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Karkala A, Kotoulas SC, Tzinas A, Massa E, Mouloudi E, Gkakou F, Pataka A. The Lung Microbiome and Its Impact on Obstructive Sleep Apnea: A Diagnostic Frontier. Diagnostics (Basel) 2025; 15:1431. [PMID: 40507003 PMCID: PMC12154070 DOI: 10.3390/diagnostics15111431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2025] [Revised: 05/29/2025] [Accepted: 06/03/2025] [Indexed: 06/16/2025] Open
Abstract
Obstructive sleep apnea (OSA), a prevalent disorder characterized by recurrent upper airway collapse, is increasingly recognized as a systemic inflammatory condition influenced by microbial dysregulation. Emerging evidence underscores the lung microbiome as a mediator in OSA pathophysiology, where dysbiotic shifts driven by intermittent hypoxia, oxidative stress and mechanical airway trauma amplify inflammatory cascades and perpetuate respiratory instability. This review synthesizes current knowledge on the bidirectional interplay between OSA and lung microbial communities. It aims to highlight how hypoxia-induced alterations in microbial ecology disrupt immune homeostasis, while inflammation-driven mucosal injury fosters pathogenic colonization. Clinical correlations between specific taxa like Streptococcus and Prevotella, and disease severity, suggest microbial signatures as novel biomarkers for OSA progression and treatment response. Furthermore, oxidative stress markers and pro-inflammatory cytokines emerge as potential diagnostic tools that bridge microbial dysbiosis with sleep-related outcomes. However, challenges persist in sampling standardization of the low-biomass lower airways, as well as in causative mechanisms linking microbial dysbiosis to OSA pathophysiology. By integrating microbial ecology with precision sleep medicine, this paradigm shift promises to transform OSA management from mechanical stabilization to holistic ecosystem restoration.
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Affiliation(s)
- Aliki Karkala
- Respiratory Failure Unit, General Hospital of Thessaloniki “G. Papanikolaou”, Exochi, 57010 Thessaloniki, Greece; (A.T.); (A.P.)
| | | | - Asterios Tzinas
- Respiratory Failure Unit, General Hospital of Thessaloniki “G. Papanikolaou”, Exochi, 57010 Thessaloniki, Greece; (A.T.); (A.P.)
| | - Eleni Massa
- Intensive Care Unit, “Hippokration” Hospital of Thessaloniki, 54642 Thessaloniki, Greece; (E.M.); (E.M.)
| | - Eleni Mouloudi
- Intensive Care Unit, “Hippokration” Hospital of Thessaloniki, 54642 Thessaloniki, Greece; (E.M.); (E.M.)
| | - Foteini Gkakou
- Department of Pulmonology, General Hospital of Thessaloniki “G. Papanikolaou”, Exochi, 57010 Thessaloniki, Greece;
| | - Athanasia Pataka
- Respiratory Failure Unit, General Hospital of Thessaloniki “G. Papanikolaou”, Exochi, 57010 Thessaloniki, Greece; (A.T.); (A.P.)
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Petrongari D, Ciarelli F, Di Filippo P, Di Ludovico A, Di Pillo S, Chiarelli F, Pellegrino GM, Sferrazza Papa GF, Nosetti L, Attanasi M. Risk and Protective Factors for Obstructive Sleep Apnea Syndrome Throughout Lifespan: From Pregnancy to Adolescence. CHILDREN (BASEL, SWITZERLAND) 2025; 12:216. [PMID: 40003319 PMCID: PMC11854123 DOI: 10.3390/children12020216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/09/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025]
Abstract
BACKGROUND Obstructive sleep apnea syndrome (OSAS) in children is indeed a significant and often underdiagnosed condition. The risk factors for OSAS vary across different stages of life. OBJECTIVES Identifying risk factors early can help in taking preventive measures to reduce the likelihood of developing OSAS, and different life stages may require different interventions. RESULTS During pregnancy, maternal factors such as obesity, smoking, and genetic predispositions can increase the risk of OSAS, while breastfeeding serves as a protective factor. For children aged 2 to 12, adenotonsillar hypertrophy is the primary cause of airway narrowing, with other contributing factors including obesity, craniofacial abnormalities, and increased nasal resistance. In adolescence, obesity and craniofacial abnormalities remain the main risk factors. CONCLUSIONS By reviewing and understanding these risk factors, healthcare providers can offer more personalized and effective care, ultimately leading to better health outcomes for individuals at all stages of life.
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Affiliation(s)
- Duilio Petrongari
- Department of Pediatrics, Pediatric Allergy and Pulmonology Unit, University of Chieti-Pescara, Via Dei Vestini 5, 66100 Chieti, Italy; (D.P.); (F.C.); (P.D.F.); (A.D.L.); (S.D.P.); (F.C.)
| | - Francesca Ciarelli
- Department of Pediatrics, Pediatric Allergy and Pulmonology Unit, University of Chieti-Pescara, Via Dei Vestini 5, 66100 Chieti, Italy; (D.P.); (F.C.); (P.D.F.); (A.D.L.); (S.D.P.); (F.C.)
| | - Paola Di Filippo
- Department of Pediatrics, Pediatric Allergy and Pulmonology Unit, University of Chieti-Pescara, Via Dei Vestini 5, 66100 Chieti, Italy; (D.P.); (F.C.); (P.D.F.); (A.D.L.); (S.D.P.); (F.C.)
| | - Armando Di Ludovico
- Department of Pediatrics, Pediatric Allergy and Pulmonology Unit, University of Chieti-Pescara, Via Dei Vestini 5, 66100 Chieti, Italy; (D.P.); (F.C.); (P.D.F.); (A.D.L.); (S.D.P.); (F.C.)
| | - Sabrina Di Pillo
- Department of Pediatrics, Pediatric Allergy and Pulmonology Unit, University of Chieti-Pescara, Via Dei Vestini 5, 66100 Chieti, Italy; (D.P.); (F.C.); (P.D.F.); (A.D.L.); (S.D.P.); (F.C.)
| | - Francesco Chiarelli
- Department of Pediatrics, Pediatric Allergy and Pulmonology Unit, University of Chieti-Pescara, Via Dei Vestini 5, 66100 Chieti, Italy; (D.P.); (F.C.); (P.D.F.); (A.D.L.); (S.D.P.); (F.C.)
| | - Giulia Maria Pellegrino
- Department of Neurorehabilitation Sciences, Casa di Cura Igea, 20144 Milan, Italy; (G.M.P.); (G.F.S.P.)
| | | | - Luana Nosetti
- Department of Pediatrics, Pediatric Sleep Disorders Center, F. Del Ponte Hospital, Insubria University, 21100 Varese, Italy;
| | - Marina Attanasi
- Department of Pediatrics, Pediatric Allergy and Pulmonology Unit, University of Chieti-Pescara, Via Dei Vestini 5, 66100 Chieti, Italy; (D.P.); (F.C.); (P.D.F.); (A.D.L.); (S.D.P.); (F.C.)
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Cholerzyńska H, Zasada W, Tselios K, Grygiel-Górniak B. Sleep Disorders in Connective Tissue Diseases-Coexisting Diseases or Disease Components? J Clin Med 2024; 13:3656. [PMID: 38999222 PMCID: PMC11242285 DOI: 10.3390/jcm13133656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/17/2024] [Accepted: 06/20/2024] [Indexed: 07/14/2024] Open
Abstract
This comprehensive review examines the complex relationship between sleep disorders and rheumatic diseases, supported by findings from the latest research articles. It encompasses various rheumatic conditions, including rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. The review reveals the bidirectional relationship between sleep disorders and these diseases, emphasizing their impact on disease progression and quality of life. Conventional and alternative therapeutic interventions for connective tissue diseases are presented, focusing on improving sleep quality and alleviating rheumatic symptoms. The role of pro-inflammatory cytokines and their potential modulation through pharmacological agents is also discussed. In the treatment of sleep disorders, various options are proposed, such as cognitive behavioral therapy for insomnia, physical activity, dietary modifications, and alternative approaches like reflexology and acupuncture. Thus, this review offers a nuanced understanding of the connection between sleep disorders and rheumatic diseases, supported by evidence from diverse studies. Such an approach is particularly important because it enhances sleep quality for overall patient well-being in the holistic management of rheumatic conditions.
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Affiliation(s)
- Hanna Cholerzyńska
- Department of Rheumatology, Rehabilitation and Internal Diseases, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Wiktoria Zasada
- Department of Rheumatology, Rehabilitation and Internal Diseases, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | | | - Bogna Grygiel-Górniak
- Department of Rheumatology, Rehabilitation and Internal Diseases, Poznan University of Medical Sciences, 61-701 Poznan, Poland
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Golshah A, Sadeghi E, Sadeghi M. Association of Tumor Necrosis Factor-Alpha, Interleukin-1β, Interleukin-8, and Interferon-γ with Obstructive Sleep Apnea in Both Children and Adults: A Meta-Analysis of 102 Articles. J Clin Med 2024; 13:1484. [PMID: 38592305 PMCID: PMC10932105 DOI: 10.3390/jcm13051484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/20/2024] [Accepted: 02/29/2024] [Indexed: 04/10/2024] Open
Abstract
Background: Cytokines may have a significant impact on sleep regulation. In this meta-analysis, we present the serum/plasma levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-8, IL-1β, and interferon-gamma (IFN-γ) in both children and adults with obstructive sleep apnea (OSA) in comparison to controls. Methods: Four electronic databases were systematically searched (PubMed, Web of Science, Scopus, and Cochrane Library) through 19 October 2023, without any restrictions on language, date, age, and sex. We used Review Manager version 5.3 to perform meta-analysis and presented the data as standardized mean difference (SMD) and 95% confidence interval (CI) values to evaluate the relationships between the levels of cytokines and OSA. Results: A total of 102 articles (150 independent studies) were included in the meta-analysis. The pooled SMDs in adults were 1.42 (95%CI: 1.11, 1.73; p < 0.00001), 0.85 (95%CI: 0.40, 1.31; p = 0.0002), 0.69 (95%CI: 0.22, 1.16; p = 0.004), and 0.39 (95%CI: -0.37, 1.16; p = 0.31) for TNF-α, IL-8, IL-1β, and IFN-γ, respectively. The pooled SMDs in children were 0.84 (95%CI: 0.35, 1.33; p = 0.0008), 0.60 (95%CI: 0.46, 0.74; p < 0.00001), 0.25 (95%CI: -0.44, 0.93; p = 0.49), and 3.70 (95%CI: 0.75, 6.65; p = 0.01) for TNF-α, IL-8, IL-1β, and IFN-γ, respectively. Conclusions: The levels of proinflammatory cytokines of TNF-α, IL-8, and IL-1β in adults, and TNF-α, IL-8, and IFN-γ in children with OSA, are significantly higher than those in controls.
