Introduction

Coronavirus diseased 2019 (covid19) caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has been associated with a wide range of opportunistic fungal and bacterial infection [1]. Coronavirus disease (COVID-19) causes an immunosuppressed state and increases risk of secondary infections like mucormycosis [3]. Both aspergillus and Candida have been reported as the main fungal pathogen for co-infection in people covid-19. Recently, several cases of Mucormycosis in people with covid-19 have been increasingly reported in Worldwide, particularly from India. The primary reason that appears to be facilitating Mucorales spores to germinate in people with covid-19 is an ideal environment of low oxygen (hypoxia), high glucose like DM, new onset Hyperglycemia, steroid-induced hyperglycemia, acidic medium metabolic acidosis, diabetic ketoacidosis (DKA), high iron levels (increased ferritins) and decreased phagocytic activity of white blood cells (WBC) due to immunosuppression (sars-cov-2 mediated, steroid-mediated or background comorbidities) coupled with several other shared risk factors including prolonged hospitalization with or without mechanical ventilators.

Mucormycosis is a fungal infection caused by a group of microorganisms belonging to the phylum glomeromycotan. Mucor mycosis is a rare, opportunistic, highly fatal fungal infection that typically occurs in individuals with underlying compromising conditions, such as diabetes mellitus, corticosteroid use, hematologic malignancies, neutropenia, solid organ/allogeneic stem cell transplants, primary immunodeficiency, and treatment with immunosuppressants. Nevertheless, such infections can be found in apparently immunocompetent patients, although these cases are extremely rare. After second wave of covid 19 disease there is notable surge in cases of fungal rhinosinusitis. Non-judicious use of steroids leads to extended immunocompromised state. The disease originated from nasal and sinus mucosae after inhalation of fungal spores and extended to neighboring structures. The standardized definition of acute invasive fungal rhinosinusitis (AIFRS) includes presence of tissue invasion by fungal elements over an acute clinical course of less than 4 weeks. According to the epidemiology of Mucormycosis in India reported in 2021, the estimated prevalence of Mucor mycosis 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 [4]. The purpose of this study is to describe clinic-epidemiology of patients of AIFRS reported in our center and their surgical complications encountered.

Method

It is retrospective study, from February 2021 to April 2022 done in tertiary care center, Government medical college Akola. Approval was taken from ethical committee of government medical college Akola. Written and informed consent was taken from all patient for participation in the study. Confidentiality of patients maintained.

Detailed history noted and thorough clinical examination (including oral cavity and ophthalmologic examination) were done for all patients clinically suspicious of AIFRS. All patients underwent rigid nasal endoscopic examination at time of presentation, and nasal biopsy or swab for KOH and fungal culture was taken. Necessary radiological investigation (CT contrast PNS with orbit and/or MRI PNS with orbit and Brain) was done. All patients underwent surgery and tissue sample send for histopathological examination.

Inclusion Criteria

Histopathologically & Microbiologically (KOH & fungal culture) Proven AIFRS

All patients were treated with Injectable antifungal (Inj. liposomal amphotericin B 5–10 mg/kg)) and oral antifungal (Tab/syrup Posaconazole) depending on severity and extension of disease. During treatment course their predisposing factors (associated comorbidities) were treated accordingly. Regular hematological examination was done to check for nephrotoxicity due to use of Amphotericin B and doses adjusted accordingly.

Based on endoscopic and imaging findings patients underwent different surgical debridement. During surgery, all necrotic tissue was removed down to the level of viable tissue. In addition, all involved sinuses were opened to facilitate drainage of fungal elements. Any suspicious tissue was examined and sent for histopathology and microbiology examination.

Patients were observed for surgical complications encountered during intraoperative and post operative period till 6 months. Post-operative nasal endoscopy was conducted, under local anesthesia, in order to remove crusts and to examine the nasal and sinus cavities for recurrence, until healing was complete. Any patients with recurrence underwent repeated surgical debridement.

Results

Total 160 patients were screened who showed clinical symptoms suggestive of AIFRS. Out of which only 146 patients were included in our study depending on their microbiological and/or histopathological report.

In our study group, out of 146 patients 98 were male and 55 were females. Male to female ratio was 1.7:1.

In this study youngest patient was of age 12 years and oldest one of 88 years. Most affected age group found was between 40 and 60 years. There were 4 patients who were less than 20 years of age, 28 patients were between 21 and 40 years, 74 patients between 40 and 60 years, 52 patients were between 61 and 80 years and only 2 patients were above 81 years.

