T-Cell Immune Responses in Newborns and Long-Term Sequelae in Congenital Cytomegalovirus Infection (CYTRIC Study).

OBJECTIVE: The objective of this study was to assess the role of T-lymphocyte immune responses in newborns with congenital cytomegalovirus (CMV) infection (cCMV) and their potential association with the development of long-term sequelae. STUDY DESIGN: A multicenter, prospective study from 2017 to 2022 was conducted across 8 hospitals in Spain. Blood samples were collected within the first month of life from neonates diagnosed with cCMV. Intracellular cytokine staining was employed to evaluate the presence of CMV-specific interferon-gamma (IFN-γ)-producing CD8+ and CD4+ T lymphocytes (CMV-IFN-γ-CD8+/CD4+) using flow cytometry. The development of sequelae, including hearing loss and neurologic impairment, was assessed during follow-up. RESULTS: In total, 64 newborns were included; 42 infants (65.6%) had symptomatic cCMV. The median age at the last follow-up visit was 25.3 months (IQR 20.1-34.4). Eighteen infants had long-term sequelae (28.1%), predominantly hearing loss (20.3%) and neurologic disorders (15.6%). No relationship was observed between total count or percentage of CMV-specific IFN-γ-CD8+ or CD4+ lymphocytes and long-term sequelae. Multivariable analysis demonstrated an association between lower total lymphocyte count and long-term sequelae (aOR 0.549, 95% CI: 0.323-0.833), which requires further study. CONCLUSIONS: CMV-specific IFN-γ-CD4+ and CD8+ T-lymphocyte responses in neonates with cCMV were not predictive of long-term sequelae.

Immunogenicity, otitis media, hearing impairment, and nasopharyngeal carriage 6-months after 13-valent or ten-valent booster pneumococcal conjugate vaccines, stratified by mixed priming schedules: PREVIX_COMBO and PREVIX_BOOST randomised controlled trials.

BACKGROUND: Australian First Nations children are at very high risk of early, recurrent, and persistent bacterial otitis media and respiratory tract infection. With the PREVIX randomised controlled trials, we aimed to evaluate the immunogenicity of novel pneumococcal conjugate vaccine (PCV) schedules. METHODS: PREVIX_BOOST was a parallel, open-label, outcome-assessor-blinded, randomised controlled trial. Aboriginal children living in remote communities of the Northern Territory of Australia were eligible if they had previously completed the three-arm PREVIX_COMBO randomised controlled trial of the following vaccine schedules: three doses of a 13-valent PCV (PCV13; PPP) or a ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; SSS) given at 2, 4, and 6 months, or SSS given at 1, 2, and 4 months followed by PCV13 at 6 months (SSSP). At age 12 months, eligible children were randomly assigned by a computer-generated random sequence (1:1, stratified by primary group allocation) to receive either a PCV13 booster or a PHiD-CV10 booster. Analyses used intention-to-treat principles. Co-primary outcomes were immunogenicity against protein D and serotypes 3, 6A, and 19A. Immunogenicity measures were geometric mean concentrations (GMC) and proportion of children with IgG concentrations of 0·35 µg/mL or higher (threshold for invasive pneumococcal disease), and GMCs and proportion of children with antibody levels of 100 EU/mL or higher against protein D. Standardised assessments of otitis media, hearing impairment, nasopharyngeal carriage, and developmental outcomes are reported. These trials are registered with ClinicalTrials.gov (NCT01735084 and NCT01174849). FINDINGS: Between April 10, 2013, and Sept 4, 2018, 261 children were randomly allocated to receive a PCV13 booster (n=131) or PHiD-CV10 booster (n=130). Adequate serum samples for pneumococcal serology were obtained from 127 (95%) children in the PCV13 booster group and 126 (97%) in the PHiD-CV10 booster group; for protein D, adequate samples were obtained from 126 (96%) children in the PCV13 booster group and 123 (95%) in the PHiD-CV10 booster group. The proportions of children with IgG concentrations above standard thresholds in PCV13 booster versus PHiD-CV10 booster groups were the following: 71 (56%) of 126 versus 81 (66%) of 123 against protein D (difference 10%, 95% CI -2 to 22), 85 (67%) of 127 versus 59 (47%) of 126 against serotype 3 (-20%, -32 to -8), 119 (94%) of 127 versus 91 (72%) of 126 against serotype 6A (-22%, -31 to -13), and 116 (91%) of 127 versus 108 (86%) of 126 against serotype 19A (-5%, -13 to 3). Infant PCV13 priming mitigated differences between PCV13 and PHiD-CV10 boosters. In both groups, we observed a high prevalence of otitis media (about 90%), hearing impairment (about 75%), nasopharyngeal carriage of pneumococcus (about 66%), and non-typeable H influenzae (about 57%). Of 66 serious adverse events, none were vaccine related. INTERPRETATION: Low antibody concentrations 6 months post-booster might indicate increased risk of pneumococcal infection. The preferred booster was PCV13 if priming did not have PCV13, otherwise either PCV13 or PHiD-CV10 boosters provided similar immunogenicity. Mixed schedules offer flexibility to regional priorities. Non-PCV13 serotypes and non-typeable H influenzae continue to cause substantial disease and disability in Australian First Nation's children. FUNDING: National Health and Medical Research Council (NHMRC).

