UNRAVELLING (COVID) MUCORMYCOSIS, DENTISTS AT THE DEEP END – A MINI REVIEW

COVID-19 otherwise called as SARS-Cov-2 caused by severe acute respiratory syndrome declared as pandemic by WHO, resulted in increased mortality globally. Post covid recovered patients developed a wide range of opportunistic bacterial and fungal infections including mucormycosis. Even though mucormycosis is known as a life-threatening disease in immunocompromised patients and patients with uncontrolled diabetes with high rates of morbidity and mortality, application of a proper protocol and adhering to the standard guidelines in the management from initial stage to advanced complex stage can reduce the morbidity and mortality. Since the early clinical signs and symptoms arise in the oral and maxillofacial region, the role of general dentist in early detection of the clinical signs and symptoms and in particular the early surgical intervention by the Oral & Maxillofacial surgeons can definitely reduce the morbidity and mortality caused by mucormycosis. Poor prognosis and increased morbidity are often related to delayed diagnosis and delayed management without proper guidelines. This article aims to describe in brief mucormycosis with the current update and the role of an endodontist in diagnosis and management of this fungal infection.

COVID-19 otherwise called as SARS-Cov-2 caused by severe acute respiratory syndrome declared as pandemic by WHO, resulted in increased mortality globally. Post covid recovered patients developed a wide range of opportunistic bacterial and fungal infections including mucormycosis. Even though mucormycosis is known as a lifethreatening disease in immunocompromised patients and patients with uncontrolled diabetes with high rates of morbidity and mortality, application of a proper protocol and adhering to the standard guidelines in the management from initial stage to advanced complex stage can reduce the morbidity and mortality. Since the early clinical signs and symptoms arise in the oral and maxillofacial region, the role of general dentist in early detection of the clinical signs and symptoms and in particular the early surgical intervention by the Oral & Maxillofacial surgeons can definitely reduce the morbidity and mortality caused by mucormycosis. Poor prognosis and increased morbidity are often related to delayed diagnosis and delayed management without proper guidelines. This article aims to describe in brief mucormycosis with the current update and the role of an endodontist in diagnosis and management of this fungal infection.

ISSN: 2320-5407
Int. J. Adv. Res. 9(09), 940-947 941 Recently, an increase in rhino-orbital mucormycosis is being reported in people with COVID-19 due to rampant use of corticosteroids 5 . Oral mucormycosis is caused by inhalation of sporangiospores of mucormycetes, molds or direct contamination of open oral wound. The first clinical sign leading to mucormycosis diagnosis is ulceration 6,7 . High risk patients who report with dental pain and palatal ulcer necessitates appropriate diagnosis and treatment plan. Since dentists are the one who objectively assess the dental pain, they play a major role in diagnosis of mucormycosis as mucormycosis can mimic odontogenic pain.

Review of Literature: -
Mucormycosis is defined as an angio invasive insidious fungal infection caused by Mucorales and zygomycotic species 8 . It can occur as acute and aggressive forms and are caused commonly by saprophytic organisms of the genera Rhizopus, Mucor, Cunninghamella and Rhizomucor 9 .

History
Paltauf et al reported the first case of Mucormycosis in 1885 and described it as Mycosis Mucorina. Gregory et al published the first case of rhino-orbital cerebral mucormycosis in 1943 8,10 . The association between poorly controlled diabetes and Mucormycosis was reported in 1943 11 . In 1980s and 1990s rapidly increasing cases of Mucormycosis was reported in immunocompromised patients. Mucormycotina have also been found in soil and decaying fruit and vegetables, but they are not harmful. They are not a commensal in oral cavity like Candida 8 . It has also been reported to occur during natural disasters like the 2004 Indian ocean tsunami and the Missouri tornado in 2011 12 . Currently, a number of cases have been reported in association with COVID-19 13 .

Classification
Based on the anatomic location in which it occurs, Mucormycosis is classified as 1. Rhinocerebralaffects sinus and brain 2. Pulmonaryaffects the lungs 3. Cutaneousaffects the skin 4. Gastrointestinalaffects stomach and intestine 5. Disseminatedspreads through distant sites through blood 6. Uncommon presentationsaffects less commonly involved sites 14

Clinical features
Mucormycosis can occur in humans in two forms 1. Superficial and Visceral 2. Localized and Disseminated The superficial type occurs as cutaneous mucormycosis and can also be seen in external ear and finger nails. The localized form affects the lungs, intestine, sinus and brain 8,15 . Patients may experience fever, rhinorrhoea, cephalea, ocular pain, vision loss, palpebral oedema, facial oedema and proptosis.
Oral manifestations of mucormycosis may be the first clinical sign due to high vasculature of the oral tissues. Hard palate is commonly infected due to its close anatomic relationship to the paranasal sinus and nasal fossa. The initial presentation may be seen as an intraoral swelling which can ulcerate and cause tissue destruction to appear as necrotic and black 16,17,18 . Lesions affecting the sinus can cause erosion of the hard palate along with the mobility of the maxillary teeth. Perineural spread and cavernous sinus invasion can occur due to the invasion of the fungal hyphae 19 . Cases of periodontal mucormycosis have also been reported secondary to haematological malignancies. They manifest as oedematous plaques with necrotic changes and gingival pain 20 .