107 (78.6%) patients had history of COVID 19 and had treated for same. Out of these 107 documented positive cases of covid-19, 97 (90.6%) patients were received steroids (injectable and/or oral) during their hospital stay for covid-19.

Comorbidities of all patients noted. In our study we found most patients were of Diabetes mellitus (98). Other comorbidities like hypertension (46), chronic kidneydisease (14), hypothyroidism (3), renal transplant (2), heart disease (2) & meningioma (1), leukemia (1) was found. Among 98 diabetes mellitus patients 21 were recent onset DM caused by corticosteroid therapy given during COVID-19 as a part of treatment. (Table 1).

Table 1 Comorbidities in patients
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Patients presented with different clinical symptoms (Table 2). Facial pain was the most common 105 (71.91%) presenting complaint, followed by palatal involvement in the form of mild swelling to blackish discoloration to palatal perforation 72 (49.31%) (Fig. 1). Nasal obstruction and discharge 64 (43.83%), dental pain 71 (48.63%), headache 40 (27.39%), facial swelling 24 (16.43%), altered sensation 3 (2.05%) were the other symptoms. Orbital symptoms include diminution of vision 28 (19.17%), proptosis 18 (12.32%), Diplopia 8 (5.47%), periorbital abscess 2 (1.36%) (Fig. 2).

Table 2 Clinical presentation and symptoms
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Fig. 1
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Different clinical presentation of palatal involvement in AIFRS (mucormycosis)

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Fig. 2
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Ophthalmic involvement in AIFRS

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Depending on radiological findings patients were categorized into different groups. Sinuses involvement by disease were seen in all patients (146). Only 23 (15.75%) patients have disease limited to paranasal sinuses. The common site of extra sinus involvement was face and palate 72 (49.31%) and orbit 38 (26.02%) followed by orbital apex, masticator space, pterygopalatine fossa, skull base, cavernous sinus, brain and internal carotid artery. Further details of extra sinus extensions given in (Table 3).

Table 3 Extra sinus extension of disease
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According to extension of disease patients were posted for surgical procedures. During surgeries all necrotic tissues were remove down till viable tissue level, all involved sinuses were opened to facilitated drainage of fungal element and suspicious tissue was examined (Table 4).

Table 4 Surgeries performed
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During procedure most common complication faced intraoperatively was bleeding. We classified blood loss as per American college of surgeons advanced trauma life support (ATLS) classification class I to IV. Class I up to 750 ml, class II 750 to 1500 ml, class III 1500 to 2000 ml, class IV more than 2000 ml. Class III class IV needs blood transfusion. (Table 5).

Table 5 Intra-operative complications
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CSF leak was seen in 6 patients. Intra-operative leak was seen in 5 patients which was immediately managed surgically. One patient had leak in postoperative period which was detected after pack removal and thereafter surgically managed.

Nasolacrimal duct trauma was seen in 3 patients and orbital hematoma in 1 patient. In Denker’s procedure nasolacrimal ducts were deliberately cut as part of surgery, these patients are excluded from nasolacrimal duct trauma. These patients do not develop post operative epiphora.

Post operatively most common complication was synechiae found in 82 patients (56.16%). 12 patients had significant symptomatic synechia which were causing nasal obstruction or osteomeatal complex (OMU) block who required surgical intervention to facilitated sinus clearance and to relieve nasal block, rest of 60 patients did not have any symptoms related to synechia and found only during their postoperative endoscopic examination.

Oroantral fistula (OAF) in 67 patients (45.89%) noted. In 18 patients OAF seen intra-operatively and 49 patients developed post operative OAF (Fig. 3).

Fig. 3
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Oroantral fistula

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Facial deformity was seen in 54 patients due to maxillectomy, hypoesthesia/loss of sensation on face was seen in 37 (25.34%) patients. Diminished vision in 24 (16.43%) and diplopia in 8 patients (5.4%) 0.14 patients had given complaints of earache/ear fullness which was managed by oral and local decongestants and over a period those symptoms resolved. 38 patients had headache, 67 patients complaint of hyposmia and 54 had anosmia. Least common complication found was periorbital ecchymosis i.e., in one patient.

24 patients required repeated debridement owing to extensive involvement of disease and lack of preanesthetic fitness due to which debridement could not be done in single surgery. Also, intolerance to injection amphotericin-B was one of the causes for residual disease in patients. Recurrence of disease was seen in 3 patients. 3 patients succumbed to death due to extensive disease and their comorbidities. (Table 6).

Table 6 Post operative complications
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Post operative complications were more common than intraoperative complications. All these complications were irrespective of their amphotericin dosage.

In our studies Mucorale found in 132 patients, aspergillus in 4 patients and mixed species in 10 patients (Fig. 4).