The Versatile Gasdermin Family: Their Function and Roles in Diseases.

The gasdermin (GSDM) family, a novel group of structure-related proteins, consists of GSDMA, GSDMB, GSDMC, GSDMD, GSDME/DNFA5, and PVJK/GSDMF. GSDMs possess a C-terminal repressor domain, cytotoxic N-terminal domain, and flexible linker domain (except for GSDMF). The GSDM-NT domain can be cleaved and released to form large oligomeric pores in the membrane that facilitate pyroptosis. The emerging roles of GSDMs include the regulation of various physiological and pathological processes, such as cell differentiation, coagulation, inflammation, and tumorigenesis. Here, we introduce the basic structure, activation, and expression patterns of GSDMs, summarize their biological and pathological functions, and explore their regulatory mechanisms in health and disease. This review provides a reference for the development of GSDM-targeted drugs to treat various inflammatory and tissue damage-related conditions.

'Cochlear-type' hearing loss as part of aquaporin-4 neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder is an inflammatory autoimmune central nervous system condition caused in the majority of cases by aquaporin-4 IgG antibodies. Aquaporin-4 is expressed in the cochlear and vestibular nuclei regions in the brainstem and a handful of cases of retro-cochlear type hearing loss have been documented in the literature. Aquaporin-4 has also been reported within the organ of Corti and the cristae and maculae of the vestibular apparatus. We present a case where there is evidence of peripheral (labyrinthine) rather than central pathology and propose this is due to autoimmune inflammation as part of neuromyelitis optica spectrum disorder. This is the first case in the literature suggesting a 'cochlear-type' hearing loss occurring as part of neuromyelitis optica spectrum disorder. It raises the possibility of peripheral relapses of neuromyelitis optica spectrum disorder going unnoticed, resulting in patient morbidity, and highlights the importance of research within this area.

The Role of Anti-Endothelial Cell Autoantibodies and Immune Response in Acute Low-Tone Hearing Loss.

OBJECTIVE: Immunity is associated with acute low tone hearing loss. However, the exact pathophysiology of immunity-mediated acute low tone hearing loss remains unknown. In this study, we evaluated the presence, therapeutic effectiveness, and immunopathological mechanisms of anti-endothelial cell autoantibodies (AECEs) in patients with acute low-frequency hearing loss. MATERIAL AND METHODS: Forty-nine patients who were treated as inpatients having acute low-frequency hearing loss and additional symptoms, such as ear fullness, tinnitus, dizziness, or hyperacusis, were enrolled in this study. Serum samples from these patients were collected for laboratory serum autoimmunity detection, including AECAs, antinuclear antibodies, immunoglobulin, and circular immune complex. Therapeutic responses to combination therapy in short-term outcome and serum cytokine levels were compared between AECA-positive and AECA-negative patients. RESULTS: Anti-endothelial cell autoantibodies-positive patients tended to show significantly less response to standard therapy compared with AECAs controls (P < .05). Moreover, some serum cytokine levels elevated in both AECAs- and AECAs+ groups. Positive ratio of interleukin-8 and concentrations of macrophage inflammatory protein-1α were found higher in AECAs+ groups (P < .05). CONCLUSION: The results supported that AECAs might wield influence on the short-term outcome of acute low-tone hearing loss (ALHL) treatment. Furthermore, AECA-mediated acute low-frequency hearing loss possibly involved dysregulation of inflammation process and release of cytokines.

Association of inflammatory markers with hearing impairment: The English Longitudinal Study of Ageing.

