aDepartment of Pediatric Allergy and Immunology, University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey
bDepartment of Pediatric Allergy, Koc University Hospital, Istanbul, Turkey
cDivision of Respiratory Medicine, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada
dDepartment of Pediatric Allergy and Immunology, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey
*Corresponding author: Murat Capanoglua, Department of Pediatric Allergy and Immunology, University of Health Sciences, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey. Email address: [email protected]
Sleep-disordered breathing (SDB) is more common in asthmatic patients than in non-asthmatic persons, and SDB affects negatively to control asthma. A limited number of studies are discovered on the effect of SDB in preschool asthmatic children. In this study, we aimed to investigate the prevalence of SDB and its effect on control and severity of asthma in preschool children. A pediatric sleep questionnaire was completed by parents of asthmatic children. Patients who received a score of 0.33 or higher were diagnosed with SDB. Control and severity of asthma was assessed by a pediatric allergy specialist based on the Global Initiative for Asthma (GINA) criteria. The study included 249 patients, with a mean±SD age of 4.37±1.04 (range: 2–5.9) years; 69% were boys; 56.6% children had uncontrolled asthma and 28.7% had SDB. The SDB score was significantly different between controlled and uncontrolled asthma (0.19 vs 0.28; P < 0.001). The frequency of uncontrolled asthma in patients with and without SDB was 74.3% and 49.4%, respectively (P < 0.010). Based on the severity of asthma, the frequency of SDB among patients with mild, moderate, and severe asthma was 23.4%, 35.2%, and 47.4%, respectively (P = 0.010).
Conclusion: The frequency and score of SDB were higher in patients with uncontrolled asthma. Frequency and score of SDB were significantly affected by the severity of asthma. SDB must be evaluated in preschool children with uncontrolled asthma.
Key words: Asthma, Asthmatic Children, Asthma Control, Sleep Disorders, Asthma Severity
Received 1 December 2022; Accepted 31 July 2023; Available online 1 January 2024
Copyright: Capanoglu M, et al
License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/
Asthma is the most common chronic disease of childhood, and the aim of disease management is to achieve and maintain control. Therefore, conditions that disrupt control of asthma and trigger an attack must be assessed cautiously. Exercise, allergens, cold and flu, and air-pollution as well as comorbid conditions frequently trigger symptoms and worsen control of asthma. Among these comorbid conditions, sleep-disordered breathing (SDB) was reported as an important risk factor for control and severity of asthma.1
The prevalence of SDB ranges between 1% and 7% in normal population. However, it is reported more commonly in asthmatic children.2–4 Both diseases involve airway obstruction and widespread inflammation of the airways, and similar diurnal and nocturnal symptoms.4,5 The prevalence of uncontrolled asthma was significantly higher in SDB patients, and treatment of SDB led to the lessening of symptoms in patients with uncontrolled asthma.2,6
Evaluation of asthmatic patients for sleep disorders and providing them an appropriate treatment are important for disease control.7 The National Asthma Education and Prevention Program (NAEPP) also recommends investigating the presence of SDB in patients with uncontrolled asthma.5,8 A limited number of studies are observed in the literature on the effect of SDB in asthmatic patients aged less than 5 years.3,9,10 Hence, we aimed to determine the risk factors that may affect the development and control of asthma and to investigate the prevalence of SDB and its effect on control and severity of asthma in children aged less than 5 years.
Asthmatic patients aged less than 6 years that visited our Pediatric Allergy Outpatient Clinic between June 2013 and December 2014 were included in this cross-sectional study.
Inclusion criteria for the study were as follows: regular follow up at our clinic between June 2013 and December 2014 for recurrent wheezing; diagnosis of asthma at <6 years of age; at least three scheduled visits during 1 year period; and using inhaler steroid or having montelukast therapy. Exclusion criteria were as follows: patient aged >6 years; patient having been followed for less than 1 year at our clinic; and patient not using inhaler steroid or montelukast therapy.
A questionnaire about asthma risk factors and demographic and clinical features of asthma as well as pediatric sleep questionnaire (PSQ) was filled by a physician.11,12
Patients were diagnosed with asthma based on Global Initiative for Asthma (GINA) criteria;12 and had used controller drug correctly and regularly. Inhaler corticosteroids or leukotriene receptor antagonists were routinely used for 2–3 months in patients with consistent asthma manifestations and a history of recurring wheezing (three or more times). Patients who responded to treatment but their symptoms recurred after cesation of treatment; the symptoms lessened after resumption of treatment; were asymptomatic between attacks; and for whom other causes of wheezing were ruled out were diagnosed as asthmatic. Response to treatment was assessed based on symptom management and frequency of attacks. Disease control was assessed based on GINA criteria by a pediatric allergy specialist. Severity and control situation of the disease were determined according to the dosage of drugs used by patients and frequency of manifestations in patients.
