COVID-19 Related Rhino-orbital-cerebral Mucormycosis in Jammu Province of Jammu and Kashmir

INTRODUCTION

The World Health Organization’s designation of COVID-19 as a pandemic came as a result of the escalating global case counts, which precipitated a significant increase in emergency hospital visits, patient admissions, and intensive care unit (ICU) placements. COVID-19, attributable to the SARS-CoV-2 virus, exhibits a diverse spectrum of clinical presentations, from mild symptoms to acute pneumonia. The disease is frequently complicated by secondary infections, including bacterial and fungal, due to dysregulation of the immune response.¹

Secondary bacterial and fungal infections in COVID-19 patients may develop due to underlying pre-existing health conditions or as nosocomial infections, such as ventilator-associated pneumonia. The pathophysiological mechanisms for these secondary fungal infections include extensive pulmonary injury and alveolar-interstitial damage induced by the virus, coupled with a reduction in T lymphocyte levels and disturbances in innate immune function.²

Mucormycosis, a rare but severe opportunistic infection caused by filamentous fungi in the Subphylum Mucoromycotina and the Order Mucorales, is associated with significant morbidity and mortality. These fungi are commonly encountered in surrounding environments such as soil, manure, decomposing organic matter, and airborne dust. Within the Mucorales order, Rhizopus is the most frequently identified genus, followed by Mucor and Lichtheimia, among its 11 genera and approximately 27 species.³ Mucormycosis is characterized by aggressive tissue necrosis due to invasive fungal proliferation and thrombosis of blood vessels. It is often associated with conditions like diabetes mellitus, neutropenia, organ or stem cell transplantation, traumatic injuries, burns, and hematological malignancies. The disease presents in various clinical forms, including pulmonary, gastrointestinal, cutaneous, and rhino-orbital-cerebral types. The rhino-orbital-cerebral form has become particularly notable during the pandemic and can be diagnosed through computed tomography (CT) scans of the nasal cavity and paranasal sinuses, as well as magnetic resonance imaging (MRI) of the brain.^4,5

In patients with COVID-19, mucormycosis can swiftly advance to affect the sinuses and lungs, with potential extension to the intracranial and intraorbital regions. This progression is exacerbated by COVID-19 symptoms—such as hyperthermia, altered osmolarity, and hypoxemia—which establish a conducive environment for the proliferation of Mucorales fungi.⁶

Mucormycosis has surfaced as a significant and severe complication of COVID-19, carrying a mortality rate of around 50%. India has been particularly impacted, accounting for 70% of global cases. During the second wave of COVID-19 in India, there was a marked surge in mucormycosis cases. By June 2021, the reported incidence included 2,245 cases in Maharashtra with 120 fatalities, 2,651 cases in Rajasthan with 85 fatalities, and 1,196 cases in Tamil Nadu.⁷

The prevalence of mucormycosis is often underreported due to several contributing factors: Its infrequent occurrence, declining rates of post-mortem examinations, sporadic use of confirmatory tissue biopsies for diagnosis, and a lack of comprehensive population-based research.⁸

This study seeks to elucidate the experience of our tertiary care center in managing Rhino-orbital-cerebral Mucormycosis in Jammu Province of Jammu and Kashmir, India, and to examine the demographic and clinical profiles of all cases presented.

MATERIALS AND METHODS

This cross-sectional descriptive study was carried out at the Department of ENT, SMGS Hospital, GMC Jammu, with ethical approval from the Institutional Ethical Committee. The study encompassed 19 patients with biopsy-confirmed mucormycosis from Jammu Province. Biopsies were obtained from necrotic regions of the turbinate or nasal septum through nasal endoscopy, for the period May 2021 to September 2021.

RESULTS

Our study included 19 patients with biopsy-confirmed mucormycosis. The mean age at presentation was 52.42 ± 3.77 years, with ages ranging from 22 to 79 years. The cohort comprised 11 males (57.9%) and 8 females (42.1%), yielding a male-to-female ratio of 1.4:1.

All 19 patients (100%) had a confirmed diagnosis of mucormycosis through tissue biopsy and exhibited aseptate fungal hyphae on potassium hydroxide test (KOH) smear. Each patient was a post-COVID-19 case (100%), with the average interval between COVID-19 diagnosis and mucormycosis detection being 19.11 ± 2.84 days.