Fig. 4
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Fungal species microscopic view

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Discussion

Corona virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome. Coronavirus-2 (SARS-CoV-2) first documented in December 2019 in China, and over the period worldwide as pandemic. Globally, as of May 19, 2021, there were 163,869,893 confirmed cases of COVID-19, including 3,398,302 deaths as have been reported to WHO [8]. Numerous evidences are available that show that COVID-19 infection increases the risk of a patient to acquire secondary fungal infections. [5,6,7]. In India with second wave of covid-19 there was sudden notable raised in acute invasive fungal rhinosinusitis (AIFRS) among patients who are suffering or taken treatment for COVID-19 infection (Fig. 4).

Coronavirus disease causes immunosuppressed state in patients which increases the risk of secondary fungal infection like mucormycosis [2]. COVID-19 associated with onset of diabetes and diabetic ketoacidosis (DKA) due to prolong use of systemic or oral steroids and antibiotics in treatment of COVID-19. Severe COVID-19 increases insulin resistance by increased secretion of stress hormones (cortisol and others) and cytokines [9]. Moorthy et al. [15] recently reported the association of COVID-19 infection with uncontrolled DM and usage of corticosteroids. Mucormycosis most commonly seen in already known diabetes mellitus patients and patients with uncontrolled blood sugar level at presentation, [10] In our study, we also found that diabetes mellitus with uncontrolled sugar levels was most common co-morbidity (67.12%).

Other risk factors which increase susceptibility of an individual to mucormycosis include neutropenia, protein-calorie malnutrition, solid organ and bone marrow transplant, immunodeficiency, leukemia. Dialysis and iron overload patients treated with deferoxamine B (DFO), an iron and aluminum chelator, are also found more susceptible to mucormycosis [16]. Mucor produces keto-reductase as a virulence factor enabling them to grow in the acidic and glucose-rich environment generated in ketoacidotic states [6, 12,13,14]. Additionally, Müller et al. [21] have postulated that the human pancreas could be a possible target for the SARS-CoV-2 virus and that the β-cell infection may result in insulin resistance. This metabolic dysregulation, in previously nondiabetic or well-controlled diabetic COVID-19 patients, might predispose them to develop mucormycosis.

In our study mucormycosis is most commonly seen in middle aged population i.e., 40–60, it may be because of high prevalence of comorbidities in this age groups which is similar to the studies done by Dave et al. study [20] and Ravani et al. [10]. Kasapoglu et al. [22] reported predominance of Mucorale species, in our studies mucorale was most commonly found fungal species which almost contributed to 90.41% of sample.

Following the inhalation of fungal spores present in the environment, the fungi colonize and infect the nasal or sinus mucosa first, before spreading to surrounding anatomical areas including the orbit, cavernous sinus, and brain. The infection consists of angioinvasion by the fungal hyphae, vascular thrombosis, and tissue necrosis [23]. The clinical hallmark is tissue necrosis manifested as a necrotic lesion, eschar, or black discharge in the nasal or oral cavity.

Orbital involvement results from spread through the nasolacrimal duct and medial orbital wall. Imaging helps in assessing the extent of disease, identification of complications like ICA thrombosis and is indispensable for surgical planning [17]. Mnif et al. and Herrera et al. have previously shown that the disease causes aggressive sinonasal and orbital changes on imaging [18, 19]. Mohindra et al. has shown that MRI can detect cavernous sinus invasion and vascular complications such as thrombosis and ischemia [24]. Patients initially present with sinonasal involvement which later spread to the orbits, masticator space, face, pterygopalatine fossa, hard palate, maxillary alveolus, zygomatic process, skull base involving the clivus and pterygoid process and intracranial extension to involve the cavernous sinus, internal carotid artery and cerebral hemispheres. We also found similar pattern of spread of disease.

Although several routes for the extension of mucormycosis exist, we propose the pterygopalatine fossa as the main conduit for extension to other sites. Following invasion of the pterygopalatine fossa and inferior orbital fissure, thrombosis of regional vessels occurs. This results in edema of the eyelid and chemosis, frequently the first signs of the disease. The infection rapidly extends into the retrobulbar space and orbital apex, causing proptosis which is seen in 12.32% of patient in our study. Invasion into the optic nerve and/or central thrombosis of the retinal artery results in visual loss. Diplopia was noted in 5.47% of patients due to paralysis of the ocular muscle may occur due to infiltration of the retrobulbar and extra-ocular muscles. This paralysis is usually complete, though at times it may be selective. Paralysis and paresthesia of the face were found in usually due to infiltration of the facial muscles by the mucor in our study [11].

