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Otitis media affects nearly all children worldwide. Despite an enormous amount of research, our understanding of this common condition continues to be challenged. New pathogens involved in otitis media are still being identified. The importance of interactions between viral and bacterial infection and the role of new vaccines need to be clarified. The proposal that bacteria can become more resistant to therapy through biofilm formation and intracellular infection could have important implications for treatment. The most important clinical research findings have been summarised in systematic reviews. In developed countries, research supporting "watchful waiting" of otitis media with effusion and acute otitis media have had most impact on evidence-based clinical practice guidelines. Indigenous Australian children remain at risk of more severe otitis media. Research programs targeting this population have been well supported. Unfortunately, interventions that can dramatically improve outcomes have remained elusive. For children at high risk of otitis media, health care services should concentrate on accurate diagnosis, antibiotic treatment of suppurative infections, and scheduled follow-up of affected children. Despite the lack of recent studies, strategies to minimise the impact the hearing loss associated with otitis media are important. Improvements in education, hygiene practices, and living conditions are likely to reduce the incidence and severity of otitis media. Studies of these types of interventions are needed. [ABSTRACT FROM AUTHOR]

Otitis media remains a major health problem in Australia, with an unacceptably great dichotomy of incidence and severity of otitis media and its complications between Indigenous and non-Indigenous Australians. Among most children with acute otitis media, infection resolves rapidly with or without antibiotics, with ongoing middle ear effusion the only sequela. Overcrowding, poor living conditions, exposure to cigarette smoke, and lack of access to medical care are all major risk factors for otitis media. Estimates of the number of cases of otitis media in 2008 vary between 992,000 and 2,430,000 Australians, with a total estimated cost of $100 - $400 million. [ABSTRACT FROM AUTHOR]

Background: One third of children require repeat ventilation tube insertion (VTI) for otitis media. Disease recurrence is associated with persistent middle ear bacterial biofilms. With demonstration that Dornase alfa (a DNase) disrupts middle ear effusion biofilms ex vivo, we identified potential for this as an anti-biofilm therapy to prevent repeat VTI. First, safety and tolerability needed to be measured., Methods: This was a phase 1B double-blinded randomized control trial conducted in Western Australia. Children between 6 months and 5 years undergoing VTI for bilateral middle ear effusion were recruited between 2012 and 2014 and followed for two years. Children's ears were randomized to receive either Dornase alfa (1 mg/mL) or 0.9 % sodium chloride (placebo) at time of surgery. Children were followed up at 2 weeks post-VTI and at 3-monthly intervals for 2 years. Outcomes assessed were: 1) safety and tolerability, 2) otorrhoea frequency, 3) blocked or extruded ventilation tube (VT) frequency, 4) time to blockage or extrusion, 5) time to infection recurrence and/or need for repeat VTI., Results: Sixty children (mean age 2.3 years) were enrolled with 87 % reaching study endpoint. Treatment did not change otorrhoea frequency. Hearing improved in all children following VTI, with no indication of ototoxicity. Dornase alfa had some effect on increasing time until VT extrusion (p = 0.099); and blockage and/or extrusion (p = 0.122). Frequency of recurrence and time until recurrence were similar. Fourteen children required repeat VTI within the follow-up period., Conclusion: A single application of Dornase alfa into the middle ear at time of VTI was safe, non-ototoxic, and well-tolerated., Trial Registration: ACTRN12623000504617., Competing Interests: Declaration of competing interest There are no financial interests. Prof. Richmond serves on scientific advisory boards, and together with A/Prof Kirkham has received institutional funding for investigator-initiated grants, from GSK, Pfizer and MSD – all are unrelated to this work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Our goal was to identify genetic risk factors for severe otitis media (OM) in Aboriginal Australians., Methods: Illumina® Omni2.5 BeadChip and imputed data were compared between 21 children with severe OM (multiple episodes chronic suppurative OM and/or perforations or tympanic sclerosis) and 370 individuals without this phenotype, followed by FUnctional Mapping and Annotation (FUMA). Exome data filtered for common (EXaC_all ≥ 0.1) putative deleterious variants influencing protein coding (CADD-scaled scores ≥15] were used to compare 15 severe OM cases with 9 mild cases (single episode of acute OM recorded over ≥3 consecutive years). Rare (ExAC_all ≤ 0.01) such variants were filtered for those present only in severe OM. Enrichr was used to determine enrichment of genes contributing to pathways/processes relevant to OM., Results: FUMA analysis identified 2 plausible genetic risk loci for severe OM: NR3C1 (Pimputed_1000G = 3.62 × 10-6) encoding the glucocorticoid receptor, and NREP (Pimputed_1000G = 3.67 × 10-6) encoding neuronal regeneration-related protein. Exome analysis showed: (i) association of severe OM with variants influencing protein coding (CADD-scaled ≥ 15) in a gene-set (GRXCR1, CDH23, LRP2, FAT4, ARSA, EYA4) enriched for Mammalian Phenotype Level 4 abnormal hair cell stereociliary bundle morphology and related phenotypes; (ii) rare variants influencing protein coding only seen in severe OM provided gene-sets enriched for "abnormal ear" (LMNA, CDH23, LRP2, MYO7A, FGFR1), integrin interactions, transforming growth factor signaling, and cell projection phenotypes including hair cell stereociliary bundles and cilium assembly., Conclusions: This study highlights interacting genes and pathways related to cilium structure and function that may contribute to extreme susceptibility to OM in Aboriginal Australian children., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Introduction: The 2001 Recommendations for clinical care guidelines on the management of otitis media in Aboriginal and Torres Islander populations were revised in 2010. This 2020 update by the Centre of Research Excellence in Ear and Hearing Health of Aboriginal and Torres Strait Islander Children used for the first time the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach., Main Recommendations: We performed systematic reviews of evidence across prevention, diagnosis, prognosis and management. We report ten algorithms to guide diagnosis and clinical management of all forms of otitis media. The guidelines include 14 prevention and 37 treatment strategies addressing 191 questions., Changes in Management as a Result of the Guidelines: A GRADE approach is used. Targeted recommendations for both high and low risk children. New tympanostomy tube otorrhoea section. New Priority 5 for health services: annual and catch-up ear health checks for at-risk children. Antibiotics are strongly recommended for persistent otitis media with effusion in high risk children. Azithromycin is strongly recommended for acute otitis media where adherence is difficult or there is no access to refrigeration. Concurrent audiology and surgical referrals are recommended where delays are likely. Surgical referral is recommended for chronic suppurative otitis media at the time of diagnosis. The use of autoinflation devices is recommended for some children with persistent otitis media with effusion. Definitions for mild (21-30 dB) and moderate (> 30 dB) hearing impairment have been updated. New "OMapp" enables free fast access to the guidelines, plus images, animations, and multiple Aboriginal and Torres Strait Islander language audio translations to aid communication with families., (© 2021 Commonwealth of Australia and The Menzies School of Health Research. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Background: Repeat ventilation tube insertion (VTI) is common in children with recurrent acute otitis media (rAOM). Identifying risk factors associated with repeat surgery will improve clinical management and prevent repeat VTI., Methods: Surgical records were assessed at 8 years following VTI surgery for rAOM in children 6-36 months of age. Children were grouped according to detection of bacterial otopathogen in their middle ear effusion (MEE) at the time of VTI, and outcomes for future otorhinolaryngology surgery compared., Results: Age, gender, pneumococcal vaccination status, antibiotic usage, day-care attendance, number of siblings and number of AOM episodes were similar between groups. Of the 63 children who had PCR +ve MEE, 58.7% required repeat VTI compared with 31.4% of the 51 children with no otopathogen detected in their MEE (odds ratio = 3.1, 95% confidence interval [1.4-6.8]; P = 0.004). Nontypeable Haemophilus influenzae (NTHi) was the predominant otopathogen in MEE (79% of all PCR +ve MEE). Respiratory virus detection was not associated with repeat VTI., Conclusions: Presence of bacterial otopathogen, specifically nontypeable H. influenzae, in the middle ear during VTI was a predictor of children at-risk of repeat VTI. Here, we identify a modifiable microbiologic factor for repeat VTI that can be targeted to improve clinical management of rAOM.