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Affiliation(s)
- Amin Golshah
- Department of Orthodontics, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran;
| | - Edris Sadeghi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah 6714415185, Iran;
| | - Masoud Sadeghi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah 6714415185, Iran;
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Chen S, Wang J, Shui W, Xing X, Zhang Z, Hou R. Association of the TNF-α-308G>A gene polymorphism with left ventricular geometry and functional abnormalities in obstructive sleep apnea subjects. JOURNAL OF CLINICAL ULTRASOUND : JCU 2024; 52:241-248. [PMID: 38041410 DOI: 10.1002/jcu.23624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 11/18/2023] [Accepted: 11/22/2023] [Indexed: 12/03/2023]
Abstract
OBJECTIVE Tumor necrosis factor-α (TNF-α) can induce left ventricular remodeling. In this study, we investigated whether the TNF-α-308G>A polymorphism is associated with left ventricular geometry (LVG) and left ventricular functional abnormalities in obstructive sleep apnea (OSA) subjects. METHODS Two hundred and seventy-eight subjects were enrolled. Echocardiography and genetic data were assessed in all patients. Geometric patterns of the left ventricle were determined from the relative wall thickness and left ventricular mass index (LVMI). Genetic analysis for the TNF-α-308G>A SNP rs1800629 was identified by Sanger sequencing. The correlations of the TNF-α-308G>A polymorphism with LVG and left ventricular function were analyzed by difference analysis and logistic regression. RESULTS The chi-square test showed that there were differences in genotype distributions among the four groups (p = 0.033), such that the frequency of GA+AA genotypes was significantly higher in the concentric hypertrophy group than in the normal geometry group (p < 0.05). Independent sample T tests showed that the GA+AA genotypes had higher IVST, LVPWT, LVMI, E/e' values, and lower e' values than those of the GG genotype (p < 0.05). Logistic regression analysis showed that the TNF-α-308G>A polymorphism was independently correlated with eccentric hypertrophy (OR = 2.456, p = 0.047) and concentric hypertrophy (OR = 2.456, p = 0.047). CONCLUSION In OSA patients, the TNF-α-308G>A polymorphism was linked to LVG and abnormal left ventricular diastolic function, suggesting that the TNF-α-308G>A polymorphism may have an important influence on LVG alterations.
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Affiliation(s)
- Shuqiong Chen
- Department of Ultrasound, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jian Wang
- Department of Ultrasound, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Wen Shui
- Department of Ultrasound, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xueqing Xing
- Department of Ultrasound, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Zhenxia Zhang
- Department of Respiratory, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ran Hou
- Department of Ultrasound, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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Solanki N, Jurel SK, Singh BP, Chand P, Kant S, Nigam N. Evaluation of mandibular advancement device placement based on levels of TNF-alpha in participants with obstructive sleep apnea: A clinical study. J Prosthet Dent 2023; 130:581-585. [PMID: 34973834 DOI: 10.1016/j.prosdent.2021.10.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 10/15/2021] [Accepted: 10/15/2021] [Indexed: 11/21/2022]
Abstract
STATEMENT OF PROBLEM Objective assessments of the effect of mandibular advancement device on patients with obstructive sleep apnea are lacking. PURPOSE The purpose of this clinical study was to compare levels of serum tumor necrosis factor alpha (TNF-alpha), Epworth Sleepiness Scale score, and Berlin Questionnaire score in patients with mild to moderate obstructive sleep apnea before and after treatment with a mandibular advancement device. MATERIAL AND METHODS Twenty participants diagnosed with mild to moderate obstructive sleep apnea based on polysomnography testing were enrolled. A custom nonadjustable mandibular advancement device with 70% mandibular protrusion was provided for each participant for management of the obstructive sleep apnea. Evaluation of TNF-alpha levels was performed before treatment (baseline) and 3 and 6 months after starting mandibular advancement device therapy by using a Human TNF-alpha enzyme-linked immunoassay (ELISA) sandwich kit. The Epworth Sleepiness Scale and Berlin Questionnaire were also filled out by the participants at the same time intervals (α=.05). RESULTS A statistically significant decline in the levels of TNF-alpha was observed at 3 and 6 months compared with baseline (P<.001). The Epworth Sleepiness Scale scores showed a statistically significant reduction at 3 and 6 months compared with baseline (P<.001). The risk of obstructive sleep apnea assessed by using the Berlin Questionnaire was found to be significantly reduced at 6 months compared with baseline (P=.001). CONCLUSIONS Patients with mild to moderate obstructive sleep apnea showed reduced levels of TNF-alpha and Epworth Sleepiness Scale and Berlin Questionnaire scores when treated with a mandibular advancement device.
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Affiliation(s)
- Neeti Solanki
- Senior Resident, Department of Prosthodontics, Crown and Bridge, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Sunit Kumar Jurel
- Professor Jr Grade, Department of Prosthodontics, Crown and Bridge, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Balendra Pratap Singh
- Professor, Department of Prosthodontics, Crown and Bridge, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Pooran Chand
- Professor, Department of Prosthodontics, Crown and Bridge, King George's Medical University, Lucknow, Uttar Pradesh, India.
| | - Surya Kant
- Professor, Department of Pulmonary and Critical Care Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Nitu Nigam
- Associate Professor, Center for Advance Research, King George's Medical University, Lucknow, Uttar Pradesh, India
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Zhang Z, Duolikun D, Dang T, Wang Y, Ma L, Ma X, Yao Q. Association of tumor necrosis factor-α-308G/A polymorphism with the risk of obstructive sleep apnea: A meta-analysis of 14 case-control studies. PLoS One 2023; 18:e0290239. [PMID: 37595008 PMCID: PMC10437904 DOI: 10.1371/journal.pone.0290239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 08/04/2023] [Indexed: 08/20/2023] Open
Abstract
Although numerous studies have suggested the association between TNF-α-308G/A polymorphism and susceptibility to obstructive sleep apnea (OSA), the results remained controversial and ambiguous. We performed the present meta-analysis to derive a more precise estimation.The PubMed, Embase, Cochrane library, Web of Science, China National Knowledge Infrastructure, Wanfang databases, and Weipu databases (until January 8, 2022) were accessed to retrieve relevant articles. Pooled odds ratios (ORs) with 95% confidence interval (95% CI) were calculated using the STATA statistical software.Totally, fourteen studies involving 2595 cases and 2579 controls were enrolled in this meta-analysis. Pooled results demonstrated significant association between TNF-α-308G/A polymorphism and OSA risk for the overall population(allele model:OR = 1.87 [1.47, 2.38] (n = 14), dominant model: OR = 1.88[1.48, 2.39] (n = 14), recessive model:OR = 2.83 [2.00, 4.00] (n = 11), homozygous model:OR = 3.30 [2.32, 4.68] (n = 11), and heterozygous model:OR = 1.67 [1.36, 2.06] (n = 14); P<0.001, respectively).Subgroup analysis showed that in both Caucasians and Asians, the A allele conferred increased risk to OSA compared to the G allele (Caucasians: OR = 1.40[1.03, 1.90] (n = 5), P = 0.033, Asians: OR = 2.30 [1.62, 3.26] (n = 9), P< 0.001). In subgroup analysis restricted to hospital-based individuals, significant association between TNF-α-308G/A polymorphism and OSA risk was identified under each genetic model. Whereas, in population-based individuals, increased risk of OSA were only found in homozygous model (OR = 2.19[1.23, 3.90] (n = 3), P = 0.008) and recessive model (OR = 1.77 [1.00, 3.13] (n = 3), P = 0.048). There was a substantial between-study heterogeneity (I2 = 69.10%) across studies which was explained by source of control participants (P = 0.036) by meta-regression. The results of leave-one-out meta-analysis and publication bias suggested the reliability and stability of our results.This meta-analysis suggested that TNF-α-308A allele may be a risk factor for the development of OSA. However, large scale,multi-center and well-designed case-control studies are needed in the future.
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Affiliation(s)
- Zhenlian Zhang
- Department of Physiology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China
- Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Dilihumaier Duolikun
- Department of Physiology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Tingting Dang
- Third Clinical Medical College, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Yuanyuan Wang
- Third Clinical Medical College, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Lijuan Ma
- Department of Physiology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China
- Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xueyun Ma
- Department of Physiology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China
- Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Qiaoling Yao
- Department of Physiology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China
- Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Xinjiang Medical University, Urumqi, Xinjiang, China
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Celik Y, Peker Y, Yucel-Lindberg T, Thelander T, Behboudi A. Association of TNF-α (-308G/A) Gene Polymorphism with Changes in Circulating TNF-α Levels in Response to CPAP Treatment in Adults with Coronary Artery Disease and Obstructive Sleep Apnea. J Clin Med 2023; 12:5325. [PMID: 37629366 PMCID: PMC10455347 DOI: 10.3390/jcm12165325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/10/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
RATIONALE We recently demonstrated that patients with coronary artery disease (CAD) and obstructive sleep apnea (OSA) carrying the tumor necrosis factor-alpha (TNF-α) A allele had increased circulating TNF-α levels compared with the ones carrying the TNF-α G allele. In the current study, we addressed the effect of TNF-α (-308G/A) gene polymorphism on circulating TNF-α levels following continuous positive airway pressure (CPAP) therapy. METHODS This study was a secondary analysis of the RICCADSA trial (NCT00519597) conducted in Sweden. CAD patients with OSA (apnea-hypopnea index) of ≥15 events/h and an Epworth Sleepiness Scale (ESS) score of <10 were randomized to CPAP or no-CPAP groups, and OSA patients with an ESS score of ≥10 were offered CPAP treatment. Blood samples were obtained at baseline and 12-month follow-up visits. TNF-α was measured by immunoassay (Luminex, R&D Systems). Genotyping of TNF-α-308G/A (single nucleotide polymorphism Rs1800629) was performed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS In all, 239 participants (206 men and 33 women; mean age 64.9 (SD 7.7) years) with polymorphism data and circulating levels of TNF-α at baseline and 1-year follow-up visits were included. The median circulating TNF-α values fell in both groups between baseline and 12 months with no significant within- or between-group differences. In a multivariate linear regression model, a significant change in circulating TNF-α levels from baseline across the genotypes from GA to GA and GA to AA (standardized β-coefficient -0.129, 95% confidence interval (CI) -1.82; -0.12; p = 0.025) was observed in the entire cohort. The association was more pronounced among the individuals who were using the device for at least 4 h/night (n = 86; standardized β-coefficient -2.979 (95% CI -6.11; -1.21); p = 0.004)), whereas no significant association was found among the patients who were non-adherent or randomized to no-CPAP. The participants carrying the TNF-α A allele were less responsive to CPAP treatment regarding the decline in circulating TNF-α despite CPAP adherence (standardized β-coefficient -0.212, (95% CI -5.66; -1.01); p = 0.005). CONCLUSIONS Our results suggest that TNF-α (-308G/A) gene polymorphism is associated with changes in circulating TNF-α levels in response to CPAP treatment in adults with CAD and OSA.
