key: cord-0742465-gf410jyh
authors: Upadhyay, Shalini; Bharara, Tanisha; Khandait, Manisha; Chawdhry, Ankit; Sharma, Bharat Bhushan
title: Mucormycosis – resurgence of a deadly opportunist during COVID-19 pandemic: Four case reports
date: 2021-12-26
journal: World J Clin Cases
DOI: 10.12998/wjcc.v9.i36.11338
sha: 0aadc3284d7277ea29cad7e99753c1a59ce868a2
doc_id: 742465
cord_uid: gf410jyh

BACKGROUND: Coronavirus disease 2019 (COVID-19) patients who suffer severe infection or comorbidities have an increased risk of developing fungal infections. There is a possibility that such infections are missed or misdiagnosed, in which case patients may suffer higher morbidity and mortality. COVID-19 infection, aggressive management strategies and comorbidities like diabetes render patients prone to opportunistic fungal infections. Mucormycosis is one of the opportunistic fungal infections that may affect treated COVID patients. CASE SUMMARY: We present a case series of four adult males who were diagnosed with mucormycosis post-COVID-19 recovery. All the patients had diabetes and a history of systemic corticosteroids for treatment of COVID-19. The mean duration between diagnosis of COVID-19 and development of symptoms of mucor was 15.5 ± 14.5 (7–30) d. All patients underwent debridement and were started on antifungal therapy. One patient was referred to a higher center for further management, but the others responded well to treatment and showed signs of improvement at the last follow-up. CONCLUSION: Early diagnosis and management of mucormycosis with appropriate and aggressive antifungals and surgical debridement can improve survival.

Author contributions: Upadhyay S, Bharara T and Khandait M reviewed the literature and contributed to manuscript drafting; Upadhyay S, and Bharara T performed the microbiological analyses and interpretation; Chowdhry A was the oral and maxillofacial surgeon who took the history and performed detailed analysis of the cases; Sharma B analyzed and interpreted the imaging findings; Khandait M and Bharara T performed the revision of the manuscript for important intellectual content; all authors have read and approve the final manuscript.

Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is known to infect alveolar epithelial cells (pneumonia and acute respiratory distress syndrome) as well as monocytes/macrophages leading to a cytokine storm (multiorgan failure and death) [1] . The cytokine storm seen in severe cases has led to increased use of steroids and other immunosuppressive therapy in moderate-to-severe cases. Coronavirus disease 2019 (COVID- 19) infection, aggressive management strategies and comorbidities such as diabetes mellitus (DM) render patients prone to opportunistic fungal infections [2, 3] .

Mucormycosis is a deadly and rapidly progressive fungal infection of humans. The usual presentation is rhinocerebral mucormycosis [4] . Oral mucormycosis is an unusual manifestation of the disease mainly affecting immunocompromised patients such as those with DM, corticosteroid treatment, leukemia, lymphoma, human immunodeficiency virus (HIV) infection etc. [3, 5, 6] . Although there are few publications on fungal co-infections associated with COVID-19, it is pertinent to point out that there is a high chance of missed or misdiagnosis in these cases.

To analyze mucor infections in COVID-19 patients, we searched PubMed, Scopus and Web of Science, using the keywords ''mucor'', ''mucormycosis'', ''opportunistic fungal infection'', ''oral fungal infections'', ''post COVID infection'', ''COVID-19'' or ''SARS-CoV-2'' (up to April 16, 2021). Through this report, we provide an insight into clinical features, laboratory diagnosis and significance of timely management of post-COVID mucormycosis infection through a series of four cases who presented to the outpatient department of our hospital.

All the cases presented to the department of oral and maxillofacial surgery with chief complaints of pain, swelling and pus discharge from their oral cavity.

Case 1: A 39-year-old man presented to the outpatient department (OPD) complaining of pain and mobility in the teeth of the upper jaw region for the past 2 mo. The patient gave a history of extraction of a tooth in the upper jaw 2 mo previously, after which he developed a nonhealing painful lesion. The pain gradually spread to the entire left maxilla ( Figure 1A ). past 1 wk ( Figure 1B ). The patient presented to the OPD with the same complaints 1 wk previously and was prescribed antibiotics, however, he did not obtain any relief.

A 45-year-old man presented to the OPD with chief complaints of pain, bleeding and ulcers in the gums.

A 55-year-old man presented to the OPD with chief complaints of pus discharge and bleeding from the gums ( Figure 1C ).