Recurrent and chronic otitis media (OM) are often refractory to antibiotics due to bacterial persistence in biofilm within the middle ear. In vitro and in vivo studies have demonstrated that antimicrobial proteins and peptides (AMPs) are bactericidal against otopathogens, indicating potential therapeutic value for recalcitrant OM. We measured concentrations of 6 AMPs and 14 cytokines in middle ear effusion (MEE) from 67 children undergoing ventilation tube insertion for recurrent acute OM. Sixty one percent of children had bacterial otopathogens detected in their MEE, 39% by PCR and 22% by PCR and culture. Groups were defined as: PCR-negative/culture-negative (absence of bacterial otopathogen), n = 26; PCR-positive/culture-negative (presence of nonculturable bacterial otopathogen), n = 26; PCR-positive/culture-positive (presence of culturable bacterial otopathogen), n = 15. Age, antibiotic usage, day-care attendance, presence of respiratory viruses in MEE and number of AOM episodes were similar between groups. AMP and cytokine concentrations were higher in children with bacterial otopathogens in their MEE compared to those with no bacterial otopathogens. Median concentrations of AMPs (except HBD2) were 3 to 56-fold higher in MEE from children with bacterial otopathogens detected in their MEE (P ≤ 0.01). Similarly, median cytokine concentrations (except TGFβ) were >16-fold higher in MEE with bacterial otopathogens detected (P ≤ 0.001). This is the first study to measure AMPs in MEE and together with the cytokine data, results suggest that elevated AMPs and cytokines in MEE are a marker of inflammation and bacterial persistence. AMPs may play an important role in OM pathogenesis., Competing Interests: Professor Peter Richmond has served on vaccine scientific advisory boards, and together with Dr Kirkham has received institutional funding for investigator-initiated grants from GlaxoSmithKline and Pfizer that are unrelated to this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: To determine the degree of agreement of diagnoses by audiologists and otolaryngologists of otitis media (OM) in Aboriginal children., Design: Cross-sectional study of agreement between diagnoses., Setting: Study of Environment on Aboriginal Resilience and Child Health (SEARCH), a prospective cohort study of Aboriginal children attending four Aboriginal Community Controlled Health Services in New South Wales (three metropolitan, one regional) during 2008-2012., Participants: 1310 of 1669 SEARCH participants (78.5%; mean age, 7.0 years; SD, 4.4 years) were assessed and received a diagnosis from one of five experienced audiologists. Test results (but not case histories) were forwarded to one of three otolaryngologists for blinded independent assessment., Main Outcome Measures: Agreement of OM diagnoses by audiologists and otolaryngologists at ear and child levels; correctness of audiologist diagnoses (otolaryngologist diagnosis as reference)., Results: Paired diagnoses by audiologists and otolaryngologists were available for 863 children at the child level and 1775 ears (989 children) at the ear level. Otolaryngologists diagnosed OM in 251 children (29.1%), including 11 (1.3%) with tympanic membrane perforation, and in 396 ears (22.3%), including 12 (0.7%) with perforation. Agreement between audiologists and otolaryngologists for OM at the ear level was 92.2% (κ = 0.78; 95% CI, 0.74-0.82), and at the child level 91.7% (κ = 0.81; 95% CI, 0.77-0.85). No otolaryngologist-diagnosed perforation was missed by audiologists. Among 1000 children triaged by an audiologist, there would be 45 false positives and 30 false negatives when compared with assessments by an otolaryngologist, with no missed perforations., Conclusions: There was substantial agreement between audiologists' and otolaryngologists' diagnoses of OM in a high prevalence population of Aboriginal children. In settings with limited access to otolaryngologists, audiologists may appropriately triage children and select those requiring specialist review.

