<div>COVID-19-associated mucormycosis involving the maxilla</div><div>Abstract</div><div>It is important to increase the awareness and knowledge of head and neck
surgeons about the recent surge of craniofacial mucormycosis in COVID-19
patients, because early diagnosis and appropriate treatment are
essential to improve the outcomes. Here, we describe clinical features,
treatment protocols, and outcomes of treatment in 8 patients with
COVID-19-associated mucormycosis in the maxilla. Consistent with the
findings of previous studies, our experience in the management of these
8 patients shows that early administration of amphotericin B and prompt
aggressive surgery are essential for optimal control of the disease.</div><div>Introduction</div><div>Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a
virus named severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2). The virus causes infection in the lower respiratory tract,
potentially leading to diffuse alveolar damage, acute respiratory
distress syndrome, and ground-glass opacification of the lungs. Due to a
severe systemic inflammatory reaction, COVID-19 alters the cell-mediated
immune response by decreasing the number of T-lymphocytes, especially
the cytotoxic and helper T cells. This makes the patient susceptible to
a wide range of super-infections, particularly fungal
infections.<sup>1</sup></div><div>Mucormycosis is an acute and rapidly progressing infection caused by a
family of fungi called mucoromycetes. The family includes many different
species of fungi including Rhizopus, Mucor, Lichtheimia, etc. The
Rhizopus is the most common type and responsible for nearly 60% of
mucormycosis cases in humans.<sup>2</sup> Mucormycosis mostly
involves head and neck area and begins when fungal spores reach the
paranasal sinuses by means of inhalation, and spread into adjacent
structures including the maxillary bone, the orbital cavity, and the
cranium.<sup>3</sup> A correct diagnosis of mucormycosis depends
on histopathologic examination of tissue samples and detection of the
hyphae of the Mucorales in the specimens.</div><div>Before the COVID-19 outbreak, mucormycosis was limited to patients with
decreased immunity due to uncontrolled diabetes, end-stage renal
failure, organ transplantation, and hematological malignancies. A few
months after the outbreak of COVID-19, many case reports have described
cranio-maxillofacial mucormycosis associated with the
disease.<sup>4</sup> It seems that both COVID-19 itself and
medications that are used for the management of COVID-19 are responsible
for underlying conditions that promote the germination of spores in
tissues. These conditions include hypoxia due to lung damage, a decline
in the number and activity of white blood cells, steroid-induced
hyperglycemia and immunosuppression, acidic medium created by metabolic
acidosis, and high ferritin levels due to inflammation. Among these
conditions, immunosuppression is probably the most important
contributing factor. Studies have demonstrated that there is a more
intense level of lymphocytopenia in severe COVID-19 compared to mild
disease.<sup>5</sup> Furthermore, high doses of corticosteroids
are commonly prescribed as a life-saving measure in patients with severe
COVID-19.<sup>6</sup> Corticosteroids suppress the immune system
by decreasing the number of cytotoxic and helper T cells. In this way,
corticosteroids fight against severe inflammation caused by the virus,
but create a favorable environment for other opportunistic infections.
Therefore, administration of corticosteroids makes the immunocompromised
COVID-19 patients even more susceptible to fungal co-infections.</div><div>Case report</div><div>In 2021, during a period of 4 months, we admitted and treated 8 patients
with COVID-19-associated mucormycosis in the Shariati hospital in
Tehran, Iran. All patients had been previously hospitalized and had
received intravenous corticosteroids for the management of severe
COVID-19 pneumomia. They had been discharged with stable conditions
before being admitted to our department for the management of
mucormycosis in the upper jaw. The mean time interval between the
diagnosis of COVID-19 and admission to our department for the management
of mucormycosis was 41 days. All patients initially presented with acute
maxillary sinusitis as well as pain and tooth mobility in the upper jaw.