BACKGROUND: Hearing impairment is common at an older age and has considerable social, health and economic implications. With an increase in the ageing population, there is a need to identify modifiable risk factors for hearing impairment. A shared aetiology with cardiovascular disease (CVD) has been advanced as CVD risk factors (e.g. obesity, type 2 diabetes) are associated with a greater risk of hearing impairment. Moreover, low-grade inflammation is implicated in the aetiology of CVD. Accordingly, our aim was to investigate the association between several markers of inflammation - C-reactive protein, fibrinogen and white blood cell count - and hearing impairment. METHODS: Participants of the English Longitudinal Study of Ageing aged 50-93 were included. Inflammatory marker data from both wave 4 (baseline, 2008/09) and wave 6 (2012/13) were averaged to measure systemic inflammation. Hearing acuity was measured with a simple handheld tone-producing device at follow-up (2014/15). RESULTS: Among 4879 participants with a median age of 63 years at baseline, 1878 (38.4%) people presented hearing impairment at follow-up. All three biomarkers were positively and linearly associated with hearing impairment independent of age and sex. After further adjustment for covariates, including cardiovascular risk factors (smoking, physical activity, obesity, diabetes, hypertension, cholesterol), memory and depression, only the association with white blood cell count remained significant: odds ratio per log-unit increase; 95% confidence interval = 1.46; 1.11, 1.93. CONCLUSIONS: While white blood cell count was positively associated with hearing impairment in older adults, no relationships were found for two other markers of low-grade inflammation.

BDNF, NT-3 and Trk receptor agonist monoclonal antibodies promote neuron survival, neurite extension, and synapse restoration in rat cochlea ex vivo models relevant for hidden hearing loss.

Neurotrophins and their mimetics are potential treatments for hearing disorders because of their trophic effects on spiral ganglion neurons (SGNs) whose connections to hair cells may be compromised in many forms of hearing loss. Studies in noise or ototoxin-exposed animals have shown that local delivery of NT-3 or BDNF has beneficial effects on SGNs and hearing. We evaluated several TrkB or TrkC monoclonal antibody agonists and small molecules, along with BDNF and NT-3, in rat cochlea ex vivo models. The TrkB agonists BDNF and a monoclonal antibody, M3, had the greatest effects on SGN survival, neurite outgrowth and branching. In organotypic cochlear explants, BDNF and M3 enhanced synapse formation between SGNs and inner hair cells and restored these connections after excitotoxin-induced synaptopathy. Loss of these synapses has recently been implicated in hidden hearing loss, a condition characterized by difficulty hearing speech in the presence of background noise. The unique profile of M3 revealed here warrants further investigation, and the broad activity profile of BDNF observed underpins its continued development as a hearing loss therapeutic.

Microglial activation in the cochlear nucleus after early hearing loss in rats.

OBJECTIVE: Microglia are highly specialized tissue macrophages in the central nervous system. Their activation in the auditory system has been reported in adult hearing loss models, but their status in the developing auditory system is less understood. Therefore, we investigated microglial status in the cochlear nucleus (CN) during normal developing periods and after exposing rats to amikacin, a potent ototoxin, around the time of hearing onset. METHODS: To develop the deafness model, rats were administered with a daily intraperitoneal injection of amikacin (500 mg/kg) from postnatal day 7 (P7) to P15. To evaluate the expression of ionized calcium binding adaptor molecule 1 (Iba1), we performed immunohistochemical analysis using rat brains from P10-60. To compare the expression of microglia-related gene, reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis were performed. RESULTS: Immunohistochemical analysis revealed that, under normal conditions, microglia had relatively large cell bodies with several extended processes that surrounded other cells at P10, while the sizes and number of these cells gradually decreased afterward. In contrast, when amikacin was administered from P7 to P15, microglia maintained large cell bodies with relatively shorter processes at both P15 and P21. Furthermore, RT-qPCR analysis revealed upregulation of genes including phagocytotic and anti-inflammatory markers after amikacin administration. CONCLUSION: These results suggest that microglia are activated in the CN, and they may contribute to tissue remodeling after early hearing loss in the developing auditory system.

Biomarkers of Systemic Inflammation and Risk of Incident Hearing Loss.

