Clinicoepidemiological study of acute invasive fungal rhinosinusitis in a tertiary care centre

INTRODUCTION

Coronavirus disease 2019 (COVID-19) is a new disease entity caused by a novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first documented in China in December2019 and subsequently causing a worldwide pandemic.¹ In second wave of covid it was observed that there was a notable surge in Acute invasive fungal rhinosinusitis (AIFRS). Coronavirus disease (COVID-19) causes an immunosuppressed state and increases risk of secondary infections like mucormycosis.² AIFRS is a potentially fatal infection that is remarkably found in comorbid, immnocompromised patients and considered the most aggressive subtype of fungal sinusitis with subsequent serious morbidity and mortality. AIFRS defined as presence of tissue invasion by fungal elements over an acute clinical course of less than 4 weeks. AIFRS is a time-sensitive condition that must be recognized and treated promptly to avoid life-threatening complications. Secondary infections occur mainly after severe disease and in ICU treated cases of COVID-19 comprising around 10–30% of cases. According to the Epidemiology of Mucormycosis in India reported in 2021, the estimated prevalence of Mucormycosis was at an alarming rate of nearly 70 times higher than the global data. The incident rate of mucormycosis varies from 0.005 to 1.7 per million population.³ The main objective of this study is to evaluate about the different clinical and epidemiological features of AIFRS patients in our tertiary care centre.

METHODS

In February 2021 we observed a notable surge of AIFRS in COVID-19 patients. This retrospective observational study was done in 136 patients from February 2021 to August 2021.Patients selected in our study were diagnosed with acute invasive fungal sinusitis clinically and radiologically.

Inclusion criteria

Subjects included in study were clinically and radiologically proven cases of AIFRS. All patients enrolled underwent detail history taking, clinical examination, nasal endoscopies and radiological evaluation.

Exclusion criteria

Pregnant patients were excluded in our study.

This study was approved by institutional ethical committee. The statistical data was entered in MS excel 2007 and analysed using Statistical package for social sciences (SPSS) 16.0 version. In current study 78.67 % patients had history of recent covid infection with definite diagnosis of covid 19 confirmed on polymerase chain reaction. Both prompt surgical debridement with antifungal medications along with treatment of any associated comorbidity was done in all patients. Antifungal therapy was the prime line of management in patients proven on evaluation. Injection liposomal amphotericin B (5 mg-10/kg), depending upon the severity and extension of disease and associated comorbidity, the dosage were calculated, along with timely regular assessment of blood parameters, to rule out toxicity of drugs. Patients were discharged on Tablet Posaconazole which was continued till clinical and radiological clearance of disease. Postoperative treatment included nasal saline irrigation thrice a day for at least 3 months. In cases with bacterial coinfection, systemic antibiotic therapy was administered on the basis of nasal swab culture sensitivity. All patients were prospectively followed up through endoscopic monitoring performed within 7 days intervals and continued till 3 months after surgery.

RESULTS

In our study of 136 patients 97 were males (66.91%) and 39 were females (28.67%). 78.67% patients were diagnosed with AIFRS in relation to COVID-19 infection. All patients were diagnosed in the recent post COVID-19 infection period, with maximum patient 52.20% affected after 1 week of COVID infection.

The maximum no. of patients were in 51-70 age group i.e., 52.94%, followed by 41.91% in the age group of 31-50 years. Demographic data associated co-morbidities is mentioned in table 1.

The most common associated comorbidity was diabetes mellitus seen in 74 patients, out of which 21 patients had recent onset DM caused after corticosteroid treatment given during COVID-19 treatment. Other associated comorbidities were hypertension (18.38%), chronic kidney disease (10.29%), for whom regular nephrologist consultation was taken. Four Patients of chronic renal disease were on dialysis, out of which 2 patients had history of renal transplant. In our study 21.32% patients were covid negative with no history of any COVID admission but were diagnosed to be comorbid with uncontrolled diabetes mellitus.