Indigenous populations experience high rates of otitis media (OM), with increased chronicity and severity, compared to those experienced by their nonindigenous counterparts. Data on immune responses to otopathogenic bacteria in these high-risk populations are lacking. Nontypeable Haemophilus influenzae (NTHi) is the predominant otopathogen in Australia. No vaccines are currently licensed to target NTHi; however, protein D (PD) from NTHi is included as a carrier protein in the 10-valent pneumococcal polysaccharide conjugate vaccine (PHiD10-CV), and other promising protein vaccine candidates exist, including outer membrane protein 4 (P4) and protein 6 (P6). We measured the levels of serum and salivary IgA and IgG against PD, P4, and P6 in Aboriginal and non-Aboriginal children with chronic OM who were undergoing surgery and compared the levels with those in healthy non-Aboriginal children (controls). We found that Aboriginal cases had lower serum IgG titers to all NTHi proteins assessed, particularly PD. In contrast, serum IgA and salivary IgA and IgG titers to each of these 3 proteins were equivalent to or higher than those in both non-Aboriginal cases and healthy controls. While serum antibody levels increased with age in healthy controls, no changes in titers were observed with age in non-Aboriginal cases, and a trend toward decreasing titers with age was observed in Aboriginal cases. This suggests that decreased serum IgG responses to NTHi outer membrane proteins may contribute to the development of chronic and severe OM in Australian Aboriginal children and other indigenous populations. These data are important for understanding the potential benefits of PHiD10-CV implementation and the development of NTHi protein-based vaccines for indigenous populations., (Copyright © 2017 Thornton et al.)

Background: The Australian Aboriginal population experiences disproportionately high rates of otitis media (OM). Streptococcus pneumoniae is one of the main pathogens responsible for OM and currently no vaccine offering cross strain protection exists. Vaccines consisting of conserved antigens to S. pneumoniae may reduce the burden of OM in high-risk populations; however no data exists examining naturally acquired antibody in Aboriginal children with OM., Methods: Serum and salivary IgA and IgG were measured against the S. pneumoniae antigens PspA1 and 2, CbpA and Ply in a cross sectional study of 183 children, including 36 non-Aboriginal healthy control children and 70 Aboriginal children and 77 non-Aboriginal children undergoing surgery for OM using a multiplex bead assay., Results: Significant differences were observed between the 3 groups for serum anti-PspA1 IgA, anti-CbpA and anti-Ply IgG and for all salivary antibodies assessed. Aboriginal children with a history of OM had significantly higher antibody titres than non-Aboriginal healthy children with no history of OM and non-Aboriginal children with a history of OM for several proteins in serum and saliva. Non-Aboriginal children with a history of OM had significantly higher salivary anti-PspA1 IgG than healthy children, while all other titres were comparable between the groups., Conclusions: Conserved vaccine candidate proteins from S. pneumoniae induce serum and salivary antibody responses in Aboriginal and non-Aboriginal children with a history of OM. Aboriginal children do not have an impaired antibody response to the antigens measured from S. pneumoniae and they may represent vaccine candidates in Indigenous populations., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Otitis media (OM) is a common childhood disease characterised by middle ear effusion and inflammation. Susceptibility to recurrent acute OM and chronic OM with effusion is 40-70% heritable. Linkage studies provide evidence for multiple putative OM susceptibility loci. This study attempts to replicate these linkages in a Western Australian (WA) population, and to identify the etiological gene(s) in a replicated region., Methods: Microsatellites were genotyped in 468 individuals from 101 multicase families (208 OM cases) from the WA Family Study of OM (WAFSOM) and non-parametric linkage analysis carried out in ALLEGRO. Association mapping utilized dense single nucleotide polymorphism (SNP) data extracted from Illumina 660 W-Quad analysis of 256 OM cases and 575 controls from the WA Pregnancy Cohort (Raine) Study. Logistic regression analysis was undertaken in ProbABEL. RT-PCR was used to compare gene expression in paired adenoid and tonsil samples, and in epithelial and macrophage cell lines. Comparative genomics methods were used to identify putative regulatory elements and transcription factor binding sites potentially affected by associated SNPs., Results: Evidence for linkage was observed at 10q26.3 (Zlr = 2.69; P = 0.0036; D10S1770) with borderline evidence for linkage at 10q22.3 (Zlr = 1.64; P = 0.05; D10S206). No evidence for linkage was seen at 3p25.3, 17q12, or 19q13.43. Peak association at 10q26.3 was in the intergenic region between TCERG1L and PPP2R2D (rs7922424; P = 9.47 × 10-6), immediately under the peak of linkage. Independent associations were observed at DOCK1 (rs9418832; P = 7.48 × 10-5) and ADAM12 (rs7902734; P = 8.04 × 10-4). RT-PCR analysis confirmed expression of all 4 genes in adenoid samples. ADAM12, DOCK1 and PPP2R2D, but not TCERG1L, were expressed in respiratory epithelial and macrophage cell lines. A significantly associated polymorphism (rs7087384) in strong LD with the top SNP (rs7922424; r2 = 0.97) alters a transcription factor binding site (CREB/CREBP) in the intergenic region between TCERG1L and PPP2R2D., Conclusions: OM linkage was replicated at 10q26.3. Whilst multiple genes could contribute to this linkage, the weight of evidence supports PPP2R2D, a TGF-β/Activin/Nodal pathway modulator, as the more likely functional candidate lying immediately under the linkage peak for OM susceptibility at chromosome 10q26.3.

