Factors affecting the occurrence of otitis media with effusion in preschool and elementary school children: a comparative cross-sectional study
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* Ratna Dwi Restuti
* Susyana Tamin
* Dwi Agustawan Nugroho
* Syahrial Marsinta Hutauruk
* Muchtaruddin Mansyur

## Abstract

**Objective** Identify the risk factors for otitis media with effusion (OME), especially laryngopharyngeal reflux (LPR), adenoid hypertrophy and allergic rhinitis, that could be used to develop prevention strategies in children.

**Design** A comparative cross-sectional study was conducted to make sure the adequacy of proportions of OME and non-OME cases in finding the related factors.

**Setting** History taking, ear/nose/throat (ENT) examination, and tympanometry were performed in preschool and elementary schools. Flexible fibreoptic nasopharyngolaryngoscopy was performed in a bronchoesophagology outpatient clinic in a tertiary referral hospital in Jakarta, Indonesia.

**Participants** Preschool and elementary children in East Jakarta, Indonesia were recruited for this study. A total of 2016 participants underwent history taking, ENT examination and tympanometry. The case group was 46 children with OME, and the control group was 46 children without OME. The number of subjects fulfilled the minimum sample size for two proportions comparison.

**Main outcome measures** A type B tympanogram indicated OME. A Reflux Finding Score of more than 7 indicated LPR. Adenoid hypertrophy was diagnosed using flexible fibreoptic nasopharyngolaryngoscopy. Allergic rhinitis was diagnosed using a questionnaire based on the International Study of Asthma and Allergies in Childhood phase III that has been validated for Indonesians.

**Results** The proportion of LPR in the OME group was significantly higher than in the non-OME group, at 78.3% and 52.2%. The probability of OME occurrence in patients with LPR was 3.3 times higher than in patients without LPR (OR 3.3; 95% CI 1.33 to 8.189; p=0.01). There was no significant relationship between adenoid hypertrophy and OME (p=0.211; 95% CI 0.71 to 3.97), and also between allergic rhinitis and OME (p=0.463; 95% CI 0.61 to 4.28).

**Conclusion** The probability of OME occurrence in patients with LPR was 3.3 times higher than in patients without LPR. LPR should be considered in patients with OME and vice versa.

*   Audiology
*   Paediatric otolaryngology
*   Laryngology

### STRENGTHS AND LIMITATIONS OF THIS STUDY

*   Stratified random sampling, multistage random sampling and spatial random sampling were used for sample selection to represent the large population.

*   The control group was randomly chosen from patients without otitis media with effusion who were age and sex matched with the case group.

*   Flexible fibreoptic nasopharyngolaryngoscopy was performed blindly between the two groups to reduce examiner bias.

*   Allergic rhinitis was not diagnosed using gold-standard examination because of the risks in the school setting; therefore, the examination was conducted using validated International Study of Asthma and Allergies in Childhood phase III questionnaires.

*   The time relationship between risk factors and the outcomes could not be explained.

## Introduction

Otitis media with effusion (OME) is a disease that is characterised by inflammation of the middle ear with fluid formation, without signs or symptoms of acute infection, and with intact tympanic membrane. This disease commonly occurs in children and can appear symptomless.1 Diagnosis and management of OME are usually late and are associated with complications. OME is the most common cause of hearing loss in children in developing countries and can impair the child’s behavioural and language development.2

OME is one of the most common childhood illnesses in the USA, with more than 2.2 million cases diagnosed yearly. It is estimated that 80% of children will have at least one episode of OME by the age of 10 years.3 In the UK, it is estimated that 5% of children aged 5 years have persistent bilateral hearing impairment due to OME. Furthermore, OME is one of the most common reasons for referral to surgery in children in the UK.4 The prevalence rate of OME is 15.5% in children in Upper Egypt; 17.89% in Kuala Lumpur, Malaysia; and 5.3% in Hong Kong for children aged 6–7 years old.5–7

