COVID-19 associated mucormycosis: efforts and challenges

Hari Meyyappan M¹,*, Hari Prasad R², Balaji M², Abhishek Johnson Babu², Ganesh Kumar³

¹Department of ENT, Head & Neck Surgery, Kauvery Hospital, Trichy, Tamil Nadu, India

²Department of Oral and Maxillofacial Surgery, Kauvery Hospital, Trichy, Tamil Nadu, India

³Department of Ophthalmology, Kauvery Hospital, Trichy, Tamil Nadu, India

Background:

The world is still trying to come to terms with the new and strange coronavirus disease 2019 (COVID-19) which made its landfall in Dec 2019 and was declared a pandemic towards the end of January 2020. This dreaded infection has added to its dire acute complications an aftermath of post-COVID complications which has burdened both patients and their physicians all over the world. But India seems to have been exclusively targeted to greatly suffer from a disease unique to it, COVID Associated Mucormycosis (CAM) and its particularly challenging and potentially fatal presentation- viz- Rhino-Orbital-Cerebral Mucormycosis (ROCM) [1-3]. The very invasive nature of the disease and the acute shortage in the country of therapeutic agents resulted in very unfortunate outcomes. India witnessed a steep rise in incidence of post-COVID mucormycosis across the country during the second wave of the pandemic, associated with considerable morbidity and a higher mortality. Subsequently, CAM was also declared an epidemic across the country. Several factors including steroid use, hyperglycaemic conditions and virus mediated lymphopenia have been linked to the pathogenesis of CAM. India reported the largest number of the reported cases for mucormycosis globally [4]. India is also the diabetes capital of the world and COVID-19 patients with diabetes mellitus are more prone to mucormycosis infection. The deadly triad of COVID-19, mucormycosis and diabetes severely affects the prognosis of the patients. Therefore, a very comprehensive approach is vital for successful outcomes.

COVID-19 and Mucormycosis: A Bidirectional Relationship

The hallmark of mucormycosis infection is vascular invasion with concomitant thrombosis and tissue infarction/necrosis. Mucormycosis always occurs in patients with impaired host defence mechanisms and/or an elevated available serum iron. The infection is progressive leading to death unless treatment with surgical excision and antifungal therapy are initiated.

Immunosuppression from COVID-19 infection, along with pre-existing disease conditions, such as diabetes mellitus, and the use of steroids prepare the ground for secondary and opportunistic infections.

Clinical Presentation

Rhinocerebral mucormycosis is the most common form of the disease. Nearly one third to one half of the patients with mucormycosis present with rhino-cerebral complications [5]. Among the 74 patients, most of the patients were within the age group of 40-60 years. Out of the total 74 patients, 29.7% of the patients were having active COVID-19 illness. 72.2% of patients presented at the later stages of COVID-19 infection. Radiological, tissue cultures and histological investigations were carried out for disease confirmation. All patients underwent nasal endoscopy, CT scan and/or Contrast enhanced MRI.

The predominant symptom in COVID-19 patients with rhino-orbital mucormycosis was headache followed by facial pain. A greater percentage of patients had periorbital edema. A few patients presenting with orbital involvement had ophthalmoplegia due to involvement of the third, fourth and sixth cranial nerves. We noted numbness in 21% of the patients. Numbness was an important sign which signified involvement of infraorbital nerves and maxillary sinus. Toothache, loosening of teeth and radiologic involvement of the jaw were reported in many patients. These patients developed symptoms of rhino-orbital mucormycosis from day 5 to 45 of diagnosing COVID-19 infection (Fig. 1).

Fig 1. Presenting symptoms of ROCM in COVID-19 patients.

Predisposing Factors

Out of the 74 patients, all patients in our case series had diabetes mellitus. Out of 74 patients, 51 patients had a history of diabetes mellitus whereas 23 patients developed diabetes in the clinical course of COVID-19 illness. We inferred that diabetes mellitus is a major risk factor which impacts the overall prognosis.

Role of Surgery

Mucormycosis is relentlessly progressive and antifungal therapy alone is not the panacea to control the infection. Surgery is essential for the clearance of tissue necrosis occurring in mucormycosis. Immediate action to surgically debride infected and necrotic tissue without delay can most certainly save the day for the patient.

The mode of surgical management chosen to optimize outcomes in mucormycosis was according to the different stages of the disease each patient presented in. We achieved complete disease clearance using an endoscopic approach. We avoided external approaches for better cosmetic outcomes. Endoscopy guided debridement was predominantly done in all patients. The uninvolved sinuses constitute 12% of disease invasion which eventually required re-debridement. Hence extensive sinus debridement was performed. All the foramina were cleared of disease to prevent fungal extension into the adjacent structures.

