Atypical clinical features of post COVID‐19 mucormycosis: A case series

Abstract Objectives This case series aims to evaluate patients affected with post COVID‐19 mucormycosis from clinical presentation to surgical and pharmacological treatment to improve the disease prognosis. Material and Methods This case series was conducted at a specialized surgery hospital in Baghdad Medical City for over 10 months. Fifteen cases who had mild to severe COVID‐19 infections followed by symptoms similar to aggressive periodontitis, such as mobility and bone resorption around the multiple maxillary teeth, were included in this case series. Results All patients did not receive COVID‐19 vaccination; seven had a history of diabetes mellitus type 2, another five patients had a history of diabetes‐like syndrome during the COVID‐19 infection, and the remaining three patients had no history of any systemic diseases. No intracranial involvement was seen in all patients, and bilateral sinus involvement was seen in three patients. Conclusion Being highly suspicious of all patients affected with COVID‐19 is highly recommended to avoid the complications of the late diagnosis of mucormycosis. In addition, our knowledge and methods in diagnosing and treating classical mucormycosis should be modified regarding post COVID‐19 mucormycosis.

Mucormycosis represents a rare acute infection caused by a mucorales, a saprophytic aerobic fungus with great affinity to the paranasal sinuses. It rarely affects otherwise healthy people (Deeplata et al., 2021;Said Ahmed et al., 2021). The most common presentation of mucormycosis is orbital and maxillary cellulitis with mobility of the teeth in the affected maxillary segment (Nambiar et al., 2021;Sharma et al., 2021). Traditionally, mucormycosis starts in the nose and paranasal sinuses of patients with immunocompromising diseases, especially uncontrolled diabetes mellitus, which rarely affect healthy people (Morduchowicz et al., 1986).
Patients with phagocytic dysfunction caused by neutropenia, ketoacidosis, or high serum iron levels are at risk of developing mucormycosis. The innate immune system is enough to eradicate the infection in healthy patients except for those with severely contaminated exposed wounds (Bitar et al., 2009).
The prevalence of this disease had increased in the last few decades due to the increased life span of immunocompromised patients and improved diagnostic methods. However, the incidence of reported cases in the pre COVID-19 era was still low in developed countries, with bloodrelated malignancies as the main predisposing factor. In contrast, uncontrolled diabetes is responsible for increasing mucormycosis in developing countries (Bitar et al., 2009;Skiada et al., 2018).
Interestingly, Marchand et al. (2020) reported the first case of what is called diabetes-like symptoms in a patient who presented with diabetes mellitus 1 month after being infected with COVID-19, despite being normoglycemic in the initial hospitalization (Marchand et al., 2020).
Developing the post COVID-19 diabetes-like symptoms was thought to be related to the autoimmune mechanism initiated by the cytokine storm in genetically susceptible individuals or due to temporary loss of the β-cell function with the increased angiotensin-II enzyme. These patients were classified as having Type 1 diabetes (Roberts et al., 2021).
However, the available data regarding the management and prognosis of this disease were still obtained from case reports and case series because of the impossibility of performing a large randomized controlled trial with such disease (Deeplata et al., 2021;Morduchowicz et al., 1986). Because the number of Rhinocerebral Mucormycosis cases worldwide before the COVID-19 pandemic was infrequent, diagnosis and treatment of such cases may become difficult for the general practitioner (Song et al., 2020). This case series reviewed 15 patients who had mild to severe COVID-19 infections, followed by symptoms similar to aggressive periodontitis, such as mobility and bone resorption around multiple maxillary teeth. In these patients, one side of the upper jaw usually moved as one segment, and histopathological examinations proved the diagnosis of mucormycosis.

| PATIENTS AND METHODS
The case series was conducted at a specialized surgery hospital in Baghdad Medical City for over 10 months. All patients with a history of COVID-19 infection presented or were referred to the maxillofacial consultation clinic due to recurrent episodes of facial swelling and sinusitis with mobility of teeth on the affected side of the maxilla.