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Affiliation(s)
- Yeliz Celik
- Department of Pulmonary Medicine, Koc University School of Medicine, and Koc University Research Center for Translational Medicine (KUTTAM), Koc University, 34010 Istanbul, Turkey;
| | - Yüksel Peker
- Department of Pulmonary Medicine, Koc University School of Medicine, and Koc University Research Center for Translational Medicine (KUTTAM), Koc University, 34010 Istanbul, Turkey;
- Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
- Department of Clinical Sciences, Respiratory Medicine and Allergology, Faculty of Medicine, Lund University, 22185 Lund, Sweden
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115, USA
| | | | - Tilia Thelander
- Division of Biomedicine, School of Heath Sciences, University of Skövde, 54128 Skövde, Sweden; (T.T.); (A.B.)
| | - Afrouz Behboudi
- Division of Biomedicine, School of Heath Sciences, University of Skövde, 54128 Skövde, Sweden; (T.T.); (A.B.)
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Neurocognitive Consequences in Children with Sleep Disordered Breathing: Who Is at Risk? CHILDREN 2022; 9:children9091278. [PMID: 36138586 PMCID: PMC9497121 DOI: 10.3390/children9091278] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/22/2022] [Accepted: 08/22/2022] [Indexed: 11/23/2022]
Abstract
Sleep-disordered breathing (SDB) is a prevalent disease in children characterized by snoring and narrowing of the upper airway leading to gas exchange abnormalities during sleep as well as sleep fragmentation. SDB has been consistently associated with problematic behaviors and adverse neurocognitive consequences in children but causality and determinants of susceptibility remain incompletely defined. Since the 1990s several studies have enlightened these associations and consistently reported poorer academic performance, lower scores on neurocognitive tests, and behavioral abnormalities in children suffering from SDB. However, not all children with SDB develop such consequences, and severity of SDB based on standard diagnostic indices has often failed to discriminate among those children with or without neurocognitive risk. Accordingly, a search for discovery of markers and clinically useful tools that can detect those children at risk for developing cognitive and behavioral deficits has been ongoing. Here, we review the advances in this field and the search for possible detection approaches and unique phenotypes of children with SDB who are at greater risk of developing neurocognitive consequences.
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Prabhu N, Shetty V. Inflammatory Biomarkers for Children with Sleep Disorders: A Review. JOURNAL OF HEALTH AND ALLIED SCIENCES NU 2022. [DOI: 10.1055/s-0042-1742371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Abstract
Introduction Obstructive sleep apnea (OSA) syndrome is a highly prevalent problem in children. Unfortunately sleep disorders in children remain largely unreported and underdiagnosed due to various reasons. Overnight in-laboratory polysomnography (PSG) is the gold standard diagnostic method for OSA; however, it has several drawbacks. Hence there is a need for simple alternative diagnostic methods, such as biomarkers. Children with OSA seem to have an inflammatory aspect to its pathophysiology; thus the rationale for evaluating inflammatory biomarkers.
Objective This narrative review aimed to evaluate the existing knowledge regarding inflammatory biomarkers for children with sleep disorders.
Materials and Methods An extensive search of all literature linked to the topic was performed in PubMed, Medline, EBSCOhost, Cochrane library database CENTRAL, and Google Scholar search engine. Keywords used in the search included combinations of the following: inflammation, sleep disorders, children, and biomarkers. Studies in the list of references of relevant literature were also included. A total of 155 articles published in the period from 1997 to 2021 were initially included in this review. Selected articles comprised original research, meta-analysis, and systematic reviews.
Results Studies have mainly centered their investigations on serum inflammatory biomarkers, namely interleukin-6, tumor necrosis factor-α, and C-reactive protein. Very few studies investigated salivary inflammatory biomarkers in children.
Conclusion Evidence suggests that children with sleep disorders have elevated levels of salivary as well as serum inflammatory biomarkers in comparison to normal healthy children. Also increased levels of these biomarkers correlate with disease severity. However, more studies are needed to determine the sensitivity and specificity of salivary inflammatory biomarkers for children with sleep disorders.
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Affiliation(s)
- Nagashree Prabhu
- Department of Pediatric and Preventive Dentistry, AB Shetty Memorial Institute of Dental Sciences, Nitte (Deemed to be University), Mangalore, Karnataka, India
| | - Vabitha Shetty
- Department of Pediatric and Preventive Dentistry, AB Shetty Memorial Institute of Dental Sciences, Nitte (Deemed to be University), Mangalore, Karnataka, India
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11
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Much Ado about Sleep: Current Concepts on Mechanisms and Predisposition to Pediatric Obstructive Sleep Apnea. CHILDREN 2021; 8:children8111032. [PMID: 34828745 PMCID: PMC8623682 DOI: 10.3390/children8111032] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/11/2021] [Accepted: 10/18/2021] [Indexed: 12/22/2022]
Abstract
Obstructive Sleep Apnea (OSA) is a form of sleep-disordered breathing characterized by upper airway collapse during sleep resulting in recurring arousals and desaturations. However, many aspects of this syndrome in children remain unclear. Understanding underlying pathogenic mechanisms of OSA is critical for the development of therapeutic strategies. In this article, we review current concepts surrounding the mechanism, pathogenesis, and predisposing factors of pediatric OSA. Specifically, we discuss the biomechanical properties of the upper airway that contribute to its primary role in OSA pathogenesis and examine the anatomical and neuromuscular factors that predispose to upper airway narrowing and collapsibility.
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12
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Association of TNF-α (-308G/A) Gene Polymorphism with Circulating TNF-α Levels and Excessive Daytime Sleepiness in Adults with Coronary Artery Disease and Concomitant Obstructive Sleep Apnea. J Clin Med 2021; 10:jcm10153413. [PMID: 34362196 PMCID: PMC8348542 DOI: 10.3390/jcm10153413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 07/24/2021] [Accepted: 07/30/2021] [Indexed: 12/02/2022] Open
Abstract
Obstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), in which inflammatory activity has a crucial role. The manifestation of OSA varies significantly between individuals in clinical cohorts; not all adults with OSA demonstrate the same set of symptoms; i.e., excessive daytime sleepiness (EDS) and/or increased levels of inflammatory biomarkers. The further exploration of the molecular basis of these differences is therefore essential for a better understanding of the OSA phenotypes in cardiac patients. In this current secondary analysis of the Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA (RICCADSA) trial (Trial Registry: ClinicalTrials.gov; No: NCT 00519597), we aimed to address the association of tumor necrosis factor alpha (TNF-α)-308G/A gene polymorphism with circulating TNF-α levels and EDS among 326 participants. CAD patients with OSA (apnea–hypopnea-index (AHI) ≥ 15 events/h; n = 256) were categorized as having EDS (n = 100) or no-EDS (n = 156) based on the Epworth Sleepiness Scale score with a cut-off of 10. CAD patients with no-OSA (AHI < 5 events/h; n = 70) were included as a control group. The results demonstrated no significant differences regarding the distribution of the TNF-α alleles and genotypes between CAD patients with vs. without OSA. In a multivariate analysis, the oxygen desaturation index and TNF-α genotypes from GG to GA and GA to AA as well as the TNF-α-308A allele carriage were significantly associated with the circulating TNF-α levels. Moreover, the TNF-α-308A allele was associated with a decreased risk for EDS (odds ratio 0.64, 95% confidence interval 0.41–0.99; p = 0.043) independent of age, sex, obesity, OSA severity and the circulating TNF-α levels. We conclude that the TNF-α-308A allele appears to modulate circulatory TNF-α levels and mitigate EDS in adults with CAD and concomitant OSA.
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13
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Bhatt SP, Guleria R, Kabra SK. Metabolic alterations and systemic inflammation in overweight/obese children with obstructive sleep apnea. PLoS One 2021; 16:e0252353. [PMID: 34086720 PMCID: PMC8177414 DOI: 10.1371/journal.pone.0252353] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 05/12/2021] [Indexed: 02/07/2023] Open
Abstract
Aim and objective Systemic inflammation has been documented in obstructive sleep apnea (OSA). However studies on childhood OSA and systemic inflammation are limited. This study aimed to determine the relation between OSA in overweight/obese children and various inflammatory markers. Material and methods In this cross sectional study, we enrolled 247 overweight/ obese children from pediatric outpatient services. We evaluated demographic and clinical details, anthropometric parameters, body composition and estimation of inflammatory cytokines such as interleukin (IL) 6, IL-8, IL-10, IL-17, IL-18, IL-23, macrophage migration inhibitory factor (MIF), high sensitive C-reactive protein (Hs-CRP), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1) and leptin levels. Overnight polysomnography was performed. Findings A total of 247 children (190 with OSA and 57 without OSA) were enrolled. OSA was documented on polysomnography in 40% of patients. We observed significantly high values body mass index, waist circumference (WC), % body fat, fasting blood glucose (FBG), alanine transaminase (ALT), alkaline phosphate, fasting insulin and HOMA-IR in children with OSA. Inflammatory markers IL-6, IL-8, IL-17, IL-18, MIF, Hs CRP, TNF- α, PAI-1, and leptin levels were significantly higher in OSA patients (p<0.05). There was strong positive correlation of IL-6, IL-8, IL-17, IL-23, MIF, Hs CRP, TNF-A, PAI-1 and leptin with BMI, % body fat, AHI, fasting Insulin, triglyceride, FBG, WC, HOMA-IR, AST and ALT. Conclusion Children with OSA have increased obesity, insulin resistance and systemic inflammation. Further studies are require to confirm our findings and evaluate their utility in diagnosis of OSAs, assessing severity and possible interventions.
