Although our knowledge about fungal co-infection in COVID-19 patients increases day by day , little is known about the impact of severe COVID-19 on ROM. Severely ill COVID-19 patients have higher pro-inflammatory cytokines, including interleukin-1 (IL-1), IL-2, IL-6, tumor necrosis factor-α, increase in IL-4 and IL-10 levels of anti-inflammatory cytokines, less CD4 interferon-γ expression, and fewer CD4 and CD8 cells [2, 3]. Besides the disease’s immunological features, most people affected by severe COVID-19 are old and have other predisposing conditions such as type 2 diabetes mellitus. In addition to these, the patients frequently receive broad-spectrum antibiotics and corticosteroids. Also, they are supported by invasive or non-invasive ventilation due to severe ARDS. As a result, critically ill COVID-19 patients are candidates for very high-risk ROM. Although there is no direct relationship between COVID-19 and mucormycosis, the findings mentioned above suggest the existence of an indirect association. In the present study population, being an average of 73 years of age, the presence of diabetes mellitus in 72.7% of the patients, the use of steroids for COVID-19-related ARDS in all patients, and the fact that 45.5% of the patients were treated in the ICU illustrate the above. While the total number of patients with ROM was six over 2 years between 2013 and 2016 in our previous study , having eleven patients in the last 9 months shows how much the disease incidence has increased in severe COVID-19 patients. To raise awareness, we shared our study results with the physicians working in all pandemic wards and ICU in our hospital and emphasized the severity of the disease and the importance of early diagnosis.
Because Mucorales have a ketone reductase enzyme, they thrive in hyperglycemic and diabetic ketoacidosis states associated with poor prognosis. In Pub-Med research, there were only eight microbiologically confirmed ROM co-infection cases in COVID-19 patients, and all of them had diabetes [11,12,13,14]. These cases and our patients’ clinical data show that uncontrolled diabetes or diabetic ketoacidosis can make COVID-19 patients susceptible to mucormycosis infection.
Corticosteroids not only reduce the activity of the immune system but also cause drug-induced hyperglycemia. Both of these aggravate the clinical course of the patients. Corticosteroids were immediately discontinued, and diabetes was controlled with insulin therapy to improve patients’ metabolic control.
Endophthalmitis developed in six patients. Ocular ultrasound showed posterior scleritis in all endophthalmitis’ patients; two developed retinochoroiditis followed by retinoschisis. OCT revealed intraretinal fluid accumulation in the retinochoroiditis area and finally resulted in retinoschisis (Fig. 2e, g). These results show that ocular involvement develops following direct invasion from the adjacent orbital structures. The most striking clinical difference in our patients was the frequency of endophthalmitis. While endophthalmitis frequency was reported as 1–6% in non-COVID-19 studies [15, 16], it was 54.5% in our series.
CT scans and MRI demonstrated evidence of mucosal thickening, sinuses opacification, orbital and intracranial involvement. In this study, seven rhino-orbital and three patients of rhino-orbital-cerebral mucormycosis were identified by these imaging modalities. In this study, the most frequently involved sinuses were ethmoid (90.9%), followed by maxillary sinuses (81.8%), which is in line with the literature .
ROM is diagnosed by typical clinical presentation and by detecting broad aseptate hyphae with right-angled branching in KOH mounts (Fig. 1d). Lactophenol cotton blue is used to visualize microscopic structures better, identifying aseptate hyphae and sporangiospores (Fig. 1e). Staining with Grocott-Gomori methenamine silver best shows the hyphae in invaded tissues (Fig. 1f). Periodic acid-Schiff and hematoxylin & eosin stains can be used to show pathological changes in tissues, including acute suppurative inflammation with focal areas of granulomatous inflammation and angioinvasion by hyphae with consequent thrombosis and infarction (Figs. 2, 3, and 4). The immunohistochemical investigation, polymerase chain reaction for fungal DNA, and in situ hybridization can be used for tissue diagnosis as alternate techniques .
In this study, in vitro susceptibility testing of Mucor spp. against amphotericin B and voriconazole showed that the MIC of amphotericin B was lower than voriconazole (Table 1). According to the global guideline for diagnosing and managing mucormycosis  and the present study results, amphotericin B should be the first-line drug in mucormycosis treatment. It should be initiated as soon as the diagnosis is suspected. All our patients received systemic liposomal amphotericin B, which is more effective and less toxic in facilitating prolonged administration without side effects . Mucormycosis endophthalmitis can be successfully treated with intravitreal amphotericin B . Retrobulbar injection of amphotericin B should be considered an adjunctive treatment modality to prevent exenteration . In our clinical practice, we use a retrobulbar injection of amphotericin B in all ROM patients and apply intravitreal amphotericin B in the presence of endophthalmitis.
Antifungal treatment alone is ineffective due to vascular thrombosis and an extensive ischemic necrosis barrier, preventing antifungal agents’ entry in adequate concentrations. Therefore, radical debridement of infected and necrotic tissue with drainage of infected paranasal sinuses should be performed as soon as possible to minimize the fungal load in the tissue. All our patients developed these symptoms while being treated in the hospital, and all underwent surgery within an average of 5.1 days. Simultaneously, both systemic and retrobulbar amphotericin B treatments were given to all patients. Also, intravitreal amphotericin B treatment was given to six patients with endophthalmitis. All these treatments were repeated when necessary, according to the clinical course of the patients. As a result, the overall survival rate of our patients was 36.4%. However, it should be kept in mind that two of our patients were lost from ARDS due to COVID-19. If we exclude these two patients, the survival rate in ROM was 44.4%. In a previous review, including ROM in non-COVID-19 patients, the overall survival rate was 59.5% . Previous literature [11,12,13] and this study’s outcomes show that the coexistence of ROM and severe COVID-19 infection is associated with higher mortality rates than previously reported non-COVID-19 patients. In contrast, death was not reported in a recent COVID-19 case series of six patients . However, the authors did not give detailed information about the severity of COVID-19, and all, except one patient, presented after recovering from COVID-19.
This study’s limitation is that our results may not reflect the exact survival rate of ROM in COVID-19 patients. Because two of our patients died in the ICU from ARDS due to COVID-19, we do not know whether they would have died due to ROM. However, even if we accept that these two patients would not have died from ROM, the survival rate would still be lower than in the previous study.
In conclusion, this study’s outcomes show that ROM incidence has dramatically increased with higher mortality rates in severe COVID-19 patients. These results suggest that the prognosis of preexisting ROM may be worse after severe SARS-CoV-2 infection. SARS-CoV-2-related immune dysregulation, the widespread use of steroids/broad-spectrum antibiotics, and ventilatory support seem to be the main factors that make patients susceptible. Physicians should be aware of the possibility of this infection in patients with COVID-19. An aggressive multidisciplinary approach to ROM can help reduce mortality. Early diagnosis, control of the systemic predisposing factors, prompt initiation of systemic and retrobulbar antifungal therapy, intravitreal amphotericin B injection in patients having intraocular involvement, and radical debridement of involved sinuses are crucial to improving outcomes.