Regie Lyn P. Santos-Cortez
Garth D. Ehrlich
Allen F. Ryan5,6*- 1Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- 2Center for Children’s Surgery, Children’s Hospital Colorado, Aurora, CO, United States
- 3Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA, United States
- 4Departments of Otolaryngology-Head and Neck Surgery, and Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, United States
- 5Division of Otolaryngology, Department of Surgery, University of California San Diego School of Medicine, La Jolla, CA, United States
- 6Veterans Affairs Medical Center, La Jolla, CA, United States
Editorial on the Research Topic
Otitis Media Genomics and the Middle Ear Microbiome
Otitis Media as a Clinical Disease and a Public Health Issue
Otitis media (OM), defined as inflammation of the middle ear (ME), usually occurs after ME infection and may cause hearing loss (HL) at any age, but most frequently in early childhood when development of speech and cognition occurs (Davis and Hind, 1999; Chonmaitree et al., 2016; Singer et al., 2018). Globally in 2019, 64% of children 1–5 years have HL due to OM (GBD, 2021). Antibiotics are prescribed for 67–98% of children with OM (Hersh et al., 2016; Frost et al., 2020), which contributes to antibiotic resistance and drug-specific adverse effects, even if administered appropriately (Fleming-Dutra et al., 2016; DeMuri et al., 2017; Islam et al., 2020). 4–10% of children require surgery due to recurrent acute (RA) OM or chronic OM with effusion (COME) (Beyea et al., 1999; Bhattacharyya and Shay, 2020). RAOM is diagnosed in children with ≥3 OM episodes in 6 months or ≥4 in 12 months, and COME if ME effusion behind the intact eardrum persists for >2 months (Rosenfeld et al., 2016). Combined, these OM types and surgery are associated with 4–11× risk of permanent HL (Rach et al., 1988; Beyea et al., 1999). RAOM/COME cause defects in language ability, auditory perception, sound localization and auditory processing in 5–11% of school-age children, which impedes academic progress (Morrongiello, 1989; Zargi and Boltezar, 1992; Moore, 2007; Hind et al., 2011; Skarzynski et al., 2015; Graydon et al., 2017; Cordeiro et al., 2018; Leach et al., 2020). In 10–24% of chronic OM cases a highly destructive, cyst-like ME lesion, cholesteatoma, can later grow and erode functionally critical bony and neural structures (Schmidt Rosito et al., 2017). Complications of OM/cholesteatoma besides HL include balance disorders, facial nerve paralysis, soft tissue abscess, or intracranial infection (O’Connor et al., 2009). Cholesteatoma is treated surgically, but often recurs (Kuo et al., 2012; Nardone et al., 2012). Novel strategies for prevention and early treatment of OM are needed to decrease the health burden worldwide due to OM and HL. Unfortunately, OM and its comorbidities remain severely understudied compared to other common diseases.
OM phenotypes (acute OM, RAOM, COME, chronic OM, cholesteatoma) are not distinct entities but fall within a spectrum. However, the mechanisms by which common acute OM progresses in severity despite treatment are poorly understood. Elucidation of molecular mechanisms of genetic susceptibility in humans, and of host-microbiota interactions are key to understanding OM progression and improving current protocols for prevention, diagnosis and treatment (Marsh et al., 2020; Santos-Cortez et al., 2020; Thornton et al., 2020).
What This Research Topic Contributes to Scientific Knowledge on Otitis Media
Three reviews in this research topic (Mittal et al.; Geng et al.; Giese et al.) provide comprehensive overviews of the current knowledge on the genomics of host-microbial interactions within the context of OM. They enumerate the genes that have been identified in humans and animal models as predisposing to OM, as well as their effects on the nasopharyngeal and ME microbiotas. Additionally, Lappan et al. summarized what is known about two bacterial species Alloiococcus otitidis and Turicella otitidis that are identified by sequencing in the ME and/or external ear. They suggested studies to delineate the role of these two bacteria in the ME, including microbiota, transcriptomic and animal model studies to aid understanding metabolic functions, strain heterogeneity, inflammatory effects and changes in OM severity due to A. otitidis or T. otitidis alone, or in concert with other otopathogens.