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Affiliation(s)
- Surya Prakash Bhatt
- Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
- * E-mail:
| | - Randeep Guleria
- Department of Pulmonary, Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - S. K. Kabra
- Pediatric Pulmonology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
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14
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Tan HL, Kaditis AG. Phenotypic variance in pediatric obstructive sleep apnea. Pediatr Pulmonol 2021; 56:1754-1762. [PMID: 33543838 DOI: 10.1002/ppul.25309] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/26/2021] [Accepted: 01/27/2021] [Indexed: 01/31/2023]
Abstract
It is crucial that clinicians understand what underpins the considerable phenotypic variance in pediatric obstructive sleep apnea syndrome (OSAS), if they are to implement individually tailored phenotype-based approaches to diagnosis and management. This review summarizes the current literature on how disease severity, comorbidities, genetic and environmental/lifestyle factors interact to determine the overall OSAS phenotype. The first part discusses the impact of these factors on OSAS-related morbidity in the context of otherwise healthy children, whilst the second half details children with complex conditions, particularly focusing on the anatomical and functional abnormalities predisposing to upper airway obstruction unique to each condition. One can then understand the need for a multidimensional assessment strategy for pediatric OSAS; one that incorporates the history, physical examination, sleep study results, and biomarkers to enable precise stratification, so vital for effective determination of the timing and the nature of the therapeutic interventions required.
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Affiliation(s)
- Hui-Leng Tan
- Department of Pediatric Respiratory Medicine, Royal Brompton Hospital, London, UK
| | - Athanasios G Kaditis
- Division of Pediatric Pulmonology, First Department of Pediatrics, National and Kapodistrian University of Athens School of Medicine and Aghia Sophia Children's Hospital, Athens, Greece
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15
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Zhao L, Liu Y, Wang X. TNF-α promotes insulin resistance in obstructive sleep apnea-hypopnea syndrome. Exp Ther Med 2021; 21:568. [PMID: 33850540 PMCID: PMC8027756 DOI: 10.3892/etm.2021.10000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/22/2021] [Indexed: 11/06/2022] Open
Abstract
Obstructive sleep apnea hypopnea syndrome (OSAHS) is the most serious among children with sleep disordered breathing. The present study aimed to investigate whether TNF-α could decrease the glucose transporter type 4 insulin-responsive (GLUT-4) expression to promote insulin resistance through the TNF-α/IKKβ/IKβ/NF-κB signaling pathway in OSAHS. In total, 30 obese children with OSAHS and 30 non-OSAHS obese children were enrolled into the present study. TNF-α expression in adenoid tissues was detected by western blot analysis and immunohistochemistry. The expression of inflammatory factors (IL-1β, IL-6 and IFN-γ) and TNF-α/IKKβ/IKβ/NF-κB signaling pathway-associated proteins was also detected by western blot analysis. The expression of insulin resistance-associated factors, insulin receptor substrate 1 (IRS1) and GLUT4, was determined by western blot analysis and immunohistochemistry. TNF-α expression was increased in adenoid tissues of children with OSAHS, which was also confirmed by immunohistochemistry. The expression levels of IL-1β, IL-6 and IFN-γ were all upregulated in adenoid tissues of children with OSAHS. The expression of IRS1 and GLUT4 was decreased in adenoid tissues of obese children with OSAHS and the result of immunohistochemistry was consistent with the result of western blot analysis. The protein level of TNF-α, and ratio of phosphorylated (p-)/total (t)-IKKβ, p/t-IKβ and p/t-NF-κB was increased in adenoid tissues of children with OSAHS. TNF-α could suppress the GLUT4 expression to promote insulin resistance by TNF-α/IKKβ/IKβ/NF-κB signaling pathway in OSAHS.
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Affiliation(s)
- Lin Zhao
- Department of Endocrinology, The 8th Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100091, P.R. China
| | - Yang Liu
- Department of Endocrinology, The 8th Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100091, P.R. China
| | - Xiangrong Wang
- Department of Nursing, Jiangsu Union Technical Institute Nantong Health Branch, Nantong, Jiangsu 226010, P.R. China
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16
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Liu X, Ma Y, Ouyang R, Zeng Z, Zhan Z, Lu H, Cui Y, Dai Z, Luo L, He C, Li H, Zong D, Chen Y. The relationship between inflammation and neurocognitive dysfunction in obstructive sleep apnea syndrome. J Neuroinflammation 2020; 17:229. [PMID: 32738920 PMCID: PMC7395983 DOI: 10.1186/s12974-020-01905-2] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 07/20/2020] [Indexed: 12/14/2022] Open
Abstract
Obstructive sleep apnea syndrome (OSAS), a state of sleep disorder, is characterized by repetitive apnea, chronic hypoxia, oxygen desaturation, and hypercapnia. Previous studies have revealed that intermittent hypoxia (IH) conditions in OSAS patients elicited neuron injury (especially in the hippocampus and cortex), leading to cognitive dysfunction, a significant and extraordinary complication of OSAS patients. The repeated courses of airway collapse and obstruction in OSAS patients resulted in apnea and arousal during sleep, leading to IH and excessive daytime sleepiness (EDS) and subsequently contributing to the development of inflammation. IH-mediated inflammation could further trigger various types of cognitive dysfunction. Many researchers have found that, besides continuous positive airway pressure (CPAP) treatment and surgery, anti-inflammatory substances might alleviate IH-induced neurocognitive dysfunction. Clarifying the role of inflammation in IH-mediated cognitive impairment is crucial for potentially valuable therapies and future research in the related domain. The objective of this article was to critically review the relationship between inflammation and cognitive deficits in OSAS.
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Affiliation(s)
- Xiangming Liu
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Research Unit of Respiratory Disease, Central South University, Changsha, 410011, Hunan, China
| | - Yiming Ma
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Research Unit of Respiratory Disease, Central South University, Changsha, 410011, Hunan, China
| | - Ruoyun Ouyang
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Research Unit of Respiratory Disease, Central South University, Changsha, 410011, Hunan, China
| | - Zihang Zeng
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Research Unit of Respiratory Disease, Central South University, Changsha, 410011, Hunan, China
| | - Zijie Zhan
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Research Unit of Respiratory Disease, Central South University, Changsha, 410011, Hunan, China
| | - Huanhuan Lu
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Research Unit of Respiratory Disease, Central South University, Changsha, 410011, Hunan, China
| | - Yanan Cui
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Research Unit of Respiratory Disease, Central South University, Changsha, 410011, Hunan, China
| | - Zhongshang Dai
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Research Unit of Respiratory Disease, Central South University, Changsha, 410011, Hunan, China
| | - Lijuan Luo
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Research Unit of Respiratory Disease, Central South University, Changsha, 410011, Hunan, China
| | - Chenjie He
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Research Unit of Respiratory Disease, Central South University, Changsha, 410011, Hunan, China
| | - Herui Li
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Research Unit of Respiratory Disease, Central South University, Changsha, 410011, Hunan, China
| | - Dandan Zong
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China. .,Research Unit of Respiratory Disease, Central South University, Changsha, 410011, Hunan, China.
| | - Yan Chen
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China. .,Research Unit of Respiratory Disease, Central South University, Changsha, 410011, Hunan, China.
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17
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Wu Y, Feng G, Xu Z, Li X, Zheng L, Ge W, Ni X. Identification of different clinical faces of obstructive sleep apnea in children. Int J Pediatr Otorhinolaryngol 2019; 127:109621. [PMID: 31521054 DOI: 10.1016/j.ijporl.2019.109621] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 08/01/2019] [Accepted: 08/01/2019] [Indexed: 12/23/2022]
Abstract
OBJECTIVE This study aimed to identify the heterogeneity of obstructive sleep apnea syndrome clinical presentation in children. PARTICIPANTS Children who were 3-14 years old and with obstructive sleep apnea syndrome after polysomnography monitoring (apnea and hypopnea index>5 or obstructive apnea index>1) in the sleep center of Beijing Children's Hospital were included. METHODS A sleep disorder questionnaire including different combinations of symptoms and co-morbidities of obstructive sleep apnea syndrome in children was used. A cluster analysis was used to classify the data. RESULTS The apnea hypopnea index alone is not adequate to predict clinical phenotypes. Based on symptoms and co-morbidities of obstructive sleep apnea syndrome, three distinct clusters were identified. They were "nocturnal snoring and daytime sleepiness group" (cluster 1), "hyperactivity group" (cluster 2), and "minimally symptomatic group" (cluster 3). A prediction model was built according to eight variables which showed statistical significance by pairwise comparison among clusters. Overall accuracy of the prediction model could reach 86%. Both the sensitivity and specificity of cluster 2 and 3 prediction were around 90%. CONCLUSION Children with obstructive sleep apnea syndrome have different patterns of clinical presentation and the identification of the different clinical profiles of obstructive sleep apnea syndrome can provide clues for more personalised diagnoses and therapies.
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Affiliation(s)
- Yunxiao Wu
- Beijing Key Laboratory of Pediatric Otolaryngology, Head & Neck Surgery, Beijing Pediatric Research Institute, China
| | | | | | - Xiaodan Li
- Otolaryngology, Head and Neck Surgery Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Li Zheng
- Otolaryngology, Head and Neck Surgery Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Wentong Ge
- Otolaryngology, Head and Neck Surgery Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Xin Ni
- Otolaryngology, Head and Neck Surgery Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
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18
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Gulotta G, Iannella G, Vicini C, Polimeni A, Greco A, de Vincentiis M, Visconti IC, Meccariello G, Cammaroto G, De Vito A, Gobbi R, Bellini C, Firinu E, Pace A, Colizza A, Pelucchi S, Magliulo G. Risk Factors for Obstructive Sleep Apnea Syndrome in Children: State of the Art. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:E3235. [PMID: 31487798 PMCID: PMC6765844 DOI: 10.3390/ijerph16183235] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 08/19/2019] [Accepted: 08/25/2019] [Indexed: 12/27/2022]
Abstract
The obstructive sleep apnea syndrome (OSAS) represents only part of a large group of pathologies of variable entity called respiratory sleep disorders (RSD) which include simple snoring and increased upper airway resistance syndrome (UARS). Although the etiopathogenesis of adult OSAS is well known, many aspects of this syndrome in children are still debated. Its prevalence is about 2% in children from 2 to 8 years of age, mostly related to the size of the upper airways adenoid tissue. Several risk factors linked to the development of OSAS are typical of the pediatric age. The object of this paper is to analyze the state of the art on this specific topic, discussing its implications in terms of diagnosis and management.
