Aspergillus Sinusitis: Risk Factors and Phenotyping.

Background: Aspergillus can cause fungal rhinosinusitis (FRS). We aimed to identify risk factors for sinonasal Aspergillus disease. Methods: Patients with a positive sinonasal mycological culture for Aspergillus species diagnosed in our hospital located in a continental climate were included in the 9-year retrospective study. Results: Of the 86 patients, 3 had invasive FRS (IFRS), 51 had fungal ball (FB) disease, and 32 had chronic rhinosinusitis with fungus (CFRS). In the IFRS group, all patients had a malignancy and were immunocompromised. Allergies, allergic rhinitis, asthma, nasal polyps, and the use of inhaled and nasal steroids were more common in the CFRS group, and IgE levels were greater than those in the FB and IRFS groups (p < 0.05). Conclusion: FB disease is a relatively symptom-free single-sinus disease among elderly individuals, and IFRS is dominant among immunocompromised patients. We discovered a third patient group, predominantly with nasal polyps, atopy, asthma, and elevated blood IgE and eosinophils, that did not fulfill the allergic FRS (AFRS) criteria. It is possible that a less fulminant category of underdiagnosed AFRS exists in cold climates. Treatment with local debridement is usually sufficient for FRS, apart from IFRS, and relapses are not common in cold climates.

Inheritance of NSAID-Exacerbated Respiratory Disease.

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) has been considered an acquired condition. Positive first-degree family history has been reported in 1% of cases. The geographic and genetic isolation of the Finnish population offers exceptional opportunities for inheritance studies. In this questionnaire study, we explored the familial aggregation of N-ERD in 66 Finnish families of patients with N-ERD. The majority of patients (67%) had a positive family history of NSAID intolerance, asthma, nasal polyposis, or N-ERD. Furthermore, 55% had a positive first-degree family history of asthma, 21% nasal polyposis, 20% NSAID intolerance, and 11% N-ERD. The prevalence of asthma, nasal polyposis, NSAID intolerance, and N-ERD among first-degree relatives was 13%, 5%, 4%, and 2%, respectively. We present the pedigrees of the 44 affected families. According to our findings, Finnish patients with N-ERD seem to have a genetic susceptibility to it.

Malignant lymphoma presenting as bilateral sensorineural hearing loss-A case report.

Bilateral Sensorineural Hearing Loss is a rare disease that is often associated with other complex medical conditions. Primary central nervous system lymphoma is an uncommon and aggressive variant of non-Hodgkin lymphoma that can mimic many other neurological diseases. Herein, we present a rare case of lymphoma of the CNS as the etiology for progressive SSNHL. We describe a 58-year-old male with previous IgG4-disease presentation who was diagnosed with progressive sensorineural hearing loss. The condition evolved rapidly despite proper, conventional therapy. The patient acquired vestibular symptoms and other cranial nerve deficiencies and he was diagnosed with intracranial lymphoma, mainly in the cerebellar region. This case demonstrates that rare intracranial lymphoma can present initially as sensorineural hearing loss. A higher suspicion for malignancy should be held in mind for patients with a history of IgG4-related diseases and for patients presenting with progressing bilateral SSNHL that is not responding to therapy.

Effects of social distancing on the incidence of Bell's palsy and sudden sensorineural hearing loss.

BACKGROUND: The aetiology of idiopathic facial nerve palsy (Bell's palsy, BP) and sudden sensorineural hearing loss (SSNHL) are not known. It has been proposed that common respiratory tract viruses play a part in the pathophysiology of these diseases. OBJECTIVES: The incidence of many infectious diseases decreased during the lockdown of the society that took place during the COVID-19 pandemic. We investigated a possible change in the incidence of BP and SSNHL during the lock-down. MATERIAL AND METHODS: We searched the patient records for all BP and SSNHL cases between 1 Jan 2017 - 31 Aug 2020 at the hospital district of Helsinki and Uusimaa that covers a population of about 1.2 million. RESULTS: The mean monthly incidence on BP decreased during the COVID-19 pandemic lock-down. No change in the SSNHL incidence was discovered. CONCLUSIONS AND SIGNIFICANCE: There is reason to speculate that one aetiologic reason for BP are transmittable respiratory tract pathogens.

The role of CDHR3 in susceptibility to otitis media.