In current study maximum patients presented with features within 1 week (52.20%), out of which 24 patients were with active COVID infection (17.64%). In study of Selarka et al mean time elapsed from COVID-19 diagnosis to mucormycosis was 12.1±4.6 days, and eleven (23.4%) subjects succumbed to their disease, mostly (n=8, 72.7%) within 7 days of diagnosis.⁴

Out of 136 patients, 107 patients (78.67%) were documented positive for covid.88 patients (64.70%) were on Steroid treatment and 9 patients in our study had received the covid vaccine out of which 4 patients had taken one dose only. In study of Selarka et al, majority suffered from diabetes mellitus (n=36, 76.6%). Most were not COVID-19 vaccinated (n=31, 66.0%).⁴

Once AIFRS is suspected, a nasal endoscopy is essential to evaluate the signs of fungal involvement. Pale mucosae, ulcers, and granulation are present in up to 75% of patients examined by endoscopy.⁵ Endoscopic findings and MRI contrast scan showed various stages of sinonasal (100%), palatine (39.70%) orbital (35.29%), and cerebral (13.23%), involvement. MRI with gadolinium contrast is necessary in order to rule out the suspected invasion of paranasal sinus fungal ball to the surrounding structures, such as cavernous sinus, intraorbital and intracranial compartments, or remodelled bony walls.⁶ On MRI images, fungal ball usually appears as an intrasinusal mass that is iso- or hypointense on T1-w and markedly hypointense on T2-w.The lowered signal intensity on T2-w, which can extend as far as to a signal void, is caused both by high iron and manganese concentrations and the presence of calcium under the form of microcalcifications, which have all been noted as the characteristic features of AFRS.^7,8 The contents of calcium and heavy metals, such as iron, zinc, and manganese, within fungal hyphae most prominently affect the appearance of FB on both CT and MRI imaging.⁹

In our study, maximum patients presented with complaints of facial pain (66.91%), palatal changes were seen in 45.58% patients, dental pain in 36.02%. Patients with orbital involvement had complaints of pain and sudden diminution of vision (17.64%), proptosis in 13.23% patients. Three patients presented with altered sensorium because of intracranial extension of disease, and one presented with change in voice due to laryngeal involvement. One case had necrosis of cheek area where skin involvement was seen.

Controversy remains regarding the classification of fungal rhinosinusitis, however the most accepted categorization of this entity was proposed by deShazoet al who differentiated fungal rhinosinusitis into noninvasive and invasive forms based on histopathological findings.¹⁰ Histopathological evaluation of mucosal biopsies in our study confirmed that the main causative fungi were Mucor species in 68.38% and Aspergillus fumigatus in 1.47% while nine patients (6.61%) were infected with both. The remaining 32 patients (23.52%) were negative on hematoxylin and eosin staining, periodic acid Schiff, Gomori and methenamine silver staining for mucormycosis, but were strongly positive, clinically and radiologically. Histopathological evaluation of these patients who were negative for mucor showed abundant necrosis, osteomyelitis of bone and inflammation, however their tooth scrapings were positive for fungal element.

Mycological tissue culture is also helpful in evaluating AIFRS as it can determine the fungi species and direct the antifungal drug sensitivity. However, it does not show invasiveness of mucosa and, therefore, cannot establish the definitive diagnosis of AIFRS.

Moreover, it usually takes a minimum of 7-21 days to obtain the results, and a significant number of negative results is expected.^11,12

In current study the commonest predilection was lateral nasal wall with maxillary involvement (82.11%) with ethmoid (78.86%) and sphenoid (61.6%) sinuses being the most commonly affected sinuses. Orbital involvement showed evidence of subperiosteal abscess in 14 patients (10.29%), extension of inflammation giving symptoms of orbital apex syndrome (21.79%). Among 18 patients with intracranial extension, 7 patients had cavernous sinus thrombosis, 3 cases had involvement of anteromedial temporal lobe, Clivus along with meckels cave was involved in 3 cases, fronto parietal lobe along with involvement of cortical and subcortical region enhancement in three patients. One patients had involvement of left cerebellar hemisphere with edema of 4th ventricle.

Injection liposomal amphotericin B was given to all patients with an induction dose ranging from 5-10 mg/kg till a cumulative dose of 2.5 gm and further till clinical and radiological clearance of disease and also according to extent of disease, along with nephrologist consultation and regular monitoring of serum creatinine and serum electrolytes. All patients were discharged on tablet Posaconazole till post op biopsy negative for fungal element. Surgical approach was purely endoscopic in 78 patients, combined endoscopic and open approaches were utilized in the remaining 58 patients. Debridement of necrotic tissues is important in AIFRS patients since the removal of devitalized tissue increases the ability of antifungal drugs to reach infected areas, reducing the fungal burden and slowing the progression of the disease. Also, this action is not only local, since it reduces the stress on the development of neutrophils, facilitating bone marrow recovery.¹³

