COVID-19 and mucormycosis: the dual threat

R. Anbuchezian*,

Department of ENT, Head and Neck Surgery, Kauvery Hospital, Hosur, India

*Correspondence:  [email protected]

Background

India has experienced two waves COVID-19, the latter more devastating in every parameter. The associated outbreak of mucormycosis caused very high morbidity and mortality in the country. The challenges encountered were difficulty in establishing an early diagnosis, including limited availability of validated serological methods, lack of availability, at the onset of the outbreak, of appropriate antifungal drugs for effective treatment, and the resultant overwhelming of the healthcare system, leading to great suffering for the people.

Mucormycosis

Mucormycosis is an invasive fungal infection of the zygomycetes family. Mucorales are thermoresistant fungi primarily found in soil and decaying organic matter and rarely cause diseases because of low virulence. Rhizopus is the most common fungal infection in immunosuppressed population, though Aspergillus sp. are also frequently encountered. The spores of Mucorales primarily reach the respiratory tract via inhalation. These spores adhere to the nasal mucosa and are naturally cleared. The innate immune system is responsible for the elimination of these fungal structures.

Mucormycosis can be differentiated into invasive and non-invasive forms. The manifestation of non-invasive fungus is easily treatable as they do not spread very fast. Mucormycosis has the propensity to spread very fast in the blood channels. This phenomenon is known as vascular invasion. Subsequently, this is followed by a cascade of events characterized by tissue necrosis, thrombosis and dissemination of the organism. Early and aggressive treatment is pivotal for successful outcome.

Generally, there exists an underlying health condition that makes the hosts vulnerable to the infection. The clinical forms of infection are: pulmonary, gastrointestinal, cutaneous, rhinocerebral, and disseminated [1]. In relatively immunocompromised patients, the establishment of host defence mechanism is hampered by a variety of factors and these innocuous organisms can jeopardize their health. The greatest challenge is the early identification of Mucormycosis.

Predisposing Factors

Invasive fungal infections usually manifest in patients with severely immunocompromised states, who had solid organ transplantation, have haematological malignancies and are on, or had, corticosteroid therapy.

Steroid use is a principal risk factor for opportunistic infections, including mycoses. The study conducted by the Indian Council of Medical Research – India Diabetes (ICMR-INDIAB)- reported that the prevalence of diabetes was 7.3% and prediabetes was 10.3%, thus emphasizing the need for active screening [2]. As a result of over-zealous use of corticosteroids and sub-optimal control of the resultant hyper glycaemic states, these patients have a greater risk of development of fungal infections.

Diagnosis

Histopathology

The growth of the fungi is demonstrated in the biopsy of infected tissue. The diagnosis is confirmed in tissue staining techniques and frozen section. This aids in distinguishing mucormycosis from other fungal diseases.

Serology

Currently, there is no specific serologic or antigenic method available for the diagnosis of mucormycosis. Nevertheless, polymerase chain reaction (PCR) exist for the identification of fungal infection.

Recently, by using an Enzyme Linked Immunospot (ELISpot) assay, the presence of Mucorales-specific CD8 T cells in peripheral blood (PB) could be investigated in haematological patients with active Invasive Mucormycosis and is a path breaking discovery. Research is underway on the application of such assay for detection of active Invasive Mucormycosis.

Imaging modality

Contrast-enhanced MRI possesses high-quality soft-tissue resolution. Computed Tomography (CT) imaging for the bony component assessment provides excellent information for the early diagnosis of invasive fungal infection.

Magnetic resonance imaging (MRI) plays a pivotal role in the early and accurate diagnosis of invasive and non-invasive fungal rhino-sinusitis. MRI is superior to CT. The extent of intracranial and intra orbital invasion like orbital apex syndrome, seizures, stroke can be assessed with the help of MR imaging. MRI scan helps in visualization of bony architecture variations.

Both CT and MRI guide clinicians in planning surgical treatment in COVID-19 patients to help reduce a possible adverse outcome [3].

Management of COVID-19 Associated Mucormycosis: Our Experience

Clinical Presentation

Majority of patients with COVID-19-associated Mucormycosis presented with cheek pain followed by cheek swelling. Out of 36 patients, 13 patients reported with ophthalmoplegia. Rhino-orbital Cerebral Mucormycosis (ROCM) accounts for 45-74% of the reported patients with Mucormycosis from India [4].

Other symptoms include nasal block/discharge, loss of vision, altered sensorium, loosening of teeth, palatal discolouration and facial palsy. We had only one patient with dysphagia and poor gag reflex. Mucormycosis can infect the eyes, eventually leading to blindness.

Meanwhile, it relentlessly progresses to the brain, causing headaches and even seizures. The most frequent form is rhino-orbito-cerebral mucormycosis followed by pulmonary mucormycosis. We observed the average duration between the diagnosis of COVID-19 and the onset of mucormycosis symptoms to be 10-30 days in our patients.

Surgical Management

Surgical removal of nonviable tissues, antifungal agents and correction of metabolic derangements are the mainstay for the management of mucormycosis. The surgical management of invasive fungal rhinosinusitis has evolved over the years following endoscopic sinus surgery. We had 36 patients who presented with invasive fungal sinusitis at our centre. Tissue culture and histopathology revealed R. arrhizus in 31 patients. Five patients were diagnosed with mixed fungal infection (A. fumigatus and R. arrhizus).