The Otitis Media-Related Microbiotas of the Pediatric Middle Ear and Nasopharynx (NP)
Three microbiota studies were performed using ME and NP samples from children with OM. Brugger et al. showed that the NP microbiota increased in richness but decreased in evenness with age, suggesting a personalized microbiota becoming more similar to adults with time; e.g., increased relative abundance of Staphylococcus and Corynebacterium. Xu et al. determined that microbiota from nasal washes or ME fluid at onset of acute OM were similar, but lower in biodiversity than the healthy state in the same children 3 weeks prior. These findings highlight the importance of temporal specificity when collecting paired NP and ME samples for OM studies. On a different note, Kolbe et al. found that in children with COME, the ME had less microbial biodiversity if the child had lower respiratory tract (LRT) disease i.e., asthma, bronchiolitis. Children with both COME and LRT disease also had greater relative abundances for Haemophilus, Staphylococcus and Moraxella but less Turicella or Alloiococcus in ME fluid. Altogether these ME and NP microbiota findings will be useful as guide in the design and interpretation of future microbial profiling and metagenomic studies.
The Middle Ear Transcriptome in Health and Otitis Media
Among five studies on ME gene expression, two were performed on human samples while three studies included rodent ME tissues. Microarray profiling of leukocytes from ME fluid of children with COME revealed enriched hypoxia signaling pathways and increased VEGF (compared to blood or plasma) that decreased with age (Bhutta et al.). This was concurrent with upregulation of inflammatory networks and increased myeloid cell signature and neutrophil counts in mucoid ME effusions; in contrast, lymphocytes and eosinophils were higher in serous ME fluid. Baschal et al. performed bulk mRNA-sequencing on human cholesteatoma and ME mucosal tissues from chronic OM patients, compared to published datasets from sinus and LRT. Their main findings include 1,806 differentially expressed genes (DEGs) and 68 enriched pathways in cholesteatoma compared to ME mucosa, as well as DEGs (including novel genes CR1 and SAA1) and pathways that overlap among the ME, upper and lower airways.
Ryan et al. performed the first single-cell RNA-sequencing study of ME tissue, using wildtype, non-infected mice. They extensively described transcriptomic profiles across 22 ME cell types, including genes involved in innate immunity and basic cellular pathways related to infection responses. Zhao et al. studied the endoplasmic reticulum (ER) stress pathway, characterizing histologic, hearing, multi-gene expression and oxidative stress responses in inflamed mouse MEs with or without an ER stress inhibitor. The ME inflammatory responses were reduced by administration of ER stress inhibitor, suggesting ER stress pathways as a potential target for treatment of OM. Similarly, Yadav et al. demonstrated in rat ME that Asian sand dust, in concert with pneumococcal infection, promoted bacterial colonization, biofilm growth, cell apoptosis, ROS production, pro-inflammatory responses, and differential expression of host genes in multiple pathways such as immune defence, cell differentiation and neurogenesis. Expression of microbial genes involved with competence, biofilm and toxin production was also increased. These transcriptome studies serve as seminal references for future identification of novel genes, pathways and responses to various agents contributing to OM.
Genetic or Environmental Mouse Models and the Otitis Media Phenotype
Three mouse models were reported within this topic. Double-mutant Id1-Id3 mice had hearing loss, and ME fluid depending on genotype (Zheng et al.). Histologic analysis confirmed ME polymorphonuclear cell infiltration, fibrosis and mucosal thickening, likely due to immune effects of Id gene knockout (KO). In a study of Fbxo11 variants, the Jeff mouse which has an Fbxo11 missense variant developed chronic OM and HL while the KO-mouse only had a milder craniofacial defect and ME mucosal thickening but no ME fluid or auditory phenotype (Kubinyecz et al.). Profile differences in cytokine levels and cell populations for innate or adaptive immunity were also stronger in the Jeff mouse than the KO (Vikhe et al.). These disparate phenotypes suggest a gain-of-function effect of the Jeff missense mutation. In summary, these mouse models demonstrate downstream effects of changes in the immune and TGF-beta pathways that aid understanding of the OM phenotype.