The case series was ethically approved by the Research Ethics
Committee of the College of Dentistry, University of Baghdad (Project No. 633122).
Intraoral examination revealed painless aggressive periodontitis with hypermobile teeth and swollen bright red mucosa. A little or no gingival recession involving all teeth on the affected side (right or left) was also noted.
A cone beam computed tomography (CBCT) revealed bony resorption around the affected side of the maxillary teeth, with obliteration of the maxillary and ethmoidal paranasal sinuses on the same side. Many patients had previous periodontic or endodontic treatments for these teeth but with no noted benefit.
Laboratory investigations regarding the level of HbA1c showed that Drainage for decompression of the buccal space cellulitis was done in some cases and revealed yellowish bone with total resorption of the buccal bone plate over the affected maxillary teeth; no bleeding was elicited after scratching the affected bone, hence, raising the suspicion about the diagnosis (Figure 1).
A biopsy was taken from the affected bone and sent for histopathological examination. Patients were then prepared for curettage surgery once the histopathological report confirmed the diagnosis of mucormycosis.
The affected teeth were extracted with curettage of the bone, maxillary sinus, copious irrigation with normal saline, and then wound packed with iodoform gauze (Figure 2).
The iodoform pack was changed daily with irrigation of the wound done three times per day, using normal saline mixed with hydrogen peroxide 10:1 for 2 weeks. This surgical intervention was followed by administration of meropenem powder injected 1 g twice daily, liposomal amphotericin B 5 mg/kg (slow infusion), and metronidazole 500 mg three times daily for the first eight patients.
The subsequent two patients were treated still with the surgical intervention but with meropenem powder 1 g twice daily and metronidazole 500 mg three times daily only.
F I G U R E 1 Normally attached mucosa overlying hypermobile maxillary teeth with abnormal yellowish bone from the incision made in the buccal vestibule for decompression of buccal space cellulitis.
The reason for not giving amphotericin in the remaining two cases is their imprecise primary histopathological reports, although slide revision by an oral pathologist confirmed the diagnosis of mucormycosis. At that time, both patients had complete uneventful healing. Ten months of follow-up of these cases showed no recurrence ( Figure 3).
In the last five cases, liposomal amphotericin B was changed from 5 to 1.5 mg/kg. Patients had good healing with no complications seen during the follow-up period ( Figure 4).

| RESULTS
Fifteen patients were included in this case series; all of them were examined in the oral and maxillofacial surgery consultation clinic in Baghdad Medical City from July 2021 to June 2022.
All patients in this case series were living in Baghdad City withage ranging from 35 to 78-year-old, mean age of (57.33) ± 11.6.
The average time from developing symptoms of facial swelling and seeking consultation at the clinic was 2 months.  Mucormycosis is an aggressive, lethal fungal infection with rhinocerebral extension that may affect immunocompromised patients, (Mehta & Pandey, 2020) and the standard treatment protocol involves aggressive surgical debridement with antifungal therapy (Bakathir, 2006).
Even though it has a low incidence rate, ranging from 0.005 to 1.7 per million population, a significant increase in the number of diagnosed cases was seen a few months after the outbreak of the coronavirus pandemic (Deeplata et al., 2021). If the diagnosis is delayed, the mortality rate associated with mucormycosis can be doubled from 35% to 66%, so early diagnosis and treatment (surgical and medical) are essential (Mehta & Pandey, 2020 spreads within a few days to end with a severe condition (Tran & Schmit, 2020). These findings may draw attention to the uniqueness of the post COVID-19 mucormycosis characteristics, particularly its slow spread and low pathogenicity, which might be due to the immune system response being lowered by the medications used in treating COVID-9. The opportunistic fungal infection has caused damage and necrosis, which is then slowed down due to the return of the patient's immunity to normal after controlling COVID-19 and cessation of its medical treatment. Hence, it is only a transient episode unlike in classical mucormycosis, this is not the situation as the underlying cause is still ongoing (Tang et al., 2021).
COVID-19 is considered a potential risk for developing sudden cardiac death. Several factors have been proposed to cause sudden cardiac death in post COVID-19 patients, (Yadav et al., 2020) but the exact mechanism remains uncertain.
Anticoagulant drugs were used for COVID-19 patients; however, they may develop a hypercoagulable state, (Mañón et al., 2022) which may contribute to the development of thromboembolic events. No intracranial involvement was seen in all of these patients, but bilateral sinus involvement was seen in three patients.
In conclusion, being highly suspicious of all patients affected with COVID-19 is highly recommended to avoid the complications of diagnosing mucormycosis late. In addition, our knowledge and methods in diagnosing and treating classical mucormycosis should be modified regarding post COVID-19 Mucormycosis.

AUTHOR CONTRIBUTIONS
Hassanien A. AL-jumaily: Conceptualization; methodology; intervention; and supervision. Auday M. AL-Anee: Patients' follow-up; validation; reviewing; and editing. Ahmed F. Al-Quisi: writing original draft; data curation; formal analysis; and editing. All authors participated in discussing outcomes and the final revision of the manuscript, and all of them read and approved the final manuscript.