Endoscopic Debridement included resection of the middle turbinate, wide middle meatal antrostomy, ethmoidectomy, sphenoidotomy, and modified denkers approach in some cases according to the involved sinuses. Orbital involvement in this case series was managed by a wide variety of surgical approaches including endoscopic evaluation of subperiosteal abscess, orbital decompression. Neurosurgery was consulted for operative intervention in the cases of intracranial extension. Palatal necrosis was managed by maxillectomy according to extension of disease and necrosis. Skin necrosis due to invasive fungal infection was managed by debridement only.

Overall survival in our study was 88.23%. Sixteen patients succumbed (11.76%), out of which 2 patients had extensive intracranial extension. Redebridement was needed in 24 patients, out of which 4 patients needed multiple debridement.

DISCUSSION

Mucormycosis is opportunistic fungal infection characterized by infarction and necrosis of host tissues that results from invasion of the vasculature by hyphae. ¹ Tissue necrosis, often a late sign, is a hallmark of mucormycosis, resulting from angioinvasion and vascular thrombosis. The fungi responsible for mucormycosis belong to the order Mucorales and are saprobes found in decaying matter and soil. The fungal sporangiospores enter the human body mainly by inhalation and less commonly by ingestion or direct inoculation. The large spores (example- Rhizopusarrhizus) commonly settle in the upper respiratory tract, while the smaller spores (for instance, Cunninghamella) reach the lower respiratory tract .¹⁴

The present study was carried out in department of Ear Nose Throat, Government Medical College, Akola from February 2021 to august 2021. The main purpose of this study was to evaluate the different clinical, radiological features, and the outcome of prompt surgical intervention along with antifungal treatment. Aspergillus and Mucorales account for the majority of cases of AIFRS. COVID19 associated the onset of diabetes, and diabetic ketoacidosis (DKA) has been precipitated in newly diagnosed diabetes following COVID-19. Severe COVID-19 increases insulin resistance through enhanced secretion of stress hormones (cortisol and others) and cytokines.¹⁵ The most common clinical presentation of mucormycosis is rhino-orbital-cerebral infection, believed to be secondary to inhalation of spores into the paranasal sinuses of a susceptible host.¹⁶ Studies on SARS-CoV and SARS-CoV-2 have shown that both viruses belong to the same species and have similar biological and clinical characteristics.¹⁷ In immunocompromised patients, these fungi can be angioinvasive, resulting in thrombosis and ischemia of the nasal mucosa.¹⁸ In our study we found predominance of mucorale species in 93 patients (68.38%), and aspergillus was found 2 patients (1.47%),whereas mixed species was found in 9 patients (6.61%). Kasapoglu et al also reported a predominance of Mucorale involvement.¹⁹ The conventional risk factors for invasive mold infections include neutropenia, hematological malignancies, solid organ transplantation, hematopoietic stem cell transplant, immunosuppressive therapies targeting T-cells (calcineurin inhibitors, tumor necrosis factor inhibitors, lymphocyte-specific monoclonal antibodies, prolonged use of corticosteroids at a dose of 0.3 mg/kg for 3 weeks in the past two months, and certain inherited immunodeficiency diseases.²⁰

In present study most common associated comorbidity was Diabetes mellitus seen in 54.41% patients, out of which 15.44 % were recently diagnosed with diabetes mellitus after use of corticosteroid in covid infection. Diabetes mellitus was the most common underlying risk factor for Covid 19 associated mucormycosis in India than in other countries.² In other pre-COVID pandemic studies, the most common concomitant disease was also DM.^21,22 Diabetes mellitus is a risk factor for severe COVID-19 and is associated with increased mortality due to COVID-19.²³ Diabetes impairs innate immune function by impairing phagocytic function, which significantly improves following glycemic control.^24,25 Further, impaired dendritic cell responses delay the timely activation of adaptive immune responses.²⁶ Many fungal species, Rhizopus, Mucor, Rhizomucor and Aspergillus, were reported to cause AIFR.²⁷ Most studies reported mainly the Mucorales species.^21,28