All four patients had a history of uncontrolled DM. All the cases gave a past history of suffering from COVID-19 that dated back 2-3 mo. 

All the patients were afebrile at presentation. In Case 1, both maxilla showed the presence of pus-discharging sinuses. The patient's mouth opening was found to be adequate. Case 2 showed gingival swelling and multiple draining sinuses on both anterior maxilla and also the right side of the palate. Case 3 demonstrated gingival swelling and multiple draining sinuses on both anterior maxilla and the right side of the palate. However, his mouth opening was inadequate. Case 4 had multiple sinus formation on gingiva and discoloration of the hard palate was observed ( Figure 1C ). On palpation, a maxillary fragment was mobile.

Blood chemistry, arterial blood gas analysis, urinalysis, electrocardiography and chest X-ray were normal in all four cases.

Further diagnostic work-up: All four cases tested negative for HIV antibody, hepatitis B surface antigen, and hepatitis virus antibody. Complete blood count, liver function test and kidney function test were within normal ranges.

The tissues/pus samples from the lesions were analyzed by direct microscopy and culture ( Figure 2 

Mucormycosis should be treated with liposomal amphotericin B.

NCCT of PNSs was suggestive of structural changes due to mucormycosis.

The final diagnosis of the four cases was post-COVID oral mucormycosis.

All the patients were started on intravenous infusion of liposomal amphotericin B at an initial dose of 5 mg/kg diluted in 10% dextrose. Cases 1 and 3 needed additional surgical intervention. The cases were followed up for clinical and radiological resolution of active disease.

Cases 1, 2 and 4 responded well to treatment. Case 3 could not be followed up as he was referred to a higher center.

We report a series of four cases of oral mucormycosis among male patients with DM. Mucormycosis sometimes appears as a diabetes-defining illness and remains one of the most devastating complications in uncontrolled DM. India contributes to 40% of the global burden of this deadly opportunistic infection, with an estimated prevalence of > 100 cases per million population [4] . All patients in this study had DM and similar oral lesions, and were diagnosed with the help of laboratory tests and NCCT. Two of the patients needed surgical debridement and all four were treated with liposomal amphotericin B. The patients showed improvement in their lesions. One of the patients who had extensive lesions was referred to a higher center for further care. December 26, 2021 Volume 9

Issue 36 Huang et al [7] reported a case of oral mucormycosis and extensive maxillary osteonecrosis secondary to dental extraction in a 40-year-old immunocompromised patient. The author emphasized early recognition and aggressive treatment of such patients in order to prevent morbidity and mortality [8] . Fogarty et al [9] and Kumar et al [10] also reported development of oral mucormycosis among elderly immunocompromised men. Various cases of oral mucormycosis reported so far are summarized in Table 1 [11] [12] [13] [14] [15] [16] [17] .

Another peculiar finding observed in our study was that all the patients gave a past history of COVID-19. SARS-CoV-2 is capable of infecting not only intraepithelial cells within the lungs, but also causes an abortive infection of the macrophages and dendritic cells. This leads to a storm of proinflammatory cytokines that renders the patient prone to opportunistic infections such as mucormycosis [1] . Invasive mucormycosis has not only been reported in severe cases but even in mild-tomoderate COVID. Although a few cases of oral mucormycosis have been reported in the literature, this is one of the first case series reported among COVID-19 patients.

Mucormycosis suggests the presence of a pre-existing immunosuppressive condition such as diabetes, leukemia, lymphoma, renal failure, immunosuppressive therapy, malnutrition, viral infection and severe burns. Hyperglycemia due to uncontrolled diabetes is the strongest risk factor for development of mucormycosis. It leads to polymorphonuclear dysfunction, defective chemotaxis and dysregulated intracellular killing. In ketoacidosis, free iron becomes readily available in the serum, which is efficiently taken up by Mucor for its growth and virulence. The association between DM and COVID is a known fact [18] . Corticosteroid use in severe COVID-19 patients with diabetes further impairs the functioning of neutrophils, thus making these patients highly susceptible to development of mucormycosis [3, 5, 17, 18] .

Inhalation of fungal spores or direct wound contamination are the two most common causes of oral mucormycosis [19, 20] . The most common form of this disease is maxillofacial. Early symptoms of this disease include facial cellulitis, periorbital edema and nasal inflammation, followed by widespread tissue necrosis [21] . Failure of prompt medical and surgical intervention may lead to cerebral spread, cavernous sinus thrombosis, septicemia and multiple organ failure, resulting in high morbidity and mortality [22] .

