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J Audiol Otol > Volume 27(3); 2023 > Article
Batinović, Martinić, Durdov, and Sunara: A Case of Unilateral Otologic Symptoms as Initial Manifestations of Granulomatosis With Polyangiitis

Abstract

Granulomatosis with polyangiitis (GPA) is a chronic and systematic autoimmune condition characterized by granuloma formation and necrotizing vasculitis of small to medium-sized vessels. GPA initially presents itself as respiratory and renal symptoms. Although temporal bone involvement is not uncommon, an otologic disorder is rarely the initial symptom. We present a case of a 36-year-old man who presented with unilateral ear pain, hearing loss, and facial palsy. After a series of diagnostics and temporal bone and chest imaging, he was diagnosed with GPA with multiorgan involvement. Cyclophosphamide and methylprednisolone relieved the patient’s ear pain and partially improved his hearing, facial palsy, and overall clinical condition. Although uncommon, systemic GPA may cause initial otologic symptoms and should not be dismissed as a possible cause of an otologic disease resistant to standard therapy.

Introduction

Granulomatosis with polyangiitis (GPA, previously called Wegener’s granulomatosis) is a rare, systemic, antineutrophil cytoplasmic antibody (ANCA)-associated form of vasculitis whose lesions usually affect the respiratory tract and kidneys [1]. This is an uncommon disease of an unknown etiology with the prevalence of five cases per 100,000 in the European population and equal distribution among sexes [2,3]. In general, two different forms of GPA have been described: the localized form, usually limited to the upper airway, and the systemic form, with predominant renal and pulmonary involvement [1]. Although upper airway symptoms are present in 70%-100% of GPA patients at the time of diagnosis and may be the only symptoms in the localized form [1,2], ear disorders are much less frequently the first and only manifestations of GPA, and usually occur as a consequence of sino-nasal involvement [2,3]. On the other hand, facial palsy, either alone or in combination with hearing loss, is rarely the presenting feature of the disease [4].
We present a clinical case of systemic GPA initially presenting as nocturnal otalgia, unilateral peripheral facial palsy (PFP), and severe mixed hearing loss (MHL).

Case Report

Presenting concerns

A 36-year-old male patient arrived at the ENT Emergency Department (EED) with extreme pain in his left ear and a long history of left acute otitis media and noise exposure. The patient reported several weeks of persistent otalgia, left-sided hearing loss, and a sudden-onset left-sided facial weakness.

Clinical findings and diagnostic assessments

On examination, only erythema of the external auditory canal and a purulent effusion from the perforated left eardrum was detected. A mild peripheral left-sided facial palsy was detected and categorized as House-Brackmann (HB) grade 2/6. The function of other cranial nerves was normal. The initial neurological screening done before presentation in the EED was unremarkable.
With the preliminary diagnosis of acute otitis media complicated with facial palsy, the patient was hospitalized for intravenous antibiotic and corticosteroid therapy (ceftriaxone and methylprednisolone) and further investigation. Initial laboratory tests were ordered and showed mild leukocytosis and mild elevation of C-reactive protein (CRP) levels up to 23.6 mg/L (Table 1). An initial audiological examination was conducted. Pure tone audiometry (PTA) documented normal hearing on the right ear up to 2 kHz and then severe sensorineural hearing loss up to 70 dB. On the left ear, severe mixed MHL up to 2 kHz and then profound hearing loss with no measurable response within the limits of the audiometer was recorded (Fig. 1A). A fiberoptic nasopharyngoscopy revealed only a small mucosal erosion on the right lateral nasal wall and was otherwise inconspicuous.
For further investigation, a multi-slice computed tomography (MSCT) of the temporal bones was ordered. Scans of the left temporal bone showed a total opacification of the mastoid air cells and the tympanic cavity with ossicular lysis but preserved bone septations. The ossicular chain erosion on the left was also detected (Fig. 2). We decided to watchful waiting because the differential diagnosis was not clarified. We found the conservative therapy more appropriate than to engage in tympanoplasty with a vague working diagnosis.