Patients were diagnosed with SDB based on the PSQ filled by a pediatric allergy specialist. The PSQ consists of 22 questions. Patients respond to question in the form of “Yes,” “No,” or leave it blank, while “Yes” is rated as 1 point, “No” is rated as zero (0) point. The total score of each patient was calculated and divided by 22. Patients receiving a score of 0.33 or higher are considered as having SDB. The Turkish version of PSQ was reported by Yüksel et al.13 as a reliable and valid scale used in the initial assessment of SDB symptoms in Turkish children in a study comprising 111 children, aged 2–17 years.14,15
Skin prick tests for allergens, such as Dermatophagoides pteronyssinus, Dermatophagoides farinae, Alternaria alternata, cat and dog fur, mixed tree pollens, mixed grass pollens, and Parietaria officinalis (Stallergenes, SA Antony, France), were performed in case of all patients. Positive control used was 10% histamine phosphate and 0.9% physiological saline solution was used as a negative control. Atopy was defined as having at least one positive skin test response.
Total serum immunoglobulin E (IgE) levels of the patients were measured by nephelometry (Beckman Coulter Immage 800, CA, USA).
Risk factors that trigger symptoms and worsen asthma control are smoking at least one cigarette in the house (passive smoking), living with five or more people in the house (crowded home environment), and being exposed to truck exhaust fumes once or more daily in the living environment (exposure to exhaust fumes).16,17 Height (in cm) and weight (in kg) of all the patients were measured during the period of the study. Patient was considered obese according to body mass index (BMI) value.18
The local ethics committee approved the study, and informed consent was obtained from parents of all the participants.
Statistical analyses were performed by using Statistical Package for Social Sciences (SPSS) 21.0 for Windows (IBM Corporation, Armonk, New York, USA). Mann–Whitney U test was used for the binary comparison of numerical data; Kruskal–Wallis test was used for the comparison of multiple numerical data; Chi-square test was used for the comparison of categorical data; and Spearman’s correlation test was used for correlation analyses. P < 0.05 was considered statistically significant.
A total of 249 children with a mean age of 4.37±1.04 (2–5.9) years were included in the study and 69.1% (n = 172) of them were males. The mean age at the onset of symptoms was 20.7±14.7 (1–54) months, and the mean age at diagnosis was 33.7±16.1 (range: 6–60) months. Of all the patients, 54.2% (n = 135) were taking anti-inflammatory treatment (inhaled corticosteroids [ICS] and/or leukotriene receptor antagonists [LTRA]), 56.6% (n = 141) had uncontrolled disease according to the GINA criteria, 34.8% (n = 54) had used systemic steroids for at least one attack within the past 1 year, and 15.3% (n = 54) had no attack during the past 1 year (Table 1).
Table 1 Demographic and clinical characteristics of patients.
Characteristics | Results |
---|---|
Age (year), mean ± SD | 4.37 ± 1.04 (2–5.9) |
Gender (male), n (%) | 172 (69.1) |
Age at onset of complaints (month), mean±SD | 20.7 ± 14.7 (1–54) |
Age of diagnosis (month), mean ± SD | 33.7 ± 16.1 (6–60) |
Patient using anti-inflammatory treatment (ICS and/or LTRA), n (%) | 135 (54.2) |
Patient with uncontrolled asthma (according to GINA), n (%) | 141 (56.6) |
Patient with symptoms of rhinitis, n (%) | 48 (22.3) |
Atopy, n (%) | 33 (13.6) |
Eosinophilia (≥4%), n (%) | 50 (25.8) |
Presence of SDB, n (%) | 70 (28.7) |
Score of SDB, mean ± SD | 0.24 ± 0.18 (0–0.86) |
Level of IgE (IU/mL), median (IQR) | 22.0 (8.9–92.7) |
Asthma severity, n (%) Mild Moderate Severe |
159 (63.9) 71 (28.5) 19 (7.6) |
Number of emergency admissions during last year, n (%) | 141 (56.6) |
Number of steroids used during last year, n (%) | 54 (21.7) |
Number of hospitalizations during last year, n (%) | 34 (13.7) |
SDB: Sleep-disordered breathing; ICS: inhaled corticosteroids; LTRA: leukotriene receptor antagonists; IQR: interquartile range; IgE: Immunoglobulin E.