Suspicion of mucormycosis is based on laboratory and imaging findings, risk factors and disease progression while on any antibacterial or antifungal therapy that does not cover Mucor infection. The pathognomonic feature of mucormycosis is tissue necrosis manifesting as a necrotic lesion, eschar or black discharge in the nasal or oral cavity [23] .

Rapid diagnostic methods include biopsy, KOH mount and Calcofluor stain. Since it is difficult to routinely culture Mucor, biopsy is preferred for confirmation of diagnosis [2, 21, 23] (Figure 4 ). Management includes antifungal therapy, surgical debridement, diagnosis and treatment of the underlying predisposing factors, and adjuvant therapy. Amphotericin B is the standard treatment for invasive mucormycosis[24]. Posaconazole or isavuconazole may be preferred in COVID-19 patients with acute on chronic renal failure. Isavuconazole shortens the QT interval, which may be affected by hydroxychloroquine and azithromycin therapy commonly used in COVID-19 patients [25] . Adjuvant therapy like caspofungin, deferasirox, statins, aspirin, and hyperbaric oxygen may be added as adjunctive treatment [26] .

Clinical suspicion, meticulous diagnosis, coordination between different medical departments and timely intervention were the strengths of our study. Limitation of the study were that antifungal susceptibility testing and further molecular characterization of the isolated fungal pathogen could not be done due to limitation of resources.

Clinicians should be familiar with presentations of rare opportunistic fungal infections and keep a high index of suspicion in post-COVID patients with DM. A multidisciplinary approach facilitating early diagnosis, aggressive surgical intervention, medical treatment with amphotericin B and controlling DM are the mainstay for improving the outcome of patients with mucormycosis in post-COVID patients. The incidence of oral mucormycosis may increase, either as co-infection or as a sequela of COVID-19. Therefore, urgent reporting of any new information is of importance to keep the scientific community abreast with what all can go wrong post-COVID infection, which till now is unexplored territory. Grocott-Gomori's methenamine silver; SDA: Sabouraud dextrose agar.

Current understanding, knowledge gaps and a perspective on the future of COVID-19 Infections: A systematic review

Fungal Co-infections Associated with Global COVID-19 Pandemic: A Clinical and Diagnostic Perspective from China

Diabetes mellitus as the major risk factor for mucormycosis in Mexico: Epidemiology, diagnosis, and outcomes of reported cases

Global Epidemiology of Mucormycosis

SARS-CoV-2, Uncontrolled Diabetes and Corticosteroids-An Unholy Trinity in Invasive Fungal Infections of the Maxillofacial Region?

The double-edged sword of systemic corticosteroid therapy in viral pneumonia: A case report and comparative review of influenza-associated mucormycosis versus COVID-19 associated mucormycosis

Extensive maxillary sequestration resulting from mucormycosis

Mucor in a Viral Land: A Tale of Two Pathogens

Invasive fungal infection of the maxilla following dental extractions in a patient with chronic obstructive pulmonary disease

Mucormycosis in maxilla: Rehabilitation of facial defects using interim removable prostheses: A clinical case report

Oral mucormycosis in an 18-month-old child: a rare case report with a literature review

Rhino-Orbital Mucormycosis Associated With COVID-19

Mucormycosis with orbital compartment syndrome in a patient with COVID-19

Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study

Bronchopleural fistula development in the setting of novel therapies for acute respiratory distress syndrome in SARS-CoV-2 pneumonia

Rare and Fatal Gastrointestinal Mucormycosis (Zygomycosis) in a COVID-19 Patient: A Case Report

Acute Invasive Rhino-Orbital Mucormycosis in a Patient With COVID-19-Associated Acute Respiratory Distress Syndrome

A challenging complication following SARS-CoV-2 infection: a case of pulmonary mucormycosis

COVID-19 and diabetes mellitus: from pathophysiology to clinical management

Coronavirus Disease (Covid-19) Associated Mucormycosis (CAM): Case Report and Systematic Review of Literature

Oral manifestations in a patient with a history of asymptomatic COVID-19: Case report

Mucormycosis in immunocompetent patient resulting in extensive maxillary sequestration

Mucormycosis of maxilla following tooth extraction in immunocompetent patients: Reports and review

Development of new strategies for early diagnosis of mucormycosis from bench to bedside

Fungal diseases, Treatment for Mucormycosis

Statement on Elective Surgery and Anesthesia for Patients