Future Perspectives
Overall, the findings in the articles included in this topic suggest that: (A) dysbiosis in the ME and NP microbiotas according to age, temporality with OM onset, and occurrence of LRT disease contribute to OM susceptibility; (B) although transcriptome studies identified novel genes and pathways that are involved in OM susceptibility, many more genes and pathways that are potential targets for novel therapies need to be validated or identified; and (C) animal models remain useful in elucidating mechanisms for OM susceptibility. Future meta-omic analyses will help in further understanding the metabolic functions and strain heterogeneity of bacteria in the ME and NP, and will enable detection of microbial factors (e.g., microbial genetic variants, serotypes) that favor resistance to antibiotics or antivirals, biofilm formation, immune evasion, metabolic efficiency, and virulence (Pettigrew et al., 2002; Ecevit et al., 2004; Ehrlich et al., 2005; Shen et al., 2005; Pettigrew et al., 2006; Buchinsky et al., 2007; Hiller et al., 2011; Pettigrew et al., 2011; Thomas et al., 2011; Pettigrew et al., 2012; Lewnard et al., 2016; Hu et al., 2019; Hammond et al., 2020; Harrison et al., 2020). Virulence factors of otopathogens may also identify candidate antigens for novel vaccines (Mottram et al., 2019). The continued study of the confluence of clinical, environmental, genetic, microbiota and immune profiles of patients and animal models with OM will also help identify OM sub-phenotypes that can be useful in personalizing OM treatments.
Author Contributions
RS-C, GE and AR edited this research topic and wrote the editorial.
Funding
RS-C is funded by NIH-NIDCD R01 DC015004. GE is supported by NIH-NIDCD R01 002148. AR is supported by Grants NIH-NIDCD R01 DC000129 and R01 DC012595.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Beyea, J. A., Cooke, B., Rosen, E., and Nguyen, P. (1999). Association of tympanostomy tubes with future assistive hearing devices-a population based study. BMC Pediatr. 20, 76. doi:10.1186/s12887-020-1977-6
Bhattacharyya, N., and Shay, S. G. (2020). Epidemiology of pediatric tympanostomy tube placement in the United States. Otolaryngol. Head Neck Surg. 163, 600–602. doi:10.1177/0194599820917397
Buchinsky, F. J., Forbes, M. L., Hayes, J. D., Shen, K., Ezzo, S., Compliment, J., et al. (2007). Virulence phenotypes of low-passage clinical isolates of nontypeable Haemophilus influenzae assessed using the chinchilla laniger model of otitis media. BMC Microbiol. 7, 56. doi:10.1186/1471-2180-7-56
Chonmaitree, T., Trujillo, R., Jennings, K., Alvarez-Fernandez, P., Patel, J. A., Loeffelholz, M. J., et al. (2016). Acute otitis media and other complications of viral respiratory infection. Pediatrics 137, e20153555. doi:10.1542/peds.2015-3555
Cordeiro, F. P., da Costa Monsanto, R., Kasemodel, A. L. P., de Almeida Gondra, L., and de Oliveira Penido, N. (2018). Extended high-frequency hearing loss following the first episode of otitis media. The Laryngoscope 128, 2879–2884. doi:10.1002/lary.27309
Davis, A., and Hind, S. (1999). The impact of hearing impairment: a global health problem. Int. J. Pediatr. Otorhinolaryngol. 49 (Suppl. 1), S51–S54. doi:10.1016/s0165-5876(99)00213-x