Patients were questioned about risk factors that may affect asthma control. Of the most common risk factors, passive smoking was present in 38.1% of the patients, 34.4% of the patients were living in a crowded home environment, and rhinitis manifestations were present in 22.8% of the patients. When the patients were classified as having controlled and uncontrolled disease, the frequency of risk factors for uncontrolled asthma was similar between the groups (Table 2).
Table 2 Effect of risk factors to control asthma.
Risk Factors | Total N (%) | Controlled asthma n (%) | Uncontrolled asthma n (%) | P |
---|---|---|---|---|
Passive smoking exposure | 93 (38.1) | 45 (43.7) | 48 (34.0) | 0.125 |
Presence of rhinitis symptom | 48 (22.3) | 22 (23.4) | 26 (21.5) | 0.738 |
Atopy | 33 (13.6) | 15 (14.0) | 18 (13.2) | 0.860 |
Living in a crowded home environment | 75 (34.4) | 36 (39.6) | 39 (30.7) | 0.175 |
Obesity | 24 (11.8) | 9 (10.3) | 15 (12.9) | 0.572 |
Presence of mold and moisture at home | 22 (15.4) | 8 (15.1) | 14 (15.6) | 0.941 |
Wood stove heating | 34 (15.2) | 15 (15.8) | 19 (14.8) | 0.846 |
Exposure to diesel exhaust füme | 31 (24) | 14 (28.6) | 17 (21.3) | 0.345 |
Attending nursery | 24 (17.9) | 8 (15.4) | 16 (19.5) | 0.544 |
Pets at home | 14 (6.2) | 5 (5.2) | 9 (7.0) | 0.574 |
Eosinophilia (≥4%) | 50 (25.8) | 17 (21.0) | 33 (29.2) | 0.197 |
SDB score, mean±SD | 0.24 ± 0.18 (0–0.86) | 0.19 ± 0.14 (0–0.63) | 0.28 ± 0.19 (0–0.86) | <0.001 |
SDB: Sleep-disordered breathing
In all patients, 28.7% (n = 70) were diagnosed with SDB, 16.5% had snoring, 29.7% had mouth breathing, and 11.3% had throat clearing. In all patients, mean of SDB score was 0.24±0.18 (0–0.86). The SDB score was significantly different between controlled and uncontrolled asthma (0.19 vs 0.28; P < 0.001).
The frequency of uncontrolled disease was significantly higher in asthmatic patients with SDB (74.3% vs 49.4%; P < 0.001; Table 3). The frequency of steroid use and hospitalization of the patients within the past 1 year was not statistically different. However, the number of attacks and emergency room admissions within the past 1 year was significantly higher in the group with SDB (P = 0.035 and 0.004, respectively). When the patients were classified according to the severity of their asthma as having mild, moderate, and severe asthma, the prevalance of SDB was 23.4%, 35.2%, and 47.4%, respectively (P = 0.010; Table 3 and Figure 1).
Table 3 Characteristics of patients with and without SDB.
Characteristics | SDB patients | Non-SDB patients | P |
---|---|---|---|
Patients with uncontrolled asthma (GINA), n (%) | 52 (74.3) | 86 (49,4) | <0.001 |
Number of attacks during the past yeara | 4.6 ± 4.1 (0–15) | 3.4 ± 3.3 (0–15) | 0.035 |
Number of emergency admissions during the past yeara | 3.6 ± 3.0 (0–10) | 2.3 ± 2.7 (0–10) | 0.004 |
Number of steroids used during the past yeara | 0.710 ± 1.39 (0–5) | 0.756 ± 1.31 (0–6) | 0.862 |
Number of hospitalizations during the past yeara | 0.435 ± 1.44 (0–10) | 0.151±0.41 (0–2) | 0.114 |
Presence of emergency admissions during the past yeara | 47 (67.1) | 92 (52.9) | 0.042 |
Presence of steroids used during the past yeara | 10 (14.3) | 43 (24.7) | 0.074 |
Presence of hospitalization during the past yeara | 12 (17.1) | 22 (12.6) | 0.359 |
Asthma severity Mild, n(%) Moderate, n (%) Severe, n (%) |
36 (51.4) 25 (35.7) 9 (12.9) |
118 (67.8) 46 (26.5) 10 (5.7) |
0,010 |
aMean±SD.