Otitis media (OM) is a common disease in early childhood characterised by inflammation of the middle ear. Susceptibility to recurrent acute OM (rAOM; ≥3 episodes AOM in 6 months) and chronic OM with effusion (COME; middle ear effusion ≥3 months) is 40-70% heritable. Three bacterial pathogens commonly associated with OM, Streptococcus pneumoniae (Sp), non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mc), have been observed within adenoids and as facultative intracellular pathogens that invade and survive in mononuclear cells. Case/pseudo-control conditional logistic regression analysis of variants in the SLC11A1 gene, initially identified for its role in resistance to intra-macrophage pathogens in mice, revealed association with OM at four polymorphisms (Pbest=0.025) in 531 families (660 affected children) from the Western Australian Family Study of Otitis Media. This included association at the functional promoter GTn polymorphism (rs34448891) with alleles that regulate high (allele 3; odds ratio=1.2, 95% CI 1.00-1.44, P=0.04) versus low (allele 2; odds ratio=0.83, 95% CI 0.69-0.99, P=0.04) SLC11A1 expression. Haplotype and stepwise conditional logistic regression analyses support a single genetic effect in the proximal region of SLC11A1, with the haplotype 3&#95;C&#95;C&#95;G across rs34448891&#95;rs2276631&#95;rs3731865&#95;rs2695343 significantly (P=0.008) over-transmitted to affected offspring. Stratified analysis showed no association with OM in children who had undergone adenoidectomy (296 children), whereas children with adenoids intact (364 children) showed improved significance at the GTn polymorphism (allele 3: odds ratio=1.38, 95% CI=1.10-1.75, P=0.006). Quantitative RT/PCR demonstrated high expression of SLC11A1 in mononuclear cells isolated from adenoid tissue, with a trend for decreased expression with increasing copies of GTn allele 2. Expression of SLC11A1 was enhanced at 12 (P=1.2×10(-3)) and 24h (P<1.0×10(-4)) after infection of Mono-Mac-6 cells with NTHi. This study identifies SLC11A1 as a novel candidate for OM susceptibility, particularly in children with adenoids intact. Further analysis in other cohorts is required to validate these observations., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Recurrent acute otitis media (AOM), frequently caused by Streptococcus pneumoniae, is a major paediatric health problem. A reduced antibody response against pneumococcal polysaccharides may contribute to an increased susceptibility to AOM. Using a multiplex bead-based assay we measured IgG, IgG1 and IgG2 levels against 11 pneumococcal polysaccharides in serum samples from 166 children below 3 years of age with a history of at least 3 episodes of acute otitis media receiving ventilation tubes, and 61 healthy controls. Pneumococcal serotype specific IgG was also determined in 144 middle ear effusion samples. Pneumococcal serotype specific IgG, IgG1 and IgG2 levels were similar in children with or without AOM, except for IgG and IgG1 levels against serotype 5, which were significantly higher in children with a history of frequent AOM (IgG: 137.5 μg/ml vs. 84.0 μg/ml; p=0.02; IgG1: 24.5 μg/ml vs. 18.2 μg/ml; p=0.05). The age-related development of pneumococcal serotype-specific IgG, IgG1 and IgG2 levels was similar in children with or without a history of AOM. Pneumococcal serotype specific IgG was present in middle ear effusion and these levels correlated significantly with serum titres. Children with a history of frequent AOM receiving ventilation tubes do not have a deficient IgG, IgG1 or IgG2 response against pneumococcal polysaccharides, either induced by vaccination or due to natural exposure. The strong correlation between IgG levels in serum and the middle ear suggests parenteral pneumococcal conjugate vaccination induces antibodies in the middle ear which may therefore contribute to reducing the burden of AOM., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Bacteria persist within biofilms on the middle ear mucosa of children with recurrent and chronic otitis media however the mechanisms by which these develop remain to be elucidated. Biopsies can be difficult to obtain from children and their small size limits analysis., Methods: In this study we aimed to investigate biofilm presence in middle ear effusion (MEE) from children with recurrent acute otitis media (rAOM) and to determine if these may represent infectious reservoirs similarly to those on the mucosa. We examined this through culture, viability staining and fluorescent in situ hybridisation (FISH) to determine bacterial species present. Most MEEs had live bacteria present using viability staining (32/36) and all effusions had bacteria present using the universal FISH probe (26/26). Of these, 70% contained 2 or more otopathogenic species. Extensive DNA stranding was also present. This DNA was largely host derived, representing neutrophil extracellular traps (NETs) within which live bacteria in biofilm formations were present. When treated with the recombinant human deoxyribonuclease 1, Dornase alfa, these strands were observed to fragment., Conclusions: Bacterial biofilms, composed of multiple live otopathogenic species can be demonstrated in the MEEs of children with rAOM and that these contain extensive DNA stranding from NETs. The NETs contribute to the viscosity of the effusion, potentially contributing to its failure to clear as well as biofilm development. Our data indicates that Dornase alfa can fragment these strands and may play a role in future chronic OM treatment.

Background: Vaccines including conserved antigens from Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi) have the potential to reduce the burden of acute otitis media. Little is known about the antibody response to such antigens in young children with recurrent acute otitis media, however, it has been suggested antibody production may be impaired in these children., Methods: We measured serum IgG levels against 4 pneumococcal (PspA1, PspA 2, CbpA and Ply) and 3 NTHi (P4, P6 and PD) proteins in a cross-sectional study of 172 children under 3 years of age with a history of recurrent acute otitis media (median 7 episodes, requiring ventilation tube insertion) and 63 healthy age-matched controls, using a newly developed multiplex bead assay., Results: Children with a history of recurrent acute otitis media had significantly higher geometric mean serum IgG levels against NTHi proteins P4, P6 and PD compared with healthy controls, whereas there was no difference in antibody levels against pneumococcal protein antigens. In both children with and without a history of acute otitis media, antibody levels increased with age and were significantly higher in children colonised with S. pneumoniae or NTHi compared with children that were not colonised., Conclusions: Proteins from S. pneumoniae and NTHi induce serum IgG in children with a history of acute otitis media. The mechanisms in which proteins induce immunity and potential protection requires further investigation but the dogma of impaired antibody responses in children with recurrent acute otitis media should be reconsidered.