CT predominantly showed minimally enhancing hypodense sinonasal soft tissue which was either isodense or slightly hypodense to surrounding masticator muscles. As Silverman et al. described, presence of retroantral, facial and orbital fat stranding indicated the aggressive nature of the infection [25]. In our studies with radiological imaging the site of extrasinus involvement found in face and palate as soft tissue infiltration and fat stranding and lytic destruction or erosion of palatal bone. In orbit as orbital cellulitis, optic neuritis, extension of soft tissue into extraconal space, thickening and edema of rectus muscles. Soft tissue infiltration and fat stranding in orbital apex. Fat stranding in pterygopalatine fossa and infratemporal fossa, cavernous sinus partial or complete thrombosis, internal carotid artery thrombosis, brain changes like meningeal enhancement, cerebritis, infarcts, abscess, etc. was found. As per Jacob Therakathu et al. studies CT and MRI are invaluable tools which are complementary to clinical evaluation in assessing the extent of disease and diagnosis of complications.

In this study most common complication of endoscopic sinus surgery was bleeding. In mucormycosis fungi invades surrounding blood vessels and causes thrombosis and infarction and necrosis of tissue. Although bleeding should be less expected in mucormycosis due to necrosis diffuse bleeding is sign of viable tissue. In our study we found diffuse bleeding in 129 patients and severe bleeding was found in 7 patients due to involvement of major blood vessels like maxillary artery which required debridement.

Major complication was CSF leak, Intra operative CSF leaks were treated using allogenic connective tissue like middle turbinate in 1 patient and fascia Lata in 1 patient, and by cauterization in 3 patients. In 1 patient CSF leak was diagnosed postoperatively and thus managed by surgical interventions. In all patients fibrinogen glue was used. These CSF leak found in patients with extensive skull base involvement by disease.

Post operatively small OAF developed due to either give away of sutures or infection over suture site and they were managed by antibiotics and re-suturing. Due to extensive palatal necrosis and lack of healthy surrounding tissue for approximation after total maxillectomy intra-operative large OAF developed in some patients which were managed either by dental prosthesis given by maxillofacial surgeon or by plastic surgeons by local flaps.

During extensive debridement surgeries, there were large raw areas left behind which led to synechiae formation post-operatively. We found that these synechiae helped our patient, as they overcome ill effects of drying and crusting by making nasal cavity less exposed to drying effects of air currents, it helped in reducing crust formation and promoted mucosal healing. In some of our patients synechiae formation leads to obliteration of OMU and nasal blockage, such symptomatic synechiae divided endoscopically under local anesthesia.

Other minor surgical complications like hypoesthesia, anosmia, dental pain and facial pain, etc., were inevitable because extensive surgery performed due to aggressive nature of disease spread.

Management had three aspects: firstly, control of the underlying disease; secondly, systemic antifungal therapy (amphotericin B); thirdly, the surgical debridement of dead tissue.

The amphotericin-B drug is fungistatic, usually at dosage of around 0.5–1 mg/kg for conventional amphotericin-b. Unfortunately, renal impairment can occur at these doses and other toxic effects include hypokalemia, hepatic impairment, fever and chills. Due to toxicity of conventional form of amphotericin-b, liposomal amphotericin-b was preferred over it and was given in dosage of 3–5 mg/kg for duration depending on severity and extensive nature of disease also considering compliance of patient to drug. The mechanism of action of the drug complex is considered to be an enhancement of intracellular delivery of the drug to phagocytes, although several other mechanisms may be simultaneously active. Oral antifungal Posaconazole was given as salvage treatment in dosage of 300 mg twice a day on day 1 followed by 300 mg once a day for 2–3 weeks.

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 [3]. In our studies mortality death was 2.05% We focused on post operative deaths which were 3 due to disseminated nature of disease. The mortality rate depends upon the underlying comorbid condition of the patient, aggressive nature of involved fungus, and extensive nature of disease.

Conclusion

Mucormycosis is an aggressive fungal infection which can lead to fatal complications in immunocompromised patients if not managed promptly and energetically. Powered endoscopic debridement is efficient and feasible, leading to excellent local control and which ultimately led to reduced morbidity and mortality. Early diagnosis and treatment are essential in AIFRS patients. Histopathology study facilitate the confirmation of diagnosis. Prompt surgical debridement of devitalized tissue and early adequate dosage of antifungal (inj. Amphotericin-b) treatment are necessary as delay in surgical debridement and treatment can worsen the prognosis of disease. Among all complications faced maximum were manageable with early interventions but few of them were inevitable due to extensive nature of disease.