Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154*) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202*) variant co-segregates with otitis media in a Filipino pedigree (LOD ¼ 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p ¼ 1.2 3 10 À5) and US trios (TDT p ¼ 0.01). The c.461G>A (p.Trp154*) variant was also overtransmitted in US trios (TDT p ¼ 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10 À7) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p ¼ 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154*, and p.Arg202*-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.

Background Otologic and vestibular symptoms have been seen in patients confirmed to have COVID‐19 disease. Further discussion of these symptoms may provide insight into short‐ and long‐term management for these patients. Objective The aim of this review was to describe the otologic and vestibular symptoms that present in patients with COVID‐19. The primary outcomes of this review were onset, duration and clinical outcomes of these symptoms. Sources of Evidence Pub Med, APAMed Central, Herdin, CINAHL, Scopus, Springer Link, ProQuest Coronavirus Research Database, and Google Scholar were searched for the articles to be included. Eligibility Criteria Studies included were those involving adult patients diagnosed with COVID‐19 who experienced hearing loss, ear pain, ear discharge, otitis media, vertigo, or tinnitus. Studies were eligible for inclusion if there was a description of the otologic dysfunction, specifically onset, duration, or clinical outcomes. Results The majority of patients who experienced hearing loss (68%), tinnitus (88%), vertigo/dizziness (30%), ear pain (8%), and discharge (100%) did so within a month of experiencing the typical symptoms of COVID‐19. A majority also experienced complete resolution of their symptoms within 2 weeks. Standard treatment for COVID‐19 was usually provided but when specific diagnoses are made for these symptoms (e.g., sudden sensorineural hearing loss, otitis media, vestibular neuritis), they are treated in the same manner as one would for non‐COVID‐19 cases, in addition to the management for COVID‐19. In certain cases, there may be a need for additional work‐up to rule out other causes. Conclusions Otologic and vestibular symptoms were present in COVID‐19 patients, majority as part of the systemic nature of the disease. The onset, duration, and course were consistent with the natural history of a systemic viral infection. COVID‐19 should be considered in any patient with a new‐onset hearing loss, tinnitus, or vertigo/dizziness, even in the absence of infectious or respiratory symptoms.

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BackgroundOtitis 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.MethodsWe 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.ResultsA 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.ConclusionSPINK5 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.

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