Background: Otitis media (OM) is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; ≥ 3 episodes of AOM in 6 months) and chronic OM with effusion (COME; MEE ≥ 3 months) is 40-70% heritable. Few underlying genes have been identified to date, and no genome-wide association study (GWAS) of OM has been reported., Methods and Findings: Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation) were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine) Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR = 1.90; 95%CI 1.47-2.45; P(adj-PCA) = 8.3 × 10(-7)) on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR = 1.60; 95%CI 1.29-1.99; P(adj-PCA) = 2.2 × 10(-5)) observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (P(Gene) = 2 × 10(-5)) and BPIFA1 (P(Gene) = 1.07 × 10(-4)) in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (P(adj-PCA)<10(-5)) in this GWAS, with pathway analysis showing a connection between top candidates and the TGFβ pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals) from the Western Australian Family Study of Otitis Media (WAFSOM). Lack of replication may be explained by sample size, difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS., Conclusions: This first discovery GWAS for an OM phenotype has identified CAPN14 and GALNT14 on chromosome 2p23.1 and the BPIFA gene cluster on chromosome 20q11.21 as novel candidate genes which warrant further analysis in cohorts matched more precisely for clinical phenotypes.

Both bacteria and viruses play a role in the development of acute otitis media, however, the importance of specific viruses is unclear. In this study molecular methods were used to determine the presence of nucleic acids of human rhinoviruses (HRV; types A, B, and C), respiratory syncytial viruses (RSV; types A and B), bocavirus (HBoV), adenovirus, enterovirus, coronaviruses (229E, HKU1, NL63, and OC43), influenza viruses (types A, B, and C), parainfluenza viruses (types 1, 2, 3, 4A, and 4B), human metapneumovirus, and polyomaviruses (KI and WU) in the nasopharynx of children between 6 and 36 months of age either with (n = 180) or without (n = 66) a history of recurrent acute otitis media and in 238 middle ear effusion samples collected from 143 children with recurrent acute otitis media. The co-detection of these viruses with Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis was analyzed. HRV (58.3% vs. 42.4%), HBoV (52.2% vs. 19.7%), polyomaviruses (36.1% vs. 15.2%), parainfluenza viruses (29.4% vs. 9.1%), adenovirus (25.0% vs. 6.1%), and RSV (27.8% vs. 9.1%) were detected significantly more often in the nasopharynx of children with a history of recurrent acute otitis media compared to healthy children. HRV was predominant in the middle ear and detected in middle ear effusion of 46% of children. Since respiratory viruses were detected frequently in the nasopharynx of both children with and without a history of recurrent acute otitis media, the etiological role of specific viruses in recurrent acute otitis media remains uncertain, however, anti-viral therapies may be beneficial in future treatment and prevention strategies for acute otitis media., (Copyright © 2011 Wiley-Liss, Inc.)

Background: Bacteria which are metabolically active yet unable to be cultured and eradicated by antibiotic treatment are present in the middle ear effusion of children with chronic otitis media with effusion (COME) and recurrent acute otitis media (rAOM). These observations are suggestive of biofilm presence or intracellular sequestration of bacteria and may play a role in OM pathogenesis. The aim of this project is to provide evidence for the presence of otopathogenic bacteria intracellularly or within biofilm in the middle ear mucosa of children with COME or rAOM., Methods: Middle ear mucosal biopsies from 20 children with COME or rAOM were examined for otopathogenic bacteria (either in biofilm or located intracellularly) using transmission electron microscopy (TEM) or species specific fluorescent in situ hybridisation (FISH) and confocal laser scanning microscopy (CLSM). One healthy control biopsy from a child undergoing cochlear implant surgery was also examined., Results: No bacteria were observed in the healthy control sample. In 2 of the 3 biopsies imaged using TEM, bacteria were observed in mucus containing vacuoles within epithelial cells. Bacterial species within these could not be identified and biofilm was not observed. Using FISH with CLSM, bacteria were seen in 15 of the 17 otitis media mucosal specimens. In this group, 11 (65%) of the 17 middle ear mucosal biopsies showed evidence of bacterial biofilm and 12 demonstrated intracellular bacteria. 52% of biopsies were positive for both biofilm and intracellular bacteria. At least one otopathogen was identified in 13 of the 15 samples where bacteria were present. No differences were observed between biopsies from children with COME and those with rAOM., Conclusion: Using FISH and CLSM, bacterial biofilm and intracellular infection with known otopathogens are demonstrated on/in the middle ear mucosa of children with COME and/or rAOM. While their role in disease pathogenesis remains to be determined, this previously undescribed infection pattern may help explain the ineffectiveness of current treatment strategies at preventing or resolving COME or rAOM.

In Australia the 7-valent pneumococcal conjugate vaccine (PCV7) is administered at 2, 4 and 6 months of age, with no booster dose. Information on bacterial carriage and the aetiology of recurrent acute otitis media (rAOM) after introduction of PCV7 using the 3+0 schedule is required to evaluate the potential impact of second generation pneumococcal vaccines. We found that 2-4 years after introduction of PCV7 in the National Immunisation Program, nontypeable Haemophilus influenzae (NTHi) was the predominant pathogen isolated from the nasopharynx and middle ear of children with a history of rAOM. Compared with healthy controls (n=81), NTHi and Streptococcus pneumoniae carriage rates were significantly higher in children with a history of rAOM (n=186) (19% vs. 56% p<0.0001 and 26% vs. 41%, p=0.02, respectively). Carriage of PCV7 pneumococcal serotypes was rare, whereas PCV7-related and non-PCV7 serotypes were isolated of 38% of cases and 24% of controls. Serotype 19A was the most common serotype isolated from the nasopharynx and middle ear and accounted for 36% (14/39) of total pneumococcal isolates with reduced susceptibility to cotrimoxazole. Of the 119 children carrying NTHi, 17% of isolates were β-lactamase positive. The scarcity of PCV7 serotypes in children with and without a history of rAOM indicates that the 3+0 PCV7 schedule is preventing carriage and rAOM from PCV7 serotypes. Introduction of new vaccines in Australia with increased pneumococcal serotype and pathogen coverage, including 19A and NTHi, should decrease the circulation of antibiotic-resistant bacteria and reduce the burden of rAOM., (Copyright © 2011. Published by Elsevier Ltd.)