BACKGROUND: Chronic inflammation may lead to cochlear damage, and the only longitudinal study that examined biomarkers of systemic inflammation and risk of hearing loss found an association with a single biomarker in individuals <60 years of age. The purpose of our study was to determine whether plasma inflammatory markers are associated with incident hearing loss in two large prospective cohorts, Nurses' Health Studies (NHS) I and II. METHODS: We examined the independent associations between plasma levels of markers of systemic inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and soluble tumor necrosis factor receptor 2 [TNFR-2]) and self-reported hearing loss. The participants in NHS I (n = 6194 women) were 42 to 69 years of age at the start of the analysis in 1990, while the participants in NHS II (n = 2885 women) were 32 to 53 years in 1995. After excluding women with self-reported hearing loss before the time of blood-draw, incident cases of hearing loss were defined as those women who reported hearing loss on questionnaires administered in 2012 in NHS I and 2009 or 2013 in NHS II. The primary outcome was hearing loss that was reported as moderate or worse in severity, pooled across the NHS I and NHS II cohorts. We also examined the pooled multivariable-adjusted hazard ratios for mild or worse hearing loss. Cox proportional hazards regression was used to adjust for potential confounders. RESULTS: At baseline, women ranged from 42 to 69 years of age in NHS I and 32 to 53 years of age in NHS II. Among the NHS I and II women with measured plasma CRP, there were 628 incident cases of moderate or worse hearing loss during 100,277 person-years of follow-up. There was no significant association between the plasma levels of any of the three inflammatory markers and incident moderate or worse hearing loss (multivariable-adjusted pooled p trend for CRP = 0.33; p trend IL-6 = 0.54; p trend TNFR-2 = 0.70). There was also no significant relation between inflammatory marker levels and mild or worse hearing loss. While there was no significant effect modification by age for CRP or IL-6 in NHS I, there was a statistically significant higher risk of moderate or worse hearing loss (p interaction = 0.02) as well as mild or worse hearing loss (p interaction = 0.004) in women ≥60 years of age who had higher plasma TNFR-2 levels. CONCLUSIONS: Overall, there was no significant association between plasma markers of inflammation and risk of hearing loss.

Response of the inner ear to lipopolysaccharide introduced directly into scala media.

In an attempt to develop an animal model of immune mediated Meniere's disease, we have injected lipopolysaccharide (LPS) directly into scala media of guinea pigs and monitored functional and morphological changes over a period of 6 weeks. Depending on the concentration of LPS, changes ranged from moderate-to-severe hearing loss and endolymphatic hydrops with minimal cellular infiltrate or fibrosis, to dense cellular infiltration that filled the scalae. Interestingly, higher concentrations of LPS not only induced severe cellular infiltration, hydrops, and hearing loss, but also a substantial enlargement of the endolymphatic duct and sac. Moreover, LPS injections into perilymph failed to induce hydrops, yet still resulted in cellular infiltration and fibrosis in the cochlea. This suggests that chronic hydrops resulting from an immune challenge of the cochlea may not be due to blockage of the endolymphatic duct and sac, restricting fluid absorption. Furthermore, injecting antigen into endolymph may produce chronic immune-mediated hydrops, and provide a more promising animal model of Meniere's, although animals did not display signs of vestibular dysfunction, and the hearing loss was relatively severe.

¿Puede la tomografía por emisión de positrones ayudar en la caracterización de la enfermedad inmunomediada del oído interno? / Can positron emission tomography support the characterization of immune-mediated inner ear disease?

Introducción: Evaluar la utilidad de la PET/TC con 18F-FDG en la caracterización de la enfermedad inmunomediada del oído interno primaria (EIOI) aportando datos que ayuden a valorar la actividad inflamatoria y la existencia o ausencia de enfermedad sistémica asociada. Material y métodos: Estudio prospectivo sobre 28 pacientes con sospecha de EIOI o EIOI primaria diagnosticada y 4 controles ajustados por edad y sexo, sin enfermedad ótica conocida, a los cuales se había realizado una PET con 18F-FDG por otro motivo. Dieciocho pacientes presentaban EIOI primaria y 10EIOI secundaria. A todos se les realizó una PET/TC con 18F-FDG para valorar la actividad metabólica en el oído interno y la presencia de afectación sistémica. La interpretación del resultado de la PET fue realizada por 2médicos nucleares sin conocimiento de la clínica del paciente. Para valorar la reproductibilidad de las medidas se realizaron análisis Bland y Altman y correlación de coeficientes intraclase. Resultados: Se encontraron hallazgos sospechosos de afectación sistémica en 13 pacientes. Cuatro de ellos correspondieron a pacientes diagnosticados previamente de EIOI primaria que mostraron actividad inflamatoria (tiroidea y aórtica). En cuanto al análisis semicuantitativo de la actividad metabólica en el oído interno, la variabilidad interobservador fue muy alta y no fue posible establecer diferencias adecuadas entre grupos. Conclusiones: Este estudio demuestra que la PET/TC con 18F-FDG puede tener un papel en la evaluación de pacientes con sospecha de EIOI primaria descartando la presencia de datos que sugieran inflamación sistémica. Consideramos que no es adecuado tratar de cuantificar la actividad metabólica del oído interno probablemente por el pequeño tamaño del mismo

