Unilateral autoimmune inner ear disease in a patient with lung cancer treated with nivolumab
Ontology highlight
ABSTRACT:
SUBMITTER: Rajapakse A
PROVIDER: S-EPMC7507864 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:ObjectiveAutoimmune inner ear disease (AIED) is a rare disorder characterized by rapidly progressive, sensorineural hearing loss that demonstrates good responsiveness to corticosteroid and immunosuppressive therapy. The pathophysiology is likely driven by chronic trafficking of immune cells into the inner ear, targeting inner ear proteins to coordinate inflammation. Suppression or modulation of the immune response can minimize cochleitis allowing for potential recovery of hearing. It is an otologic emergency requiring a multidisciplinary approach to management to commence immunosuppressive therapy. This can be achieved using steroids, immunomodulators, plasmapheresis, intravenous immunoglobulin, or biologic agents. Treatment decisions are further complicated in pregnancy and require supervision by an obstetrician and maternal-fetal medicine (MFM) specialist. Concerns include safe dosing of steroids and potential for transplacental migration of immune complexes. We provide the first comprehensive literature review on AIED and its implications in pregnancy. We frame our discussion in the context of the second reported case of primary AIED in pregnancy and the first to show excellent response to immunosuppressive therapy.MethodsWe reviewed the presented case and literature on AIED.ResultsA 27-year-old, pregnant, HSP-70 positive woman was diagnosed with AIED and had excellent recovery of hearing and balance following a combination of steroid treatment, augmented by oral immunomodulators, plasmapheresis, and IVIG.ConclusionAIED is a diagnostic challenge, and treatment considerations are complex when encountered in pregnancy. Management requires multidisciplinary involvement between otolaryngologists, immunologists, and obstetricians to balance maternal and fetal health outcomes.
| S-EPMC8956394 | biostudies-literature
Project description:Autoimmune Inner Ear Disease (AIED) is characterized by bilateral, fluctuating sensorineural hearing loss with periods of hearing decline triggered by unknown stimuli. Here we examined whether an environmental exposure to mold in these AIED patients is sufficient to generate a pro-inflammatory response that may, in part, explain periods of acute exacerbation of disease. We hypothesized that molds may stimulate an aberrant immune response in these patients as both several Aspergillus species and penecillium share homology with the LCCL domain of the inner ear protein, cochlin. We showed the presence of higher levels of anti-mold IgG in plasma of AIED patients at dilution of 1:256 (p?=?0.032) and anti-cochlin IgG 1:256 (p?=?0.0094 and at 1:512 p?=?0.024) as compared with controls. Exposure of peripheral blood mononuclear cells (PBMC) of AIED patients to mold resulted in an up-regulation of IL-1? mRNA expression, enhanced IL-1? and IL-6 secretion, and generation of IL-17 expressing cells in mold-sensitive AIED patients, suggesting mold acts as a PAMP in a subset of these patients. Naïve B cells secreted IgM when stimulated with conditioned supernatant from AIED patients' monocytes treated with mold extract. In conclusion, the present studies indicate that fungal exposure can trigger autoimmunity in a subset of susceptible AIED patients.
| S-EPMC3809107 | biostudies-literature
Project description:BackgroundAutoimmune inner ear disease (AIED) is a rare disease that results in progressive sensorineural hearing loss. Patients with AIED initially respond to corticosteroids; however, many patients become unresponsive to this treatment over time, and there is no effective alternative therapy for these individuals.MethodsWe performed a phase I/II open-label, single-arm clinical trial of the IL-1 receptor antagonist anakinra in corticosteroid-resistant AIED patients. Given that the etiology of corticosteroid resistance is likely heterogeneous, we used a Simon 2-stage design to distinguish between an unacceptable (≤10%) and an acceptable (≥30%) response rate to anakinra therapy. Subjects received 100 mg anakinra by subcutaneous injection for 84 days, followed by a 180-day observational period.ResultsBased on patient responses, the Simon 2-stage rule permitted premature termination of the trial after 10 subjects completed the 84-day drug period, as the target efficacy for the entire trial had been achieved. Of these 10 patients, 7 demonstrated audiometric improvement, as assessed by pure tone average (PTA) and word recognition score (WRS). In these 7 responders, reduced IL-1β plasma levels correlated with clinical response. Upon discontinuation of treatment, 3 subjects relapsed, which correlated with increased IL-1β plasma levels.ConclusionWe demonstrated that IL-1β inhibition in corticosteroid-resistant AIED patients was effective in a small cohort of patients and that IL-1β plasma levels associated with both clinical hearing response and disease relapse. These results suggest that a larger phase II randomized clinical trial of IL-1β inhibition is warranted.Trial registrationClinicalTrials.gov NCT01267994.FundingNIH, Merrill & Phoebe Goodman Otology Research Center, and Long Island Hearing & Speech Society.