Treatment and follow-up

Antibiotic therapy was initiated with ceftriaxone 2 g/day intravenously (IV), methylprednisolone 40 mg/day IV, and topical ciprofloxacin without improvement.
On the fourth day of hospitalization, the patient began coughing severely and developed a continuous fever of 39.5°C. The nocturnal ear pain became unbearable (9 out of 10 on the visual analog pain scale). The facial nerve palsy deteriorated to HB grade 4/6 (Fig. 3) and his CRP level significantly rose from 23.6 mg/L to 155 mg/L (Table 1).
A plain chest X-ray was ordered and showed multiple nodules on both lung fields. A chest MSCT revealed numerous cavitary lung masses measuring up to 3.8 cm and mediastinal lymphadenopathy (Fig. 4). Urine cultures were negative.
Laboratory screening for possible autoimmune diseases was ordered and showed significant elevation of cytoplasmic-pattern of ANCA (c-ANCA) measuring 59 IU/mL, while myeloperoxidase-ANCA (p-ANCA) and antinuclear antibodies (ANA) were negative which pointed to a possible systematic autoimmune disorder (Table 1).
The patient, therefore, underwent a kidney ultrasound examination which was unremarkable. The otologic surgery was the patient’s last resort, so the pulmonologist did the bronchoscopy with lavage and blind biopsy of the tracheal carina.
Finally, the histological finding of the transbronchial biopsy confirmed GPA. In the underlying stroma, there was a dense infiltration of plasma cells, lymphocytes, and eosinophils, as well as a necrotic granuloma (Fig. 5A). A necrotic small vessel was surrounded by palisading histiocytes and a few giant multinuclear cells in the center of a granuloma (Fig. 5B). The final diagnosis of GPA was made three weeks after the onset of symptoms.
Treatment with 1,000 mg IV cyclophosphamide (CYC), along with 800 mg IV methylprednisolone daily, at 7-day intervals, was initiated in consultation with a rheumatologist. Antibiotic treatment was discontinued. One week after the initiation of immunosuppressive therapy, the symptoms of cough, fever, and ear pain diminished. Control ear examination revealed a thickened, pale, and nontransparent left eardrum with a retraction pocket in the Prussak’s space, without effusion. Facial palsy improved from HB grade 4 to grade 2.
A control PTA recorded a mild improvement from severe MHL to moderate MHL up to 2 kHz and profound hearing loss with no measurable response within the limits of the audiometer on the left ear (Fig. 1B). The patient was transferred to the Pulmonology Department where the methylprednisolone dosage was tapered slowly for the next 15 months. The rheumatologist limits the risk of relapse with CYC (1,000 mg/day IV), which was continued every 2 weeks for 1 month (day 1, day 15, day 30), then 500 mg/day IV every 3 weeks. No significant side effects were reported on immunosuppressive agents (Fig. 6).
In the 2-month follow-up, there was no significant hearing improvement on the left ear on PTA. Tympanometry documented a shallow A-type tympanogram on the left ear. The facial nerve function remained HB grade 2.
On a 6-month follow-up, the hearing thresholds were unchanged, and his facial palsy could still be categorized as HB grade 2.