Otitis media (OM) is a common childhood disease characterised by middle ear inflammation following infection. Susceptibility to recurrent acute OM (rAOM) and chronic OM with effusion (COME) is highly heritable. Two murine mutants, Junbo and Jeff, spontaneously develop severe OM with similar phenotypes to human disease. Fine-mapping of these mutants identified two genes (Evi1 and Fbxo11) that interact with the transforming growth factor β (TGFβ) signalling pathway. We investigated these genes, as well as four Sma- and Mad-related (SMAD) genes of the TGFβ pathway, as candidate rAOM/COME susceptibility genes in two predominantly Caucasian populations. Single-nucleotide polymorphisms (SNPs) within FBXO11 (family-based association testing Z-Score=2.61; P(best)=0.009) were associated with severe OM in family-based analysis of 434 families (561 affected individuals) from the Western Australian Family Study of OM. The FBXO11 association was replicated by directed analysis of Illumina 660W-Quad Beadchip data available for 253 cases and 866 controls (OR=1.55 (95% CI 1.28-1.89); P(best)=6.9 × 10(-6)) available within the Western Australian Pregnancy Cohort (Raine) Study. Combined primary and replication results show P(combined)=2.98 × 10(-6). Neither cohort showed an association with EVI1 variants. Family-based associations at SMAD2 (P=0.038) and SMAD4 (P=0.048) were not replicated. Together, these data provide strong evidence for FBXO11 as a susceptibility gene for severe OM.

Objective: To describe diagnoses and correlates of middle ear disease in Aboriginal primary school children in a targeted school-testing program in Perth, Western Australia., Design and Setting: Analysis of records of ear testing carried out over a 6-year period in three primary schools in Perth., Participants: Aboriginal children of primary school age (4-12 years) who attended the schools on the day of testing. Data on middle ear disease and hearing impairment were available for 119 and 94 children, respectively, from their first test., Main Outcome Measures: Proportions of children with middle ear disease and hearing loss., Results: Middle ear disease was diagnosed in 50 children (42.0%; 95% CI, 33.0%-51.4%). Rates were lower in older children (P = 0.002) but did not differ according to season of testing. Hearing loss (mild or moderate) was detected in 18 children (19.1%; 95% CI, 11.8%-28.6%). Hearing impairment was also less prevalent in older children (P = 0.007) and had no association with season of testing., Conclusions: Middle ear disease is a significant problem for Aboriginal children in Perth, and is associated with mild-moderate hearing loss. Health authorities must continue to focus on appropriate identification and management of the disease in this population.

Objective: Otitis media (OM) is an inflammation of the middle ear. It is very common and associated with serious complications, including hearing loss. This study aimed to estimate the treatment costs of OM in Australia and the associated burden of disease (in disability-adjusted life-years)., Methods: Little Australia-wide epidemiological information is available, so international studies in the main were used to estimate the incidence and prevalence by age and gender. These were triangulated against the available Australian data. Australian health data sets and data collected from the emergency department of a tertiary pediatric hospital were used to estimate the costs of primary care, pharmaceuticals, pathology and imaging, emergency department presentations, specialists, and admitted hospital care., Results: Excluding the costs of the complications and comorbidities associated with OM, treatment costs for the disease in 2008 were between AUS$100 and 400 million. Visits to general practitioners and medicines constituted a high proportion of these costs. Antibiotic prescribing rates remain high despite clear evidence for a limited benefit from antibiotics for most OM cases and concerns regarding bacterial resistance., Conclusion: Treatment costs of OM in Australia are high and can only be estimated within a broad range. Further research on the links between antibiotics for OM and antibiotic resistance, and on the cost-effectiveness of prevention or amelioration of OM would be useful.

Objectives: To determine the risk of otitis media (OM) associated with passive smoking in young children, and any competing effect between passive smoking and childcare attendance., Design, Participants and Setting: Prospective cohort study of 100 Aboriginal and 180 non-Aboriginal children born in Kalgoorlie Regional Hospital between 1 April 1999 and 31 January 2003. These children underwent routine clinical examinations by an ear, nose and throat specialist up to three times before the age of 2 years, and tympanometry at routine field follow-up visits from the age of 4 months. Childrens' mothers were interviewed at 1-3 weeks postpartum to provide sociodemographic data., Main Outcome Measures: Associations between OM and exposure to environmental tobacco smoke (ETS) and childcare attendance., Results: 82 Aboriginal and 157 non-Aboriginal children attended for routine clinical examinations. OM was diagnosed at least once in 74% of Aboriginal children and 45% of non-Aboriginal children; 64% of Aboriginal children and 40% of non-Aboriginal children were exposed to ETS. Exposure to ETS increased the risk of specialist-diagnosed OM in Aboriginal children (OR, 3.54; 95% CI, 1.68-7.47); few attended childcare. Non-Aboriginal children exposed to ETS but not attending childcare were at increased risk of OM (OR, 1.91; 95% CI, 1.07-3.42) while those attending childcare had no increased smoking-related risk. Tympanometry was performed on 87 Aboriginal and 168 non-Aboriginal children; a type B tympanogram (suggesting fluid in the middle ear) was also associated with passive smoking in Aboriginal children., Conclusions: Reducing the exposure of children to ETS is a public health priority, especially for the Aboriginal population. A smoke-free environment will help reduce the burden of OM.