Otitis media (OM) is common in young children and can cause hearing loss and speech, language, and developmental delays. OM has high heritability; however, little is known about OM-related molecular and genetic processes. CDHR3 was previously identified as a locus for OM susceptibility, but to date, studies have focused on how the CDHR3 p.Cys529Tyr variant increases epithelial binding of rhinovirus-C and risk for lung or sinus pathology. In order to further delineate a role for CDHR3 in OM, we performed the following: exome sequencing using DNA samples from OM-affected individuals from 257 multi-ethnic families; Sanger sequencing, logistic regression and transmission disequilibrium tests for 407 US trios or probands with OM; 16S rRNA sequencing and analysis for middle ear and nasopharyngeal samples; and single-cell RNA sequencing and differential expression analyses for mouse middle ear. From exome sequence data, we identified a novel pathogenic CDHR3 splice variant that co-segregates with OM in US and Finnish families. Additionally, a frameshift and six missense rare or low-frequency variants were identified in Finnish probands. In US probands, the CDHR3 p.Cys529Tyr variant was associated with the absence of middle ear fluid at surgery and also with increased relative abundance of Lysobacter in the nasopharynx and Streptomyces in the middle ear. Consistent with published data on airway epithelial cells and our RNA-sequence data from human middle ear tissues, Cdhr3 expression is restricted to ciliated epithelial cells of the middle ear and is downregulated after acute OM. Overall, these findings suggest a critical role for CDHR3 in OM susceptibility. KEY MESSAGES: • Novel rare or low-frequency CDHR3 variants putatively confer risk for otitis media. • Pathogenic variant CDHR3 c.1653 + 3G > A was found in nine families with otitis media. • CDHR3 p.Cys529Tyr was associated with lack of effusion and bacterial otopathogens. • Cdhr3 expression was limited to ciliated epithelial cells in mouse middle ear. • Cdhr3 was downregulated 3 h after infection of mouse middle ear.

Patient-Reported Control of Asthma, Nasal Polyposis, and Middle-Ear Symptoms in NSAID-Exacerbated Respiratory Disease.

Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is an adult-onset inflammatory condition of the upper and lower airways. It is characterized by the co-existence of asthma, nasal polyposis, and hypersensitivity to NSAIDs. Over one-fourth of patients also have symptoms of chronic middle-ear infection. The clinical course of NERD is often severe and generally requires multimodal treatment with recurrent surgical measures. Studies presenting the disease burden and subjective symptom control of NERD are limited. In this qualitative questionnaire study, we present the clinical characteristics of asthma, nasal polyposis, NSAID intolerance and possible recurrent or chronic middle-ear infection of 66 confirmed NERD patients treated at our tertiary referral center between January 2016 and May 2017. Additionally, we present the patient-reported disease control of asthma, nasal polyposis, and middle-ear symptoms on a four-category Likert scale. The proportion of NERD patients with recurrent or chronic middle-ear infection was 18%. The proportion of good or very good subjective disease control was 83% for asthma, 58% for nasal polyposis, and 33% for chronic middle-ear infection, if present. Chronic middle-ear infection is common among NERD patients and should more often be recognized as part of the entity. Together with nasal polyposis, chronic middle-ear infection seems to affect patients more than asthma. The patient's perspective of disease control should be considered when planning the interdisciplinary follow-up and treatment of NERD.

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.

Multi-omic studies on missense PLG variants in families with otitis media.

Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045 T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045 T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.

Panel 3: Genomics, precision medicine and targeted therapies.

OBJECTIVE: To review the most recent advances in human and bacterial genomics as applied to pathogenesis and clinical management of otitis media. DATA SOURCES: PubMed articles published since the last meeting in June 2015 up to June 2019. REVIEW METHODS: A panel of experts in human and bacterial genomics of otitis media was formed. Each panel member reviewed the literature in their respective fields and wrote draft reviews. The reviews were shared with all panel members, and a merged draft was created. The panel met at the 20th International Symposium on Recent Advances in Otitis Media in June 2019, discussed the review and refined the content. A final draft was made, circulated, and approved by the panel members. CONCLUSION: Trans-disciplinary approaches applying pan-omic technologies to identify human susceptibility to otitis media and to understand microbial population dynamics, patho-adaptation and virulence mechanisms are crucial to the development of novel, personalized therapeutics and prevention strategies for otitis media. IMPLICATIONS FOR PRACTICE: In the future otitis media prevention strategies may be augmented by mucosal immunization, combination vaccines targeting multiple pathogens, and modulation of the middle ear microbiome. Both treatment and vaccination may be tailored to an individual's otitis media phenotype as defined by molecular profiles obtained by using rapidly developing techniques in microbial and host genomics.

