Clinico-Pathological Study of Invasive Fungal Sinusitis in Ibadan, Nigeria: A Case Series

Background: Invasive fungal sinusitis is one of the less common forms of fungal infection more commonly described in North Africa and Asia. It affects healthy and immunologically competent individuals typically compli-cating chronic rhinosinusitis. Surgical debridement and adjuvant antifungal treatment are the mainstay of management of this condition. Objective: To describe the clinical presentation, pathological features and management of patients with invasive fungal sinusitis managed at a tertiary health facility, southwestern Nigeria. Method: Medical records of all patients with invasive fungal sinusitis managed between January 2009 and December 2018 were retrospectively reviewed. Results: Six patients with invasive fungal sinusitis were managed during the study period. All patients were immunocompetent and the mean age at presentation was 30.7 years ± 7.2 years. The average duration of symptoms prior to presentation was 18.5 months (Interquartile range, 67.5 months), and all six patients had orbital involvement and intracranial extension of the mass at presentation. They all had surgical debridement, and the specimens were sent for histological examination. Mycological studies carried out on two specimens isolated Aspergillus fumigatusas the fungal agent and all patients were started on post-operative oral antifungal chemotherapy. Five patients completed their chemotherapy and fared well with no recurrence while one patient had irregular and incomplete antifungal treatment, and developed recurrent infection before abandoning further treatment. Conclusion: Chronic invasive fungal sinusitis is an uncommon infection and fairly difficult to manage. However, timely diagnosis and com-bined surgical and medical treatment can give good outcomes in the patients.


Introduction
Fungal sinusitis, broadly classified as invasive or non-invasive, is an uncommon infection, but there has been an increase in its incidence in the past few decades. Invasive fungal sinusitis can be acute or chronic in presentation. Chronic invasive fungal sinusitis (CFS), unlike acute invasive fungal sinusitis, occurs in immunocompetent, non-atopic patients who often have a history of chronic rhinosinusitis. It runs an indolent course and frequently extends beyond the sinus walls thus mimicking locally aggressive neoplasms [1] [2]. Initially asymptomatic, CFS can later present with pain, chronic headache, proptosis and cranial nerve deficits from invasion of adjacent structures. [1] Mycological studies had demonstrated majorly Aspergillus and a few Dermatiaceous species in the aetiology of the disease. [3] [4] Computed tomogram and magnetic resonance imaging are typically used to assess the extent of involvement of the paranasal sinuses and invasion of adjacent structures. Surgical debridement is required to treat this infection with extensive removal of involved tissue and bone. Antifungal chemotherapy also plays a major role in the management of the infective disease. The disease has been reported to be endemic in Sudan [5] and Northern India [4] due to the hot and dry climate in these areas which has been postulated to play a role in the aetiopathogenesis of the infection but has been rarely reported in Nigeria. To the best knowledge of the authors, there are no published reports of chronic invasive fungal sinusitis in our locality, hence this report of the cases managed at a tertiary health facility in southwestern Nigeria.

Method
Medical records of patients with chronic invasive fungal sinusitis managed over 10 years (January 2009 -December 2018) at a tertiary health facility, southwestern Nigeria were reviewed. Patients' clinical presentation, immune status, radiological imaging, surgical intervention, histological findings as well as treatment and outcome were studied. Diagnosis of chronic invasive fungal sinusitis was made by histopathological examination of all surgical specimens and mycological studies where possible, supported by radiological imaging in the patients.
This study adhered to the Tenets of Declaration of Helsinki and informed consent was obtained from each patient for the publication of the case series.

Case Series
Case 1: A 35-year-old female presented with gradual protrusion of the right eye, associated with loss of vision and pain of 6 years duration. She also had spontaneous, intermittent right epistaxis with bilateral nasal blockage, hyposmia and mucopurulent nasal discharge. There were no ear or throat symptoms and she O. Fasina et al. had no features suggestive of immunosuppression. Clinical examination revealed a pale mass completely obstructing right nasal cavity, not bleeding to touch and the ear and throat appeared normal. Ocular examination revealed acuity of hand movement in the right eye, severe non-axial proptosis, and a firm mass in the supero-medial orbit. Computed Tomogram (CT) revealed an isodense mass in the right orbit andright maxillary, ethmoidal and frontal sinuses. There was an extensive aerocele into the left frontal region with direct communication with the nasal cavity. She subsequently underwent right extended lateral rhinotomy, for medial maxillectomy, right orbitotomy and bi-frontal craniotomy for excision of the tumuor and aerocele. Intraoperatively, a firm, well circumscribed irregularly shaped mass extending from the right antrum to the right ethmoid and the orbit, displacing the right eyeball laterally was excised. Histopathological examination of the tissue revealed chronic invasive fungal sinusitis. She was commenced on oral antifungal drug (Voriconazole) post-operatively with regular monitoring of the liver function and she fared well on regular follow up for about six months before she was lost to follow-up.
Case 2: A 24-year-old male presented with purulent left nasal discharge of a year duration and protrusion of the left eyeball of 8 months duration. There was associated nasal obstruction which was initially intermittent but later became persistent with accompanying hyposmia and frontal headache, but no fever. The proptosis was non-axial, progressive, painful and associated reduced vision.
There were no features suggestive of immunosuppression in the patient and clinical examination showed reduced patency of the left nasal cavity which was filled with a brownish mass arising from its lateral wall. The mass was not sensitive, and there was no bleeding to touch. Ear and throat examinations were normal. CT scan of paranasal sinuses showed an isodense lesion in left maxillary, ethmoidal and frontal sinuses with orbital and intracranial involvement. He subsequently had left external frontoethmoidectomy, orbitotomy, and craniotomy for tumor excision. Histopathological examination of the specimen revealed an invasive fungal sinusitis. He was commenced on oral antifungal (ketoconazole) and discharged to Out-patient Clinic. However, he was irregular with the antifungal treatment and follow-up visits and re-presented with recurrent swelling for which a repeat debridement was advised, but he declined and was eventually lost to follow up.