| S-EPMC4160092 | biostudies-literature
Project description:Interleukin-1β (IL-1β) is a key proinflammatory cytokine involved in the progression of many autoinflammatory and autoimmune diseases, including autoimmune inner ear disease (AIED). IL-1β inhibition has been shown to result in clinical hearing improvement in a small cohort of corticosteroid-resistant patients with AIED. Canonical processing of pro-IL-1β by caspase-1 generates an active 17-kDa fragment, capable of instigating a proinflammatory microenvironment. However, in response to LPS, PBMCs from patients with AIED uniquely express a 28-kDa IL-1β fragment, as compared with PBMCs from control subjects. We synthesized and compared the biologic activity of the 28-kDa fragment to the 17-kDa IL-1β product and the pro-IL-1 31-kDa protein. The 28-kDa IL-1β fragment induces IL-6, TNF-α, and CCL3 in PBMCs. Uniquely, only caspase-7 treatment showed a dose- and time-dependent increase in 28-kDa band generation. Mass spectrometry confirmed the putative caspase-7 cleavage site of pro-IL-1β, which was used to generate the 28-kDa fragment used for PBMC stimulation studies. Collectively, these results provide insight into the function of a poorly understood, processed 28-kDa form of IL-1β in patients with AIED that is uniquely generated by caspase-7 and is capable of activating further downstream proinflammatory cytokines. Further investigation may provide novel pharmacologic targets for the treatment of this rare disease.
| S-EPMC7098783 | biostudies-literature
Project description:Autoimmune inner ear disease (AIED) is a poorly understood disease marked by bilateral, rapidly progressive hearing loss triggered by unknown stimuli, which is corticosteroid responsive in 60 % of patients. Although the mechanism of the disease is not precisely understood, a complex interaction of cytokines is believed to contribute toward the inflammatory disease process and hearing loss. Previously, we showed the role of TNF-? in steroid-sensitive and IL-1? in steroid-resistant immune-mediated hearing loss. N-Acetylcysteine (NAC), a broad spectrum antioxidant, has been effective in other autoimmune disorders. Other studies have shown NAC to have a protective adjunct role in human idiopathic sudden hearing loss, where the addition of NAC resulted in better hearing recovery than with steroids alone, although the mechanism of this protection was not elucidated. In the present study, we observed PBMCs from AIED patients exhibited higher baseline TNF-? and MPO levels compared with normal healthy controls. NAC effectively abrogates LPS-mediated TNF-? release from PBMC of both AIED patients and controls. We demonstrated that in AIED patients, the TNF-? downstream signaling pathway appears aberrantly regulated, influencing both MPO and IL-8 expression. Given that NAC effectively abrogated LPS-mediated TNF-? release and exerted minimal effects on the downstream targets of this pathway, we feel NAC may be a rational adjunct therapy for this enigmatic disease, worthy of clinical exploration.