ABO Genotype and Blood Type Are Associated with Otitis Media.

Aim: To determine if there is an association between ABO variants or blood types and otitis media. Methods: DNA samples from 214 probands from Finnish families with recurrent acute (RAOM) and/or chronic otitis media with effusion (COME) were submitted for exome sequencing. Fisher exact tests were performed when (a) comparing frequencies of ABO genotypes in the Finnish probands with otitis media vs. counts in gnomAD Finnish, and (b) within the Finnish family cohort, comparing occurrence of RAOM vs. COME according to ABO genotype/haplotype and predicted blood type. Results: Female sex is protective against having both RAOM and COME. The wildtype genotype for the ABO c.260insG (p.Val87_Thr88fs*) variant resulting in blood type O was protective against RAOM. On the other hand, type A was associated with increased risk for COME. These findings remained significant after adjustment for age and sex. Conclusions: Within the Finnish family cohort, the wildtype genotype for the ABO c.260insG (p.Val87_Thr88fs*) variant and type O are protective against RAOM while type A increases risk for COME. This suggests that the association between the ABO locus and otitis media is specific to blood type, otitis media type and cohort.

A mouse-to-man candidate gene study identifies association of chronic otitis media with the loci TGIF1 and FBXO11.

Chronic otitis media with effusion (COME) is the most common cause of hearing loss in children, and known to have high heritability. Mutant mouse models have identified Fbxo11, Evi1, Tgif1, and Nisch as potential risk loci. We recruited children aged 10 and under undergoing surgical treatment for COME from 35 hospitals in the UK, and their nuclear family. We performed association testing with the loci FBXO11, EVI1, TGIF1 and NISCH and sought to replicate significant results in a case-control cohort from Finland. We tested 1296 families (3828 individuals), and found strength of association with the T allele at rs881835 (p = 0.006, OR 1.39) and the G allele at rs1962914 (p = 0.007, OR 1.58) at TGIF1, and the A allele at rs10490302 (p = 0.016, OR 1.17) and the G allele at rs2537742 (p = 0.038, OR 1.16) at FBXO11. Results were not replicated. This study supports smaller studies that have also suggested association of otitis media with polymorphism at FBX011, but this is the first study to report association with the locus TGIF1. Both FBX011 and TGIF1 are involved in TGF-ß signalling, suggesting this pathway may be important in the transition from acute to chronic middle ear inflammation, and a potential molecular target.

Panel 3: Genetics and Precision Medicine of Otitis Media.

Objective The objective is to perform a comprehensive review of the literature up to 2015 on the genetics and precision medicine relevant to otitis media. Data Sources PubMed database of the National Library of Medicine. Review Methods Two subpanels were formed comprising experts in the genetics and precision medicine of otitis media. Each of the panels reviewed the literature in their respective fields and wrote draft reviews. The reviews were shared with all panel members, and a merged draft was created. The entire panel met at the 18th International Symposium on Recent Advances in Otitis Media in June 2015 and discussed the review and refined the content. A final draft was made, circulated, and approved by the panel members. Conclusion Many genes relevant to otitis media have been identified in the last 4 years in advancing our knowledge regarding the predisposition of the middle ear mucosa to commensals and pathogens. Advances include mutant animal models and clinical studies. Many signaling pathways are involved in the predisposition of otitis media. Implications for Practice New knowledge on the genetic background relevant to otitis media forms a basis of novel potential interventions, including potential new ways to treat otitis media.

Genome-wide association analysis reveals variants on chromosome 19 that contribute to childhood risk of chronic otitis media with effusion.