Several studies have been performed to identify the risk factors for OME. Craniofacial dysmorphology, adenoid hypertrophy, respiratory tract infections, obstruction of the nasopharynx and allergies have been suggested as risk factors for OME.8 Other risk factors for OME are gender, race, environment, climatic conditions, humidity, a crowded home, socioeconomic status, breastfeeding duration, kindergarten nursery, passive smoking and gastro-oesophageal reflux.9 However, the risk factors for OME reported in several studies remain controversial.10 A systematic review by Lechien *et al* concluded that the association between laryngopharyngeal reflux (LPR) and OME was unclear.11 Several studies have reported on the association between adenoid hypertrophy and OME.12 13 However, a study by Durgut and Dikici concluded that adenoid size and location were not associated with hearing thresholds and the duration of OME.14 Several studies found an association between allergic rhinitis and OME in children in subtropical countries15–17; however, there are several differences in the main sensitisers in allergic patients living in tropical urban environments and subtropical areas.18

Based on the high prevalence of OME and the problems that this disease can cause in children, it is important to identify the risk factors for OME. This study aimed to determine whether LPR, allergic rhinitis and adenoid hypertrophy are risk factors for OME. We hope that the results improve the prevention of OME in children, medical services for communities in general and the management of OME.

## Materials and methods

This comparative cross-sectional study was conducted in an educational unit of preschool and elementary children in East Jakarta district, Indonesia. The inclusion criteria for the OME group included preschool and elementary children in East Jakarta, willingness to participate in the study, and diagnosis with OME based on history, ear/nose/throat (ENT) examination, otoscopy, and tympanometry. The inclusion criteria for the non-OME group included preschool and elementary children in East Jakarta, willingness to participate in the study and no diagnosed OME. The exclusion criteria included uncooperative patients, upper respiratory tract infections, and congenital defects, such as palatoschisis, laryngomalacia, and other neuromuscular disorders.

A total of 2016 preschool and elementary school children in the district were chosen from the population using stratified random sampling, multistage random sampling and spatial random sampling. The children underwent history taking, ENT examination and tympanometry. The tympanometer used in this study was the Intercoustics Impedance Audiometer AT-235. A type B tympanogram indicated OME. Using the exclusion and inclusion criteria, 46 children with OME were selected for the case group; 46 children were randomly chosen for the control group using stratified random sampling from patients without OME age and sex matched with the case group. Both groups were treated equally regarding history taking, questionnaire completion, ENT examination and examination using a flexible fibreoptic nasopharyngolaryngoscope. For questionnaire completion, participants were asked to fill out questionnaires with their parents’ or teachers’ help regarding allergic rhinitis based on the International Study of Asthma and Allergies in Childhood (ISAAC) phase III and LPR based on the Reflux Symptoms Index (RSI). The ISAAC questionnaire has been validated in Indonesia with 90% sensitivity, 83.58% specificity, 68.2% positive predictive value and 95.73% negative predictive value.19 Flexible fibreoptic nasopharyngolaryngoscopy, which evaluates adenoid hypertrophy and LPR using the Reflux Finding Score (RFS), was performed in the bronchoesophagology outpatient clinic at the Otorhinolaryngology-Head and Neck Surgery Department, Faculty of Medicine, Universitas Indonesia (FMUI)–Cipto Mangunkunsumo Hospital, Jakarta, Indonesia. Endoscopy was performed blindly between the two groups by one staff member of the Endoscopic Broncho-Esophagology Division FMUI. The adenoids were evaluated based on the percentage of adenoid tissue that caused blockage of the posterior choana (choanal obstruction ratio) into four grades: grade I, adenoid tissue obstructs 0%–25% of the posterior choana; grade II, adenoid tissue obstructs 26%–50% of the posterior choana; grade III, adenoid tissue obstructs 51%–75% of the posterior choana; and grade IV, adenoid tissue obstructs 76%–100% of the posterior choana. Patients were considered to have adenoid hypertrophy if the choanal obstruction ratio was >50% (grades III and IV). Patients were considered to have LPR if the total RFS was >7.

The sample size was calculated based on the formula for comparing the proportions of the two groups. Assuming a type 1 error of 0.05, 80% power, 95% confidence level, 64% proportion of LPR in patients with OME and 25% proportion of LPR in patients without OME, a sample size of 46 cases and 46 controls was required.

All statistical tests were performed using the SPSS software V.26 (IBM Corporation). Data processing was performed using bivariate analysis to determine the relationship between independent and dependent variables. Afterwards, determinant factors for OME and other contributing factors were processed using multivariate logistic regression analysis.

### Patient and public involvement

None.

## Results

The largest age group of patients with OME in this study was 5–7 years old (45.7%), while the smallest group was aged 11–13 years old (13%). The largest gender group for OME was male (52.2%). In this study, 26 children (56.5%) with OME had adenoid hypertrophy based on nasopharyngeal examination. Moreover, 13 children (28.3%) with OME had allergic rhinitis as a risk factor. In the OME group, 36 out of 46 children (78.3%) had LPR. Complete data are presented in table 1.