DeMuri, G. P., Sterkel, A. K., Kubica, P. A., Duster, M. N., Reed, K. D., and Wald, E. R. (2017). Macrolide and clindamycin resistance in Group A Streptococci isolated from children with pharyngitis. Pediatr. Infect. Dis. J. 36, 342–344. doi:10.1097/inf.0000000000001442
Ecevit, I. Z., McCrea, K. W., Pettigrew, M. M., Sen, A., Marrs, C. F., and Gilsdorf, J. R. (2004). Prevalence of the hifBC , hmw1A , hmw2A , hmwC , and hia Genes in Haemophilus influenzae Isolates. J. Clin. Microbiol. 42, 3065–3072. doi:10.1128/jcm.42.7.3065-3072.2004
Ehrlich, G. D., Hu, F. Z., Shen, K., Stoodley, P., and Post, J. C. (2005). Bacterial plurality as a general mechanism driving persistence in chronic infections. Clin. Orthopaedics Relat. Res. &NA;, 20–24. doi:10.1097/00003086-200508000-00005
Fleming-Dutra, K. E., Hersh, A. L., Shapiro, D. J., Bartoces, M., Enns, E. A., File, T. M., et al. (2016). Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA 315, 1864–1867. doi:10.1001/jama.2016.4151
Frost, H. M., Becker, L. F., Knepper, B. C., Shihadeh, K. C., and Jenkins, T. C. (2020). Antibiotic prescribing patterns for acute otitis media for children 2 years and older. J. Pediatr. 220, 109–115. doi:10.1016/j.jpeds.2020.01.045
GBD Hearing Loss Collaborators (2021). Hearing loss prevalence and years lived with disability, 1990-2019: findings from the Global Burden of Disease Study 2019. Lancet 397, 996–1009.
Graydon, K., Rance, G., Dowell, R., and Van Dun, B. (2017). Consequences of early conductive hearing loss on long-term binaural processing. Ear Hear 38, 621–627. doi:10.1097/aud.0000000000000431
Hammond, J. A., Gordon, E. A., Socarras, K. M., Chang Mell, J., and Ehrlich, G. D. (2020). Beyond the pan-genome: current perspectives on the functional and practical outcomes of the distributed genome hypothesis. Biochem. Soc. Trans. 48, 2437–2455. doi:10.1042/bst20190713
Harrison, A., Hardison, R. L., Fullen, A. R., Wallace, R. M., Gordon, D. M., White, P., et al. (2020). Continuous microevolution accelerates disease progression during sequential episodes of infection. Cel Rep. 30, 2978–2988e3. doi:10.1016/j.celrep.2020.02.019
Hersh, A. L., Fleming-Dutra, K. E., Shapiro, D. J., Hyun, D. Y., and Hicks, L. A. (2016). Outpatient Antibiotic Use Target-Setting WorkgroupFrequency of first-line antibiotic selection among US ambulatory care visits for otitis media, sinusitis, and pharyngitis. JAMA Intern. Med. 176, 1870–1872. doi:10.1001/jamainternmed.2016.6625
Hiller, N. L., Eutsey, R. A., Powell, E., Earl, J. P., Janto, B., Martin, D. P., et al. (2011). Differences in genotype and virulence among four multidrug-resistant Streptococcus pneumoniae isolates belonging to the PMEN1 clone. PLoS One 6, e28850. doi:10.1371/journal.pone.0028850
Hind, S. E., Haines-Bazrafshan, R., Benton, C. L., Brassington, W., Towle, B., and Moore, D. R. (2011). Prevalence of clinical referrals having hearing thresholds within normal limits. Int. J. Audiol. 50, 708–716. doi:10.3109/14992027.2011.582049
Hu, F. Z., Król, J. E., Tsai, C. H. S., Eutsey, R. A., Hiller, L. N., Sen, B., et al. (2019). Deletion of genes involved in the ketogluconate metabolism, Entner-Doudoroff pathway, and glucose dehydrogenase increase local and invasive virulence phenotypes in Streptococcus pneumoniae. PLoS One 14, e0209688. doi:10.1371/journal.pone.0209688