SDB: Sleep-disordered breathing
Figure 1 Frequency of patients with/without SDB according to asthma severity.
In this study, we observed that of the 249 children, followed for the diagnosis of preschool asthma, 56.6% had uncontrolled disease, and 28.7% had SDB. The prevalence of uncontrolled asthma in patients with and without SDB was 74.3% and 49.4%, respectively. The frequency of SDB increased with increase in the severity of asthma; also, SDB was more common among uncontrolled asthmatic pediatric patients aged less than 5 years.
One of the most important issues observed in asthmatic patients is the control of asthma. Despite all improvements in treatment and all published guidelines, the rate of controlled asthma is around 50%. In the two studies conducted in Turkey, the rate of controlled asthma according to the GINA criteria among pediatric patients aged 5 years was 55%.11,19 In a meta-analysis comprising 988 asthmatic patients aged <16 years from 12 countries of Asia, the prevalence of uncontrolled disease according to the GINA criteria was 53.4%.20 In our study, the frequency of uncontrolled asthma was found to be 56.6%, consistent with the literature.
Sleep-disordered breathing can have a clinical manifestation ranging from a simple snore to apnea. Snoring has been found in 3.2–12.1% of healthy children and 6.2–35.5% of asthmatic patients. In this study, the prevalence of snoring in asthmatics was found as 16.5%, which is consistent with previous studies.21,22 The prevalence of SDB is reported in 1–7% of pediatric patients.
Studies have shown that the rate of SDB was higher among asthmatic patients. In a study using PSQ, the frequency of SDB was 25.9% in asthmatic children and 10.6% in healthy controls.3 In another meta-analysis, 45,155 children, with a mean age of 8.6 years from 17 separate studies, were evaluated. SDB was reported in 23.9% of asthmatic children and 16.7% of non-asthmatic children.4 In another study comprising 194 asthmatic children aged 4–10 years, the frequency of SDB was found as 33%.23 Ginis et al. found the frequency of SDB as 34.6% in 408 asthmatic patients aged 4–18 years.2 Similarly, Rivera et al. found the frequency of SDB as 40.8% in 70 asthmatic patients aged 2–5 years.24 However, in our study, the prevalence of SDB was as 28.7%.
Asthma treatment is directed toward achieving and maintaining control on the disease. Some factors, such as allergen exposure in sensitized patients, severe allergic rhinitis, passive smoking, living in a crowded family, and obesity, are reported to have negative effect on asthma control. However, in the present study, no difference was found between controlled and uncontrolled patients in terms of passive smoking, crowded living conditions, and the presence of atopy. These results suggested that there could be additional factors that may affect disease control in preschool asthmatic children. Among these factors, presence of SDB has been suggested as a risk factor for uncontrolled disease.31–35 In our study, the frequency of SDB in uncontrolled patients was higher than in controlled patients (37.7% and 17.0%, respectively; P < 0.001).
Sleep-disordered breathing plays an important role in the development of attacks in asthmatic patients, and SDB patients require higher doses of preventer inhalers.36,37 In a study comprising 102 asthmatic children aged 3–10 years, asthmatic manifestations, the annual number of attacks, and the weekly requirement of beta-agonists were found to be significantly higher in SDB patients, compared to the non-SDB group.6 It has been also reported that the use of continuous positive airway pressure (CPAP) therapy for sleep-related obstructive apnea and snoring facilitate the management of asthmatic patients.38
In our study, the frequency of uncontrolled disease according to the GINA criteria was significantly higher in the SDB group, compared with the non-SDB group (74.3% and 49.4%, respectively; P < 0.001). The number of attacks and emergency admissions in the SDB group within the past 1 year was found to be higher, compared to the non-SDB group (P = 0.035 and P = 0.004, respectively). In addition, the presence of SDB was found to be different in patients with controlled and uncontrolled asthma (37.7% and 17.0%, respectively; P < 0.001).
Limited studies have been observed concerning SDB and the severity of asthma. The current study investigated the relationship between SDB and severity of asthma in children aged 2–15 years. In the group with severe persistent asthma, significantly higher presence of SDB was observed.3,6 Similarly, in our study, the frequency of SDB was higher in severe asthmatic patients.