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Affiliation(s)
- Giampiero Gulotta
- Department of "Organi di Senso", University "Sapienza", 00185 Rome, Italy
| | - Giannicola Iannella
- Department of "Organi di Senso", University "Sapienza", 00185 Rome, Italy.
- Department of Head-Neck Surgery, Otolaryngology, Head-Neck and Oral Surgery Unit, Morgagni Pierantoni Hospital, 47121 Forlì, Italy.
| | - Claudio Vicini
- Department of Head-Neck Surgery, Otolaryngology, Head-Neck and Oral Surgery Unit, Morgagni Pierantoni Hospital, 47121 Forlì, Italy
- Ear-Nose-Throat & Audiology Unit, University of Ferrara, 44121 Ferrara, Italy
| | - Antonella Polimeni
- Department of Oral and Maxillo Facial Sciences, University "Sapienza", 00185 Rome, Italy
| | - Antonio Greco
- Department of "Organi di Senso", University "Sapienza", 00185 Rome, Italy
| | | | | | - Giuseppe Meccariello
- Department of Head-Neck Surgery, Otolaryngology, Head-Neck and Oral Surgery Unit, Morgagni Pierantoni Hospital, 47121 Forlì, Italy
| | - Giovanni Cammaroto
- Department of Head-Neck Surgery, Otolaryngology, Head-Neck and Oral Surgery Unit, Morgagni Pierantoni Hospital, 47121 Forlì, Italy
| | - Andrea De Vito
- Department of Head-Neck Surgery, Otolaryngology, Head-Neck and Oral Surgery Unit, Morgagni Pierantoni Hospital, 47121 Forlì, Italy
| | - Riccardo Gobbi
- Department of Head-Neck Surgery, Otolaryngology, Head-Neck and Oral Surgery Unit, Morgagni Pierantoni Hospital, 47121 Forlì, Italy
| | - Chiara Bellini
- Department of Head-Neck Surgery, Otolaryngology, Head-Neck and Oral Surgery Unit, Morgagni Pierantoni Hospital, 47121 Forlì, Italy
| | - Elisabetta Firinu
- Department of Head-Neck Surgery, Otolaryngology, Head-Neck and Oral Surgery Unit, Morgagni Pierantoni Hospital, 47121 Forlì, Italy
| | - Annalisa Pace
- Department of "Organi di Senso", University "Sapienza", 00185 Rome, Italy
| | - Andrea Colizza
- Department of "Organi di Senso", University "Sapienza", 00185 Rome, Italy
| | - Stefano Pelucchi
- Ear-Nose-Throat & Audiology Unit, University of Ferrara, 44121 Ferrara, Italy
| | - Giuseppe Magliulo
- Department of "Organi di Senso", University "Sapienza", 00185 Rome, Italy
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19
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Smith DF, Amin RS. OSA and Cardiovascular Risk in Pediatrics. Chest 2019; 156:402-413. [PMID: 30790552 DOI: 10.1016/j.chest.2019.02.011] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 01/21/2019] [Accepted: 02/08/2019] [Indexed: 02/07/2023] Open
Abstract
OSA occurs in approximately 1% to 5% of children in the United States. Long-term cardiovascular risks associated with OSA in the adult population are well documented. Although changes in BP regulation occur in children with OSA, the pathways leading to chronic cardiovascular risks of OSA in children are less clear. Risk factors associated with cardiovascular disease in adult populations could carry the same future risk for children. It is imperative to determine whether known mechanisms of cardiovascular diseases in adults are like those that lead to pediatric disease. Early pathophysiologic changes may lead to a lifetime burden of cardiovascular disease and early mortality. With this perspective in mind, our review discusses pathways leading to cardiovascular pathology in children with OSA and provides a comprehensive overview of recent research findings related to cardiovascular sequelae in the pediatric population.
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Affiliation(s)
- David F Smith
- Division of Pediatric Otolaryngology-Head and Neck Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Division of Pulmonary and Sleep Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Raouf S Amin
- Division of Pulmonary and Sleep Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
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20
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Obstructive Sleep Apnea and Inflammation: Proof of Concept Based on Two Illustrative Cytokines. Int J Mol Sci 2019; 20:ijms20030459. [PMID: 30678164 PMCID: PMC6387387 DOI: 10.3390/ijms20030459] [Citation(s) in RCA: 207] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 01/12/2019] [Accepted: 01/15/2019] [Indexed: 12/19/2022] Open
Abstract
Obstructive sleep apnea syndrome (OSAS) is a markedly prevalent condition across the lifespan, particularly in overweight and obese individuals, which has been associated with an independent risk for neurocognitive, behavioral, and mood problems as well as cardiovascular and metabolic morbidities, ultimately fostering increases in overall mortality rates. In adult patients, excessive daytime sleepiness (EDS) is the most frequent symptom leading to clinical referral for evaluation and treatment, but classic EDS features are less likely to be reported in children, particularly among those with normal body-mass index. The cumulative evidence collected over the last two decades supports a conceptual framework, whereby sleep-disordered breathing in general and more particularly OSAS should be viewed as low-grade chronic inflammatory diseases. Accordingly, it is assumed that a proportion of the morbid phenotypic signature in OSAS is causally explained by underlying inflammatory processes inducing end-organ dysfunction. Here, the published links between OSAS and systemic inflammation will be critically reviewed, with special focus on the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), since these constitute classical prototypes of the large spectrum of inflammatory molecules that have been explored in OSAS patients.
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21
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Shi Y, Luo H, Liu H, Hou J, Feng Y, Chen J, Xing L, Ren X. Related biomarkers of neurocognitive impairment in children with obstructive sleep apnea. Int J Pediatr Otorhinolaryngol 2019; 116:38-42. [PMID: 30554705 DOI: 10.1016/j.ijporl.2018.10.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 10/09/2018] [Accepted: 10/10/2018] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Different experiment approaches have demonstrated that children with obstructive sleep apnea (OSA) exhibit neurocognitive and behavioral deficits. This review summarized the potential biomarkers of OSA-associated neurocognitive impairment in children. METHODS A scoping review of studies on children with OSA that evaluated the potential value of different markers in identifying neurocognitive impairment was undertaken. Additionally, the biomarkers were categorized according to the different research methods, including brain imaging studies, serological indicators and urine markers. RESULTS Majority of the studies that evaluated blood biomarkers, plasma insulin growth factor-1 (IGF-1) and Alzheimer's disease (AD)-related biomarkers appeared to exhibit a favorable profile, and could discriminate between OSA children with or without neurocognitive impairments. Brain imaging studies and urinary neurotransmitters could also be helpful for screening OSA cognitive morbidity in children. CONCLUSION Due to limited research methods available in children, the cognitive susceptibility of children with OSA has been rarely studied. The main reason for this may be the limited research methods in children. Numerous study populations of children and complex psychological tests are required, which involve major labor and costs.Multi-center prospective studies are needed to identify suitable biomarkers for the timely prediction and effective intervention to prevent neurocognitive impairment in children with OSA and to explore further opportunities in this arena.
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Affiliation(s)
- Yewen Shi
- Department of Otorhinolaryngology, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Huanan Luo
- Department of Otorhinolaryngology, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Haiqin Liu
- Department of Otorhinolaryngology, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Jin Hou
- Department of Otorhinolaryngology, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Yani Feng
- Department of Otorhinolaryngology, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Jinwei Chen
- Department of Otorhinolaryngology, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Liang Xing
- Department of Otorhinolaryngology, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Xiaoyong Ren
- Department of Otorhinolaryngology, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, Shaanxi, China.
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22
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Kalashnikova TP, Anisimov GV, Yastrebova AV, Starikova NL. [Etiopathogenesis of obstructive sleep apnoea and its consequences in the children]. Vestn Otorinolaringol 2018; 83:79-83. [PMID: 30412183 DOI: 10.17116/otorino20188305179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The article presents the modern view of etiology of the obstructive sleep apnoea/hypopnoea syndrome (OAHSS) in the children taking into consideration the ontogenetic stage and the principal mechanisms of its formation including the short-term and long-term consequences of sleep apnoea with special reference to the pathogenetic commonness of OAHSS with endothelial dysfunction, metabolic syndrome, cardiac disorders, and systemic chronic inflammation. The role of ENT diseases in the children with obstructive sleep apnoea is discussed. The results of genetic studies of the processes influencing the formation of the risk of development of sleep apnoea/hypopnoea syndrome and its outcomes in the children are discussed.
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Affiliation(s)
- T P Kalashnikova
- V.P. Pervushin Department of Neurology, Academician E.A. Vagner Perm State Medical University, Ministry of Health of the Russian Federation, Perm, Russia
| | - G V Anisimov
- The First Medico-Pedagogical Centre 'Lingva Bona', Perm, Russia
| | - A V Yastrebova
- V.P. Pervushin Department of Neurology, Academician E.A. Vagner Perm State Medical University, Ministry of Health of the Russian Federation, Perm, Russia
| | - N L Starikova
- Department of Neurology, Faculty of Advanced Training and Professional Retraining of Specialists with the course of neurorehabitology, Academician E.A. Vagner Perm State Medical University, Ministry of Health of the Russian Federation, Perm, Russia
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Pak VM, Mazzotti DR, Keenan BT, Hirotsu C, Gehrman P, Bittencourt L, Pack AI, Tufik S. Candidate gene analysis in the São Paulo Epidemiologic Sleep Study (EPISONO) shows an association of variant in PDE4D and sleepiness. Sleep Med 2018; 47:106-112. [DOI: 10.1016/j.sleep.2017.12.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 12/30/2017] [Indexed: 12/24/2022]
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Garbarino S, Scoditti E, Lanteri P, Conte L, Magnavita N, Toraldo DM. Obstructive Sleep Apnea With or Without Excessive Daytime Sleepiness: Clinical and Experimental Data-Driven Phenotyping. Front Neurol 2018; 9:505. [PMID: 29997573 PMCID: PMC6030350 DOI: 10.3389/fneur.2018.00505] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 06/08/2018] [Indexed: 12/15/2022] Open
Abstract
Introduction: Obstructive sleep apnea (OSA) is a serious and prevalent medical condition with major consequences for health and safety. Excessive daytime sleepiness (EDS) is a common-but not universal-accompanying symptom. The purpose of this literature analysis is to understand whether the presence/absence of EDS is associated with different physiopathologic, prognostic, and therapeutic outcomes in OSA patients. Methods: Articles in English published in PubMed, Medline, and EMBASE between January 2000 and June 2017, focusing on no-EDS OSA patients, were critically reviewed. Results: A relevant percentage of OSA patients do not complain of EDS. EDS is a significant and independent predictor of incident cardiovascular disease (CVD) and is associated with all-cause mortality and an increased risk of metabolic syndrome and diabetes. Male gender, younger age, high body mass index, are predictors of EDS. The positive effects of nasal continuous positive airway pressure (CPAP) therapy on blood pressure, insulin resistance, fatal and non-fatal CVD, and endothelial dysfunction risk factors have been demonstrated in EDS-OSA patients, but results are inconsistent in no-EDS patients. The most sustainable cause of EDS is nocturnal hypoxemia and alterations of sleep architecture, including sleep fragmentation. These changes are less evident in no-EDS patients that seem less susceptible to the cortical effects of apneas. Conclusions: There is no consensus if we should consider OSA as a single disease with different phenotypes with or without EDS, or if there are different diseases with different genetic/epigenetic determinants, pathogenic mechanisms, prognosis, and treatment.The small number of studies focused on this issue indicates the need for further research in this area. Clinicians must carefully assess the presence or absence of EDS and decide accordingly the treatment. This approach could improve combination therapy targeted to a patient's specific pathology to enhance both efficacy and long-term adherence to OSA treatment and significantly reduce the social, economic, and health negative impact of OSA.