Introduction: To evaluate the utility of 18F-FDG PET/TC as an imaging tool for the characterization of immune-mediated inner ear disease (IMIED), providing measurements of the inner ear region activity as well as detecting possible involvement of other organs. Material and methods: The study included 28 patients with IMIED and 4 sex-matched and age-matched control subjects with no history of ear disease. Eighteen patients were considered to be suffering from primary IMIED and 10 patients from secondary. PET/CT scans with 18F-FDG were performed to assess systemic involvement as well as inner ear region activity. Interpretation of PET/CT scans was performed independently by 2nuclear medicine physicians blinded to clinical history. In order to assess inter-rater agreement before performing the analysis of the inner ear, different Bland & Altman plots and the intraclass correlation coefficients were estimated. Results: Different metabolically active foci findings were reported in 13 patients. Four patients diagnosed as primary IMIED showed thyroid and aorta activity. Regarding the inner-ear semiquantitative analysis, the inter-rater agreement was not sufficiently high. Comparisons between groups, performed using Mann-Whitney test or Kruskal-Wallis tests, showed no differences. Conclusions: The study showed 18F-FDG PET/TC could be an important tool in the evaluation of IMIED as it can support the characterization of this entity providing the diagnosis of unknown or underestimated secondary IMIED. Nevertheless, we consider PET is not an adequate tool to approach the inner ear because of the small size and volume of the cochlea which makes the assessment very difficult

La azatioprina reduce el riesgo de recaída audiométrica en hipoacusia inmunomediada / Azathioprine reduces the risk of audiometric relapse in immune-mediated hearing loss

INTRODUCCIÓN: Los esquemas actuales de tratamiento de la hipoacusia inmunomediada con corticoides, dosis baja y pauta corta, son insuficientes. MÉTODOS: Para determinar el papel de la azatioprina en el control del deterioro auditivo se ha llevado a cabo un estudio observacional descriptivo longitudinal con 20 pacientes tratados con azatioprina por vía oral (1,5-2,5 mg/kg/día en dos dosis) durante 1año. Se consideró recaída la pérdida de 10 dB en dos frecuencias consecutivas o de 15 dB en una frecuencia aislada. RESULTADOS: La edad media de los pacientes fue de 52,50 años (IC 95%: 46,91-58,17), y la mitad fueron mujeres. La afectación bilateral fue del 65%. Un 75% presentaban enfermedad organoespecífica y un 25%, enfermedad autoinmune sistémica. La diferencia entre la PTA basal (46,49 dB; DE18,90) y la PTA a los 12meses (45,47 dB; DE 18,88) no alcanzó significación estadística (p = 0,799). Existía una correlación positiva moderada entre sexo femenino y presencia de enfermedad sistémica (R = 0,577). Aplicando t de Student para datos apareados se obtuvo una diferencia significativa (p = 0,042) entre el descenso de la PTA en frecuencias hasta 1.000Hz (PTA125-1.000Hz). La tasa relativa de incidencia de recaída por año fue de 0,52 recaídas/año (IC 95%: 0,19-1,14). El tiempo medio de supervivencia libre de recaída audiométrica fue de 9,70 meses (DE 1,03). CONCLUSIONES: La azatioprina mantiene el umbral de audición, disminuye el riesgo de recaída y frena la velocidad con la que los pacientes recaen, alterando el curso de la enfermedad inmunomediada del oído interno

INTRODUCTION: Current schemes for treatment of immune-mediated hearing loss with sporadic short-course, low-dose corticosteroids, are insufficient. METHODS: To determine the role of azathioprine in the control of auditory impairment, a longitudinal, observational, descriptive study was performed with 20 patients treated with azathioprine (1.5-2.5 mg/kg/day into two doses) for 1year. The loss of 10 dB on two consecutive frequencies or 15 dB on an isolated frequency was considered as relapse. RESULTS: The mean age of the patients was 52.50 years (95% CI: 46.91-58.17), half were women. Bilateral affectation was 65%. 75% had organ specific disease and 25% had systemic autoimmune disease. The difference between baseline PTA (46.49 dB; DS 18.90) and PTA at 12 months (45.47dB; DS 18.88) did not reach statistical significance (P = .799). There was a moderate positive correlation between female sex and the presence of systemic disease (R = .577). By applying Student's t for paired data, a significant difference (P = .042) was obtained between the PTA in frequencies up to 1000 Hz (PTA125-1000Hz). The relative incidence rate of relapse per year was .52 relapses/year (95% CI: .19-1.14]). The median time to audiometric relapse-free was 9.70 months (DS 1.03). CONCLUSIONS: Azathioprine maintains the hearing threshold, decreases the risk of relapse, and slows down the rate at which patients relapse, altering the course of immune-mediated inner ear disease