Out of 19 patients, 11 patients (57.9%) had bilateral radiological involvement while 8 patients (42.1%) had unilateral radiological involvement. Out of 19 patients, 5 patients (26.3%) had brain involvement radiologically. Out of 19 patients, 11 patients had vision loss (57.9%).

Out of 19 patients, maxillary sinus was involved in all 19 patients (100%), ethmoidal sinus in 17 patients (89.5%), frontal sinus in 17 patients (89.5%), and sphenoid sinus in 17 patients (89.5%).

Out of 19 patients, all 19 patients (100%) had received steroids as per their COVID-19 treatment regimen. Out of 19 patients, all 19 patients had uncontrolled diabetes mellitus (100%). Besides diabetes mellitus, 6 patients had hypertension (31.6%), 2 had diabetic ketoacidosis (10.5%), and 1 had chronic kidney disease (5.3%).

Out of 19 patients, 18 patients (94.7%) were treated with initial medical management using liposomal amphotericin B, then by surgical management; 1 patient (5.3%) left against medical advice without receiving any treatment. Out of 18 patients, endoscopic sinus surgery was performed in 16 patients (88.9%) and maxillectomy in 2 patients (11.1%) with palate involvement. Orbital exenteration was performed in 1 case only (5.5%).

In all 18 patients, postoperative histopathological reports came out to be suggestive of Mucormycosis (100%).

On follow-up, out of 19 total patients, 6 patients died (31.6%) while 13 patients recovered (68.4%). The reason for death was cardiac arrest in 5 patients (83.3%) and sepsis in 1 patient (16.6). (Figs 1 to 4).

DISCUSSION

While the majority of COVID-19 patients experience mild to moderate respiratory symptoms, severe manifestations are more likely in the elderly and those with pre-existing health conditions. Secondary bacterial and fungal infections following severe COVID-19 are influenced by various factors including diabetes mellitus, existing respiratory disorders, use of immunosuppressive treatments, hospital-acquired infections, and systemic immune dysregulation induced by COVID-19 itself.⁹

In healthy individuals, the clearance of Mucorales is primarily managed by mononuclear and polymorphonuclear phagocytes with the generation of oxidative metabolites and defensins.¹⁰ However, in COVID-19 patients, lymphopenia exacerbates viral replication, leading to an increased influx of neutrophils and monocytes into the bloodstream. This disruption in the balance between neutrophils and lymphocytes heightens the susceptibility of COVID-19 patients to systemic fungal infections.¹⁰

Mucormycosis is a rapidly progressing condition where even a slight delay in diagnosis or treatment can have grave outcomes. The best results are achieved with the prompt identification of warning signs and symptoms, especially in individuals with active or recent COVID-19, combined with immediate and aggressive medical and surgical interventions. Critical warning signs to observe include nasal congestion, discharge (whether mucoid, purulent, or blood-tinged), erythema of the nasal mucosa, discoloration or necrosis, swelling or discoloration of the eyelids, face, or palate, facial pain, proptosis, ptosis, sudden loss of vision, restricted ocular movement, altered mental status, and focal seizures. Preventing mucormycosis in the context of COVID-19 necessitates careful and monitored use of corticosteroids and tocilizumab, stringent control of diabetes mellitus, and adherence to rigorous aseptic techniques during oxygen therapy, along with maintaining high standards of personal and environmental hygiene.

Our study examined 19 patients with biopsy-confirmed mucormycosis, with an average age of 52.42 ± 3.77 years, spanning from 22 to 79 years. These findings are consistent with the mean ages reported by Mishra et al.¹¹ and Pal et al.¹² which are 55.8 years and 53.3 years, respectively. The cohort comprised 11 males (57.9%) and 8 females (42.1%), resulting in a male-to-female ratio of 1.4:1, reflecting the male predominance observed by Sarkar et al.¹³ and Moorthy et al.¹⁴

All patients (100%) had both biopsy confirmation and positive KOH smear results for aseptate fungal hyphae. Each patient was a post-COVID-19 case (100%), with an average interval of 19.11 ± 2.84 days between COVID-19 diagnosis and mucormycosis detection. This duration is similar to the 15 days reported by Sen et al.¹⁵ though Pakdel et al.¹⁶ observed a shorter mean duration of 5 days. Factors contributing to mucormycosis development in post-COVID patients likely include compromised immune function, suboptimal glycemic control in diabetics, and delays in medical care due to lockdowns, potentially leading to increased diabetic ketoacidosis incidents.