Morbidly obese children undergoing adenotonsillectomy, often with co-morbid obstructive sleep apnoea, may be considered at a higher risk of postoperative respiratory compromise. This retrospective study aimed to assess the frequency and severity of postoperative respiratory complications in these patients and to identify preoperative risks factors for such morbidity. Medical and nursing chart review of all consecutive elective post-adenotonsillectomy admissions of morbidly obese children (defined as >95th centile for body mass index adjusted for age and gender) to our intensive care unit over a 30-month period was performed. A total of 26 morbidly obese children were identified. The majority (14/26) had an uncomplicated recovery following surgery. Of those cases that required postoperative intervention, 10 patients required supplemental oxygen with or without suctioning and/or repositioning alone, whilst two required continuous positive airway pressure therapy. No patient required re-intubation. An oxygen saturation nadir of < 70% and the presence of more than one central apnoea, noted on preoperative overnight polysomnography, were associated with postoperative respiratory complications requiring intervention. Although the intervention group were younger, more obese and had a higher respiratory disturbance index, none of these factors were statistically significant. Routine admission to the paediatric intensive care unit of all morbidly obese children undergoing adenotonsillectomy may be unnecessary, once a suitable high level of nursing is available in an alternative setting, to administer simple positional and suctioning intervention and to perform regular patient observation. Special consideration should be given to the postoperative nursing environment for those patients with a SaO2 nadir < 70% noted preoperatively, indicating the presence of a significant central disease component.

Obstructive sleep apnea syndrome is a common occurrence in the obese pediatric population. As this subgroup is rapidly expanding, these children will be increasingly encountered by the otolaryngologist in practice. The literature regarding the etiology, pathogenesis, diagnosis and surgical treatment of obstructive sleep apnea in morbidly obese children is reviewed and pertinent data presented.

Objective: To determine if digitised still eardrum images, with a clinical history, and audiometry and tympanometry data provide sufficient information to an ear specialist to make an assessment of a patient., Methods: 66 children (9 months to 16 years) from remote communities were assessed by an ear specialist by standard otoscopy, using a clinical history, audiometry and tympanometry. Up to five images of each ear were digitised. At a later date, the ear specialist made observations, diagnoses and recommendations for management from the images and clinical data., Results: There was a significant correlation (p<0.01) between image quality and age of the subject. There were significant agreements for the clinically important observations of otorrhea, perforation, retracted tympanic membrane and atrophy of the tympanic membrane (p<0.05). There were significant agreements for the diagnoses of acute otitis media, chronic suppurative otitis media, otitis media with effusion and Eustachian tube dysfunction. The rate of recommendations for review or referral after a tele-otology assessment were between 4 and 16% higher than those in made in the field. The agreements between the various forms of advice or recommendations made in the field to those made by tele-otology were statistically significant (p<0.01)., Conclusions: A tele-otology system that incorporates good quality digitised images of the tympanic membrane, audiological and tympanometric data, and a comprehensive clinical history provides the ear specialist with sufficient information to make a confident diagnose of existing middle ear disease, and provide management advice to the patients' primary care provider.

Aim: To report the preliminary findings of a pilot program to screen newborn babies for congenital bilateral permanent hearing loss., Setting: The five largest maternity hospitals in Perth, Western Australia. Screening was gradually introduced over seven months from February to August 2000., Participants: All babies born at these hospitals after the introduction of hearing screening until 30 June 2001., Methods: One or both of two automated screening devices were used: one measuring transient evoked otoacoustic emissions (TEOAE) and the other automated auditory brainstem responses (AABR). If a "pass" was not obtained in both ears, screening was repeated. All babies who did not obtain a pass in either ear at follow-up were referred for audiological assessment., Main Outcome Measures: Prevalence of permanent bilateral hearing loss., Results: Of 13 214 eligible babies, 12 708 (96.2%) received screening. The main reason for missing screening was early hospital discharge (309; 2.3%). Of the screened babies, 99% had a pass response in both ears at either the initial or follow-up screen. Twenty-three babies were referred for audiological assessment, and nine were diagnosed with bilateral permanent hearing loss (0.68/1000; 95% CI, 0.31-1.28)., Conclusions: Despite our program meeting process quality indicators, our detection rate was low. Before extending the program to smaller hospitals, we need to validate our screening instruments and put in place a system to monitor false negative results.

A 4-year old boy scheduled for insertion of ventilation tubes suffered significant aural hemorrhage following incision of the tympanic membrane. Examination under anaesthetic resulted in further hemorrhage. Investigation by carotid angiography revealed an anomalous internal carotid artery coursing through the middle ear with a small pseudoaneurysm. Subsequent management of this patient and review of the literature is presented.

The Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma, suggesting an etiologic relationship. We have under-taken studies (1) to quantitate the relationship between antibody titers to EBV-associated antigens and nasopharyngeal carcinoma in American patients since most of the patients in previous studies were of either Asian or African descent and (2) to determine the relationship between antibody titers and the clinical course of the disease. Sera from patients with primary or recurrent nasopharyngeal carcinoma and from patients in remission, from patients with various other head and neck tumors (including occult primary lesions and lymphomas), and from normal controls were titrated for IgG antibodies to viral capsid antigen (VCA) and early antigen and IgA antibodies to VCA, using indirect immunofluorescence procedures previously detailed. High titers of antibodies to EBV-induced early antigens and VCA in the IgG fraction and VCA in the IgA fraction were frequently found in the sera of patients with nasopharyngeal carcinoma. A significant reduction in these titers was observed with clinical remission of the disease in treated patients. Preliminary findings suggest that EBV serology may be useful in the evaluation and treatment of patients with nasopharyngeal carcinoma and also in patients with cervical metastases from clinically occult promary sites in order to identify those with occult nasopharyngeal carcinoma.

Thirty-five sera from American patients with nasopharyngeal carcinoma were examined for Epstein-Barr virus (EBV)-associated antigens and compared with 85 sera from patients with other head and neck cancers, 80 sera from patients with lymphoma, and 47 sera from healthy control subjects. There was a definite correlation between the presence of nasopharyngeal carcinoma and the level of antibody titers to EBV. In particular, two tests that detected antibody to early antigen and antibody to viral capsid antigen in the serum IgA fraction were highly specific for the presence of nasopharyngeal carcinoma. There was a significant decrease in these antibody titers with clinical remission of the disease in treated patients with nasopharyngeal carcinoma. Clinically, these tests should have important application in the management and follow-up of patients with nasopharyngeal carcinoma.

