Challenges in Management of Uncommon Otologic Fungal Disease – a Case Series and Review of Literature

Abstract

The purpose of this study is to describe challenges in diagnosis and treatment of otologic fungal infections.; 2) Methods: Case series and literature review 3) Results: Three patients treated at Louisiana State University Health Sciences Center – Shreveport between November 2020 – November 2023 were identified with complicated fungal otitis externa requiring detailed radiologic and histopathologic workup to aid in diagnosis and management. 4) Conclusion: Diagnosis of otologic fungal infection is often complex due to similar presentation of more common pathogens, overlapping features among common fungal specimens, and limitations of available diagnostic methods. Patient factors, including diabetes with poor glycemic control, may further complicate this challenging disease. High index of clinical suspicion, collaboration between multidisciplinary teams is essential to differentiate between common and uncommon fungal ear infections. A combination of mechanical debridement, topical and/or systemic therapy, and longitudinal follow-up with otolaryngology and infectious disease teams is required for successful treatment.

Introduction

Fungal disease of the ear has a wide spectrum of presentations. Otomycosis is typically used to describe fungal infections of the external ear, auricle, external auditory canal (EAC), tympanic membrane (TM) and middle ear [1]. More aggressive infection of the EAC involving the mastoid and skull base is described as invasive necrotizing otitis externa (NOE) and tends to originate at the bony cartilaginous junction [1]. Otomycosis typically presents with otalgia, pruritus, and otorrhea, hearing loss and/or aural fullness while NOE may demonstrate these symptoms in addition to increasingly severe otalgia and resistance for local therapy for at least ten days. Patients with severe disease involving the skull base may progress to facial nerve or other cranial nerve neuropathies. The most common species isolated are candida and aspergillus, though many other species have been identified. Common risk factors include humid climate, presence of cerumen, instrumentation of the ear, frequent use of topical antibiotics/steroids, immunocompromised status, history of mastoidectomy, and hearing aid with occlusive mold use [2]. Diagnosis may be achieved with fungal cultures, however, often tissue diagnosis and histopathologic exam is required when the diagnosis is unclear or in the setting of severe disease. Computed tomography (CT), Magnetic resonance imaging (MRI), or nuclear scans can aid in assessing the soft tissue extent of disease, assess for bony erosion, and evaluate for intracranial extension in NOE. First line management of early fungal disease includes topical antifungals and frequent debridement, while progression of disease including NOE may require oral (PO) or intravenous (IV) antifungals, or surgical intervention to clear disease. While management tends to be straightforward when the diagnosis is clear, fungal pathogens are often difficult to isolate, and negative cultures may lead to delays in diagnosis and treatment. Here, we present several cases of otologic fungal disease diagnosed and treated at our institution, describe challenges encountered in diagnosis, and discuss management strategies for successful treatment.

Case 1: Histoplasmosis of the External Auditory Canal

This is a 76-year-old male with a past medical history of type II diabetes mellitus (T2DM) who initially presented with a several month history of recurrent otitis media, otalgia, left otorrhea, and headaches. The patient had persistent symptoms after multiple courses of antibiotics and antifungals after inconclusive cultures and biopsy at an outside facility. On microscopic exam, a 1–1.5 cm ulcerative lesion of the left antero-superior quadrant of the outer one-third of the left external auditory canal wall was visualized. The patient underwent repeat in-office biopsy of the lesion and additional cultures. In-office histopathology favored granulomatous inflammatory reaction, while initial cultures reported Fusarium species. Due to inconclusive results on initial biopsy and continued symptoms, an operative biopsy was pursued. Final pathology demonstrated subepidermal granulomatous inflammation with periodic acid schiff (PAS)-positive 2–5 micron intracellular micro-organisms consistent with Histoplasma species (Fig. 1A, B and C)

Fig. 1.

A H&E stain X200): Subepithelial granulomatous inflammation composed of foamy histiocytes with intracellular yeasts. B (PAS stain X400) A higher magnification shows numerous PAS-positive intracellular yeast (green arrow). C (GMS stain x400) highlights intracytoplasmic GMS-positive fungal elements measuring 2–5 microns, compatible with Histoplasma sp

No evidence of Fusarium was noted on operative histopathology. Serum testing for Histoplasma antibody was positive, Histoplasma urine antigen was negative. The patient was initiated on sulfacetamide drops and referred to the infectious disease team and subsequently began treatment with oral itraconizole. Several weeks postoperatively, the patient experienced worsening otalgia requiring admission and IV amphotericin B (IVAB) was administered. Ultimately the patient was discharged on six weeks of oral voriconizole and symptoms resolved during close follow up with otology and infectious disease teams.

