM patients in our study were in the sixth decade of life, which is similar to other studies 8. However, the male predominance in our study was lesser (54.7%) compared to other studies (71 to 73%) 8,14. The latest meta-analysis on a total of 3718 COVID-19 associated ROCM patients 2 revealed DM as the most frequent underlying disease among these patients (89%), and reported that the pooled prevalence of systemic corticosteroid use in the treatment setting of COVID-19 disease was 79%, which all are consistent with our results (82.8% and 73.7%, respectively). According to the literature on non-COVID-19 associated 15 and COVID-19 associated mucormycosis, the mean age of the patients and the existence of DM and corticosteroid use are quite similar in both groups. Lately, a case-control study confirmed the role of diabetes mellitus and corticosteroids use in CAM infection 16. The inflammatory state and reduced immune response during hyperglycemic status that is intensified via SARS-CoV-2, the increased expression of GRP-78 (glucose-regulated protein 78) on epithelial and endothelial cells in response to increased glucose concentration and ketone bodies, and the increased free iron level that is intensified by ketoacidosis in COVID-19 patients altogether lead to a suitable environment for angioinvasion, hematogenous spread, and proliferation of mucormycosis 1,7,14,17,18.
Also, utilizing systemic corticosteroids in the treatment strategy of COVID-19 infection results in hyperglycemic media and together with the cytokine storm through the inflammatory state provide a suitable condition for the fungi 7. Impairment of immune function against mucormycosis caused by corticosteroids could increase the infection risk 14.
Similar to the results of other studies, most of the COVID-19 associated ROCM patients were not vaccinated against COVID-19 19,20. Although the mean duration from COVID-19 infection to the CAM diagnosis (about 25 days) among the included patients is comparable with the data (25.6 days) from a recent systematic review 3, some other studies reported lower intervals 8,21. Most of the patients had mild or moderate lung involvement due to COVID-19 infection; this may state that CA-ROCM occurs more frequently in patients with less COVID-19 severity compared to other CAM clinical forms, which is suggested by another study 14. The frequency of oxygen administration during COVID-19 infection among the patients included in our study (68.2%) was higher than the results of a systematic review and meta-analysis on 2,312 proven CAM patients 13 and a retrospective study on 2826 probable/ possible/ proven CA-ROCM Indian patients 8 (57% both). The mentioned retrospective study 8 reported that hospitalization and mechanical ventilation rates due to COVID-19 were 72% and 4%, respectively, which are quite smaller than the rates among the patients of our study. Mechanical ventilation and the increased time of hospitalization in COVID-19 severe cases may increase their exposure to fungal infections 1. However, a case-control study suggested that the requirement of oxygenation or hospital admission does not affect CAM infection risk 16.
In concurrence with our study, the most common presenting symptoms reported by a cross-sectional study on 270 CA-ROCM patients and a prospective study on 49 CA-ROCM patients were facial/periorbital pain and swelling 19,22. A systematic review and meta-analysis on 2,312 proven CAM patients reported headache (54%), periorbital swelling/pain (53%), facial swelling/pain (43%), ophthalmoplegia (42%), proptosis (41%), and nasal discharge/congestion (36%), decreased or loss of vision (31%), ptosis (28%), dental pain or loosened teeth (25%), palatal discoloration or ulcers (22%) as common symptoms 13, which are almost consistent with our study.
Consistent with other studies, the most commonly involved paranasal sinuses among CA-ROCM patients were ethmoid and maxillary sinuses 23. Mucormycosis usually starts from the maxillary sinus and extends to the ethmoid or sphenoid and can invade the orbit through ethmoid foramina or splitting lamina papyracea 7.
Orbital involvement among COVID-19 associated ROCM patients in our study (92.3%) was higher compared to a meta-analysis conducted on 3718 patients (61%) 2. Also, in a study on 2826 probable/ possible/ proven ROCM Indian patients, orbital involvement among the patients was reported at 72% 8. Consistent with other studies 20,22, ptosis, periorbital edema, periocular pain/tenderness, ophthalmoplegia, and proptosis are common ocular and periocular signs and symptoms among CA-ROCM patients. Of 35 involved eyes in a cross-sectional study, retinal artery occlusion and disc edema were observed in 23% and 11%, respectively 20. In another study on 49 CA-ROCM patients 19, the observed keratopathy, CRAO, and CRVO rates were reported at 24.49%, 4.08%, and 2.04%, respectively.
Although different studies elucidated various mortality rates among CA-ROCM patients (14% − 37%) 8,14,19,24, the pooled prevalence of all-cause mortality was reported as 24% 2. However, the rate of mortality during hospitalization of the cases in our study was 10.9%. According to the literature, it could be said that ROCM among non-COVID-19 patients had a higher mortality rate (42%)15 than among CA-ROCM patients. A study on 49 CA-ROCM patients which followed them up for 6 months reported that, of the non-survivors, 81.8% were older than 60 years old, 90.9% had intracranial involvement, and all of them had HBA1C > 8.0% 19. In a similar pattern to our result, a retrospective case-control study on 73 CA-ROCM cases who have been followed up for 30 days at minimum, showed no significant differences in age, gender, vaccination status, DM presence, remdesivir and tocilizumab use among survivors and non-survivors 25. In opposition to the mentioned study 25, our study elucidated considerable differences in corticosteroid usage and treatment methods among the patients who were discharged from hospitals and patients who expired. Although the univariate analysis in a systematic review and meta-analysis on 851 non-COVID-19 associated mucormycosis cases elucidated DM and corticosteroid use as substantial mortality-associated factors, those lost significance in multivariate analysis 26. Conversely, our results showed reduced odds of mortality in CA-ROCM patients who had received systemic corticosteroids in the COVID-19 treatment setting. COSMIC study 8 elucidated that mortality and disease progression was considerably higher in stage 3c or worse when compared to stage 3b or better. Likewise, the results of our study demonstrated that patients with higher CA-ROCM stages had a significantly higher mortality ratio. A review study on CAM cases from 18 countries reported higher mortality rates in case of CNS involvement among CA-ROCM patients 14. A multicenter study on 287 CAM and non-COVID-19 associated mucormycosis patients showed that higher age, cerebral involvement, and ICU admission were associated with higher mortality odds ratios at 6 weeks 27. Our results confirmed that patients who expired had lower visual acuity at the time of CAM diagnosis in comparison to the patients who were discharged from hospitals. The reduced model suggested that higher stage of CAM, treatments in the setting of ocular involvement, bilateral ocular involvement, and history of cigarette smoking and ICU admission due to COVID-19 could be considered as possible mortality associated factors.
This is the preliminary report of our study project and readers are cautioned about interpreting the mortality results. Due to the method of the project (the absence of a control cohort), drawing definite conclusions about the exact effect of the risk factors was not possible. So, we suggest large-scale case-control studies.