Discussion
Chronic invasive fungal sinusitis is uncommon in our environment. A hospitalbased study [6] on microorganisms aspirated from the maxillary sinus in patients with sinusitis demonstrated the presence of fungi in 14.58% of patients.
The fungi isolated in the study [6] were Aspergillus flavus, Aspergillus fumigatus and Candida albicans. All six cases in our series were healthy individuals without any features of immunosuppression. Chronic invasive fungal sinusitis has been shown to have a clinical course greater than 12 weeks, occurring in immunecompetent individuals, and Aspergillus flavusas the most common fungal agent identified indifference to acute invasive fungal sinusitis which occurs in immunecompromised individuals, and frequently implicated fungal agents include Aspergillus species and fungi in the order of mucorale [7]. Mould-Shalom et al in their study [8] on acute invasive fungal sinusitis reported diabetes mellitus and other immune compromise in their patients.
The mean age of our patients was 30.7 years ± 7.2 years similar to the report of Alrajhi et al. [9] and an equal gender distribution was also noted in our series (Table 1). Mostly, young, active and immunocompetent individuals of both sexes are affected by this condition [2] [9].
All the patients presented late to our facility (mean duration of symptoms, 38.5 months; range, 6 to 96 months) with orbital and intracranial involvement at presentation ( Table 2). A slow progression of this disease has been documented, usually over months to years and patients usually present when the swelling extends to the orbit or base of the skull [1]. The typical presenting symptoms are related to chronic rhinosinusitis, upper respiratory allergies or nasal polyposis. Erosion into the orbit leads to proptosis while skull base involvement can cause chronic headache, seizures, decreased mental status or focal neurological deficits.
Extension through the sphenoid sinus can give rise to orbital apex syndrome or cavernous sinus syndrome [10]. Similar to a previous report [1], proptosis was the main ocular presenting complaint in our cases.
All six patients had pre-operative contrast enhanced CT scan, which though not confirmatory, is a useful radio-imaging in defining the extent of the disease.
Magnetic resonance imaging is useful in identifying involvement of the dura as well as the extent of intradural disease [2]. Chronic fungal sinusitis typically starts from the maxillary sinus on radio-imaging studies; however, it was not possible to accurately determine the paranasal sinus of origin in our patients as they presented with advanced disease and multiple sinus involvement (Table 2). Differentiating between invasive fungal sinusitis and malignant tumors of the paranasal sinuses is difficult both clinically and on radio-imaging, therefore, distinction is usually made onexamination of the tissue specimen at histology. The infective agents can also be identified through culture and microscopic visualization of broad, non-septate hyphae [7] [11] [12], Diagnoses of chronic fungal sinusitis was made in our series by histopathological identification of fungal organism in the tissue specimenin all six cases, and mycological studies in two patients identified Aspergillus flavusas the aetiological agent (Table 3). Aspergillus speciesare the most common agent isolated in chronic fungal sinusitis, and tissue cultures are positive in about 50% of the cases [7] [11]. Regarding treatment for chronic invasive fungal sinusitis, several authors have advocated combination therapy which includes surgical debridement with adjuvant antifungal therapy. The extent of surgery required to extirpate the disease has however been controversial, but wide aeration of the sinuses and long-term antifungal therapy is advocated [2] [13] [14]. Amphotericin B as well as the Azoles has been used as adjuvant therapy post-surgical debridement. All our patients had wide surgical debridement and the azole group of antifungals as adjuvant therapy (Table 3) with good response and satisfactory outcome achieved in five patients who completed their treatment. One of the patients however, was non-compliant with his medication due to financial constraints, had recurrent infection and was eventually lost to follow-up.
Our study is limited in the context that specific fungal identification by culture could not be done in four of the cases due to non-availability of the service in our facility at those periods. Case Reports in Clinical Medicine

Conclusion
In conclusion, chronic invasive fungal sinusitis is uncommon in our locality and affects young, active and immunocompetent individuals. Appropriate imaging studies and histopathological examination of excised tissue help in making the diagnosis of this infective disease and satisfactory treatment outcome can be achieved by effective surgical debridement and oral antifungal mediations.