Case 2: Invasive Aspergillosis

This is a 62-year-old male with a history of T2DM, bilateral recurrent acute otitis media with history of right sided mastoidectomy presented to our service with a three-month history of left sided neck pain, otalgia. The patient continued to experience recurrent infection despite medical and surgical treatment, ultimately developing worsening infection after tympanostomy tube placement at an outside facility. On our initial evaluation, the left ear demonstrated purulent drainage and erythematous tympanic membrane. A left abducens palsy was noted. Initial cultures were without bacterial or fungal growth. Imaging findings on Gallium-67-citrate (Ga-67) scan were concerning for left petroclival osteomyelitis. Patient was discharged on 6 weeks of oral levofloxacin per infectious disease recommendations. Shortly after discharge, the patient experienced worsening of symptoms including facial pain, left sided facial palsy, otorrhea, nausea, vomiting, and leg weakness. The patient was admitted and initiated on empiric IV antibiotics; CT imaging findings (Fig. 2) demonstrated progression of disease including left carotid sheath, temporomandibular joint, hypoglossal canal, and jugular foramen involvement and possible posterior fossa dural meningitis.

Fig. 2.

Axial CT imaging demonstrating erosive bony changes (arrows) associated with Left petroclival osteomyelitis with cortical erosion secondary to invasive Aspergillosis

Due to progression of disease and new neurologic findings, the patient underwent left sided mastoidectomy and left facial nerve decompression. Repeat cultures taken intraoperatively demonstrated Aspergillus fumigatus species. Patient was then initiated on long term voriconazole. The left facial nerve and left abducens palsy ultimately resolved during treatment. Repeat Ga-67 scan 1 year after diagnosis and long term voriconazole therapy demonstrated resolution of infection.

Case 3: Fungal Granuloma

A 53 year-old female with history of T2DM, valley fever presented to our service with a 15 year history of otalgia, recurring black foul drainage from right ear unresolved with antibiotic treatment. Patient underwent CT imaging demonstrating anterior canal bony erosion, tegmen defect, and soft tissue in the EAC with bony erosion (Fig. 3A and B).

Fig. 3.

A and B Axial and Coronal CT imaging demonstrating erosive bony changes (arrows) associated with right sided EAC lesion

Intraoperative findings demonstrated squamous debris lining the EAC, bony erosion of the posterior, inferior, and medial EAC sparing the annulus. A pocket of squamous debris was noted anteroinferiorly. Affected tissue was drilled down to healthy bone. Patient did well and was without fungal debris on postoperative followup. Final histopathology demonstrated fungal balls invading through bone, favoring Zygomycetes, though initial diagnosis was concerning for Aspergillus spp. (Figures 4 and 5)

Fig. 4.

HE stained slide demonstrating fungal species (black arrows) are infiltrating through the necrosed bone (blue arrows)

Fig. 5.

(PAS stain X400) Silver stain is showing that fungal species are branched and with septa (orange arrows)

Discussion

As demonstrated by the above cases, otologic fungal disease can present with varying degrees of severity. Often, initial diagnosis is complicated by lack of growth on fungal and bacterial cultures, leading to alternative antimicrobial treatment until the true diagnosis is obtained. Bacterial pathogens are responsible for approximately 90% of cases of otitis externa, which further contributes to the tendency to empirically treat with antibiotics rather than antifungals [3]. Additionally, imaging findings in invasive or erosive fungal disease tend to be nonspecific and do not help differentiate fungal versus bacterial etiologies. Another significant challenge is the frequency of overlapping morphologic features among fungal organisms.

A variety of tools exist for the diagnosis of otologic fungal disease, including microscopic examination, histopathology, and microbiologic cultures. Additional tools may include other laboratory-based assays including polymerase chain reaction among others, however, most of these assays are approved for viral or bacterial etiologies and very few are available for fungal diagnostics [4]. Cultures are the gold standard in diagnosing fungal disease, and when successful, allow susceptibility testing to be performed. While cultures are the ideal method for diagnosis, cultures must often be grown for several days to several weeks, and require incubation at ideal temperatures for species growth, often necessitating multiple samples. Alterations in sample preparation or maintenance may lead to lack of fungal growth. This can lead to delayed diagnosis, particularly in cases where bacterial etiology is suspected rather than fungal.