Análisis de supervivencia libre de recaída audiométrica en pacientes con hipoacusia inmunomediada tratados exclusivamente con corticoides / Analysis of audiometric relapse-free survival in patients with immune-mediated hearing loss exclusively treated with corticosteroids

OBJETIVO: Describir los resultados en términos de supervivencia libre de recaída audiométrica y el ritmo de recaída en pacientes con hipoacusia inmunomediada tratados exclusivamente con corticoides. MÉTODO: Estudio retrospectivo de pacientes, con recaídas audiométricas, en seguimiento desde 1995 hasta 2014, en 2 centros de la Comunidad de Madrid. RESULTADOS: Se evaluaron 31 pacientes con una media de edad de 48,52 años (14,67 DE) de los cuales el 61,3% fueron mujeres. La mayoría de las hipoacusias fueron fluctuantes (48,4%). Solo el 16,1% de los pacientes presentaban enfermedad autoinmune sistémica. Existe una correlación positiva moderada entre ser mujer y presentar afectación sistémica (coeficiente de correlación de Spearman = 0,356). La tasa relativa de incidencia de recaída en el primer año en nuestra serie fue de 2,01 recaídas/año con un IC95% (1,32-2,92). El tiempo de supervivencia medio del evento (recaída audiométrica) fue de 5,25 meses (DE 0,756). Con el análisis multivariante, la única variable que consiguió significación estadística fue la edad, con una hazard ratio de 1,032 (IC95%; 1,001-1,063, p = 0,043). CONCLUSIONES: La enfermedad inmunomediada del oído interno es una enfermedad crónica con recaídas. La mitad de los pacientes tratados exclusivamente con corticoides recaen antes de los 6 meses de seguimiento. Además, si un paciente no ha presentado recaída, tiene más riesgo de recaer cada año que pasa. El análisis de la supervivencia libre de recaída audiométrica permitirá comparar el efecto de tratamientos futuros y su capacidad para reducir el ritmo de recaídas

OBJECTIVE: To describe the results in terms of audiometric relapse-free survival and relapse rate in immunomediated hearing loss patients treated exclusively with corticosteroids. METHOD: Retrospective study of patients with audiometric relapses, monitored from 1995 to 2014, in two centres of the Community of Madrid. RESULTS: We evaluated 31 patients with a mean age of 48.52 years (14.67 SD), of which 61.3% were women. Most hearing loss was fluctuating (48.4%). Only 16.1% of patients had systemic autoimmune disease. There is a moderate positive correlation between the sex variable and the systemic involvement variable (Spearman's correlation coefficient = 0.356): specifically, between being female and systemic disease. The relative incidence rate of relapse in the first year was 2.01 relapses/year with a 95% CI (1.32 to 2.92). The mean survival time of the event (audiometric relapse) was 5.25 months (SD 0.756). With multivariate analysis, the only variable that achieved statistical significance was age, with a hazard ratio of 1.032 (95% CI; 1.001-1.063, P = .043). CONCLUSIONS: Immune-mediated disease of the inner ear is a chronic disease with relapses. Half of the patients with immunomediated hearing loss treated exclusively with corticosteroids relapse before 6 months of follow-up. In addition, if a patient has not relapsed, they are more likely to relapse as each year passes. Analysis of the of audiometric relapse- free survival will enable the effect of future treatments to be compared and their capacity to reduce the rhythm of relapses

Azathioprine reduces the risk of audiometric relapse in immune-mediated hearing loss. / La azatioprina reduce el riesgo de recaída audiométrica en hipoacusia inmunomediada.