A few mechanisms have been suggested to explain the association between SDB and severe asthma. TNF-alpha levels are higher in asthmatic patients than in healthy controls.39 It has also been found high in sleep disorders. These results suggest that proinflammatory TNF-alpha could have a role in the relationship between severity of asthma and presence of SDB. Another mechanism that suggested the relationship between SDB and severity of asthma was neutrophilic inflammation, which affected the control of asthma in the airways, as also observed in SDB patients.35,39,40 It is known that as the severity of asthma increases, inflammation in the airways shifts toward the neutrophilic side. Neutrophilic inflammation has also been shown in the respiratory tract of SDB patients. This could be another mechanism to explain the relationship between the severity of asthma and the presence of SDB. In our study, the prevalence of SDB increased with increase in the severity of asthma in asthmatic patients aged <5 years.
In the present study, the relationship between severity and asthma control and the presence of SDB was studied at a single center and cannot be generalized for the whole population; however, it was conducted with a larger number of patients than the numbers reported in other studies. The inability to perform polysomnography on patients was a limitation of the present study. The gold standard for the diagnosis of SDB in children is execution of polysomnography in a sleep laboratory.41 However, this technique cannot be executed easily in daily clinical practice. The PSQ developed for this reason has 81% sensitivity and 87% specificity, hence used in the present analysis. In addition, a number of studies have demonstrated that PSQ could be used instead of polysomnography for diagnosis of SDB.14,42,43
In the present study, it was shown that the frequency and score of SDB were higher in patients with uncontrolled asthma, and the same were significantly affected by the severity of asthma. Evaluating of SDB in asthmatic patients and recommending appropriate therapy could increase the rate of control of asthma.
1. de Groot EP, Duiverman EJ, Brand PL. Comorbidities of asthma during childhood: possibly important, yet poorly studied. Eur Respir J. 2010;36(3):671–78. 10.1183/09031936.00185709
2. Ginis T, Akcan FA, Capanoglu M, Toyran M, Ersu F, Kocabas CN, et al. The frequency of sleep-disordered breathing in children with asthma and its effects on asthma control. J Asthma. 2017;54(4):403–10. 10.1080/02770903.2016.1220012
3. Goldstein NA, Aronin C, Kantrowitz B, Hershcopf R, Fishkin S, Lee H, et al. The prevalence of sleep-disordered breathing in children with asthma and its behavioral effects. Pediatr Pulmonol. 2015;50(11):1128–36. 10.1002/ppul.23120
4. Brockmann PE, Bertrand P, Castro-Rodriguez JA. Influence of asthma on sleep disordered breathing in children: a systematic review. Sleep Med Rev. 2014;18(5):393–97. 10.1016/j.smrv.2014.01.005
5. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the diagnosis and management of Asthma-Summary Report 2007 [published correction appeared in J Allergy Clin Immunol. 2008 Jun;121(6):1330]. J Allergy Clin Immunol. 2007;120(5 Suppl):S94–138. 10.1016/j.jaci.2007.09.029
6. Kheirandish-Gozal L, Dayyat EA, Eid NS, Morton RL, Gozal D. Obstructive sleep apnea in poorly controlled asthmatic children: Effect of adenotonsillectomy. Pediatr Pulmonol. 2011;46(9):913–8. 10.1002/ppul.21451
7. Prasad B, Nyenhuis SM, Weaver TE. Obstructive sleep apnea and asthma: Associations and treatment implications. Sleep Med Rev. 2014;18(2):165–71. 10.1016/j.smrv.2013.04.004
8. Ciftci TU, Ciftci B, Guven SF, Kokturk O, Turktas H. Effect of nasal continuous positive airway pressure in uncontrolled nocturnal asthmatic patients with obstructive sleep apnea syndrome. Respir Med. 2005;99(5):529–34. 10.1016/j.rmed.2004.10.011
