With more than one year since the emergence of COVID-19 in China, there is still lack of a definitive and specific treatment against SARS-CoV-2. Several therapeutic agents have been investigated for the management of critically ill patients with COVID-19, such as corticosteroids, antiviral and immunomodulatory drugs; none have been clinically efficacious though [5, 6].
Administration of systemic corticosteroids has been shown to decrease mortality in particular subgroups of patients with COVID-19, with the greatest efficacy shown in patients receiving invasive mechanical ventilation [7, 8]. Nevertheless, treatment with systemic corticosteroids causes immunosuppression, thereby predisposing patients to invasive fungal rhinosinusitis. According to the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) consensus, prolonged use of corticosteroids at a therapeutic dose of ≥ 0.3 mg/kg for at least three weeks in the past 60 days is considered a risk factor for invasive fungal diseases [9]. Also, COVID-19 patients with diabetes are not only at increased risk of developing severe disease, but are also more prone to invasive fungal infections [10]. Diabetes mellitus can alter the body’s immunological response to pathogens by enhancing fungal proliferation and diminishing the phagocytic capacity of host immune cells [11]. In addition, the ketone reductase enzyme in Rhizopus organisms allows them to thrive in high glucose, acidic conditions. This is the reason for the stimulated growth of these organisms in patients with diabetic ketoacidosis [12]. The case presented here, however, did not have diabetic ketoacidosis. Furthermore, IL-6-inhibiting drugs such as tocilizumab may cause immune dysregulation and increase the risk of secondary infections without providing substantial clinical benefit in patients with COVID-19 [13, 14]. COVID-19 patients with acute respiratory distress might be susceptible to secondary infections as a result of immune dysregulation [15]. Patients infected with SARS-CoV-2 have declined levels of circulating lymphocytes and T cell subsets, resulting in suboptimal cell-mediated immune responses [16]. With these in mind, one can anticipate that critically ill patients with COVID-19 are at increased risk of developing severe invasive fungal infections.
Acute invasive fungal rhinosinusitis is characterized by thrombosis, infarction and necrosis of involved tissues due to vascular invasion by the fungus, which manifests as black palatal or gingival eschars and/or perforation of the nasal septum. Rhinocerebral mucormycosis usually presents with an acute onset of fever, facial pain, nasal congestion, headache, perinasal swelling, facial numbness, and visual changes such as diplopia and proptosis. Facial numbness, as seen in the present case, is caused by fifth cranial nerve involvement, which indicates that the infection has spread beyond the sinuses. With the rapid spread of the fungal infection to the brain, obtundation, cranial nerve palsy, cavernous sinus thrombosis, and carotid artery involvement may occur. Cavernous sinus thrombosis is a complication that is usually seen when the fungal infection enters through direct wound contamination into the oral cavity, thereby involving the mandible. On the other hand, palatal ulcers are commonly seen in infections originating from the nose and PNS [11].
Based on the available literature, six studies corresponding to 11 patients, including ours, have reported rhino-orbito-cerebral mucormycosis in association with COVID-19. Detailed descriptions of these cases are provided in Table 2. Based on these studies, all patients had diabetes, either previously diagnosed or detected during COVID-19 admission; however, not all patients had received corticosteroids before initiation of symptoms related to mucormycosis. Importantly, PCR and DNA sequencing has only been performed in our study. So, the most common species causing invasive rhinocerebral mucormycosis could not be determined among these patients. It is worthy to note that while few patients developed symptoms during hospital stay, others, such as our case, developed symptoms after being discharged from the hospital for COVID-19 treatment. Therefore, it is very important to make all physicians aware of the fact that invasive fungal infections might occur after patients with COVID-19 have been discharged and so, patients, particularly those with predisposing conditions, should be informed about the red flag symptoms of invasive mucormycosis.
Mucormycosis has been diagnosed postmortem in two patients with COVID-19 [17, 18]; hence, it is rational to assume that a fatal outcome may possibly be precipitated by invasive fungal infections such as mucormycosis in a number of COVID-19 patients with predisposing factors, and that this devastating infection might have been underdiagnosed during the pandemic. Therefore, the early diagnosis of invasive fungal infections, such as rhino-orbito-cerebral mucormycosis, is of critical importance in COVID-19 patients with sinus complaints, particularly those with underlying diseases and those who have received systemic corticosteroids, since prompt, aggressive treatment is essential for an optimal outcome. Indeed, early diagnosis and timely management with surgical debridement plus amphotericin B most probably contributed to the favorable outcome achieved in the patient presented here. However, in four previously reported case reports of rhino-orbito-cerebral mucormycosis associated with COVID-19, patients died despite receiving therapy [19–22].
In conclusion, defining the characteristics of patients with invasive mucormycosis associated with COVID-19 may help to better evaluate the course of fungal infection in patients with COVID-19 and to determine the most appropriate and applicable preventive measures in highly susceptible COVID-19 patients with the intention to reduce morbidity and mortality. In addition, it is important to note that corticosteroids may be associated with potentially fatal side effects in COVID-19 patients, acting as a double-edged sword.
Table 2. Description of previously reported cases of rhino-orbito-cerebral mucormycosis in patients with COVID-19
† Date of admission for COVID-19 is considered as baseline (Day 0).
‡ These patients developed symptoms suggestive of mucormycosis after discharge.