To identify genetic risk factors of childhood otitis media (OM), a genome-wide association study was performed on Finnish subjects, 829 affected children, and 2118 randomly selected controls. The most significant and validated finding was an association with an 80 kb region on chromosome 19. It includes the variants rs16974263 (P = 1.77 × 10(-7), OR = 1.59), rs268662 (P = 1.564 × 10(-6), OR = 1.54), and rs4150992 (P = 3.37 × 10(-6), OR = 1.52), and harbors the genes PLD3, SERTAD1, SERTAD3, HIPK4, PRX, and BLVRB, all in strong linkage disequilibrium. In a sub-phenotype analysis of the 512 patients with chronic otitis media with effusion, one marker reached genome-wide significance (rs16974263, P = 2.92 × 10(-8)). The association to this locus was confirmed but with an association signal in the opposite direction, in a UK family cohort of 4860 subjects (rs16974263, P = 3.21 × 10(-4), OR = 0.72; rs4150992, P = 1.62 × 10(-4), OR = 0.71). Thus we hypothesize that this region is important for COME risk in both the Finnish and UK populations, although the precise risk variants or haplotype background remain unclear. Our study suggests that the identified region on chromosome 19 includes a novel and previously uncharacterized risk locus for OM.

Predisposition to Childhood Otitis Media and Genetic Polymorphisms within the Toll-Like Receptor 4 (TLR4) Locus.

BACKGROUND: Predisposition to childhood otitis media (OM) has a strong genetic component, with polymorphisms in innate immunity genes suspected to contribute to risk. Studies on several genes have been conducted, but most associations have failed to replicate in independent cohorts. METHODS: We investigated 53 gene polymorphisms in a Finnish cohort of 624 cases and 778 controls. A positive association signal was followed up in a tagging approach and tested in an independent Finnish cohort of 205 cases, in a British cohort of 1269 trios, as well as in two cohorts from the United States (US); one with 403 families and the other with 100 cases and 104 controls. RESULTS: In the initial Finnish cohort, the SNP rs5030717 in the TLR4 gene region showed significant association (OR 1.33, P = .003) to OM. Tagging SNP analysis of the gene found rs1329060 (OR 1.33, P = .002) and rs1329057 (OR 1.29, P = .003) also to be associated. In the more severe phenotype the association was stronger. This finding was supported by an independent Finnish case cohort, but the associations failed to replicate in the British and US cohorts. In studies on TLR4 signaling in 20 study subjects, the three-marker risk haplotype correlated with a decreased TNFα secretion in myeloid dendritic cells. CONCLUSIONS: The TLR4 gene locus, regulating the innate immune response, influences the genetic predisposition to childhood OM in a subpopulation of patients. Environmental factors likely modulate the genetic components contributing to the risk of OM.

Current knowledge of the genetics of otitis media.

Otitis media is one of the most common childhood infections leading to doctor's visits and a leading cause of antibiotic prescriptions in children. Twin and family studies have confirmed that the predisposition of developing a bacterial middle ear infection is genetically determined. Several case-control studies have been performed to analyze genes involved in inflammatory processes in search of potential associations. Modern genome-wide association approaches that require no prior assumptions of the involvement of a given gene locus in the risk of otitis media are currently being used to identify otitis media genes, and will hopefully give more detailed information on the pathogenesis of childhood otitis media. That information could be used in finding the high-risk patient, in the prevention of the disease, and in the design of new treatments.

Genetic background and the risk of otitis media.

OBJECTIVE: Otitis media is a multifactorial disease where genetic background may have an important role. For genome-wide association studies, it is important to understand the degree of heritability. The objective of this study was to estimate the heritability of recurrent acute otitis media and chronic otitis media with effusion. METHODS: Children operated because of recurrent or chronic otitis media at the Helsinki University Central Hospital, Finland, as well as their families were recruited during 2008-2009. A cohort of 2436 subjects was enrolled consisting of 1279 children and their parents. The study subjects answered a questionnaire concerning their otitis media history and treatment, as well as tobacco exposure, allergy and asthma history. Heritability estimates were calculated for recurrent acute, chronic and any episodes of otitis media using software especially designed for estimating heritability in family cohorts. RESULTS: Altogether 901 subjects suffered from recurrent otitis media and 559 from chronic otitis media with effusion. The heritability estimates in our cohort were 38.5% for recurrent (P=7.3 × 10(-9)), 22.1% for chronic (P=4.6 × 10(-3)) and 47.8% for any otitis media (P=1.5 × 10(-11)). CONCLUSIONS: Our results demonstrate a moderately strong and statistically significant genetic component for both recurrent acute otitis media and chronic otitis media with effusion. These results highlight the importance of unraveling the genetic factors for otitis media that are still poorly known.