View this table:
[Table 1](http://bmjopen.bmj.com/content/12/9/e065291/T1)

Table 1 
Sociodemographic and clinical characteristics of the patients

In the OME group, 15 children (32.6%) complained of ear fullness, and hearing impairment was found in 17 children (37%). Complaints of sneezing, runny nose and nasal blockage in the OME group were reported in 19 children (41.3%); however, only in 13 children (28.3%) had persistent complaints for more than 12 months. The most common complaint in the OME group with adenoid hypertrophy was breathing through the mouth, which was reported in 17 children (37%). The RSI questionnaire was used to calculate the severity of LPR symptoms. The number of children with an RSI score above 13 was 13 (28.3%) in the OME group.

In table 2, after bivariate analysis, a significant relationship was observed between OME and LPR (p=0.016). According to the logistic regression test, the probability of OME occurrence in patients with LPR was 3.3 times higher than in patients without LPR (OR 3.3; 95% CI 1.33 to 8.189; p=0.01). Furthermore, no significant relationship was observed between OME and adenoid hypertrophy (p=0.211) or allergic rhinitis (p=0.463). Multivariate analysis was performed by inserting variables that had p<0.25 in the bivariate analysis. Adjusted OR was obtained using a multiple regression logistic test, while crude OR was obtained using a simple regression logistic test.

View this table:
[Table 2](http://bmjopen.bmj.com/content/12/9/e065291/T2)

Table 2 
Relationship between otitis media with effusion and risk factors

## Discussion

We found that the prevalence of OME was higher in young children (5–7 years old) compared with older children (11–13 years old). Our results are similar to a study by Humaid *et al* in which OME was significantly higher in young children (6–7 years old) compared with older children (8–12 years old).20 In various studies, higher incidence of OME was commonly associated with the younger age group.4 5 21 The youngest patients in our study were 5 years old because our study was conducted on an education unit that included preschool and elementary school children. In Indonesia, children usually enrol in kindergarten or preschool at 4 or 5 years old.22 In addition, children under 5 years old cannot reliably or accurately self-report health outcomes. To communicate their health or illness, children must be able to focus, discriminate response options, recall health experiences, and understand the basic notions of illness and health.23 This should be considered because our study used a questionnaire to assess allergic rhinitis.

Several studies have reported a higher risk of OME incidence in children with allergic rhinitis.5 15–17 The correlation between allergic rhinitis and OME may be caused by Eustachian tube (ET) obstruction due to local hypersensitivity caused by the allergens. In addition, supporting the United Airway Concept, the middle ear mucosa has a similar allergy mediator and is as capable as the rest of the upper respiratory tract of responding to allergens.24 25 In our study, there was no significant difference in allergic rhinitis in the OME and non-OME groups. This is probably due to the different methods of diagnosing allergic rhinitis. In our study, allergic rhinitis was diagnosed based on the ISAAC phase III questionnaire. Previous studies using questionnaires have been conducted to assess the association between allergic rhinitis and OME in children.16 26 Diagnosing allergic rhinitis ideally involves a skin prick test; however, it is unsafe to perform skin prick tests in school, and it is technically difficult to bring the children to the hospital to perform the skin prick test.

The ISAAC questionnaire is a standardised questionnaire from worldwide ISAAC multicentre studies used to assess disease frequency, prevalence and severity.27 It has been validated in Indonesia with high sensitivity, specificity, positive predictive value and negative predictive value.19 In several studies, the ISAAC questionnaire was reported to have a high specificity for identifying patients with allergic rhinitis. Validation of the ISAAC questionnaire in Switzerland showed a high positive predictive value and specificity ranging from 77.5% to 97.6%.27 Validation of the ISAAC questionnaire in Korea reported moderate sensitivity (57.5%) and specificity (58.4%), with a high negative predictive value (70.6%).28 The ISAAC questionnaire was reported to have 73% sensitivity and 98% specificity in Congo.29 In addition, the ISAAC questionnaire uses uncomplicated medical terminology and ordinary language to avoid incorrect answers and refusal to answer questions.19 The advantages of using screening tools are that they have low cost, are non-invasive, provide rapid results and are easy to administer.30 Parents and teachers could assist the patients with filling out the questionnaire in our study because the ISAAC questionnaire requires perceived and visible symptoms in the patients, such as sneezing, itchy/watery eyes, and runny and blocked nose.