Additional challenges posed in the diagnosis of fungal infection include varied sensitivity of microscopy in diagnosis of individual agents, the quality of the specimen, and the experience of the laboratory diagnostician [4]. Standard preparations, including potassium hydroxide, hematoxylin, and eosin (H&E) staining, and periodic acid-Schiff staining may be beneficial in identifying fungal hyphae but have their limitations. H&E can aid in identifying fungal elements of some species, but also stains surrounding non-fungal structures which can often obscure the diagnosis, thus necessitating additional stains. Special stains improve the ability to diagnose fungal disease, including Grocott’s methenamine silver stain which stains fungal cell walls brown black allowing for easier identification [5].

Furthermore, fungal culture of some organisms may demonstrate atypical morphologies or multiple morphologies [6]. Although it is one of the most common fungal otologic pathogens, Aspergillus species can often be complex to diagnose. Aspergillus is described as a septate dichotomously branched hyaline hyphae on microscopy [7]. Several studies have described the challenges in identification of some fungal organisms due to overlapping morphologic features among fungal specimens, with Aspergillus species being susceptible to misclassification [8]. Sangoi et al. also describes some of the specific challenges in histopathologic diagnosis of Aspergillus due to overlapping morphologic features, including similarities to Zygomycetes, Hyalinohyphomyces (i.e., Fusarium, Scedosporium, and Penicillium species) and other hyaline septate molds (dermatophytes) [8].

In the setting of failure to improve and lack of culture growth, operative biopsy can aid in obtaining sufficient samples for adequate diagnosis of fungal disease. Histopathologic exam allows examiners to determine if specimens represent contamination, colonization, or true infection, and can assess for vascular invasion or necrosis [9]. In all three cases, multiple sets of cultures were negative for fungal growth. In the third case, our patient experienced a milder but more chronic course of disease, and operative histopathology was nonspecific but consistent with Zygomycetes class. Final diagnosis was obtained through operative biopsy in all three cases due to lack of growth on bedside cultures. This demonstrates the importance of collaboration between surgeons, microbiologists, and pathologists in identification of invasive fungal disease.

CT and MRI imaging are useful for determining the extent of NOE; however, each have their limitations. CT is useful for assessing the degree of bony erosion and may identify aggressive features consistent with NOE such as destruction of fat planes [10]. MRI is optimal for evaluating intracranial extension, thrombosis or vascular complications, and meningeal enhancement, among other findings [10]. Varied findings were noted on CT imaging for our patients. In our Histoplasmosis patient, disease was found to be isolated to the EAC. In our Aspergillus patient, initial imaging demonstrated aggressive findings of clival osteomyelitis/petrous apicitis and erosive ear disease which further progressed to intracranial disease. In our fungal granuloma patient, CT demonstrated bony erosion leading to primary concern for possible cholesteatoma. While CT imaging is not specific for diagnosis of otologic fungal disease, in our cases it was useful for guiding extent and timing of operative intervention.

Ga-67 imaging is useful in diagnosis and assessing treatment response in invasive fungal disease and was used at multiple intervals in our Aspergillus NOE patient. Ga-67 scans target acute-phase reactant and bind leukocytes engaged in the inflammatory response [11]. A normal Ga-67 scan, even in the setting of an abnormal bone scan can exclude skull base osteomyelitis, whereas increased uptake confirms infection [11]. Repeat Ga-67 scan after long term treatment was ultimately used in confirming the safety of discontinuing long term oral antifungal treatment in this patient.

Primary risk factors for invasive fungal disease of the ear include diabetes, immunosuppressed status, and longtime use of local anti-inflammatory drugs or steroids [5]. Furthermore, existing diabetes and poor glycemic control have been demonstrated to lead to longer hospitalization, increased healthcare costs, and increased mortality [12]. Microvascular angiopathy due to uncontrolled diabetes also plays a role in subsequent invasive infections and resulting skull base osteomyelitis, though interestingly, in our Histoplasmosis case, glucose did not demonstrate significant elevations. In our invasive aspergillosis patient and fungal granuloma patients, hemoglobin A1c was elevated on initial presentation: 7.2% and 8.3%, respectively. The cerumen of diabetics tends to be more alkaline at baseline compared to the slightly acidic pH of healthy individuals, which is approximately 6.9 [13]. Studies have noted that acute otitis externa also corresponds to a more alkaline EAC environment with a return to more acidic pH with resolution of infection [13]. Additionally, patients with NOE have been noted to have EAC pH as high as 8.0 [13]. Restoration of the acidic environment aids in treatment of otitis externa, and the altered microenvironment of the diabetic EAC at baseline represents another difficulty in managing chronic or recurrent fungal infections.