Discussion

Classically, the ELK (ear, nose, and throat; lung; and kidney) acronym is used to describe the usual clinical involvement of the three systems in the systemic form of GPA [2]. According to the American College of Rheumatology, if at least two of the four criteria; 1) sinus involvement; 2) alteration in pulmonary radiology; 3) urinary sediment with hematuria or red cell casts, and; 4) histology with the presence of perivascular granulomas, are met the diagnosis of GPA can be determined with 88.2% and 92.0% sensitivity and specificity, respectively [1,5].
Our patient’s pulmonary involvement, bronchial findings, and elevated c-ANCA are sufficient criteria for GPA diagnosis. The presence of c-ANCA is observed in more than 90% of patients with GPA, but a negative result does not exclude the diagnosis [1].
At a large tertiary academic referral center, Kiessling, et al. [6] retrospectively analyzed 29 patients with skull base GPA. Twelve patients tested positive for c-ANCA and PR3 and eleven had facial weakness, while only four had MHL. In contrast to their study, our case showed audiometric verification of MHL. Furthermore, we documented gradation and improvement of PFP and MHL.
According to the literature, otologic manifestations appear in 6% to 56% of patients suffering from GPA [3]. Serous otitis media with conductive hearing loss is the most common middle ear disorder found in GPA. GPA patients, on the other hand, are less likely to have sensorineural hearing loss, vertigo, or PFP with hypoacusis, which has been identified as a possible indicator of GPA activity [3,4].
GPA rarely presents as an isolated ear disorder, especially without the preceding sino-nasal involvement [2,3] and even more infrequently as facial palsy [4]. So, the presenting symptoms of facial palsy, ear suppuration, and MHL initially did not point to GPA. Rather an acute otitis media with or without cholesteatoma was primarily suspected.
Sahyouni, et al. [7] reported a series of 11 patients who presented at a neurotology clinic with otologic symptoms with no previous diagnosis of GPA. In that series, 10 patients presented with hypoacusis, more than half of which were bilateral. Upon audiometric examination, only 1 patient had unilateral MHL with otalgia and facial palsy [7].
Wierzbicka, et al. [8] noted only 1 case of unilateral MHL as the first symptom in 7 patients with GPA, the other 6 had bilateral severe MHL with hearing improvement after ipsilateral paracentesis and steroid therapy. Mur, et al. [9] described a patient with GPA-induced serous otitis media and unilateral PFP which was resolved with spontaneous remission of paresis after tympanostomy tube placement. These studies depict several treatment options found effective in patients with GPAs with MHL and PFP. On the other hand, our therapy of choice was immunosuppressive therapy which also showed a beneficial effect on MHL and PFP.
Facial palsy, in association with GPA, is noticed in about 5% of patients [4] and it is commonly caused by compression in the middle ear facial nerve course or vasculitis of the vasa nervorum [3,4]. Unilateral PFP has been reported in advanced local disease [6,8] but it is extremely rarely the presenting feature. Moreover, two case reports described ipsilateral facial nerve paralysis with bilateral sensorineural hearing loss as initial GPA presentation [10,11]. On the other hand, we showed the combination of ipsilateral PFP and unilateral severe MHL as presenting signs of the GPA.
The standard treatment for the systemic form of GPA is an immunosuppressive such as CYC or rituximab, along with corticosteroids in high doses [1]. Kim, et al. [10] described significant effect of rituximab on hearing loss and PFP. In our case, pulse doses of 1,000 mg/day IV CYC and 10 mg/kg/day IV methylprednisolone were given for the first 7 days. Classically, the doses were adjusted for condition, comorbidities, and kidney function to obtain better tolerability without a decrease in efficacy. After 7-day therapy, PFP and hearing thresholds partially improved. Although commonly, CYC and corticosteroids are a mainstay of GPA therapy, relapses are common (up to 93%) [2].
The outcomes of GPA initially presenting with otologic dysfunction and afterward progressing to the generalized form is poor and mortality, without treatment, reaches 90% within 2 years [2,8]. Therefore, clinical suspicion, early diagnosis, and treatment are of utmost importance [2]. The GPA presenting with otologic manifestations can be very insidious and present a challenge for the ENT specialist. Because GPA is a multisystem disease with variable symptomatology, patients must be treated holistically. In our case, the ENT specialist included a multidisciplinary team of physicians (neurology, radiology, pathology, pulmonology, and rheumatology specialists) who effectively addressed the patient’s diagnostic and treatment needs.
This case is limited by its incomplete data collection due to missing documentation from pulmonary control and detailed rheumatology treatment and specific tests such as audiometric data after 6 month follow-up. However, the apparent strength of our case is an important consideration that GPA should be a differential diagnosis of prolonged and painful acute otitis media resistive to standard treatments in adults. Finally, a multidisciplinary approach is mandatory in the treatment of patients with the otologic manifestation of GPA.
In summary, although ENT symptoms are expected during a course of localized or systemic GPA, GPA presenting with unilateral MHL, PFP, and ear pain is uncommon and can present a clinical challenge. Ear pain and effusion with accompanying PFP not responding to antibiotic treatment should raise the concern of the otologic GPA, and a holistic approach to the patient must be included.

Acknowledgments

The authors would like to thank Vana Košta, MD, PhD, neurologist; Josipa Kokeza, MD, pulmonologist; Ivona Božić, MD, rheumatologist; Sanja Lovrić Kujundžić, MD, PhD, radiologist, for their treatment advice and technical assistance. We would also like to thank professor Dalibora Rako for the professional proofreading of the case in English.

Notes

Ethics Statement

This case report was approved by the Ethical Committee of the University Hospital of Split (No. 2181-147/01/06/M.S.-22-02). Written informed consent for data and image publication was obtained.

Conflicts of Interest

The authors have no financial conflicts of interest.