Adenoid hypertrophy is the most common cause of tubal dysfunction in the paediatric population.31 The effects of adenoid hypertrophy on the development of OME are obstruction of the ET with mass effect, accumulation of secretions, disruption of nasopharyngeal ventilation, oedema caused by inflammation and allergic mediator release from adenoid mast cells.32 In our study, even though there was no significant difference between adenoid hypertrophy and OME, there was a clinically important difference. The difference was seen in 71.4% of patients with grade IV adenoid hypertrophy in the OME group. In grade IV adenoid hypertrophy, the adenoid covers almost all of the tubal opening, which leads to total choanal obstruction and causes ET obstruction and ventilation dysfunction.33 Abdel Tawab and Tabook12 reported a highly significant relationship between grade IV adenoid hypertrophy and type B tympanometry. Furthermore, they reported the correlation between grade IV adenoid hypertrophy and middle ear effusion viscosity.12 Another study by Nwosu *et al*13 found that a higher grade of adenoid size was associated with an increased incidence of OME.13 In addition to adenoid size, the correlation between the adenoids and OME may be caused by microbial reservoirs for ascending infection to the middle ear.34

Several studies correlate LPR with OME by identifying pepsin in middle ear effusions.12 35–39 Correlation between LPR and OME may be caused by excessive vagal reactivity and direct noxious exposure of the middle ear mucosa to gastric acid contents, causing swelling, ciliary dyskinesia, mucus hypersecretion and stimulation of inflammatory mediator secretion that leads to ET dysfunction.40 The structure of the ET in children is not yet fully developed, with a horizontal position that enables gastric contents to enter the middle ear.39 According to our study, children diagnosed with LPR have a threefold higher risk of suffering OME than children without LPR.

The prevalence of LPR in children is high, with approximately one in five children likely having reflux disease.41 Furthermore, the prevalence of OME is high in children, and 80% of children will have at least one episode of OME by the age of 10 years.3 However, OME is easily missed in children because it is often asymptomatic.8 Persistent OME leads to tympanic membrane damage and permanent hearing loss, affecting socialisation and communication. Hearing loss in children can cause delayed language development and learning problems that lead to behavioural disorders and poor school performance.1 2 8 From our study, it is important to assess OME in children with LPR to prevent undetected cases of OME and further complications due to untreated OME. In addition, it is important to assess LPR in children with OME to make its treatment more effective by addressing one of its risk factors.

The ideal design to study risk factors for disease is a case–control study. However, our study could not explain the time relationship between exposure (LPR, allergic rhinitis, adenoid hypertrophy) and the outcome (OME) as a case–control study because the risk factors and the outcomes were measured at the same time. This becomes one of our limitations. However, our cross-sectional study used two groups (case and control) based on the dependent variable so that, from the beginning of the study, it was known which group would develop OME, and the risk factors between the case and control groups could be compared. The control group was randomly chosen from patients without OME age and sex matched with the case group so that other risk factors could be eliminated. The second limitation of our study was that we only used a questionnaire to assess allergic rhinitis. However, the results were valid due to the high specificity, sensitivity and applicability of the questionnaire in our subject group. In addition, our study assessed a large number of participants, with a total of 2016 children. Although 46 patients were assessed to have OME, it fulfilled our study’s minimum sample size (46 patients for each group). Our study participants were more significant than previous studies. Previous studies by Karyanta *et al* and Górecka-Tuteja *et al* assessed 28 patients with LPR.40 42 A study by Galić and Klančnik assessed a total of 65 patients.43 A study by Sharifian *et al* assessed 37 children as a case group and 52 children as a control group.44 Moreover, our study used a 95% CI with a relatively narrow of range results, so it had adequate power.

## Conclusion

This study reported a significant difference in the incidence of LPR in children with OME and without OME. The proportion of LPR in the OME group (case group) was higher than in the non-OME (control) group, at 78.3% and 52.2%, respectively. According to the results, it can be concluded that children with LPR have a 3.3-fold increased risk of OME than children without LPR. The correlation between other risk factors (allergic rhinitis and adenoid hypertrophy) and OME in children was clinically significant even though there was no statistically significant difference.

## Data availability statement

All data relevant to the study are included in the article or uploaded as supplemental information.