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Affiliation(s)
- Sergio Garbarino
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal/Child Sciences, University of Genoa, Genoa, Italy.,Department of Health Sciences, University of Genoa, Genoa, Italy
| | - Egeria Scoditti
- Institute of Clinical Physiology, National Research Council (CNR), Lecce, Italy
| | - Paola Lanteri
- Department of Neurological Science, G. Gaslini Institute, Genoa, Italy
| | - Luana Conte
- Interdisciplinary Laboratory of Applied Research in Medicine (DReAM), "V Fazzi" University Hospital, ASL Lecce, Lecce, Italy.,Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy
| | - Nicola Magnavita
- Institute of Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Domenico M Toraldo
- Rehabilitation Department, Cardio-Respiratory Care Unit, "V Fazzi" Hospital, ASL Lecce, Lecce, Italy
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25
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Li Q, Zheng X. Tumor necrosis factor alpha is a promising circulating biomarker for the development of obstructive sleep apnea syndrome: a meta-analysis. Oncotarget 2018; 8:27616-27626. [PMID: 28187003 PMCID: PMC5432362 DOI: 10.18632/oncotarget.15203] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 01/27/2017] [Indexed: 12/16/2022] Open
Abstract
Obstructive sleep apnea syndrome (OSAS) is a chronic inflammatory disorder. The relationship between tumor necrosis factor alpha (TNF-alpha) and OSAS has been widely evaluated, but the results thus far remain inconclusive. We thereby decided to quantify the changes of TNF-alpha between OSAS patients and controls by a meta-analysis. This study complies with the MOOSE guidelines. Two reviewers independently searched articles and abstracted relevant data. In total, 47 articles (59 studies) were analyzed, including 2857 OSAS patients and 2115 controls. Overall, OSAS patients had a significantly higher level of circulating TNF-alpha than controls (weighted mean difference [WMD]: 9.66 pg/mL, 95% confidence interval [CI]: 8.66 to 11.24, P<0.001), but with significant heterogeneity (I2: 99.7%). After adjusting for potential missing studies, the overall estimate was weakened but still significant (filled WMD: 2.63 pg/mL, 95% CI: 2.56 to 2.70, P<0.001). When studies were stratified by OSAS severity, the changes in circulating TNF-alpha between patients and controls increased gradually with the more severe grades of OSAS. In patients with mild, mild-to-moderate, moderate, moderate-to-severe and severe OSAS, circulating TNF-alpha was higher than respective controls by 0.99, 1.48. 7.79, 10.08 and 8.85 pg/mL, with significant heterogeneity (I2: 91.2%, 74.5%, 97.6%, 99.0% and 98.1%). In conclusion, our findings demonstrated that circulating TNF-alpha was significantly higher in OSAS patients than in controls, and this difference became more pronounced with the more severe grades of OSAS, indicating that TNF-alpha might be a promising circulating biomarker for the development of OSAS.
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Affiliation(s)
- Qingsheng Li
- Department of Emergency Pediatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Xin Zheng
- Department of Basic Medicine, Fujian Health Collage, Fuzhou, China
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26
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Prasad B, Steffen AD, Van Dongen HPA, Pack FM, Strakovsky I, Staley B, Dinges DF, Maislin G, Pack AI, Weaver TE. Determinants of sleepiness in obstructive sleep apnea. Sleep 2018; 41:4850639. [PMID: 29444292 DOI: 10.1093/sleep/zsx199] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 09/18/2017] [Indexed: 01/15/2023] Open
Abstract
STUDY OBJECTIVES Significant interindividual variability in sleepiness is observed in clinical populations with obstructive sleep apnea (OSA). This phenomenon is only partially explained by the apnea-hypopnea index (AHI). Understanding factors that lead to sleepiness is critical to effective management of patients with OSA. We examined demographic and other factors associated with sleepiness in OSA. METHODS Prospective study of 283 patients with newly diagnosed OSA by polysomnography (AHI ≥ 5 per hour). Subjective sleepiness (Epworth Sleep Scale [ESS] ≥ 11) and objective sleepiness (psychomotor vigilance task [PVT] mean lapse ≥ 2) were assessed. RESULTS Participants were classified into four groups (1: sleepy by ESS and PVT, 2: sleepy by PVT only, 3: sleepy by ESS only, and 4: nonsleepy reference group) and compared by generalized logit model. Shorter daily sleep duration by actigraphy and less morningness were associated with higher risk of sleepiness (Odds ratio [OR] = 0.52, 95% confidence interval [CI] 0.33-0.82 and OR = 0.89, CI 0.80-0.98, respectively). African-American race was associated with sleepiness (group 1, OR = 8.8, CI 2.8-27.3; group 2, OR = 16.6, CI 3.3-83.6; and group 3, OR = 3.3, CI 1.0-10.1). IL-6 level was higher in groups 1 and 3 (OR = 1.9, CI 1.0-3.4 and OR 2.0, CI 1.1-3.7, respectively). CONCLUSIONS African-American race, short sleep duration, chronotype, and increased proinflammatory cytokine IL-6 level were associated with sleepiness in OSA. These findings will inform future investigations determining mechanisms of sleepiness in OSA.
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Affiliation(s)
- Bharati Prasad
- Department of Medicine, Pulmonary, Critical Care, Sleep and Allergy, College of Medicine, University of Illinois at Chicago, Chicago, IL.,Jesse Brown VA Medical Center, Chicago, IL.,Center for Narcolepsy, Sleep and Health Research, College of Nursing, University of Illinois at Chicago, Chicago, IL
| | - Alana D Steffen
- Center for Narcolepsy, Sleep and Health Research, College of Nursing, University of Illinois at Chicago, Chicago, IL.,Department of Health System Science, College of Nursing, University of Illinois at Chicago, Chicago, IL
| | - Hans P A Van Dongen
- Sleep and Performance Research Center, Washington State University, Spokane, WA
| | - Francis M Pack
- Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Inna Strakovsky
- Office of Clinical Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Bethany Staley
- Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - David F Dinges
- Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Department of Psychiatry, Unit for Experimental Psychiatry, Division of Sleep and Chronobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Greg Maislin
- Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Allan I Pack
- Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Terri E Weaver
- Center for Narcolepsy, Sleep and Health Research, College of Nursing, University of Illinois at Chicago, Chicago, IL.,Department of Biobehavioral Health Science, College of Nursing, University of Illinois at Chicago, Chicago, IL
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27
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Gan-Or Z, Alcalay RN, Rouleau GA, Postuma RB. Sleep disorders and Parkinson disease; lessons from genetics. Sleep Med Rev 2018; 41:101-112. [PMID: 29449121 DOI: 10.1016/j.smrv.2018.01.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 10/04/2017] [Accepted: 01/15/2018] [Indexed: 02/08/2023]
Abstract
Parkinson disease is a common, age-related neurodegenerative disorder, projected to afflict millions of individuals in the near future. Understanding its etiology and identifying clinical, genetic or biological markers for Parkinson disease onset and progression is therefore of major importance. Various sleep-related disorders are the most common group of non-motor symptoms in advanced Parkinson disease, but they can also occur during its prodromal phase. However, with the exception of REM sleep behavior disorder, it is unclear whether they are part of the early pathological process of Parkinson disease, or if they develop as Parkinson disease advances because of treatments and neurodegeneration progression. The advancements in genetic studies in the past two decades have generated a wealth of information, and recent genetic studies offer new insight on the association of sleep-related disorders with Parkinson disease. More specifically, comparing genetic data between Parkinson disease and sleep-related disorders can clarify their association, which may assist in determining whether they can serve as clinical markers for Parkinson disease risk or progression. In this review, we discuss the current knowledge on the genetics of sleep-related disorders in Parkinson disease context, and the potential implications on research, diagnosis, counseling and treatment.
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Affiliation(s)
- Ziv Gan-Or
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
| | - Roy N Alcalay
- Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Guy A Rouleau
- Montreal Neurological Institute, McGill University, Montréal, QC, Canada; Department of Human Genetics, McGill University, Montréal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
| | - Ronald B Postuma
- Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
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Application of Personalized, Predictive, Preventative, and Participatory (P4) Medicine to Obstructive Sleep Apnea. A Roadmap for Improving Care? Ann Am Thorac Soc 2018; 13:1456-67. [PMID: 27387483 DOI: 10.1513/annalsats.201604-235ps] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Dr. Leroy Hood promotes a paradigm to advance medical care that he calls P4 medicine. The four Ps are: personalized, predictive, preventative, and participatory. P4 medicine encourages a convergence of systems medicine, the digital revolution, and consumer-driven healthcare. Might P4 medicine be applicable to obstructive sleep apnea (OSA)? OSA should be personalized in that there are different structural and physiological pathways to disease. Obesity is a major risk factor. The link between obesity and OSA is likely to be fat deposits in the tongue compromising the upper airway. Clinical features at presentation also vary between patients. There are three distinct subgroups: (1) patients with a primary complaint of insomnia, (2) relatively asymptomatic patients with a high prevalence of cardiovascular comorbidities, and (3) excessively sleepy patients. Currently, there have been limited efforts to identify subgroups of patients on the basis of measures obtained by polysomnography. Yet, these diagnostic studies likely contain considerable predictive information. Likewise, there has currently been limited application of -omic approaches. Determining the relative role of obesity and OSA for particular consequences is challenging, because they both affect the same molecular pathways. There is evidence that the effects of OSA are modified by the level of obesity. These insights may lead to improvements in predicting outcomes to personalized therapies. The final P-participatory-is ideally suited to OSA, with technology to obtain extensive data remotely from continuous positive airway pressure machines. Providing adherence data directly to patients increases their use of continuous positive airway pressure. Thus, the concept of P4 medicine is very applicable to obstructive sleep apnea and can be the basis for future research efforts.