Mucormycosis treatment requires a multidisciplinary approach owing to its widespread nature. Our team comprised of experts from various specialities:

Intensivist
Anaesthesiologist
ENT Surgeon
Ophthalmologist
Oral and Maxillofacial Surgeon
Microbiologist
Pathologist
Radiologist

We classified the patients into four categories based on disease progression. Radiological and histological investigations were carried out for the clinical assessment and staging of the disease. Staging the rhino-orbital mucormycosis patients in COVID-19 illness on this hierarchical model contributed to effective management of patients in terms of reducing the mortality.

Stage I: Involvement of the nasal mucosa

Stage I comprises the following based on anatomic localization:

Limited to middle turbinate
Involvement of the inferior turbinate or ostium of the nasolacrimal duct
Involvement of the nasal septum
Bilateral nasal mucosal involvement

Endoscopy guided nasal mucosal biopsy for culture and histopathology is indicated.

Stage II: Involvement of the paranasal sinuses

One sinus
Two ipsilateral sinuses
More than two ipsilateral sinuses and/or palate/oral cavity
Bilateral paranasal sinuses involvement or involvement of the mandible or zygoma

Endoscopy guided nasal and sinus biopsy was carried out for culture and histopathology for confirmation.

Stage III: Involvement of the orbit

Nasolacrimal duct, medial orbit, vision unaffected
Diffuse orbital involvement (more than one quadrant/more than two structures), vision unaffected
Central retinal artery or ophthalmic arterial occlusion, superior ophthalmic vein thrombosis; involvement of the superior orbital fissure, inferior orbital fissure, orbital apex, loss of vision
Bilateral orbital involvement.

Stage IV: Involvement of the CNS

Focal or partial cavernous sinus involvement and/or cribriform plate
Diffuse cavernous sinus involvement or cavernous sinus thrombosis
Involvement beyond the cavernous sinus, involvement of the skull base, internal carotid artery occlusion, brain infarction
Multifocal or diffuse CNS disease

For stage III and IV, assessment was done with endoscopy guided nasal mucosal, sinus and orbital biopsy wherever feasible for culture & histopathology.

Of the 74 patients, 16 patients required a second surgical intervention due to disease extension and osteomyelitis. Majority of the second stage procedures were performed for palatal osteomyelitis.

Anti-fungal Therapy

Shortage of liposomal Inj. Amphotericin-B was the main obstacle in the treatment of mucormycosis during the second wave of COVID-19. More than half of the patients were not administered intravenous liposomal Inj. Amphotericin-B. We maintained most of the patients on oral Posaconazole as a first line antifungal agent. However, there are emerging reports of salvage Posaconazole therapy for mucormycosis. Posaconazole in combination with amphotericin was a key strategy deployed and raised the survival rates in patients with rhino-orbital mucormycosis.

Prognosis

We performed cultures and microbiological examination in COVID-19 patients which yielded mixed mycological evidence. Out of the 74 patients, 58 patients had isolated growth of Mucormycosis sp., Rhizopus arrhizus. One patient had mucormycosis with angioinvasion. Three patients displayed evidence of combined Aspergillus fumigatus and Candida along with R. arrhizus. Mucormycosis and aspergillosis were reported in nine patients. We had three patients with a diagnosis indicating invasive aspergillosis.

Unfortunately, we lost six patients in the good fight. Our mortality rate was at 8.10%. We ascertained that the loss of these lives of our patients was due to the complications relating to the progression of COVID-19 illness, secondary infection and invasive mucormycosis infection.

Conversely, 2 out of 74 patients were vaccinated with only a single dose of vaccine. The remaining 72 patients had not been administered the vaccine.

Challenges

There are always obstacles and challenges to be faced when dealing with cure and therapy in a never before pandemic. One of our primary challenges in treating COVID-19 related Mucormycosis patients was the shortage of liposomal Inj. Amphotericin-B across the country. We had used oral Posaconazole to tide over the shortage of liposomal Inj. Amphotericin-B. Several published data have reported liposomal Inj. Amphotericin-B and Posaconazole to be effective against the treatment of mucormycosis.

The staging of disease progression helped us in rationalising the appropriate treatment for patients. In order to control this progression and to reduce the mortality in the absence of liposomal Inj. Amphotericin-B, we had to perform a second surgical exploration in patients for fungal clearance. Subsequently, nearly half of the patients required additional surgical debridement.

Conclusion

We conclude that the patients recovering from COVID-19 illness should be evaluated for mucormycosis and other secondary infections. Early diagnosis of mucormycosis with combined anti-fungal therapy and sequential surgery is the key for overall prognosis and the difference between life and death. Adequate glycaemic control is also of paramount importance. Public awareness about the fungal infection through various media platforms is necessary. Vaccination plays a vital role in providing protection against COVID-19. Patient education is an important tool for managing the COVID-19 and Mucormycosis infection in India.

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