## Ethics statements

### Patient consent for publication

Parental/guardian consent obtained.

### Ethics approval

This study involves human participants and was approved by the Committee of Medical Research Ethics of the Faculty of Medicine, Universitas Indonesia, with regard to the protection of human rights and welfare in medical research with ethical number 109/PT02.FK/ETIK. The participants and their parents provided verbal and written informed consent before study participation.

## Acknowledgments

We would like to thank the Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medicine, Universitas Indonesia, and the Department of Community Medicine, Faculty of Medicine, Universitas Indonesia, for supporting this study.

## Footnotes

*   Contributors RDR, ST and SMH designed the study. RDR, ST, DAN and SMH performed the study. RDR, ST, DAN and MM analysed the data. RDR, ST and DAN drafted the manuscript. SMH and MM contributed to drafts and critical revision for intellectual content. RDR acted as a guarantor of the study. All authors approved the final manuscript.

*   Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

*   Competing interests None declared.

*   Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

*   Provenance and peer review Not commissioned; externally peer reviewed.

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## References

1.  Searight FT, Singh R, Peterson DC. Otitis media with effusion. StatPearls. Treasure Island FL: StatPearls Publishing, 2022.
    
    

2.  Vanneste P, Page C. Otitis media with effusion in children: pathophysiology, diagnosis, and treatment. A review. J Otol 2019;14:33–9.[doi:10.1016/j.joto.2019.01.005](http://dx.doi.org/10.1016/j.joto.2019.01.005)pmid:http://www.ncbi.nlm.nih.gov/pubmed/31223299
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

3.  Kucur C, Şimşek E, Kuduban O, et al. Prevalence of and risk factors for otitis media with effusion in primary school children: case control study in Erzurum, Turkey. Turk J Pediatr 2015;57:230–5.pmid:http://www.ncbi.nlm.nih.gov/pubmed/26701940
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

4.  Williamson I. Otitis media with effusion in children. BMJ Clin Evid 2011;2011:0502.pmid:http://www.ncbi.nlm.nih.gov/pubmed/21477396
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

5.  Norhafizah N, Salina H, Goh BS. Prevalence of allergic rhinitis in children with otitis media with effusion. Eur Ann Allergy Clin Immunol 2020;52:74–30.[doi:10.23822/EurAnnACI.1764-1489.119](http://dx.doi.org/10.23822/EurAnnACI.1764-1489.119)
    
    

6.  Saad K, Abdelmoghny A, Abdel-Raheem YF, et al. Prevalence and associated risk factors of recurrent otitis media with effusion in children in upper Egypt. World J Otorhinolaryngol Head Neck Surg 2021;7:280–4.[doi:10.1016/j.wjorl.2020.08.002](http://dx.doi.org/10.1016/j.wjorl.2020.08.002)pmid:http://www.ncbi.nlm.nih.gov/pubmed/34632340
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

7.  Tong MC, Yue V, Ku PK, et al. Screening for otitis media with effusion to measure its prevalence in Chinese children in Hong Kong. Ear Nose Throat J 2000;79:626–30.[doi:10.1177/014556130007900818](http://dx.doi.org/10.1177/014556130007900818)pmid:http://www.ncbi.nlm.nih.gov/pubmed/10969473
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=10969473&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

8.  Rosenfeld RM, Shin JJ, Schwartz SR, et al. Clinical practice guideline: otitis media with effusion (update). Otolaryngol Head Neck Surg 2016;154:S1–41.[doi:10.1177/0194599815623467](http://dx.doi.org/10.1177/0194599815623467)pmid:http://www.ncbi.nlm.nih.gov/pubmed/26832942
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1177/0194599815623467&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=26832942&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

9.  Eliçora Sultan Şevik, Öztürk M, Sevinç R, et al. Risk factors for otitis media effusion in children who have adenoid hypertrophia. Int J Pediatr Otorhinolaryngol 2015;79:374–7.[doi:10.1016/j.ijporl.2014.12.030](http://dx.doi.org/10.1016/j.ijporl.2014.12.030)pmid:http://www.ncbi.nlm.nih.gov/pubmed/25596647
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

10. Adhikari T, Chew Y, Zulkiflee AB. Prevalence and risk factors associated with otitis media with effusion in children visiting tertiary care centre in Malaysia. Int Med J Malays 2012;11:37–40.[doi:10.31436/imjm.v11i1.545](http://dx.doi.org/10.31436/imjm.v11i1.545)
    