Radiographic Features
CT scans can demonstrate isodense and hyperdense areas of sinuses due to obstruction 21 .MRI can show orbital soft tissues invasion, infiltration of skull base, perineural spread, intracranial changes and vascular obstruction of the internal carotid artery 22 .

Pathogenesis
Infection occurs by inhalation of spores, contamination of traumatized tissue, ingestion and direct inoculation of spores causing angioinvasion, thrombosis, ischemia and necrosis of the tissues involved 22 . Dental extractions cause bleeding and rupture of the blood vessels that can serve as an opening for the entry of the fungi 23 .

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Maxillary sinus, the biggest of the paranasal sinus, has the apex of the sinus extending into the zygomatic process of the maxilla and the base formed by the lateral wall of the nose. Floor of the orbit forms the roof and the alveolar process forms the floor. They are located above the level of the first and second premolars, the third molar and the root of the canine. Ethmoidal sinus lies between the upper parts of the nasal cavities and the orbits, and is separated from these cavities by thin bony lamellae. The maxillary sinuses are located under the orbit, the frontal sinuses above the orbit, the ethmoidal sinuses are between the orbit and the sphenoidal sinuses are behind the orbit 24,25 .
Due to the proximity of the paranasal sinus cavities and the orbit, it is not uncommon for patients with primarily sinonasal pathology to present with ophthalmologic symptoms 26 .Upon germination, the invading fungus may spread to the palate inferiorly, to the sphenoid sinus posteriorly, laterally into the cavernous sinus involving the orbits, or cranially to invade the brain. Following inhalation of spores into the paranasal sinuses, the infection begins in the nasal turbinates with a reservoir in the pterygopalatine fossa. It mimics as an acute sinusitis as it spreads from the sinus to the orbit and the hard palate. The fungi invade the blood vessels causing arterial occlusion resulting in ischemia. From the orbit, the organisms invade the cavernous sinus and then the brain causing embolization, seizures and cerebrovascular occlusion 27,28,29 .

Mucormycosis and Covid-19
COVID-19-associated pulmonary aspergillosis, candidiasis and mucormycosis have been reported 30 . In India, the prevalence of mucormycosis is approximately 0.14 cases per 1000 population, which is 80 times the prevalence in developed countries 31 .The incidence of COVID-19 associated mucormycosis cases is 8,800 as of May 23 rd 2021 32 .
The causes attributed to the rise of COVID-19 mucormycosis are uncontrolled diabetes, excessive use of corticosteroids for immunosuppression and long-term stay in the intensive care unit, malignancy, post-transplant comorbidity and variconazole therapy 33,34 . SARS-CoV-2 infection can affect CD4+ and CD8+ T-cells thereby resulting in a reduction of lymphocytes and T-cells which increases the risk of developing invasive mucormycosis 31 .
A cumulative dose of prednisolone more than 600 mg or a total methyl prednisone dose of 2-7 g prescribed, can predispose immunocompromised patients to mucormycosis 35 . The invasion and destruction of mucormycosis can be due to the low serum inhibitory activity against Rhizopus species especially in diabetic patients with ketoacidosis, reduction of pH and the reduced capacity of diabetes mellitus patients to inhibit Rhizopus germination 8 . Hyperglycemia causes reduction in iron binding allowing increased free iron. Patients with COVID-19 exhibit increase in cytokines especially interleukin-6, which further increases free iron by increasing the ferritin levels due to increased synthesis and decreased transport of iron. Free iron serves as an ideal medium for the growth of mucormycosis 36 . Receptor Glucose-Regulated Protein (GRP )78 is one of the receptors for SARS-CoV-2 entry into the cells. Hyperglycemia induce the enthodelial GRP 78 and the adhesin spore coat protein homologs (CotH) of Mucorales resulting in increased adhesion and penetration of Mucorales to the endothelium 37 . Zinc inhibits ribonucleic acid polymerase and is also a component of Angiotensin-converting enzyme 2(ACE2) which facilitates cellular entry of coronavirus 38 . It has also been observed that zinc deficiency induces stress in fungal cells and inhibits fungal development 39 .It has also been postulated that non-sterile water used in humidifiers, unsterilized oxygen equipment and non-medical oxygen cylinders can also cause mucormycosis 40 .Masks which are unhygienic masks, re-using unwashed masks and poorly ventilated rooms have also been put forward as causes for the development of mucormycosis in COVID-19 patients 41 .
Mucormycosis can occur during COVID-19 infection or a few weeks after recovery 42

. Matrix-assisted laser desorption/ionization (MALDI-TOF) 4. CT and MRI to assess disease extent
In the initial stage, the radiological signs may be minimal and subtle and may not demonstrate sinusitis and bone erosion. But the lack of these signs does not exclude diagnosis 34,43 .