Thirteen patients, six men and seven women, were seen at the Mayo Clinic with chondrosarcomas of the nasal cavity, paranasal sinuses, or nasopharynx in a 25-year period. Nasal obstruction, discharge, and bleeding were the major symptoms and a nasal mass was the most common sign. The typical chondrosarcoma is low in grade but malignant and it arises in the nasal cavity as a large, pale, glistening mass. Local excision was employed initially in seven patients and five had local recurrence. Definitive block excision cured four of six patients and the two others had a protracted clinical course and ultimately died of the disease. Long-term follow-up shows that chondrosarcomas are insidious, locally progressive tumors. Radiotherapy, used for palliation after recurrence, failed to produce any cures. Lateral rhinotomy and block excision are advocated as the primary treatment.

After extensive evaluation of patients with metastatic neck disease and clinically undetectable primary cancer of the head and neck, the clinician is often faced with the difficult question of subsequent management. In this study, sera from 11 patients with clinically occult carcinoma and metastatic lymphadenopathy were studied for Epstein-Barr virus-associated antigens. These were compared with 35 sera from patients with known nasopharyngeal carcinoma at all stages of disease and treatment and with 212 sera from control patients with other head and neck tumors, patients with lymphoma, and normal controls. There was a significant correlation between high antibody titers to Epstein-Barr virus, especially in the serum IgA fraction, and the presence of nasopharyngeal carcinoma. Thus, identification of occult nasopharyngeal carcinoma by immunologic means may have important application in the selective management of the patient with an unknown head and neck primary malignancy.

Granular cell tumors of the larynx are relatively uncommon, always benign, and most commonly located in the posterior portion of the larynx. They are easily identified and should be differentiated from other lesions. A possible problem in the differential diagnosis is the presence of pseudoepitheliomatous hyperplasia, which overlies the granular cell tumor and which may mimic squamous cell carcinoma. Careful histopathologic differentiation is important because the laryngeal granular cell lesion should be managed conservatively, with transoral local excision usually being adequate. The histogenesis of these lesions remains in doubt, with a neural or epithelial derivation being the most likely possibility.

There is now extensive immunological, biological and biochemical evidence to support a possible etiological relationship between EBV and NPC in patients from different geographical locations. Besides providing information on the question of etiology, the results from immunological investigations suggest that antibodies to some of the EBV-associated antigens might also be of clinical importance in the diagnosis and prognosis of NPC. To determine the possible clinical application of EBV serology to American NPC, sera from patients seen at the Mayo Clinic and the National Institutes of Health were examined for antibodies to EBV-associated antigens in an effort to identify those parameters which most reliably distinguish NPC from other types of cancer. The results show that high antibody titres to EBV-induced EA and the presence of antibody to EBV antigens in the IgA immunoglobulin fraction were the two most specific discriminating parameters, although neither was infallible. These findings are discussed in relation to future studies that are needed in order to determine the potential clinical value of EBV serology to the diagnosis and prognosis of NPC.

Clinically suspect but nonfatal pulmonary embolism followed vein surgery in 16 of 4,080 patients operated on over a 10-year period from 1962 to 1971, an incidence of 0.39%. The presence of superficial thrombophlebitis, previous or recent thromboembolic disease, or chronic deep venous insufficiency was a statistically significant factor in patients who had embolism. Prophylactic postoperative anticoagulant treatment in those with a thrombotic background appears justified.

Salivary gland tumors of the palate originate in the minor salivary glands located in the glandular zone of the palate. Approximately 7 per cent of all tumors of the salivary gland occur in the palate, and approximately one-half of such tumors are cancers. The salivary gland tumor is more often found in the hard palate. Of the 90 salivary gland tumors of the palate reported herein, 49 per cent were benign, and all were pleomorphic adenomas. Of the cancers, 70 per cent were cylindromas, 15 per cent mucoepidermoid cancers, and the remaining 15 per cent included acinic cell carcinomas, undifferentiated carcinomas, and papillary adenocarcinomas. There is a 50 per cent likelihood of a lump in the palate in the glandular zone being a cancer. The simplistic diagnosis of a cyst should be considered only after other lesions have been excluded. The recommended form of treatment is surgical excision. Fenestration of the palate is a potential consequence of excision in 30 to 60 per cent of patients, depending upon whether or not the lesion is benign or malignant. The results of surgical treatment are good, but fenestration shoud be accepted as a necessary result of adequate treatment. Surgical treatment of cylindromas continues to be most difficult and demands the utmost of that intangible essence known as surgical judgment. Radiotherapy has been considered as a palliative agent for the treatment of inoperable and recurring cancers, especially cylindromas.

Serous otitis media is a capricious entity that can cause conductive deafness. The condition is most common in children, who often cannot describe the attending symptoms of deafness, fullness, and pressure. The basic contributing factor is inadequate function of the eustachian tube. Function improves as the child approaches 12 years of age. Underlying factors such as infections, adenoidal hypertrophy, and allergic states also must be managed. The otitis media may be treated medically or surgically.

Between 1962 and 1971, 221 patients (197 men and 24 women) with carcinoma of the supraglottic larynx were treated at our institution. Most of the patients were in the sixth and seventh decades of life. In 89% of the patients, the epiglottis was involved. One hundred ninety patients underwent surgery, 161 for cure initially and 29 for salvage after radiation failure. Definitive surgery included laryngectomy in 117 patients and conservation procedures in 40. Fifty-five patients were treated by radiation for cure. Survival rates after laryngectomy or supraglottic laryngectomy were similar, but radiation therapy carried a poorer prognosis than did definitive surgery. Routine neck dissection was not necessary in all patients with supraglottic carcinoma.