    

11. Lechien JR, Hans S, Simon F, et al. Association between laryngopharyngeal reflux and media otitis: a systematic review. Otol Neurotol 2021;42:e801–14.[doi:10.1097/MAO.0000000000003123](http://dx.doi.org/10.1097/MAO.0000000000003123)pmid:http://www.ncbi.nlm.nih.gov/pubmed/33710157
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

12. Abdel Tawab HM, Tabook SMS. Correlation between adenoid hypertrophy, tympanometry findings, and viscosity of middle ear fluid in chronic otitis media with effusion, southern Oman. Ear Nose Throat J 2021;100:NP141–6.[doi:10.1177/0145561319875438](http://dx.doi.org/10.1177/0145561319875438)pmid:http://www.ncbi.nlm.nih.gov/pubmed/31547716
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

13. Nwosu C, Uju Ibekwe M, Obukowho Onotai L. Tympanometric findings among children with adenoid hypertrophy in Port Harcourt, Nigeria. Int J Otolaryngol 2016;2016:1276543[doi:10.1155/2016/1276543](http://dx.doi.org/10.1155/2016/1276543)pmid:27563311
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=27563311&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

14. Durgut O, Dikici O. The effect of adenoid hypertrophy on hearing thresholds in children with otitis media with effusion. Int J Pediatr Otorhinolaryngol 2019;124:116–9.[doi:10.1016/j.ijporl.2019.05.046](http://dx.doi.org/10.1016/j.ijporl.2019.05.046)pmid:http://www.ncbi.nlm.nih.gov/pubmed/31176025
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

15. Byeon H. The association between allergic rhinitis and otitis media: a national representative sample of in South Korean children. Sci Rep 2019;9:1610.[doi:10.1038/s41598-018-38369-7](http://dx.doi.org/10.1038/s41598-018-38369-7)pmid:http://www.ncbi.nlm.nih.gov/pubmed/30733549
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

16. Pau BC, Ng DK. Prevalence of otitis media with effusion in children with allergic rhinitis, a cross sectional study. Int J Pediatr Otorhinolaryngol 2016;84:156–60.[doi:10.1016/j.ijporl.2016.03.008](http://dx.doi.org/10.1016/j.ijporl.2016.03.008)pmid:http://www.ncbi.nlm.nih.gov/pubmed/27063773
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

17. Velepič M, Rožmanić V, Velepič M, et al. Gastroesophageal reflux, allergy and chronic tubotympanal disorders in children. Int J Pediatr Otorhinolaryngol 2000;55:187–90.[doi:10.1016/S0165-5876(00)00396-7](http://dx.doi.org/10.1016/S0165-5876(00)00396-7)pmid:http://www.ncbi.nlm.nih.gov/pubmed/11035175
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/S0165-5876(00)00396-7&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=11035175&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

18. Caraballo L, Zakzuk J, Lee BW, et al. Particularities of allergy in the tropics. World Allergy Organ J 2016;9:20.[doi:10.1186/s40413-016-0110-7](http://dx.doi.org/10.1186/s40413-016-0110-7)pmid:http://www.ncbi.nlm.nih.gov/pubmed/27386040
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

19. Yunus F, Antaria R, Rasmin M, et al. Asthma prevalence among high school students in East Jakarta, 2001, based on Isaac questionnaire. Med J Indones 2003;12:178.[doi:10.13181/mji.v12i3.103](http://dx.doi.org/10.13181/mji.v12i3.103)
    
    

20. Humaid A-HI, Ashraf A-HS, Masood KA, et al. Prevalence and risk factors of otitis media with effusion in school children in Qassim region of Saudi Arabia. Int J Health Sci 2014;8:325–34.pmid:http://www.ncbi.nlm.nih.gov/pubmed/25780352
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

21. Riaz N, Ajmal M, Khan MS. Frequency of otitis media with effusion among children aged 1–5 years presenting to immunization center of tertiary care hospitals, Rawalpindi.. World J Otorhinolaryngol Head Neck Surg 2021.[doi:10.1016/j.wjorl.2021.03.002](http://dx.doi.org/10.1016/j.wjorl.2021.03.002)
    
    

22. Fawina Aulia G. School starting age and academic performance: an empirical study in Indonesia. IJDP 2021;5.[doi:10.36574/jpp.v5i3.218](http://dx.doi.org/10.36574/jpp.v5i3.218)
    