 

We performed diagnostic nasal endoscopy in all patients. About 25 patients underwent endoscopic modified Denker’s medial maxillectomy. The endoscopic view provided us the window to the whole sinus for complete eradication of the lesion and to control the possible recurrence. We cleared pterygopalatine, infratemporal fossaand pterygoid muscle for fungal clearance. Through the natural connecting pathways from the pterygopalatine fossa, mucormycosis can infect the facial soft tissues, palate and infratemporal fossa [5].

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Fig. 1. Endoscopic view demonstrating black necrotic tissue in skull base (arrowhead) and necrosed Anterior Ethmoidal Artery (arrow).

COVID-19-and-Mucormycosis-2

Fig. 2:Rhino-orbital Cerebral Mucormycosis in a COVID-19 patient. Endoscopic assisted sub-total maxillectomy with clipped right Internal maxillary artery (arrowhead).

COVID-19-and-Mucormycosis-3
COVID-19-and-Mucormycosis-4
COVID-19-and-Mucormycosis-5

Fig. 3. Pictures highlighting the endoscopic surgical view of orbital clearance in patients with COVID-19 associated mucormycosis.

The endoscopic trans-nasal approach facilitates precise assessment of the anatomic structures. A, B, C. Endoscopic view of healthy frontal sinus consisting of posterior table (arrow), healthy sphenoidal sinuses with inter sphenoidal septum (arrowhead) and drilled sphenoidal floor following posterior septectomy and cut end of inferior rectus (chevron arrow)

COVID-19-and-Mucormycosis-6
COVID-19-and-Mucormycosis-7

Fig. 4. Surgical view of subtotal maxillectomy in a post COVID-19 patient with mucormycosis (a) View of the affected bone (arrow), (b) View illustrating removal of the affected bone, preserved alveolar process and granulation in the floor of orbit (arrowheads).

We performed necrotic tissue excision in the maxilla, nasal cartilage, palate, mandible, and orbit. All patients were assessed via nasal endoscopy in the post-operative period. Regular nasal toileting and debridement of nasal adhesions and crust were performed. We had few patients with purulent discharge which we managed conservatively. We performed nasal irrigation with conventional Amphotericin B and continued till fresh granulation tissue was seen in the nasal cavity.

Anti-Fungal TherapyAmphotericin B is the first-line antifungal therapy for mucormycosis. Unfortunately, we had a severe shortage of Amphotericin B across the country. For salvage treatment, posaconazole is recommended [6,7].

We administered intralesional Amphotericin injection in the sinus and nasal cavity and involved tissues of the pterygopalatine fossa, infratemporal fossa and pterygoid muscle of all patients. Three patients received transcutaneous retrobulbar amphotericin B (TRAMB) was given by ophthalmologist who had detected orbital involvement.

All patients received oral Posaconazole from the first post-operative day and continued two months following surgery.

Differential Diagnosis

Clinicians must consider different pathologies such as orbital cellulitis and cavernous sinus thrombosis.

Outcome

The prognosis is highly dependent on the degree of immunosuppression and the extent of disease spread in patients. Out of 36 patients, 12 patients succumbed to death due to secondary complications of COVID-19 infection.

Complications

The complications of mucormycosis include cavernous sinus thrombosis, periorbital destruction, palatine ulcers, osteomyelitis, disseminated infection and eventually death.

We encountered intracranial extension in four patients and unfortunately, we lost these patients to septicemia from mucormycosis. We had secondary complications resulting from anti-fungal treatment are hypokalemia, nephrotoxicity and prolonged hospitalization.

Conclusion

Mucormycosis is a deadly fungal infection with very high rates of mortality. Management requires aggressive medical and surgical treatment to prevent intracranial and intra-orbital complications. Planned therapeutic intervention with the involvement of multidisciplinary team is crucial. Early diagnosis is the critical aspect and prompt initiation of treatment regimen will embark successful outcomes.

References

  • Baradwaj R, Thilagavathy S. Mucormycosis in COVID-19: A clinico-microbiological dilemma. Available from: https://www.kauveryhospital.com/kauverian-scientific-journal/mucormycosis-in-covid-19-a-clinico-microbiological-dilemma. Accessed on 18-08-2021.
  • Anjana RM, Deepa M, Pradeepa R et al. ICMR-INDIAB Collaborative Study Group. Prevalence of diabetes and prediabetes in 15 states of India: results from the ICMR-INDIAB population-based cross-sectional study. Lancet Diabetes Endocrinol. 2017;5(8):585-96.
  • Cornely OA, Alastruey-Izquierdo A, Arenz D et al. Mucormycosis ECMM MSG Global Guideline Writing Group. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019;19(12):e405-21.
  • Prakash H, Chakrabarti A. Epidemiology of mucormycosis in India. Microorganisms. 2021;9(3):523.
  • Hosseini SM, Borghei P. Rhinocerebral mucormycosis: pathways of spread. Eur Arch Otorhinolaryngol. 2005;262(11):932-8.
  • Enoch DA, Aliyu SH, Sule O et al. Posaconazole for the treatment of mucormycosis. Int J Antimicrob Agents. 2011;38(6):465-73.
  • van Burik JA, Hare RS, Solomon HF et al. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis. 2006;42(7):e61-5.
COVID-19-and-Mucormycosis-Dr.-R.-Anbuchezian

Dr. R. Anbuchezian

ENT, Head & Neck and Cochlear Implant Surgeon

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