Six patients had necrotic bone exposure intraorally (Fig. 1). In all
patients, computed tomography (CT) scans revealed involvement of the
maxillary sinus and partial destruction of the maxillary bone (Figure
2). Table 1 summarizes demographic as well as clinical findings in these
8 patients.</div><div>All patients underwent aggressive surgery to remove hopeless teeth,
necrotic bone and pathologic tissues. Tissue specimens were submitted
for histopathologic evaluation. Microscopic evaluation revealed the
presence of rectangular-shaped aseptate hyphae in the specimens,
confirming the diagnosis of mucormycosis. In addition to surgical
intervention, all patients received intravenous amphotericin B (5
mg/kg/day) during hospitalization.</div><div>Discussion</div><div>A study of 101 patients with COVID-19-associated mucormycosis found that
80% of patients had diabetes mellitus and 76% had taken steroids for
the management of COVID-19.<sup>7</sup> It seems that COVID-19 is
potentially a diabetogenic disease. Of note, the SARS-CoV-2 can directly
damage the pancreatic cells and impede insulin secretion, leading to
acute diabetes and ketoacidosis.<sup>8,9</sup> In most hospital
centers, steroids are widely used in the management of severe cases of
COVID-19. This has been proved to be effective in reducing mortality and
hospital stay,<sup>10</sup> but the immunosuppressive and
diabetogenic effects of steroids may increase the risk of developing
mucormycosis in these patients.</div><div>All our patients were successfully recovered from COVID-19 but developed
craniofacial mucormycosis shortly after recovery. All had diabetes and
had received corticosteroids for the management of COVID-19. On the
basis of our experience, we recommend that intraoral examination should
become a routine part of medical examination in patients who have
COVID-19 or have recently recovered from the disease. This could lead to
early diagnosis of mucormycosis and a significant reduction in the rate
of mortality and morbidity associated with the disease.</div><div>In a study of 167 patients with COVID-19-associated mucormycosis, the
overall mortality rate was found to be 38%.<sup>11</sup>Furthermore, the study showed that survival rate was higher in patients
who underwent both medical and surgical management (65%) compared to
patients who received medical management only (22%).</div><div>Effective management of COVID-19-associated mucormycosis requires a
multidisciplinary approach involving several specialties including
ear-nose-trachea (ENT) surgeons, infectious disease specialists,
endocrinologist, and maxillofacial surgeons. A timely combination of
surgical debridement and antifungal therapy is mandatory to control the
disease.</div><div>Owing to the high morbidity and mortality of COVID-19-associated
mucormycosis, even the slightest clinical suspicion warrants initiation
of antifungal therapy. Amphotericin B should be started as soon as
possible and continued until improvement is evident both in clinical
examinations and in follow-up CT scans. In our experience, antifungal
therapy will be necessary for just a few weeks if adequate and prompt
surgical debridement is performed.</div><div>Mucormycosis is an angio-invasive disease which destructs blood vessels
and causes thrombosis, leading to poor tissue perfusion. This, in turn,
gives rise to poor drug bioavailability to the infection site, which
makes antifungal therapy progressively less effective. This vicious
cycle could be broken only by aggressive surgery in the earliest
possible time. Therefore, the role of surgical debridement in the
management of COVID-19 associated mucormycosis cannot be overemphasized.</div><div>Conflict of interests</div><div>The authors have none.</div><div>References</div><div>1. Yasmin F, Najeeb H, Naeem A, et al. COVID-19 Associated Mucormycosis:
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Líceník R, Najmi AK, Klugar M. COVID-19-Associated Mucormycosis (CAM):
An Updated Evidence Mapping. <i>Int J Environ Res Public Health</i>2021;18:10340</div><div>Figures and table:</div><div>Figure 1: Exposure of necrotic maxillary bone in a patient with
COVID-19-associated mucormycosis</div><div>Figure 2: Axial CT scan of the maxilla in a patient with
COVID-19-associated mucormycosis. Bone destruction is evident in the
left hemi-maxilla, involving both the alveolar bone and the basal bone.</div><div>Table 1: Demographic and clinical findings in 8 patients with
COVID-19-associated mucormycosis</div>