INTRODUCTION: Current schemes for treatment of immune-mediated hearing loss with sporadic short-course, low-dose corticosteroids, are insufficient. METHODS: To determine the role of azathioprine in the control of auditory impairment, a longitudinal, observational, descriptive study was performed with 20 patients treated with azathioprine (1.5-2.5mg/kg/day into two doses) for 1year. The loss of 10dB on two consecutive frequencies or 15dB on an isolated frequency was considered as relapse. RESULTS: The mean age of the patients was 52.50years (95%CI: 46.91-58.17), half were women. Bilateral affectation was 65%. 75% had organ specific disease and 25% had systemic autoimmune disease. The difference between baseline PTA (46.49dB; DS18.90) and PTA at 12months (45.47dB; DS18.88) did not reach statistical significance (P=.799). There was a moderate positive correlation between female sex and the presence of systemic disease (R=.577). By applying Student's t for paired data, a significant difference (P=.042) was obtained between the PTA in frequencies up to 1000 Hz (PTA125-1000Hz). The relative incidence rate of relapse per year was .52 relapses/year (95%CI: .19-1.14]). The median time to audiometric relapse-free was 9.70months (DS1.03). CONCLUSIONS: Azathioprine maintains the hearing threshold, decreases the risk of relapse, and slows down the rate at which patients relapse, altering the course of immune-mediated inner ear disease.

Analysis of audiometric relapse-free survival in patients with immune-mediated hearing loss exclusively treated with corticosteroids. / Análisis de supervivencia libre de recaída audiométrica en pacientes con hipoacusia inmunomediada tratados exclusivamente con corticoides.

OBJECTIVE: To describe the results in terms of audiometric relapse-free survival and relapse rate in immunomediated hearing loss patients treated exclusively with corticosteroids. METHOD: Retrospective study of patients with audiometric relapses, monitored from 1995 to 2014, in two centres of the Community of Madrid. RESULTS: We evaluated 31 patients with a mean age of 48.52 years (14.67 SD), of which 61.3% were women. Most hearing loss was fluctuating (48.4%). Only 16.1% of patients had systemic autoimmune disease. There is a moderate positive correlation between the sex variable and the systemic involvement variable (Spearman's correlation coefficient=0.356): specifically, between being female and systemic disease. The relative incidence rate of relapse in the first year was 2.01 relapses/year with a 95% CI (1.32 to 2.92). The mean survival time of the event (audiometric relapse) was 5.25 months (SD 0.756). With multivariate analysis, the only variable that achieved statistical significance was age, with a hazard ratio of 1.032 (95% CI; 1.001-1.063, P=.043). CONCLUSIONS: Immune-mediated disease of the inner ear is a chronic disease with relapses. Half of the patients with immunomediated hearing loss treated exclusively with corticosteroids relapse before 6 months of follow-up. In addition, if a patient has not relapsed, they are more likely to relapse as each year passes. Analysis of the of audiometric relapse- free survival will enable the effect of future treatments to be compared and their capacity to reduce the rhythm of relapses.

Clinical and Molecular Phenotypes of Low-Penetrance Variants of NLRP3: Diagnostic and Therapeutic Challenges.

OBJECTIVE: Cryopyrin-associated periodic syndromes (CAPS) result from gain-of-function mutations in the NLRP3 gene, which causes excessive release of interleukin-1ß (IL-1ß) and systemic inflammation. While pathogenetic NLRP3 variant phenotypes are well-characterized, low-penetrance NLRP3 variants represent a significant clinical challenge. The aims of this study were to determine the clinical phenotype, the in vitro biologic phenotype, and the effect of anti-IL-1 treatment in patients with low-penetrance NLRP3 variants. METHODS: A multicenter study of consecutive symptomatic patients with low-penetrance NLRP3 variants recruited from 7 centers between May 2012 and May 2013 was performed. The observed findings were transferred into a study database, from which they were extracted for analysis. Controls were patients with a known pathogenetic NLRP3 variant. Clinical presentation and CAPS markers of inflammation were captured. Functional assays of inflammasome activation, including caspase 1 activity, NF-κB release, cell death, and IL-1ß release, were performed. Treatment effects of IL-1 were determined. Comparisons between low-penetrance and pathogenetic NLRP3 variants were performed. RESULTS: The study included 45 patients, 21 of which were female (47%); 26 of the patients (58%) were children. NLRP3 low-penetrance variants identified in the patients were Q703K (n = 19), R488K (n = 6), and V198M (n = 20). In the controls, 28 had pathogenetic NLRP3 variants. Patients with low-penetrance NLRP3 variants had significantly more fever (76%) and gastrointestinal symptoms (73%); eye disease, hearing loss, and renal involvement were less common. Functional inflammasome testing identified an intermediate phenotype in low-penetrance NLRP3 variants as compared to wild-type and pathogenetic NLRP3 variants. All treated patients responded to IL-1 inhibition, with complete response documented in 50% of patients. CONCLUSION: Patients with low-penetrance NLRP3 variants display a distinct clinical phenotype and an intermediate biologic phenotype, including IL-1ß and non-IL-1ß-mediated inflammatory pathway activation.