Islam, S., Mannix, M. K., Breuer, R. K., and Hassinger, A. B. (2020). Guideline adherence and antibiotic utilization by community pediatricians, private urgent care centers, and a pediatric emergency department. Clin. Pediatr. (Phila) 59, 21–30. doi:10.1177/0009922819879462
Kuo, C.-L., Shiao, A.-S., Liao, W.-H., Ho, C.-Y., and Lien, C.-F. (2012). How long is long enough to follow up children after cholesteatoma surgery? A 29-year study. The Laryngoscope 122, 2568–2573. doi:10.1002/lary.23510
Leach, A. J., Homøe, P., Chidziva, C., Gunasekera, H., Kong, K., Bhutta, M. F., et al. (2020). Panel 6: Otitis media and associated hearing loss among disadvantaged populations and low to middle-income countries. Int. J. Pediatr. Otorhinolaryngol. 130 (Suppl. 1), 109857. doi:10.1016/j.ijporl.2019.109857
Lewnard, J. A., Huppert, A., Givon-Lavi, N., Pettigrew, M. M., Regev-Yochay, G., Dagan, R., et al. (2016). Density, Serotype Diversity, and Fitness ofStreptococcus pneumoniaein Upper Respiratory Tract Cocolonization with NontypeableHaemophilus influenzae. J. Infect. Dis. 214, 1411–1420. doi:10.1093/infdis/jiw381
Marsh, R. L., Aho, C., Beissbarth, J., Bialasiewicz, S., Binks, M., Cervin, A., et al. (2020). Panel 4: Recent advances in understanding the natural history of the otitis media microbiome and its response to environmental pressures. Int. J. Pediatr. Otorhinolaryngol. 130 (Suppl. 1), 109836. doi:10.1016/j.ijporl.2019.109836
Moore, D. R. (2007). Auditory processing disorders: acquisition and treatment. J. Commun. Disord. 40, 295–304. doi:10.1016/j.jcomdis.2007.03.005
Morrongiello, B. A. (1989). Infants' monaural localization of sounds: Effects of unilateral ear infection. The J. Acoust. Soc. America 86, 597–602. doi:10.1121/1.398749
Mottram, L., Chakraborty, S., Cox, E., and Fleckenstein, J. (2019). How genomics can be used to understand host susceptibility to enteric infection, aiding in the development of vaccines and immunotherapeutic interventions. Vaccine 37, 4805–4810. doi:10.1016/j.vaccine.2019.01.016
Nardone, M., Sommerville, R., Bowman, J., and Danesi, G. (2012). Myringoplasty in Simple Chronic Otitis Media. Otol Neurotol 33, 48–53. doi:10.1097/mao.0b013e31823dbc26
O’Connor, T. E., Perry, C. F., and Lannigan, F. J. (2009). Complications of otitis media in Indigenous and non-indigenous children. Med. J. Aust. 191, S60–S64.
Pettigrew, M. M., Fennie, K. P., York, M. P., Daniels, J., and Ghaffar, F. (2006). Variation in the presence of neuraminidase genes among Streptococcus pneumoniae isolates with identical sequence types. Infect. Immun. 74, 3360–3365. doi:10.1128/iai.01442-05
Pettigrew, M. M., Foxman, B., Marrs, C. F., and Gilsdorf, J. R. (2002). Identification of the lipooligosaccharide biosynthesis gene lic2B as a putative virulence factor in strains of nontypeable Haemophilus influenzae that cause otitis media. Infect. Immun. 70, 3551–3556. doi:10.1128/iai.70.7.3551-3556.2002
Pettigrew, M. M., Gent, J. F., Pyles, R. B., Miller, A. L., Nokso-Koivisto, J., and Chonmaitree, T. (2011). Viral-bacterial interactions and risk of acute otitis media complicating upper respiratory tract infection. J. Clin. Microbiol. 49, 3750–3755. doi:10.1128/jcm.01186-11