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29
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Krittanawong C, Tunhasiriwet A, Wang Z, Zhang H, Farrell AM, Chirapongsathorn S, Sun T, Kitai T, Argulian E. Association between short and long sleep durations and cardiovascular outcomes: a systematic review and meta-analysis. EUROPEAN HEART JOURNAL-ACUTE CARDIOVASCULAR CARE 2017; 8:762-770. [PMID: 29206050 DOI: 10.1177/2048872617741733] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND A shorter sleep duration has been identified as a risk factor for cardiovascular diseases and increased mortality. It has been hypothesized that a short sleep duration may be linked to changes in ghrelin and leptin production, leading to an alteration of stress hormone production. Here, we conducted a systematic review and meta-analysis to investigate the potential relationship between a sleep duration and cardiovascular disease mortality. METHODS We conducted a comprehensive search of Ovid Medline In-Process and other non-indexed citations, Ovid MEDLINE, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, and Scopus from database inception to March 2017. Observational studies were included if the studies reported hazard ratios or odds ratios of the associations between sleep durations (short and long) and cardiovascular disease mortality. Data were extracted by a reviewer and then reviewed by two separate reviewers. Conflicts were resolved through consensus. Using the DerSimonian and Laird random effects models, we calculated pooled hazard ratios and pooled odds ratios with 95% confidence intervals (CI). Subgroup analyses were performed to explore potential sources of heterogeneity. The quality of the included studies and publication bias were assessed. RESULTS In total, our meta-analysis included 19 studies (31 cohorts) with a total of 816,995 individuals with 42,870 cardiovascular disease mortality cases. In pooled analyses, both short (risk ratio 1.19; 95% CI 1.13 to 1.26, P<0.001, I2=30.7, Pheterogeneity=0.034), and long (risk ratio 1.37; 95% CI 1.23 to 1.52, P<0.001, I2=79.75, Pheterogeneity<0.001) sleep durations were associated with a greater risk of cardiovascular disease mortality. CONCLUSIONS Both short (<7 hours) and long sleep durations (>9 hours) can increase the risk of overall cardiovascular disease mortality, particularly in Asian populations and elderly individuals. Future epidemiological studies would ideally include objective sleep measurements, rather than self-report measures, and all potential confounders, such as genetic variants.
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Affiliation(s)
- Chayakrit Krittanawong
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, USA.,Department of Cardiovascular Diseases, Icahn School of Medicine at Mount Sinai St' Luke, Mount Sinai Heart, USA
| | | | - Zhen Wang
- Robert D and Patricia E Kern Center for the Science of Health Care Delivery, Mayo Clinic, USA.,Division of Health Care Policy and Research, Department of Health Sciences Research, Mayo Clinic. USA
| | - HongJu Zhang
- Division of Cardiovascular Diseases, Mayo Clinic, USA
| | | | - Sakkarin Chirapongsathorn
- Division of Gastroenterology and Hepatology, Mayo Clinic, USA.,Division of Gastroenterology, Phramongkutklao Hospital and College of Medicine, Royal Thai Army, Bangkok, Thailand
| | - Tao Sun
- Division of Cardiovascular Diseases, Mayo Clinic, USA
| | - Takeshi Kitai
- Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Japan.,Department of Cardiovascular Medicine, Cleveland Clinic, USA
| | - Edgar Argulian
- Department of Cardiovascular Diseases, Icahn School of Medicine at Mount Sinai St' Luke, Mount Sinai Heart, USA
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30
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Tumor necrosis factor alpha in sleep regulation. Sleep Med Rev 2017; 40:69-78. [PMID: 29153862 DOI: 10.1016/j.smrv.2017.10.005] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/16/2017] [Accepted: 10/18/2017] [Indexed: 12/14/2022]
Abstract
This review details tumor necrosis factor alpha (TNF) biology and its role in sleep, and describes how TNF medications influence sleep/wake activity. Substantial evidence from healthy young animals indicates acute enhancement or inhibition of endogenous brain TNF respectively promotes and inhibits sleep. In contrast, the role of TNF in sleep in most human studies involves pathological conditions associated with chronic elevations of systemic TNF and disrupted sleep. Normalization of TNF levels in such patients improves sleep. A few studies involving normal healthy humans and their TNF levels and sleep are consistent with the animal studies but are necessarily more limited in scope. TNF can act on established sleep regulatory circuits to promote sleep and on the cortex within small networks, such as cortical columns, to induce sleep-like states. TNF affects multiple synaptic functions, e.g., its role in synaptic scaling is firmly established. The TNF-plasticity actions, like its role in sleep, can be local network events suggesting that sleep and plasticity share biochemical regulatory mechanisms and thus may be inseparable from each other. We conclude that TNF is involved in sleep regulation acting within an extensive tightly orchestrated biochemical network to niche-adapt sleep in health and disease.
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31
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Quality of life and excessive daytime sleepiness in children and adolescents with myotonic dystrophy type 1. Sleep Med 2017; 32:92-96. [DOI: 10.1016/j.sleep.2016.12.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 12/07/2016] [Accepted: 12/08/2016] [Indexed: 11/18/2022]
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32
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Um YH, Hong SC, Jeong JH. Sleep Problems as Predictors in Attention-Deficit Hyperactivity Disorder: Causal Mechanisms, Consequences and Treatment. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2017; 15:9-18. [PMID: 28138105 PMCID: PMC5290714 DOI: 10.9758/cpn.2017.15.1.9] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 09/06/2016] [Accepted: 09/11/2016] [Indexed: 01/11/2023]
Abstract
Attention-deficit hyperactivity disorder (ADHD) is notorious for its debilitating consequences and early age of onset. The need for early diagnosis and intervention has frequently been underscored. Previous studies have attempted to clarify the bidirectional relationship between ADHD and sleep problems, proposing a potential role for sleep problems as early predictors of ADHD. Sleep deprivation, sleep-disordered breathing, and circadian rhythm disturbances have been extensively studied, yielding evidence with regard to their induction of ADHD-like symptoms. Genetic-phenotypic differences across individuals regarding the aforementioned sleep problems have been elucidated along with the possible use of these characteristics for early prediction of ADHD. The long-term consequences of sleep problems in individuals with ADHD include obesity, poor academic performance, and disrupted parent-child interactions. Early intervention has been proposed as an approach to preventing these debilitating outcomes of ADHD, with novel treatment approaches ranging from melatonin and light therapy to myofunctional therapy and adjustments of the time point at which school starts.
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Affiliation(s)
- Yoo Hyun Um
- Department of Psychiatry, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Chul Hong
- Department of Psychiatry, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong-Hyun Jeong
- Department of Psychiatry, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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33
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Ozen F, Yegin Z, Yavlal F, Saglam ZA, Koc H, Berber I. Lack of association between MAOA-uVNTR variants and excessive daytime sleepiness. Neurol Sci 2017; 38:769-774. [DOI: 10.1007/s10072-017-2836-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 01/31/2017] [Indexed: 10/20/2022]
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34
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Kheirandish-Gozal L, Gozal D. Pediatric OSA Syndrome Morbidity Biomarkers: The Hunt Is Finally On! Chest 2016; 151:500-506. [PMID: 27720883 DOI: 10.1016/j.chest.2016.09.026] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 09/12/2016] [Accepted: 09/27/2016] [Indexed: 12/31/2022] Open
Abstract
Since initial reports 40 years ago on pediatric OSA syndrome (OSAS) as a distinct and prevalent clinical entity, substantial advances have occurred in the delineation of diagnostic and treatment approaches. However, despite emerging and compelling evidence that OSAS increases the risk for cognitive, cardiovascular, and metabolic end-organ morbidities, routine assessment of such morbidities is seldom conducted in clinical practice. One of the major reasons for such discrepancies resides in the relatively labor-intensive and onerous steps that would be required to detect the presence of any of such morbidities, further adding to the already elevated cost of diagnosing the disorder. To circumvent these obstacles, the search for biomarker signatures of pediatric OSA and its cognitive and cardiometabolic consequences was launched, and considerable progress has occurred since then. Here, we review the current evidence for the presence of morbidity-related biomarkers among children with OSAS, and explore future opportunities in this promising arena.
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Affiliation(s)
- Leila Kheirandish-Gozal
- Section of Pediatric Sleep Medicine, Department of Pediatrics, Biological Sciences Division, Pritzker School of Medicine, The University of Chicago, Chicago, IL.
| | - David Gozal
- Section of Pediatric Sleep Medicine, Department of Pediatrics, Biological Sciences Division, Pritzker School of Medicine, The University of Chicago, Chicago, IL
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Pediatric Sleep Apnea Syndrome: An Update. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2016; 4:852-61. [PMID: 27372597 DOI: 10.1016/j.jaip.2016.02.022] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 02/17/2016] [Accepted: 02/26/2016] [Indexed: 01/04/2023]
Abstract
Obstructive sleep apnea syndrome (OSAS) may be central neurologic (<5%) or obstructive (>95%) in origin and is a relatively prevalent condition in children. It affects 1%-5% of children aged 2-8 years and is caused by a variety of different pathophysiologic abnormalities. Cardiovascular, metabolic, and neurocognitive comorbidities can occur in both children and adults when left untreated. It also can cause severe behavioral problems in children. The American Academy of Pediatrics recommends that all children be screened with an appropriate history and physical examination for symptoms and signs suggestive of OSAS. The diagnosis is primarily made clinically and confirmed by polysomnographic findings. Treatment depends on the child's age, underlying medical problems, polysomnography findings, and whether or not there is upper airway obstruction usually secondary to enlarged adenoids and/or tonsils, allergic and nonallergic rhinitis, acute and chronic sinusitis, and other upper airway pathology. If enlarged adenoid or tonsils or both conditions exist, an adenoidectomy, tonsillectomy, or adenotonsillectomy remains the treatment of choice. Pharmacotherapy of OSAS has shown some effect in children with mild symptoms. This paper reviews the prevalence, pathophysiology, clinical presentation, diagnosis, and treatment of OSAS.