Biochemical, Cellular, Physiological, and Pathological Consequences of Human Loss of N-Glycolylneuraminic Acid.

About 2-3 million years ago, Alu-mediated deletion of a critical exon in the CMAH gene became fixed in the hominin lineage ancestral to humans, possibly through a stepwise process of selection by pathogen targeting of the CMAH product (the sialic acid Neu5Gc), followed by reproductive isolation through female anti-Neu5Gc antibodies. Loss of CMAH has occurred independently in some other lineages, but is functionally intact in Old World primates, including our closest relatives, the chimpanzee. Although the biophysical and biochemical ramifications of losing tens of millions of Neu5Gc hydroxy groups at most cell surfaces remains poorly understood, we do know that there are multiscale effects functionally relevant to both sides of the host-pathogen interface. Hominin CMAH loss might also contribute to understanding human evolution, at the time when our ancestors were starting to use stone tools, increasing their consumption of meat, and possibly hunting. Comparisons with chimpanzees within ethical and practical limitations have revealed some consequences of human CMAH loss, but more has been learned by using a mouse model with a human-like Cmah inactivation. For example, such mice can develop antibodies against Neu5Gc that could affect inflammatory processes like cancer progression in the face of Neu5Gc metabolic incorporation from red meats, display a hyper-reactive immune system, a human-like tendency for delayed wound healing, late-onset hearing loss, insulin resistance, susceptibility to muscular dystrophy pathologies, and increased sensitivity to multiple human-adapted pathogens involving sialic acids. Further studies in such mice could provide a model for other human-specific processes and pathologies involving sialic acid biology that have yet to be explored.

Hearing impairment in patients with rheumatoid arthritis: association with anti-citrullinated protein antibodies.

It has been suggested that hearing impairment (HI) is one of the extra-articular features of rheumatoid arthritis (RA). Nevertheless, the prevalence and nature of HI in RA is still uncertain. The objectives were to study hearing function in patients with RA using audiometric tests and to examine whether HI correlates with autoantibodies. Hearing functions were investigated in 43 consecutive RA patients and 23 control subjects (less than 60 years old). Their sera were evaluated for the presence of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), and anti-mutated citrullinated vimentin (anti-MCV) antibodies. HI was observed in 46.5 % of RA patients and in 30.4 % of control subjects, p = 0.32. HI was characterized as sensorineural in 80 and 85.7 % of RA patients and control subjects with HI, respectively, p = 1.00. RA patients had a worse hearing threshold for air conduction at 6 kHz in the right ear (p = 0.019) and had a decreased amplitude of otoacoustic emissions (OAEs) at 2 kHz bilaterally (p = 0.04) compared with control subjects. In the RA group, patients with and without HI were 80 and 34.78 % anti-CCP positive, respectively, p = 0.008. RA patients with and without HI were 85 and 43.48 % anti-MCV positive, respectively, p = 0.013. HI in RA patients was mainly sensorineural and was associated with anti-CCP and anti-MCV antibodies.

[Delayed diagnosis in a case of granulomatosis with polyangiitis (Wegener's) with initial predominance of joint involvement]. / Diagnostic tardiv într-un caz de granulomatoza cu poliangeita (Wegener) cu manifestari initiale articulare.

The authors present the case of a 53-year-old female, initially admitted in a rheumatology department for fever and diffuse arthritis--being diagnosed with sero-positive rheumathoid arthritis. Although the chest X-ray and CT scan of thorax showed several abnormal features (medium lobe atelectasis, pseudo-cyst in the posterior segment of the right upper lobe with satellite milliary nodules, mediastinal lymph node enlargement), the investigations performed in our pneumology department couldn't establish the etiology of radiological abnormalities. With non-steroidal antiinflamatory treatment, the patient got worse, being readmitted in our hospital after 3 months for high fever, diffuse arthralgia with functional impairment, small hemoptysis, loss of hearing and left ear ache and on chest X-ray with bilateral macronodules, some of these with cavitation. The investigations showed a slight alveolar hemorrhagic syndrome, positive cANCA antibodies, negative antiCCP antibodies--the diagnosis of Wegener's granulomatosis with lung and ENT involvement being established. Puls-therapy with Solumedrol and i.v. Cyclophosphamide was thereafter initiated with a favorable evolution. This case is special because of the initial misdiagnosis due to the atypical pulmonary manifestations and the non-specific paraclinical findings, in the context of diffuse arthritis with positive rheumatoid factor.