| S-EPMC4651738 | biostudies-literature
Project description:Autoimmune inner ear disease is an enigmatic disorder characterized by recurring episodes of sudden or progressive sensorineural hearing loss. Hearing loss can be improved by timely corticosteroid administration, but only half of those treated respond, and for many responders, that response is lost over time. The mechanisms that control corticosteroid responsiveness in this disorder are largely uncharacterized. We have previously identified that the induction by dexamethasone of IL-1R type II (IL-1R2) expression in PBMC predicts corticosteroid responsiveness in this disorder. In this study, we asked whether IL-1? was overexpressed, and whether clinical corticosteroid responders differentially regulated IL-1? expression or release in response to dexamethasone, as compared with nonresponders. IL-1? has been reported to induce matrix metalloproteinase-9 (MMP-9) expression. Given that metalloproteinases can cleave IL-1R2, we also asked whether MMP-9 expression was altered in this disorder. In this study, we demonstrate that corticosteroid nonresponders have elevated plasma levels of IL-1? and MMP-9 as compared with clinically responsive patients (p = 0.0008 and p = 0.037, respectively). Increasing MMP-9 expression correlated with increasing IL-1? concentration, suggesting that IL-1? expression regulates MMP-9 expression. As expected, monocytes were the predominant producers of IL-1?. In vitro exposure of PBMC to dexamethasone from clinical corticosteroid responders suppressed IL-1? release. PBMC of corticosteroid nonresponders have substantially higher release of IL-1? into the conditioned media, and when exposed to dexamethasone, failed to repress IL-1? release (p = 0.05). Treatment of PBMC from clinical corticosteroid nonresponders with anakinra resulted in repression of IL-1? release, suggesting that IL-1? blockade may be a viable therapy for these patients.
| S-EPMC3031454 | biostudies-literature
Project description:ObjectiveThe diagnosis of Ménière's disease (MD), characterized by idiopathic endolymphatic hydrops (ELH), remains a clinical priority. Many ancillary methods, including the auditory and vestibular assessments, have been developed to identify ELH. The newly emerging delayed magnetic resonance imaging (MRI) of the inner ear after intratympanic gadolinium (Gd) has been used for identifying ELH in vivo. We aimed to investigate the concordance of audio-vestibular and radiological findings in patients with unilateral MD.MethodsIn this retrospective study, 70 patients with unilateral definite MD underwent three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) sequences following intratympanic application of Gd. Audio-vestibular evaluations were performed, including pure tone audiometry, electrocochleogram (ECochG), glycerol test, caloric test, cervical and ocular vestibular evoked myogenic potentials (VEMPs), and video head impulse test (vHIT). The relationship between imaging signs of ELH and audio-vestibular results was investigated.ResultsThe incidence of radiological ELH was higher than that of neurotological results, including the glycerol test, caloric test, VEMPs, and vHIT. Poor or slight agreement was observed between audio-vestibular findings and radiological ELH in cochlear and/or vestibular (kappa values <0.4). However, the pure tone average (PTA) in the affected side significantly correlated with the extent of both cochlear (r = 0.26795, p = 0.0249) and vestibular (r = 0.2728, p = 0.0223) hydrops. Furthermore, the degree of vestibular hydrops was also positively correlated with course duration (r = 0.2592, p = 0.0303) and glycerol test results (r = 0.3944, p = 0.0061) in the affected side.ConclusionIn the diagnosis of MD, contrast-enhanced MRI of the inner ear is advantageous in detecting ELH over the conventional audio-vestibular evaluations, which estimates more than hydropic dilation of endolymphatic space.