Another challenge encountered in the diagnosis of otologic fungal disease is the presence of pathogens that do not commonly affect the ear. While Histoplasmosis is the most common endemic fungal infection in North America, only two documented otologic cases currently exist in the literature [14, 15]. Culture of Histoplasmosis is challenging and can take up to 8 weeks [16]. Routine serum testing does not typically include Histoplasma in standard otomycosis workup due to low known incidence. In our case, histopathologic evaluation with standard hematoxylin and eosin stains and silver stains helped determine this diagnosis, with intracellular yeast observed (Fig. 1B). This demonstrates the utility of operative biopsy in the case of aggressive disease, as it may help expedite diagnosis in cases where culture may be difficult or time consuming.

Many different topical agents have been utilized in the treatment of otomycosis, including topical antifungals, steroids, acidic solutions, antifungal agents, and drying agents. Furthermore, prolonged treatment with antimicrobials when the etiology of infection is unclear can lead to altered growth of native flora to the EAC and promote fungal proliferation and resulting otomycosis. All three of our patients underwent multiple rounds of treatment with topical and oral antibiotics prior to presenting to our institution. While some infections may initially present as bacterial infection and are treated as such, it is important to rule out early fungal infection. Common topical antifungal agents include clotrimazole, nystatin, tolnaftate, miconazole, econazole. Use of other agents including acetic acid, potassium sorbate, Boric acid solutions, m-cresyl acetate, alcohol and gentian violet has also been described; studies have reported clotrimazole to be the most effective initial topical treatment in vivo, followed by gentian violet and nystatin [17].

A role also exists for systemic therapy in the setting of aggressive or resistant fungal ear disease. IVAB is commonly used as an empiric antifungal treatment, but has multiple adverse effects, including renal toxicity, which can be dangerous in diabetic patients. Limited data exists regarding systemic therapy for invasive otitis externa secondary to histoplasmosis due to the rarity of the ear as the primary site of infection. Systemic histoplasmosis is most rapidly cleared by liposomal IVAB, however, studies have shown that long term treatment with itraconazole is similarly effective [18]. Our histoplasmosis patient was initially treated with oral itraconazole but experienced worsening of symptoms requiring admission and IVAB. Severe presentations may require more aggressive treatment, and the risks of toxicity and underlying comorbidities must be weighed. While voriconazole is typically not first line treatment, it has been described as possible salvage therapy in the setting of failure to improve on itraconazole [19]. In this case, IVAB may have aided in clearing systemic disease and reduced disease burden, allowing for treatment of residual, milder disease with voriconazole.

Typically, voriconazole has been accepted as first-line treatment for invasive aspergillosis, though more recent studies have demonstrated non-inferiority of posaconazole due to similar disease outcomes [20]. Long term treatment with voriconazole also resulted in resolution of disease on our invasive aspergillosis patient, confirmed by follow up Ga-67 imaging. Our third patient did not require systemic therapy. This represents the diversity in clinical course of fungal otologic disease despite similar presenting symptoms. Close follow-up with the otolaryngologist and infectious disease specialist is essential to determine efficacy of active treatment to allow for changes to therapeutic plans when needed.

Conclusions

In conclusion, the diagnosis of uncommon otologic fungal disease is often challenging and often delayed. Imaging, while useful, is nonspecific. More common fungal organisms, like candida sp. may involve straightforward management with empiric topical antifungals and debridement in the immunocompetent patient, while uncommon fungal disease requires extensive work-up. Uncommon fungal infection can rarely be differentiated from common otomycosis with history and clinical examination alone. A high index of clinical suspicion, and collaboration between multidisciplinary teams involving the otolaryngologist, infectious disease specialist, radiologist, microbiologist, and histopathologist aids in more prompt diagnosis and is essential in more aggressive and unusual disease presentations.

Author Contributions

“Conceptualization, G.M and M.P. Methodology, R.M, A.C.O; resources R.M and A.C.O; data curation, M.P; writing—original draft preparation, M.P, G.M.; writing—review and editing, R.M, A.C.O; supervision, G.M; project administration,

Funding

Not applicable.

Declarations

Conflict of Interest

The authors declare no conflicts of interest.