Risk Factors of COVID-19 associated mucormycosis in Iranian patients: a multicenter study – BMC Infectious Diseases

This study revealed a mortality rate of about 11% in patients diagnosed with CAM. Factors contributing to increased odds of death included a history of cigarette smoking, ICU admission, higher CAM stage, specific treatment methods, and ocular involvement.

Although different studies elucidated various mortality rates among CAM patients (14%37%) [10, 20,21,22], the pooled prevalence of all-cause mortality was reported as 24% [23]. However, the mortality rate during hospitalization of the cases in our study was 10.9%. According to the literature, it could be said that the survival rate of patients with mucormycosis associated with Covid-19 is higher than that of patients with other concomitant diseases (oncohematological and uncontrolled diabetes mellitus) [24]. A study on 49 patients that followed them up for six months reported that 81.8% of the non-survivors, were older than 60years old, 90.9% had intracranial involvement, and all had HBA1C>8.0% [21]. In a similar pattern to our result, a retrospective casecontrol study on 73 CAM cases, which have been followed up for 30days at minimum, showed no significant differences in age, gender, vaccination status, DM presence, remdesivir, and tocilizumab use among survivors and non-survivors [25]. Patients with malignancies, hematological disorders, or poorly controlled diabetes may have a more compromised immune status, predisposing them to poorer outcomes with invasive fungal infections like mucormycosis.

In contrast, COVID-19 can lead to immune dysregulation and increase susceptibility to opportunistic infections like mucormycosis. However, the underlying immune deficit may be less severe or variable compared to conditions like advanced malignancies or long-standing uncontrolled diabetes. In opposition to some studies [25, 26], our study elucidated considerable differences in corticosteroid usage and treatment methods among patients 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 [27]. While glucocorticosteroids are a known risk factor for invasive mycoses, their role in the treatment of severe COVID-19 has been pivotal in managing the hyperinflammatory response associated with the disease. In our study, we observed that the history of systemic corticosteroid use during COVID-19 was significantly associated with reduced odds of mortality. However, it is important to note that we did not have data on the effect of steroids on survival as all patients had started steroid treatment before the study period. This finding contrasts with the established risk of corticosteroids contributing to the development of mucormycosis, suggesting that while steroids may mitigate the severe effects of COVID-19, their dosing and duration need careful consideration to avoid predisposing patients to invasive fungal infections like mucormycosis. Further research is necessary to delineate the balance between their therapeutic benefits and potential risks in this context.

COSMIC study [10] elucidated that mortality and disease progression were 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 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 ROCM patients [22]. 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 six weeks [28]. Our results confirmed that expired patients had lower visual acuity at the time of CAM diagnosis than those discharged from hospitals. The multiple logistic regression 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. Our findings regarding the potential relationship between cigarette smoking, severity of COVID-19 illness, and mortality from mucormycosis aligns with existing evidence demonstrated that smoking is known to impair lung function and increase susceptibility to respiratory infections like COVID-19 [29]. Smokers have been reported to have higher rates of severe COVID-19 illness and mortality compared to non-smokers [30]. Therefore, it is plausible that in this study, cigarette smoking may have predisposed patients to more severe COVID-19 illness, requiring ICU admission, and consequently increased the risk of mortality from the subsequent mucormycosis infection.

Secondary outcomes findings revealed that diabetes mellitus emerged as the predominant underlying condition, reflecting the high prevalence of this comorbidity in the study population. The exploration of COVID-19 characteristics brought to light a substantial positive rate for SARS-CoV-2 RT-PCR, emphasizing the association between mucormycosis and recent COVID-19 infection. Noteworthy was the observation that most patients had not received vaccination against SARS-CoV-2. ROCM clinical presentations showcased facial pain, swelling, and nasal discharge as common complaints, while ocular signs such as ptosis and periorbital swelling were highly prevalent. Imaging findings demonstrated ethmoid sinus involvement as the most common, and cavernous sinus involvement was observed in a relatively low percentage of cases. The majority of patients were classified as Stage 3 ROCM. Ocular involvement was prevalent in 92.3% of patients, with only 6.7% experiencing binocular issues. The 72.8% exhibited extraocular movement restriction, and frozen eyes were observed. Relative afferent pupillary defect (RAPD) was present in 61.8% of evaluated eyes. Chemosis was the most common ocular finding in slit-lamp biomicroscopy. Fundoscopy revealed atrophic discs in 23.3% and optic disc swelling in 3.7% of affected eyes. Microvascular events (CRAO, CRVO, BRVO) occurred in a minority of cases.

On average, CAM patients in our study were in the sixth decade of life, similar to other studies [10]. However, male predominance in our study was less (54.7%) than in other studies (71 to 73%) [10, 22]. The latest meta-analysis on a total of 3718 CAM patients [23] 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 [24] and CAM, the mean age of the patients and the existence of DM and corticosteroid use are quite similar in both groups. Lately, a casecontrol study confirmed the role of DM and corticosteroid use in CAM infection [31]. 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, 9, 22, 32, 33]. Also, utilizing systemic corticosteroids in the treatment strategy of COVID-19 infection results in hyperglycemic media and the cytokine storm through the inflammatory state, providing a suitable condition for the fungi [9]. Impairment of immune function against mucormycosis caused by corticosteroids could increase the infection risk [22].

[21, 34]. Although the mean duration from COVID-19 infection to the CAM diagnosis (about 25days) among the included patients is comparable with the data (25.6days) from a recent systematic review [35], some other studies reported lower intervals [10, 36]. Most patients had mild or moderate lung involvement due to COVID-19 infection; this may state that CAM occurs more frequently in patients with less COVID-19 severity, which is suggested by another study [22].

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 [21, 37]. 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 [38], which are almost consistent with our study.

Consistent with other studies, the most commonly involved paranasal sinuses among CAM patients were ethmoid and maxillary sinuses [39, 40]. Mucormycosis usually starts from the maxillary sinus, extends to the ethmoid or sphenoid, and can invade the orbit through ethmoid foramina or splitting lamina papyracea [9].

Orbital involvement among CAM patients in our study (92.3%) was higher compared to a meta-analysis conducted on 3718 patients (61%) [23]. Also, in a study on 2826 probable/ possible/ proven ROCM Indian patients, orbital involvement among the patients was reported at 72% [10]. Consistent with other studies [34, 37], ptosis, periorbital edema, periocular pain/tenderness, ophthalmoplegia, and proptosis are common ocular and periocular signs and symptoms among CAM patients. Of 35 involved eyes in a cross-sectional study, retinal artery occlusion and disc edema were observed in 23% and 11%, respectively [34]. In another study on 49 CAM patients [21], the observed keratopathy, CRAO, and CRVO rates were reported at 24.49%, 4.08%, and 2.04%, respectively.

In this study, the number of patients who expired was 30 (11%), while the number of patients who were discharged was 244 (89%). Unbalanced data in a relatively small sample size reduces the statistical power of the tests. Therefore, it is necessary to interpret the results with caution due to this limitation.

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Risk Factors of COVID-19 associated mucormycosis in Iranian patients: a multicenter study - BMC Infectious Diseases