Effects on hearing and tinnitus following Dupilumab treatment of severe asthma with chronic rhinosinusitis-a case report*

Background: Dupilumab (anti-IL-4R) is a novel biological agent approved for treatment of severe asthma with chronic rhinosinusitis. Beneficial effects on hearing have only been sparsely decribed. Case presentation: In this case story we present a 48-year woman, who experienced remarkably improved hearing and reduction of tinnitus after initiation of Dupilumab. Progress was monitored by respiratory physicians in collaboration with rhinologists and audiologists. SNOT-22 score improved from 83 to 27 and audiograms obtained before and during treatment illustrate a reduced air-bone gap and an improvement of speech recognition threshold from 25 dB (both ears) to 15 and 10 (left and right ear respectively). Conclusions: This case story implies a beneficial effect of Dupilumab treatment in patients with united airway disease with hearing impairment. The authors suggest an additional otological perspective in addition to standard monitoring.

In the European Position Paper on Rhinosinuitis and Polyps (EPOS) 2020 (1) otitis media is sparsely mentioned and only in relation to paediatric or secondary CRS. However, two questions in the SNOT-22 questionnaire ask about ear symptoms: "ear fullness" and "ear pain" respectively, knowing that CRS-patients have an increased risk of ear problems (2) .
Eosinophilic otitis media (EOM) is a disease entity characterized by the presence of a highly viscous yellowish effusion containing eosinophils; immunoglobulin E (IgE) and eosinophil chemoattractants (3) . In 2011, diagnostic criteria for EOM were proposed and have since been adopted worldwide (4) . These criteria include association with bronchial asthma and nasal polyposis, and resistance to conventional treatment for otitis media. In 190 patients with EOM approximately 50% showed deterioration in bone conduction threshold and 6% became deaf (5) . Standard treatment consists of mesotympanic steroid, although anti-IL-5 and anti-IgE has been successfully used in treatment of non-granulomatous EOM (6,7) . The pathogenesis The hearing status was monitored at monthly intervals. All hearing tests were performed in a double walled sound insulated audiometric booth, using calibrated audiometric equipment.
The initial audiometry showed a mixed hearing loss, consisting of a 30-40 dB bilateral conductive hearing loss combined with a mild sensorineural hearing loss in the higher frequencies and speech recognition threshold at 25 dB on both ears (Figure 1).
Otomicroscopy showed grommets in place, but the patient had

Discussion
To our knowledge, only one other recent case study reports improved hearing after treatment with Dupilumab (9) . In our patient report, improvement was shown objectively by an audiogram, but especially self-reported. This patient is a good example of a patient having global airway disease. Her asthma worsens due to upper airways symptoms. In general, the treatment with Dupilumab show promising results in asthma and CRS patients within few weeks (10) . However, little attention has been on middle ear problems in CRS patients.
Ear fullness, ear pain, and decreased hearing can be caused by large polyps obstructing the Eustachian tube and choana, thus creating a negative pressure in the middle ear. However, this was not the case in this patient since nasal endoscopy prior to Dupilumab did not find obstructive nasal polyposis. We hypothesize that the patient suffers from eosinophilic otitis media, which improved due to the biologic treatment. Though the eosinophilic ear in the recent years has been given increasing attention, literature is still sparse and little attention has been given to hearing in the treatment with biologic agents. As IgE levels in middle ear effusion has been shown to correlate with hearing, we speculate that Dupilumab as an anti-IL-4R agent may reduce this IgE concentration and thereby improve hearing. Since hearing loss worsens over time, initiation of adequate treatment as early as possible is essential to the patient's quality of life. Insertion of ventilation tubes in this patient category is debatable. While some may experience a relief with improved hearing and reduced fullness, the effect is often temporary and the possibility of chronic perforation with secretion as well as the risk involved with repeated anaesthesia must be considered.
Systematic biological treatment for chronic rhinosinusitis is about to become available. Similar to the international severe asthma registries, we find it crucial to follow these patients closely creating a database with data on sinonasal symptoms and findings, asthma symptoms and measurements, medication, allergies, eosinophilic counts and side-effects. In this database, we will now include a tympanometry and a hearing test in all patients reporting of decreased hearing.

Conclusions
The present case illustrates that severe eosinophilic asthma is a systemic disease, which may affect the ears and induce hearing impairment, as well as the well-known association with CRSwNP.
Hence, we advocate that hearing is routinely assessed through a thorough history, as well as hearing tests in patients with complaints of hearing impairment.
Finally, assessment of hearing problems should be included in clinical registries on patients with severe asthma and/or CRSwNP, to enable us to understand how common this problem is, and possible support hearing impairment to become part of the future set of indications for biological treatments for severe Type 2 disease.