Pettigrew, M. M., Laufer, A. S., Gent, J. F., Kong, Y., Fennie, K. P., and Metlay, J. P. (2012). Upper respiratory tract microbial communities, acute otitis media pathogens, and antibiotic use in healthy and sick children. Appl. Environ. Microbiol. 78, 6262–6270. doi:10.1128/aem.01051-12
Rach, G. H., Zielhuis, G. A., and van den Broek, P. (1988). The influence of chronic persistent otitis media with effusion on language development of 2- to 4-year-olds. Int. J. Pediatr. Otorhinolaryngol. 15, 253–261. doi:10.1016/0165-5876(88)90080-8
Rosenfeld, R. M., Shin, J. J., Schwartz, S. R., Coggins, R., Gagnon, L., Hackell, J. M., et al. (2016). Clinical Practice Guideline: Otitis Media with Effusion (Update). Otolaryngol. Head Neck Surg. 154, S1–S41. doi:10.1177/0194599815623467
Rosito, L. P. S., da Silva, M. N. L., Selaimen, F. A., Jung, Y. P., Pauletti, M. G. T., Jung, L. P., et al. (2017). Characteristics of 419 patients with acquired middle ear cholesteatoma. Braz. J. Otorhinolaryngol. 83, 126–131. doi:10.1016/j.bjorl.2016.02.013
Santos-Cortez, R. L. P., Bhutta, M. F., Earl, J. P., Hafrén, L., Jennings, M., Mell, J. C., et al. (2020). Panel 3: Genomics, precision medicine and targeted therapies. Int. J. Pediatr. Otorhinolaryngol. 130 (Suppl. 1), 109835. doi:10.1016/j.ijporl.2019.109835
Shen, K., Antalis, P., Gladitz, J., Sayeed, S., Ahmed, A., Yu, S., et al. (2005). Identification, distribution, and expression of novel genes in 10 clinical isolates of nontypeable Haemophilus influenzae. Infect. Immun. 73, 3479–3491. doi:10.1128/iai.73.6.3479-3491.2005
Singer, A. E. A., Abdel-Naby Awad, O. G., El-Kader, R. M. A., and Mohamed, A. R. (2018). Risk factors of sensorineural hearing loss in patients with unilateral safe chronic suppurative otitis media. Am. J. Otolaryngol. 39, 88–93. doi:10.1016/j.amjoto.2018.01.002
Skarzynski, P. H., Wlodarczyk, A. W., Kochanek, K., Pilka, A., Jedrzejczak, W., Olszewski, L., et al. (2015). Central auditory processing disorder (CAPD) tests in a school-age hearing screening programme - analysis of 76,429 children. Ann. Agric. Environ. Med. 22, 90–95. doi:10.5604/12321966.1141375
Thomas, J. C., Figueira, M., Fennie, K. P., Laufer, A. S., Kong, Y., Pichichero, M. E., et al. (2011). Streptococcus pneumoniae clonal complex 199: genetic diversity and tissue-specific virulence. PLoS One 6, e18649. doi:10.1371/journal.pone.0018649
Thornton, R. B., Hakansson, A., Hood, D. W., Nokso-Koivisto, J., Preciado, D., Riesbeck, K., et al. (2020). Panel 7 - Pathogenesis of otitis media - a review of the literature between 2015 and 2019. Int. J. Pediatr. Otorhinolaryngol. 130 (Suppl. 1), 109838. doi:10.1016/j.ijporl.2019.109838
Keywords: gene, microbiome, middle ear, nasopharynx, otitis media (OM), sequencing
Citation: Santos-Cortez RLP, Ehrlich GD and Ryan AF (2021) Editorial: Otitis Media Genomics and the Middle Ear Microbiome. Front. Genet. 12:763688. doi: 10.3389/fgene.2021.763688
Received: 24 August 2021; Accepted: 22 September 2021;
Published: 12 October 2021.
Edited and reviewed by:
Jordi Pérez-Tur, Instituto de Biomedicina de Valencia (CSIC), SpainCopyright © 2021 Santos-Cortez, Ehrlich and Ryan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Regie Lyn P. Santos-Cortez, regie.santos-cortez@cuanschutz.edu; Garth D. Ehrlich, ge33@drexel.edu; Allen F. Ryan, afryan@health.ucsd.edu