In current study, most of the patients had complaints of facial pain (66.91%), palatal changes (45.58%), nasal obstruction (41.91%), dental pain (36.02%), diminution of vision (17.64%), proptosis (13.23%), facial swelling (16.17%). Ketenci et al reported fever, facial edema, facial pain, and nasal obstruction as the most frequent symptoms.²⁹ In study of Werthman-Ehrenreich et al seventy percent of rhino-orbital-cerebral mucormycosis cases have been found to be in patients with diabetes mellitus, most of whom had also developed ketoacidosis at the time of presentation.¹ Infection usually presents with acute sinusitis, fever, nasal congestion, purulent nasal discharge and headache. All the sinuses become involved, and contiguous spread to adjacent structures such as the palate, orbit, and brain results in clinical symptoms.¹

Orbital compartment syndrome (OCS) results from an expansile process within the closed compartment of the orbit leading to increased orbital pressure, and potentially resulting in ischemia and vision loss.¹ This diagnosis should be suspected in patients presenting with acute proptosis, elevated intraocular pressure, sudden vision loss, ophthalmoplegia, fixed dilated pupil or afferent papillary defect. Causes of OCS can be retrobulbar hemorrhage (from trauma, vascular malformations, tumors), cellulitis or other infection, orbital malignancy, or previous orbital surgery.³⁰ In current study orbital involvement and intracranial extension were seen 35.29% and 13.97% patients, most of whom had uncontrolled diabetes mellitus. A multi-disciplinary approach was taken for patients with involvement of orbit and palate along with senior ophthalmologist and oro maxillofacial surgeon, and radiological. Transcutaneous retrobulbar inj Amphotericin B was given in all acute invasive fungal rhinorbital sinusitis by ophthalmologist. Improvement was seen in 30.14% cases after orbital decompression endoscopically. Orbital and intracranial extension is associated with an increased risk of death. In study of Payne et al 32.5% of patients needed at least one revision surgery.³¹ Wheareas in our current study revision debridement was needed in 17.64% cases , and multiple redebridement were needed in 2.94 %. These patients were had other associated comorbidity like uncontrolled DM, multisystem involvement.

Mortality has been reported to range from 20% to 68% in previous studies.^32,33 In our study mortality rate was found to be 11.76%. The fatality rate of cases reported from India (36.5%) was less than the globally reported cases (61.9%), probably due to the predominance of rhino-orbital mucormycosis.² According to The US Centre for Diseases Control and Prevention

(CDC), an overall all-cause mortality rate of 54% was reported for mucormycosis. The global mucormycosis case fatality rate is 46 percent.³⁴

The mortality rate depends upon the underlying condition of the patient, fungus type, and affected site in the body (for example, the mortality rate reported was 46% for patients with sinus infections, 76% for pulmonary infections, and 96% for disseminated mucormycosis).³⁵

Limitations of study

This study is limited to patients admitted in our tertiary care centre. The pathophysiology of AIFRS in non-diabetic patients, non-hospitalised covid patients with no history of systemic corticosteroids use also remains unclear and needs further research.

CONCLUSION

Early diagnosis and treatment are essential, as a delay of even 6 days is associated with a doubling of 30 day mortality from 35% to 66%. A Histopathological study faciliates the confirmation of diagnosis, however frozen section biopsy is more desirable for early intervention and management of AIFRS. The difficulty and delay in diagnosing Mucormycosis affects the outcome of the disease and may lead to poor prognosis because of its high invasiveness and its intrinsic low susceptibility to antifungal agents. Therefore, early diagnosis and treatment are necessary. Prompt early surgical debridement with adequate dosage of liposomal Amphotericin B, facilitates early discharge and prevent fatal complications.

ACKNOWLEDGEMENTS

As it is said that, gratitude, when expressed in words, it’s only half its acknowledgement. Having searched extensively through the pages of therausus and oxford, I could not find the words to express my thanks with a great sense of gratitude to my respected teacher and guide Dr. Apurva Pawde, Professor and Head, Department of ENT; Dr Rajeshree Chaurpagar, Associate Professor, under whose guidance and supervision, I had the opportunity to carry out this work. I am also grateful to Dr Parag Doifode, Assistant Professor, Dr. Bhagyashree Chiplunkar, Assistant Professor, for their constant support and encouragement, Dr Mohammed Badarul Muneer, PG Resident for providing a helping hand which led to completion of this work. I bow in gratitude to the The almighty God for inspiring me for this humble attempt to publish the article and serve the society.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: The study was approved by the Institutional Ethics Committee

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