Management
Guideline for management of Mucormycosis in Covid -19 patients by Directorate General of Health Services (DGHS) suggests the use of liposomal Amphotericin B -5mg/kg body weight (10 mg/kg body wt. in case of CNS involvement) initially. Liposomal Amphotericin B should be diluted in 5% or 10% dextrose, as it is not compatible with normal saline/ Ringer Lactate. After the disease is stabilized oral Posaconazole (300 mg delayed release tablets 1-0-1 x 1 followed by 300 mg daily) or Isavuconazole (200 mg 1-1-1 x 2 followed by 200 mg daily) can be given. If liposomal Amphotericin B is not available, the conventional form (deoxy cholate) in the dose 1-1.5mg/kg can be prescribed if the renal functions and serum electrolytes are within normal range 44 .
Amphotericin B is a polyene class of antifungals with a half-life from 24 hours to 15 days. Three types of Amphotericin B are available-Liposomal Amphotericin B, Amphotericin B lipid complex and Amphotericin B cholesteryl sulfate complex 45 . Liposomal Amphotericin B is the drug of choice for treatment of mucormycosis associated with COVID-19 43 . It acts by binding to ergosterol in the fungal cell membrane which leads to formation of ion channels resulting in the loss of protons and monovalent cations causing depolarization and concentrationdependent cell killing. It also causes oxidative damage to the cells and has a stimulatory effect on phagocytic cells resulting in cell death 45 .

Surgical Management
Different countries were following different protocols in medical and surgical management of mucormycosis. The treatment plan varied in different regions based on the different diagnostic techniques and available therapeutic options. The treatment protocol varied based on specific systemic problems and disease patterns. In January, 2018, experts from 33 countries of the European Confederation of Medical Mycology (ECMM) did the retrospective analysis of mucormycosis management and reviewed various treatment guidelines followed in different parts of the world. One of the recommendations included immediate and appropriate imaging of suspected cases of mucormycosis to find out extent of disease, which will be useful to apply the guidelines in both medical and surgical management 46 .

The European Confederation of Medical Mycology (ECMM), in association with the Mycoses Study Group
Education & Research Consortium (MSG ERC), issued a comprehensive guideline and tried to clear the doubts on confused areas in the treatment of mucormycosis.
Rapid invasive nature of the mucormycosis leads to thrombosis, tissue infarction and tissue necrosis. This prevents the penetration of antifungal agents and results in failure of antifungal agents in which condition, surgery is the next best option left. Early surgical intervention and debridement of the involved structures helps to prevent the spread and protect the adjacent structures. Surgical excision of the involved soft tissues, debridement of the involved structures like surgical resection of infected lung tissue in localized pulmonary lesions and surgical debridement in rhino orbital cerebral region is also part of the extensive surgical treatment.

Adjunctive Treatment
This includes treatment with hyperbaric oxygen therapy or adjunctive treatment with deferasirox or deferiprone. Iron chelation by deferasirox or deferiprone appears to be a rational adjunct to antifungal treatment. In rhino-orbitocerebral mucormycosis adjunctive hyperbaric oxygen appears more promising but not much results are currently available 47 . The surgical phase again depends upon the severity of extension of the lesion. It may vary from simple extraction, multiple extraction, gingivoplasty, curettage, alveoloplasty, subtotal or partial maxillectomy to entire maxillectomy or even removal of the entire middle third of the face bilaterally involving the orbital region including the globe. Minor oral surgical procedures can be performed under local anaesthesia in the dental clinics with antibiotic coverage and antifungal coverage. Major surgical interventions like maxillectomy, orbital exenteration and other osteotomy surgeries are done under General anaesthesia. Associated systemic problems like existing diabetes or post covid diabetes should also be taken into consideration before planning for surgery. If the patients are continuing the blood thinners, then, INR values should be assessed and discussion with the patient's physician about the change of blood thinners or stopping should be carried out. A good team comprising pathologists, microbiologists or virologists, maxillofacial surgeons, ENT surgeons, chest physicians and neuro surgeons will give faster and better results.