9. Greenfeld M, Sivan Y, Tauman R. The effect of seasonality on sleep-disordered breathing severity in children. Sleep Med. 2013;14(10):991–4. 10.1016/j.sleep.2013.03.026
10. Marshall NS, Almqvist C, Grunstein RR, Marks GB; Childhood asthma prevention study. predictors for snoring in children with rhinitis at age 5. Pediatr Pulmonol. 2007;42(7):584–91. 10.1002/ppul.20606
11. Buyuktiryaki B, Sahiner UM, Yavuz ST, Cavkaytar O, Arik Yilmaz E, Uysal Soyer O, et al. Validation of the Turkish version of “Test for Respiratory and Asthma Control in Kids (TRACK)” questionnaire. J Asthma. 2013;50(10):1096–101. 10.3109/02770903.2013.837481
12. Global Initative For Asthma (GINA) Reports. Global strategy for asthma management and prevention [Internet]. (2022 update). Available from: www.ginasthma.org/gina-reports/
13. Ersu R, Arman AR, Save D, Karadag B, Karakoc F, Berkem M, et al. Prevalence of snoring and symptoms of sleep--disordered breathing in primary school children in Istanbul. Chest. 2004;126(1):19–24. 10.1378/chest.126.1.19
14. Yüksel H, Sogut A, Yilmaz O, Kutluay E. Reliability and validity of the Turkish version of the pediatric sleep questionnaire: A tool for prediction of sleep-related breathing disorder. Tuberk Toraks. 2011;59(3):236–41. 10.5578/tt.2467
15. Chervin RD, Hedger K, Dillon JE, Pituch KJ. Pediatric sleep questionnaire (PSQ): Validity and reliability of scales for sleep-disordered breathing, snoring, sleepiness, and behavioral problems. Sleep Med. 2000;1(1):21–32. 10.1016/S1389-9457(99)00009-X
16. Hekking PP, Amelink M, Wener RR, Bouvy ML, Bel EH. Comorbidities in difficult-to-control asthma. J Allergy Clin Immunol Pract. 2018;6(1):108–13. 10.1016/j.jaip.2017.06.008
17. Xiang L, Zhao J, Zheng Y, Liu H, Hong J, Bao Y, et al. Uncontrolled asthma and its risk factors in Chinese children: A cross-sectional observational study. J Asthma. 2016;53(7):699–706. 10.3109/02770903.2016.1144199
18. Edalat A, Abbaszadeh M, Eesvandi M, Heidari A. The relationship of severe early childhood caries and body mass index in a group of 3-to 6-year-old children in Shiraz. J Dent. 2014;15(2):68.
19. Kaya A, Erkocoglu M, Akan A, Vezir E, Azkur D, Ozcan C, et al. TRACK as a complementary tool to GINA and NAEPP guidelines for assessing asthma control in pre-school children. J Asthma. 2014;51(5):530–5. 10.3109/02770903.2014.887729
20. Wong GW, Kwon N, Hong JG, Hsu JY, Gunasekera KD. Pediatric asthma control in Asia: Phase 2 of the Asthma Insights and Reality in Asia-Pacific (AIRIAP 2) survey. Allergy. 2013;68(4):524–30. 10.1111/all.12117
21. Li L, Xu Z, Jin X, Yan C, Jiang F, Tong S, et al. Sleep-disordered breathing and asthma: Evidence from a large multicentric epidemiological study in China. Respir Res. 2015;16(1):56. 10.1186/s12931-015-0215-5
22. Ross KR, Storfer-Isser A, Hart MA, Kibler AM, Rueschman M, Rosen CL, et al. Sleep-disordered breathing is associated with asthma severity in children. J Pediatr. 2012;160(5):736–42. 10.1016/j.jpeds.2011.10.008
23. Fagnano M, van Wijngaarden E, Connolly HV, Carno MA, Forbes-Jones E, Halterman JS. Sleep-disordered breathing and behaviors of inner-city children with asthma. Pediatrics. 2009;124(1):218–25. 10.1542/peds.2008-2525
24. Rivera N, Flores C, Morales M, Padilla O, Causade S, Brockmann SE, et al. Preschoolers with recurrent wheezing have a high prevalence of sleep disordered breathing. J Asthma. 2020;57(6):584–92. 10.1080/02770903.2019.1599385
25. Tsaoussoglou M, Bixler EO, Calhoun S, Chrousos GP, Sauder K, Vgontzas AN. Sleep-disordered breathing in obese children is associated with prevalent excessive daytime sleepiness, inflammation, and metabolic abnormalities. J Clin Endocrinol Metab. 2010;95(1):143–50. 10.1210/jc.2009-0435