Among the 19 patients, 11 (57.9%) exhibited bilateral radiological involvement, while 8 (42.1%) had unilateral involvement. Brain involvement was observed radiologically in 5 patients (26.3%). Vision loss was reported in 11 patients (57.9%). All patients (100%) had maxillary sinus involvement, 17 patients (89.5%) had ethmoidal sinus involvement, 17 (89.5%) had frontal sinus involvement, and 17 (89.5%) had sphenoid sinus involvement.

All 19 patients (100%) had been administered steroids as part of their COVID-19 treatment regimen, and all 19 (100%) had uncontrolled diabetes mellitus. Additionally, 6 patients (31.6%) had hypertension, 2 (10.5%) had diabetic ketoacidosis, and 1 (5.3%) had chronic kidney disease. Diabetes mellitus contributes to hyperglycemia, which can disrupt endothelial cells and trigger a cytokine storm, leading to multi-organ failure. In diabetic ketoacidosis, the acidic environment and elevated levels of free ferric ions promote the growth of Mucorales. Prolonged steroid use in COVID-19 patients induces severe lymphopenia and a steroid-induced diabetic state, thereby increasing susceptibility to secondary fungal infections.⁷ These observations align with the study by Sharma et al.,¹⁷ which also highlighted the significant role of steroids and diabetes in the pathogenesis of mucormycosis in COVID-19 patients.

Among the 19 patients, 18 (94.7%) were promptly treated with initial medical management using liposomal Amphotericin B, followed by surgical intervention. One patient (5.3%) left against medical advice before receiving any treatment.

Among the 18 patients, 16 individuals (88.9%) underwent endoscopic sinus surgery, while 2 patients (11.1%) required maxillectomy due to palatal involvement. This involvement generally arises from the disruption of neurovascular structures, such as the maxillary artery and its terminal branches, resulting in necrosis of the palatal mucosa and subsequent exposure of the underlying bone.¹³

Among the 18 patients, 16 individuals (88.9%) underwent endoscopic sinus surgery, while 2 patients (11.1%) required maxillectomy due to palatal involvement. This involvement generally arises from the disruption of neurovascular structures, such as the maxillary artery and its terminal branches, resulting in necrosis of the palatal mucosa and subsequent exposure of the underlying bone.

Orbital exenteration was performed in only 1 case (5.5%). This intervention was necessitated by radiological evidence of involvement of the pterygopalatine fossa, which likely facilitated the spread of infection to the maxillary nerve, subsequently extending via the infraorbital nerve into the orbit.

Histopathological examination of all 18 patients post-surgery confirmed a diagnosis of mucormycosis (100%). Among 19 total patients, 6 (31.6%) succumbed, while 13 (68.4%) recovered. The causes of death included cardiac arrest in 5 patients (83.3%) and sepsis in 1 patient (16.6%). The mortality rates in the studies of Fouad et al.¹⁸ and Mishra et al.¹¹ were 50 and 40%, respectively. The reduced mortality rate noted in our study can likely be ascribed to the prompt and early diagnosis of mucormycosis achieved through diagnostic nasal endoscopy and KOH smear, employed for patients exhibiting warning signs.

CONCLUSION

Mucormycosis, although infrequent, is an emergent fungal infection characterized by a high mortality rate. Clinicians must remain acutely aware of the risk for this invasive secondary fungal infection in patients with COVID-19, particularly those with pre-existing comorbidities such as poorly controlled diabetes or chronic renal insufficiency, as well as those receiving prolonged corticosteroid therapy. A robust multi-disciplinary approach is essential and should include targeted education on recognizing the early warning signs and symptoms of mucormycosis, expedited diagnostic procedures such as nasal endoscopy and direct microscopy of nasal swabs, and advanced imaging modalities including contrast-enhanced CT or MRI. This should be followed by aggressive treatment with full-dose liposomal amphotericin B and, when indicated, timely and appropriate surgical interventions.

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