    

23. Coombes L, Bristowe K, Ellis-Smith C, et al. Enhancing validity, reliability and participation in self-reported health outcome measurement for children and young people: a systematic review of recall period, response scale format, and administration modality. Qual Life Res 2021;30:1803–32.[doi:10.1007/s11136-021-02814-4](http://dx.doi.org/10.1007/s11136-021-02814-4)pmid:http://www.ncbi.nlm.nih.gov/pubmed/33738710
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

24. Cheng X, Sheng H, Ma R, et al. Allergic rhinitis and allergy are risk factors for otitis media with effusion: a meta-analysis. Allergol Immunopathol 2017;45:25–32.[doi:10.1016/j.aller.2016.03.004](http://dx.doi.org/10.1016/j.aller.2016.03.004)pmid:http://www.ncbi.nlm.nih.gov/pubmed/27720440
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.aller.2016.03.004&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

25. Nguyen LHP, Manoukian JJ, Sobol SE, et al. Similar allergic inflammation in the middle ear and the upper airway: evidence linking otitis media with effusion to the United airways concept. J Allergy Clin Immunol 2004;114:1110–5.[doi:10.1016/j.jaci.2004.07.061](http://dx.doi.org/10.1016/j.jaci.2004.07.061)pmid:http://www.ncbi.nlm.nih.gov/pubmed/15536418
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.jaci.2004.07.061&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=15536418&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

26. Umapathy D, Alles R, Scadding GK. A community based questionnaire study on the association between symptoms suggestive of otitis media with effusion, rhinitis and asthma in primary school children. Int J Pediatr Otorhinolaryngol 2007;71:705–12.[doi:10.1016/j.ijporl.2006.12.017](http://dx.doi.org/10.1016/j.ijporl.2006.12.017)pmid:http://www.ncbi.nlm.nih.gov/pubmed/17335912
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.ijporl.2006.12.017&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=17335912&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

27. Sastra S, Irsa L, Loebis MS, et al. Number of siblings and allergic rhinitis in children. Paediatr Indones 2016;56:1.[doi:10.14238/pi56.1.2016.1-7](http://dx.doi.org/10.14238/pi56.1.2016.1-7)
    
    

28. Kim D, Lim D, Samra M, et al. How accurate are the Isaac questions for diagnosis of allergic rhinitis in Korean children? Int J Environ Res Public Health 2018;15. doi:[doi:10.3390/ijerph15071527](http://dx.doi.org/10.3390/ijerph15071527). [Epub ahead of print: 19 07 2018].pmid:http://www.ncbi.nlm.nih.gov/pubmed/30029503
    
    

29. Piau JP, Massot C, Moreau D, et al. Assessing allergic rhinitis in developing countries. Int J Tuberc Lung Dis 2010;14:506–12.pmid:http://www.ncbi.nlm.nih.gov/pubmed/20202311
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=20202311&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

30. Sacchetti M, Baiardini I, Chini L, et al. Development and preliminary validation of a new screening questionnaire for identifying atopic children. Pediatric Health Med Ther 2017;8:99–105.[doi:10.2147/PHMT.S142271](http://dx.doi.org/10.2147/PHMT.S142271)pmid:http://www.ncbi.nlm.nih.gov/pubmed/29388629
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

31. Sarafoleanu C, Raluca E, Sarafoleanu D. Eustachian tube dysfunction of adenoid origin. Ther Pharmacol Clin Toxicol 2010:36–40.
    
    

32. Davcheva-Chakar M, Kaftandzhieva A, Zafirovska B. Adenoid vegetations - reservoir of bacteria for chronic otitis media with effusion and chronic rhinosinusitis. Pril 2015;36:71–6.[doi:10.1515/prilozi-2015-0080](http://dx.doi.org/10.1515/prilozi-2015-0080)pmid:http://www.ncbi.nlm.nih.gov/pubmed/27442398
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

33. Acharya K, Bhusal CL, Guragain RP. Endoscopic grading of adenoid in otitis media with effusion. JNMA J Nepal Med Assoc 2010;49:47–51.[doi:10.31729/jnma.135](http://dx.doi.org/10.31729/jnma.135)pmid:http://www.ncbi.nlm.nih.gov/pubmed/21180221
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=21180221&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

