Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants.

BACKGROUND: Otitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility. METHODS: We performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localisation and gene expression in infected and healthy middle ear tissues. RESULTS: A large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals cosegregates two known rare A2ML1 variants, a common FUT2 variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within SPINK5 (LOD=4.09). Carriage of the SPINK5 missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel SPINK5 variants were identified in 12 families and individuals with OM. A role for SPINK5 in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localisation in outer ear skin, faint localisation to middle ear mucosa and eardrum and increased SPINK5 expression in human cholesteatoma. CONCLUSION: SPINK5 variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota and facilitation of entry of opportunistic pathogens into the middle ear.

Genetic and Environmental Determinants of Otitis Media in an Indigenous Filipino Population.

OBJECTIVE: To identify genetic and environmental risk factors for otitis media in an indigenous Filipino population. STUDY DESIGN: Cross-sectional study. SETTING: Indigenous Filipino community. SUBJECTS AND METHODS: Clinical history and information on breastfeeding, tobacco smoke exposure, and swimming were obtained from community members. Heads of households were interviewed for family history and personal beliefs on ear health. Height and weight were measured. Otoscopic findings were described for the presence and character of perforation or discharge. An A2ML1 duplication variant that confers otitis media susceptibility was Sanger sequenced in all DNA samples. Co-occurrence of middle ear bacteria detected by 16S rRNA gene sequencing was determined according to A2ML1 genotype and social cluster. RESULTS: The indigenous Filipino population has a ~50% prevalence of otitis media. Young age was associated with otitis media (4 age strata; P = .004); however, age was nonsignificant as a bistratal or continuous variable. There was no association between otitis media and sex, body mass index, breastfeeding, tobacco exposure, or deep swimming. In multivariate analyses, A2ML1 genotype is the strongest predictor of otitis media, with an odds ratio of 3.7 (95% confidence interval: 1.3-10.8; P = .005). When otitis media diagnoses were plotted across ages, otitis media was observed within the first year of life, and chronic otitis media persisted up to adulthood, particularly in A2ML1-variant carriers. CONCLUSION: Among indigenous Filipinos, A2ML1 genotype is the primary risk factor for otitis media and main determinant of disease progression, although age, the middle ear microbiome, and social clusters might modulate the effect of the A2ML1 genotype.

The variable clinical presentation of tuberculosis otitis media and the importance of early detection.

BACKGROUND: Tuberculosis (TB) is a rare cause of otitis media. This study aims to increase awareness on the clinical presentation of TB otitis media and illustrate how early detection affects treatment outcome. METHODS: Chart review of 12 patients (13 ears) from a tertiary hospital in Manila, Philippines, seen from 2004 to 2009. Clinical predictors of the disease were summarized. Clinical, radiologic, and audiometric outcomes after treatment were compared between treatment groups. RESULTS: The 5 otoscopic presentations were multiple perforations, single perforation with refractory otorrhea and exuberant granulation tissue formation, single perforation with minimal otorrhea and no granulation tissue formation, intact tympanic membrane with middle ear effusion, and intact tympanic membrane with tumorlike tissue in the middle ear. Clinical predictors of the disease were history of pulmonary TB, work-related contamination of the infection, positive purified protein derivative test, positive chest radiographic finding and intraoperative granulation tissue with cheesy material, and temporal bone computed tomographic scan findings. Patients who had no middle ear surgery showed significantly better clinical, radiologic, and audiometric outcomes than those who were diagnosed late and had more complicated surgical procedure. CONCLUSION: The clinical presentation of TB otitis media is variable. Early detection of the early forms entail less surgical intervention and favors better treatment results.

Probabilities of ossicular discontinuity in chronic suppurative otitis media using pure-tone audiometry.

OBJECTIVE: To analyze the likelihood ratios (LRs) and predictive values of preoperative air-bone gap (ABG) levels on the presence of gross ossicular discontinuity (OD) among chronic suppurative otitis media (CSOM) patients. SETTING: Tertiary hospitals. METHODS: Records of 276 patients with CSOM 7 to 75 years old undergoing their first tympanomastoidectomy were reviewed. Association of preoperative audiogram on the presence of OD was analyzed using logistic regression analysis and chi 2 tests. Frequency-specific ABG values were compared with the presence of OD. RESULTS: In CSOM without cholesteatoma, the ABG of 20 dB or less at 500 Hz (LR [-], 0.119; 95% confidence interval [CI], 0.016-0.867) and 30 dB or less at 1 kHz (LR [-], 0.276; 95% CI, 0.087-0.876) decreased probability of OD from 33 to 5.6% and 15.5%, respectively. Air-bone gap levels of greater than 30 dB at 2 kHz (LR [+], 2.8; 95% CI, 1.4-5.9) and greater than 40 dB at 4 kHz (LR [+], 2.2; 95% CI, 1.2-3.9) increased the probability of OD from 33 to 51 to 89%. In the presence of cholesteatoma, the chance of OD was 88%. The ability of ABG to alter probability of OD was not significant in the presence of cholesteatoma. CONCLUSION: Narrow ABG at lower frequencies suggested absence of OD. Wide ABG at higher frequencies suggested presence of OD. Simple tympanoplasty can be done to patients with a small chance of OD as assessed by pure-tone audiometry, whereas a mandatory exploration of the ossicular chain with possible reconstruction was suggested on subjects with a high chance of OD. The presence of cholesteatoma warrants ossicular chain exploration.

Training of nurses in ear examination and hearing screening in the school setting.

The objectives of this study were to determine the agreement between the ear examination findings of the otorhinolaryngologist (trainer) and the elementary school nurse (trainee) after training with the use of a penlight and to determine the mean sound pressure level (SPL) produced by school nurses as a standard parameter for hearing screening using a 512 tuning fork after training on tuning fork testing by the otorhinolaryngologist. Training workshops in ear examination using a penlight and hearing screening using a 512 tuning fork were conducted for school nurses. Data for assessment of ear examination skills and production of SPL were collected by questionnaire and observation of performance. Kappa statistics were used to assess agreement between trainees' and trainer's responses. Mean and standard deviation were determined for the assessment of the SPL produced. Results showed an excellent agreement between the school nurses' and otorhinolaryngologist's observations on ear examination. These included observations of the ear canal, visualization of the tympanic membrane and identification of unusual findings such as wax and discharge. The majority of nurses responded positively in terms of the ease and confidence in performance of the procedure. Regarding tuning fork testing, the nurses were able to produce significant SPL. The mean SPL produced by the nurses using a 512 tuning fork was 56.316 dB.