26. Nagel G, Koenig W, Rapp K, Wabitsch M, Zoellner I, Weiland SK. Associations of adipokines with asthma, rhinoconjunctivitis, and eczema in German schoolchildren. Pediatr Allergy Immunol. 2009;20(1):81–8. 10.1111/j.1399-3038.2008.00740.x
27. Brockmann PE, Castro-Rodriguez JA, Holmgren NL, Cerda J, Maria Contreras A, Moya A, et al. Urinary leukotriene excretion profile in children with exercise-induced asthma compared with controls: A preliminary study. Allergol Immunopathol (Madr). 2012;40(3):181–6. 10.1016/j.aller.2011.03.012
28. Goldbart AD, Goldman JL, Veling MC, Gozal D. Leukotriene modifier therapy for mild sleep-disordered breathing in children. Am J Respir Crit Care Med. 2005;172(3):364–70. 10.1164/rccm.200408-1064OC
29. Kaditis AG, Kalampouka E, Hatzinikolaou S, et al. Associations of tonsillar hypertrophy and snoring with history of wheezing in childhood. Pediatr Pulmonol. 2010;45(3):275–80. 10.1002/ppul.21174
30. Teodorescu M, Consens FB, Bria WF, Lianou L, Papaefthimiou M, Gartagani-Panagiotopoulouet P, et al. Predictors of habitual snoring and obstructive sleep apnea risk in patients with asthma. Chest. 2009;135(5):1125–32. 10.1378/chest.08-1273
31. Bjerg A, Hedman L, Perzanowski M, Wennergren G, Lundbäck B, Rönmark E. Decreased importance of environmental risk factors for childhood asthma from 1996 to 2006. Clin Exp Allergy. 2015;45(1):146–53. 10.1111/cea.12439
32. Lawson JA, Janssen I, Bruner MW, Hossain A, Pickett W. Asthma incidence and risk factors in a national longitudinal sample of adolescent Canadians: A prospective cohort study. BMC Pulm Med. 2014;14:51. 10.1186/1471-2466-14-51
33. Patelarou E, Tzanakis N, Kelly FJ. Exposure to indoor pollutants and wheeze and asthma development during early childhood. Int J Environ Res Public Health. 2015;12(4):3993–4017. 10.3390/ijerph120403993
34. Sasaki M, Yoshida K, Adachi Y, Furukawa M, Itazawa T, Odajima H, et al. Factors associated with asthma control in children: Findings from a national Web-based survey. Pediatr Allergy Immunol. 2014;25(8):804–9. 10.1111/pai.12316
35. Irwin MR, Wang M, Campomayor CO, Collado-Hidalgo A, Cole S. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med. 2006;166(16):1756–62. 10.1001/archinte.166.16.1756
36. Alkhalil M, Schulman ES, Getsy J. Obstructive sleep apnea syndrome and asthma: The role of continuous positive airway pressure treatment. Ann Allergy Asthma Immunol. 2008;101(4):350–7. 10.1016/S1081-1206(10)60309-2
37. Salles C, Terse-Ramos R, Souza-Machado A, Cruz ÁA. Obstructive sleep apnea and asthma. J Bras Pneumol. 2013;39(5):604–12. 10.1590/S1806-37132013000500011
38. Chan CS, Woolcock AJ, Sullivan CE. Nocturnal asthma: Role of snoring and obstructive sleep apnea. Am Rev Respir Dis. 1988;137(6):1502–4. 10.1164/ajrccm/137.6.1502
39. Silvestri M, Bontempelli M, Giacomelli M, Malerba M, Rossi GA, Di Stefano A, et al. High serum levels of tumour necrosis factor-alpha and interleukin-8 in severe asthma: Markers of systemic inflammation? Clin Exp Allergy. 2006;36(11):1373–81. 10.1111/j.1365-2222.2006.02502.x
40. Li AM, Hung E, Tsang T, Yin J, So HK, Wong E, et al. Induced sputum inflammatory measures correlate with disease severity in children with obstructive sleep apnoea. Thorax. 2007;62(1):75–9. 10.1136/thx.2006.060657
41. Lumeng JC, Chervin RD. Epidemiology of pediatric obstructive sleep apnea. Proc Am Thorac Soc. 2008;5(2):242–52.
42. Goldstein NA, Abramowitz T, Weedon J, Koliskor B, Turner S, Taioli E. Racial/ethnic differences in the prevalence of snoring and sleep disordered breathing in young children. J Clin Sleep Med. 2011;7(2):163–71.
43. O'Brien LM, Lucas NH, Felt BT, Hoban TF, Ruzicka DL, Jordan R, et al. Aggressive behavior, bullying, snoring, and sleepiness in schoolchildren. Sleep Med. 2011;12(7):652–8.