34. Buzatto GP, Tamashiro E, Proenca-Modena JL, et al. The pathogens profile in children with otitis media with effusion and adenoid hypertrophy. PLoS One 2017;12:e0171049.[doi:10.1371/journal.pone.0171049](http://dx.doi.org/10.1371/journal.pone.0171049)pmid:http://www.ncbi.nlm.nih.gov/pubmed/28231295
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1371/journal.pone.0171049&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

35. He Z, O'Reilly RC, Bolling L, et al. Detection of gastric pepsin in middle ear fluid of children with otitis media. Otolaryngol Head Neck Surg 2007;137:59–64.[doi:10.1016/j.otohns.2007.02.002](http://dx.doi.org/10.1016/j.otohns.2007.02.002)pmid:http://www.ncbi.nlm.nih.gov/pubmed/17599566
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.otohns.2007.02.002&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=17599566&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000247739700010&link_type=ISI) 

36. Luo H-N, Yang Q-M, Sheng Y, et al. Role of pepsin and pepsinogen: linking laryngopharyngeal reflux with otitis media with effusion in children. Laryngoscope 2014;124:E294–300.[doi:10.1002/lary.24538](http://dx.doi.org/10.1002/lary.24538)pmid:http://www.ncbi.nlm.nih.gov/pubmed/24284944
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

37. Shewel Y, Bassiouny M, Rizk MM. Detection of gastric pepsin in middle ear fluid of children with chronic otitis media with effusion. Egypt J Otolaryngol 2014;30:78–81.[doi:10.4103/1012-5574.133176](http://dx.doi.org/10.4103/1012-5574.133176)
    
    

38. Tasker A, Dettmar PW, Panetti M, et al. Reflux of gastric juice and glue ear in children. Lancet 2002;359:493.[doi:10.1016/S0140-6736(02)07665-1](http://dx.doi.org/10.1016/S0140-6736(02)07665-1)pmid:http://www.ncbi.nlm.nih.gov/pubmed/11853797
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/S0140-6736(02)07665-1&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=11853797&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000173785600014&link_type=ISI) 

39. Tasker A, Dettmar PW, Panetti M, et al. Is gastric reflux a cause of otitis media with effusion in children? Laryngoscope 2002;112:1930–4.[doi:10.1097/00005537-200211000-00004](http://dx.doi.org/10.1097/00005537-200211000-00004)pmid:http://www.ncbi.nlm.nih.gov/pubmed/12439157
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1097/00005537-200211000-00004&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=12439157&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000179193300004&link_type=ISI) 

40. Górecka-Tuteja A, Jastrzębska I, Składzień J, et al. Laryngopharyngeal reflux in children with chronic otitis media with effusion. J Neurogastroenterol Motil 2016;22:452–8.[doi:10.5056/jnm16013](http://dx.doi.org/10.5056/jnm16013)pmid:http://www.ncbi.nlm.nih.gov/pubmed/27193974
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

41. Venkatesan NN, Pine HS, Underbrink M. Laryngopharyngeal reflux disease in children. Pediatr Clin North Am 2013;60:865–78.[doi:10.1016/j.pcl.2013.04.011](http://dx.doi.org/10.1016/j.pcl.2013.04.011)pmid:http://www.ncbi.nlm.nih.gov/pubmed/23905824
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=23905824&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

42. Karyanta M, Satrowiyoto S, Wulandari DP. Prevalence ratio of otitis media with effusion in laryngopharyngeal reflux. Int J Otolaryngol 2019;2019:7460891[doi:10.1155/2019/7460891](http://dx.doi.org/10.1155/2019/7460891)pmid:30693036
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=30693036&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

43. Galić MZ, Klančnik M. Adenoid size in children with otitis media with effusion. Acta Clin Croat 2022;60:532–9.[doi:10.20471/acc.2021.60.03.25](http://dx.doi.org/10.20471/acc.2021.60.03.25)pmid:http://www.ncbi.nlm.nih.gov/pubmed/35282481
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom) 

44. Sharifian MR, Mahmoudi M, Pourmomenarabi B. Correlation between allergic rhinitis and otitis media with effusion. Iran J Otorhinolaryngol 2019;31:209–15.[doi:10.22038/ijorl.2019.22607.1748](http://dx.doi.org/10.22038/ijorl.2019.22607.1748)pmid:31384586
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=31384586&link_type=MED&atom=%2Fbmjopen%2F12%2F9%2Fe065291.atom)