Author Contributions

Conceptualization: Franko Batinović, Davor Sunara. Data curation: Davor Sunara, Merica Glavina Durdov. Investigation: Franko Batinović, Davor Sunara. Methodology: Merica Glavina Durdov. Software: Marina Krnić Martinić. Supervision: Davor Sunara, Marina Krnić Martinić. Validation: Merica Glavina Durdov. Visualization: Franko Batinović, Merica Glavina Durdov. Writing—original draft: Franko Batinović, Marina Krnić Martinić. Writing—review & editing: Davor Sunara, Merica Glavina Durdov. Approval of final manuscript: all authors.

Fig. 1.
Initial audiogram (A) delineating normal hearing on the right ear up to 2 kHz and then severe sensorineural hearing loss up to 70 dB. On the left ear, severe mixed hearing loss at 250 Hz to 2 kHz and then profound hearing loss with no measurable response within the limits of the audiometer is recorded. Post-treatment audiogram (B) revealed mild improvement of severe mixed hearing loss in the left ear with residual profound sensorineural hearing loss with no responses within the limits of the audiometer at 2 kHz to 8 kHz.
jao-2022-00311f1.jpg
Fig. 2.
Coronal (A) and axial (B) CT scans of the temporal bone demonstrate total opacification of the mastoid air cells (B, asterisk) and the tympanic cavity with ossicular lysis but preserved bone septations. The arrow shows ossicular chain erosion (A and B, arrow). The right temporal bone with normal appearance of the middle ear ossicles and mastoid cells on coronal and axial CT scans.
jao-2022-00311f2.jpg
Fig. 3.
Peripheral facial palsy on the fourth day of hospitalization. At rest (A), the patient has slight facial asymmetry, especially around the corners of the lips. When asked to look surprised (B), the left frontalis does not contract. When closing his eyes (C), the left lids cannot be completely approximated. When attempting to smile (D), the patient experiences clear weakness of the left side of his face with his mouth pulling to the right.
jao-2022-00311f3.jpg
Fig. 4.
Multi-slice CT of the lungs on the fourth day of hospitalization. Coronal (A) views of the lungs showing mediastinal lymphadenopathy (filled arrow). Sagital (B) and axial (C) views reveal basal areas of poorly defined consolidation and multiple peripheral nodules (empty arrows).
jao-2022-00311f4.jpg
Fig. 5.
Granulomatosis with polyangiitis in the tracheal mucosa. A: Fragments of the tracheal mucosa are covered with respiratory and metaplastic squamous epithelium. Dense infiltration of plasma cells, lymphocytes, and eosinophils with a necrotic granuloma (arrow) can be seen in the underlying stroma (hematoxylin and eosin stain, magnification ×200). Scale bar: 200 µm. B: In the center of a granuloma is a necrotic small vessel surrounded by palisading histiocytes (empty arrow) and a few giant multinuclear cells (filled arrow) (hematoxylin and eosin stain, magnification ×400). Scale bar: 100 µm.
jao-2022-00311f5.jpg
Fig. 6.
Timeline of the case. HB, House-Brackmann grade; PTA, pure tone audiometry; MSCT, multi-slice CT; ANA, antinuclear antibodies; c-ANCA, cytoplasmic-pattern of antineutrophil cytoplasmic antibody; CRP, C-reactive protein; GPA, granulomatosis with polyangiitis.
jao-2022-00311f6.jpg
Table 1.
Significant laboratory test results
Test Result Normal value
Initial (June 11, 2017)
 Hemoglobin (g/dL) 137 138-185
 Hematocrit (%) 0.386 0.415-0.530
 MCV (fL) 84.2 83.0-97.2
 Leukocytes (×109/L) 10.4 3.4-9.7
 Lymphocytes (%) 23.8 20-46
 Platelets (×109/L) 282 158-424
 Urea (mmol/L) 7.0 2.8-8.3
 Creatinine (µmol/L) 83 64-104
 CRP (mg/L) 23.6 <5
 Urine analysis Normal
On hospitalization (June 18, 2017)
 Hemoglobin (g/dL) 144 138-185
 Hematocrit (%) 0.405 0.415-0.530
 Leukocytes (×109/L) 14.0 3.4-9.7
 CRP (mg/L) 155 <5
 ANA Negative Negative
 c-ANCA (IU/mL) 59 Positive >25
 p-ANCA (AU/mL) 2 Negative <20

MCV, mean corpuscular volume; CRP, C-reactive protein; ANA, antinuclear antibodies; c-ANCA, cytoplasmic-pattern of antineutrophil cytoplasmic antibody; p-ANCA, myeloperoxidase-antineutrophil cytoplasmic antibody

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