| S-EPMC10040662 | biostudies-literature
Project description:ObjectiveTo assess outcomes in autoimmune inner ear disease (AIED) after cochlear implantation (CI) through systematic review and meta-analysis.Databases reviewedPubMed, MedLine, Embase, and CINAHL.MethodsDatabases were queried for inclusion of AIED patients who underwent CI with outcomes recorded ≥3 months postoperatively. We examined demographics, pure-tone average (PTA), speech perception, preoperative imaging, intraoperative management, and postoperative complications.ResultsTwenty-six articles encompassing 124 patients met inclusion criteria. Mean implantation age was 26.2 years (range 4-65 years) with average length of follow-up at 28.2 months (range 3-120 months). Meta-analysis demonstrated significant improvement in speech perception following CI. There was a statistically significant improvement in speech recognition score (SRS) (standard mean difference [SMD] = 6.5, 95% confidence interval [CI], 4.8-8.0, P < 0.0001) as well as word recognition score (WRS) (SMD = 5.5, 95% CI, 4.2-6.8, P < 0.0001) after CI. Anomalous preoperative radiologic manifestations were reported by 57.7% (15/26) studies. Disease activity-related intraoperative adjustment was noted in 57.7% (15/26) studies; common consequences were cochlear drill-out (53.3%), difficult round window insertion (26.7%), and scala vestibuli insertion (26.7%). Frequent postoperative complications noted in 26.9% (7/26) studies included systemic AIED flares (71.4%) and wound healing delay (42.9%).ConclusionFindings of this systematic review of AIED cochlear implant literature demonstrate a lack of consistent reporting standards for PTA and speech perception as well as a lack of long-term follow-up. Despite these findings, meta-analysis suggests that CI is a viable treatment for improving speech perception in AIED patients.
| S-EPMC10969513 | biostudies-literature
Project description:ObjectiveWe aimed to evaluate the diagnostic performance of some anatomical variables with regard to endolymphatic sac (ES) and duct (ED), measured by non-contrast three-dimensional sampling perfection with application-optimized contrasts using different flip angle evolutions (3D-SPACE) magnetic resonance imaging (MRI), in differentiating vestibular migraine (VM) from unilateral Ménière's disease (MD).MethodsIn this study, 81 patients with VM, 97 patients with unilateral MD, and 50 control subjects were enrolled. The MRI-visualized parameters, such as the distance between the vertical part of the posterior semicircular canal and the posterior fossa (MRI-PP distance) and visibility of vestibular aqueduct (MRI-VA), were measured bilaterally. The diagnostic value of the MRI-PP distance and MRI-VA visibility for differentiating VM from unilateral MD was examined.Results(1) Compared with the VM patients, patients with unilateral MD exhibited shorter MRI-PP distance and poorer MRI-VA visibility. No differences in the MRI-PP distance and MRI-VA visibility were detected between patients with VM and control subjects. (2) No significant interaural difference in the MRI-PP distance and MRI-VA visibility was observed in patients with VM and those with unilateral MD, respectively. (3) Area under the curve (AUC) showed a low diagnostic value for the MRI-PP distance and MRI-VA visibility, respectively, in differentiating between the VM and unilateral MD.ConclusionsBased on non-enhanced MRI-visualized measurement, anatomical variables with regard to the endolymphatic drainage system differed significantly between the patients with VM and those with unilateral MD. Further investigations are needed to improve the diagnostic value of these indices in differentiating VM from unilateral MD.
| S-EPMC9099065 | biostudies-literature
Project description:Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for EGFR-T790M-positive non-small cell lung cancer. A high incidence of interstitial lung disease (ILD) during combination treatment with osimertinib and anti-programmed cell death-ligand 1 (PD-L1) inhibitor has been reported. The current study presents a case of ILD development during osimertinib treatment following nivolumab (an anti-PD-1 antibody) treatment. The 59-year-old female was diagnosed with stage IV lung adenocarcinoma harboring a deletion in exon 19 of the EGFR gene. Following nivolumab as a sixth-line treatment, an EGFR-T790M-encoding mutation in EGFR exon 20 was identified by re-biopsy. Osimertinib was therefore initiated as a seventh-line treatment. A partial response was subsequently noted; however, 63 days after initiation of the treatment the patient presented with dyspnea with decreased oxygenation in the absence of fever and sputum. A computed tomography scan revealed the emergence of ground-glass opacities with bronchiectasis in both lungs, and a diagnosis of ILD due to osimertinib was made. Following steroid pulse therapy with discontinuation of osimertinib, the patient's chest findings and respiratory condition improved. Therefore, it is considered that anti-PD-1 therapies may be associated with a risk of ILD during subsequent osimertinib treatment.
| S-EPMC5543261 | biostudies-other