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36
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Khalyfa A, Gileles-Hillel A, Gozal D. The Challenges of Precision Medicine in Obstructive Sleep Apnea. Sleep Med Clin 2016; 11:213-26. [DOI: 10.1016/j.jsmc.2016.01.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Abstract
Obstructive sleep apnoea (OSA) is one of the most common causes of sleep-disordered breathing (SDB) in children. It is associated with significant morbidity, potentially impacting on long-term neurocognitive and behavioural development, as well as cardiovascular outcomes and metabolic homeostasis. The low grade systemic inflammation and increased oxidative stress seen in this condition are believed to underpin the development of these OSA-related morbidities. The significant variance in degree of end organ morbidity in patients with the same severity of OSA highlights the importance of the interplay of genetic and environmental factors in determining the overall OSA phenotype. This review seeks to summarize the current understanding of the aetiology and mechanisms underlying OSA, its risk factors, diagnosis and treatment.
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Affiliation(s)
- Eleonora Dehlink
- 1 Department of Pediatric Respiratory Medicine, Royal Brompton Hospital, London, UK ; 2 National Heart and Lung Institute, Imperial College, London, UK
| | - Hui-Leng Tan
- 1 Department of Pediatric Respiratory Medicine, Royal Brompton Hospital, London, UK ; 2 National Heart and Lung Institute, Imperial College, London, UK
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38
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Vlastos I, Athanasopoulos I. Cutting-edge technologies for diagnosis and monitoring of snoring in children. World J Clin Pediatr 2016; 5:63-66. [PMID: 26862503 PMCID: PMC4737694 DOI: 10.5409/wjcp.v5.i1.63] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 10/17/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
Snoring is a very common problem in children and may be an indication of obstructive sleep apnea (OSA). Appropriate diagnosis is of importance due to detrimental effects of OSA. Polysomnography is considered the gold standard for the diagnosis of OSA. However, it is impractical for several reasons and this is why other tests have been developed as alternatives to formal polysomnography (PSG) for the assessment of children with snoring. In this mini-review basic features of PSG as well as alternative tests are presented and future perspectives are provided in addition to current guideline for the diagnosis and monitoring of childhood snoring. The aim of this review is to highlight briefly currently developed technologies that seem promising for the evaluation of snoring.
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Abstract
Sleep disorders are, in part, attributable to genetic variability across individuals. There has been considerable progress in understanding the role of genes for some sleep disorders, such as the identification of a human leukocyte antigen gene for narcolepsy. For other sleep disorders, such as insomnia, little work has been done. Optimizing phenotyping strategies is critical, as is the case for sleep apnea, for which intermediate traits such as obesity and craniofacial features may prove to be more tractable for genetic studies. Rapid advances in genotyping and statistical genetics are likely to lead to greater discoveries in the near future.
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Affiliation(s)
- Philip R Gehrman
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Suite 670, Philadelphia, PA 19104, USA.
| | - Brendan T Keenan
- Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, 125 South 31st Street, Suite 2100, Philadelphia, PA 19104-3403, USA
| | - Enda M Byrne
- Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, 125 South 31st Street, Suite 2100, Philadelphia, PA 19104-3403, USA; Queensland Brain Institute, Brisbane QLD 4072, Australia
| | - Allan I Pack
- Division of Sleep Medicine, Department of Medicine, Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, 125 South 31st Street, Suite 2100, Philadelphia, PA 19104-3403, USA
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Kaditis AG, Alonso Alvarez ML, Boudewyns A, Alexopoulos EI, Ersu R, Joosten K, Larramona H, Miano S, Narang I, Trang H, Tsaoussoglou M, Vandenbussche N, Villa MP, Van Waardenburg D, Weber S, Verhulst S. Obstructive sleep disordered breathing in 2- to 18-year-old children: diagnosis and management. Eur Respir J 2015; 47:69-94. [PMID: 26541535 DOI: 10.1183/13993003.00385-2015] [Citation(s) in RCA: 535] [Impact Index Per Article: 53.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 08/11/2015] [Indexed: 12/11/2022]
Abstract
This document summarises the conclusions of a European Respiratory Society Task Force on the diagnosis and management of obstructive sleep disordered breathing (SDB) in childhood and refers to children aged 2-18 years. Prospective cohort studies describing the natural history of SDB or randomised, double-blind, placebo-controlled trials regarding its management are scarce. Selected evidence (362 articles) can be consolidated into seven management steps. SDB is suspected when symptoms or abnormalities related to upper airway obstruction are present (step 1). Central nervous or cardiovascular system morbidity, growth failure or enuresis and predictors of SDB persistence in the long-term are recognised (steps 2 and 3), and SDB severity is determined objectively preferably using polysomnography (step 4). Children with an apnoea-hypopnoea index (AHI) >5 episodes·h(-1), those with an AHI of 1-5 episodes·h(-1) and the presence of morbidity or factors predicting SDB persistence, and children with complex conditions (e.g. Down syndrome and Prader-Willi syndrome) all appear to benefit from treatment (step 5). Treatment interventions are usually implemented in a stepwise fashion addressing all abnormalities that predispose to SDB (step 6) with re-evaluation after each intervention to detect residual disease and to determine the need for additional treatment (step 7).
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Affiliation(s)
- Athanasios G Kaditis
- Pediatric Pulmonology Unit, First Dept of Paediatrics, University of Athens School of Medicine and Aghia Sophia Children's Hospital, Athens, Greece
| | - Maria Luz Alonso Alvarez
- Multidisciplinary Sleep Unit, Pulmonology, University Hospital of Burgos and CIBER of Respiratory Diseases (CIBERES), Burgos Foundation for Health Research, Burgos, Spain
| | - An Boudewyns
- Dept of Otorhinolaryngology Head and Neck Surgery, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Emmanouel I Alexopoulos
- Sleep Disorders Laboratory, University of Thessaly School of Medicine and Larissa University Hospital, Larissa, Greece
| | - Refika Ersu
- Division of Paediatric Pulmonology, Marmara University, Istanbul, Turkey
| | - Koen Joosten
- Erasmus MC, Sophia Children's Hospital, Paediatric Intensive Care, Rotterdam, The Netherlands
| | - Helena Larramona
- Paediatric Pulmonology Unit, Dept of Paediatrics, University Autonoma of Barcelona, Corporacio Sanitaria Parc Tauli, Hospital of Sabadell, Barcelona, Spain
| | - Silvia Miano
- Sleep and Epilepsy Centre, Neurocentre of Southern Switzerland, Civic Hospital of Lugano, Lugano, Switzerland
| | - Indra Narang
- Division of Respiratory Medicine, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Ha Trang
- Paediatric Sleep Centre, Robert Debré University Hospital, EA 7334 REMES Paris-Diderot University, Paris, France
| | - Marina Tsaoussoglou
- Pediatric Pulmonology Unit, First Dept of Paediatrics, University of Athens School of Medicine and Aghia Sophia Children's Hospital, Athens, Greece
| | | | - Maria Pia Villa
- Pediatric Sleep Disease Centre, Child Neurology, NESMOS Dept, School of Medicine and Psychology, Sapienza University of Rome, S. Andrea Hospital, Rome, Italy
| | - Dick Van Waardenburg
- Paediatric Intensive Care Unit, Dept of Paediatrics, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Silke Weber
- Dept of Ophthalmology, Otolaryngology and Head and Neck Surgery, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, São Paulo, Brazil
| | - Stijn Verhulst
- Dept of Paediatrics, Antwerp University Hospital, Edegem, Belgium
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Abstract
Sleep-disordered breathing (SDB) refers to a group of disorders characterized by abnormalities of respiration or ventilation during sleep. It encompasses obstructive sleep apnea (OSA), central sleep apnea (CSA) syndromes, sleep-related hypoventilation and sleep-related hypoxemia disorders. This review will concentrate on the disorder most prevalent in pediatrics, i.e., OSA, highlighting the most recent developments in our understanding of the etiology, pathophysiology and treatment options of this condition. OSA morbidities primarily involve the neurocognitive, cardiovascular and metabolic systems. However, there can be significant phenotypic variation in terms of end organ morbidity for the same OSA severity. This is likely due to the interplay between genetic and environmental factors; recent developments in the fields of genomics and proteomics have the potential to shed light on these complex pathological cascades. As we enter the era of personalized medicine, phenotyping patients to enable clinicians to tailor bespoke clinical management plans will be of crucial importance.
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Reduced systemic levels of IL-10 are associated with the severity of obstructive sleep apnea and insulin resistance in morbidly obese humans. Mediators Inflamm 2015; 2015:493409. [PMID: 25944984 PMCID: PMC4402489 DOI: 10.1155/2015/493409] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 03/23/2015] [Accepted: 03/23/2015] [Indexed: 12/14/2022] Open
Abstract
Obstructive sleep apnea (OSA) has been related to elevation of inflammatory cytokines and development of insulin resistance in morbidly obese (MO) subjects. However, it is still unclear whether the systemic concentration of anti-inflammatory mediators is also affected in MO subjects directly related to the severity of OSA and level of insulin resistance. Normal weight and MO subjects were subjected to overnight polysomnography in order to establish the severity of OSA, according to the apnea-hypopnea index (AHI). Blood samples were obtained for estimation of total cholesterol and triglycerides, insulin, glucose, insulin resistance, tumor necrosis factor alpha (TNF-α), interleukin 12 (IL12), and interleukin 10 (IL-10). Serum levels of IL-10 were significantly lower in MO subjects with OSA than in MO and control individuals without OSA. Besides being inversely associated with serum TNF-α and IL-12, decreased IL-10 levels were significantly related to increased AHI, hyperinsulinemia, and insulin resistance. Serum IL-10 is significantly reduced in morbidly obese subjects with severe OSA while also showing a clear relationship with a state of hyperinsulinemia and insulin resistance probably regardless of obesity in the present sample. It may be of potential clinical interest to identify the stimulatory mechanisms of IL-10 in obese individuals with OSA.
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El-Sharkawy AA, Abdelmotaleb GS, Aly MK, Kabel AM. Effect of metformin on sleep disorders in adolescent girls with polycystic ovarian syndrome. J Pediatr Adolesc Gynecol 2014; 27:347-352. [PMID: 25256878 DOI: 10.1016/j.jpag.2014.01.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 01/09/2014] [Accepted: 01/13/2014] [Indexed: 10/24/2022]
Abstract
OBJECTIVE Patients with polycystic ovarian syndrome (PCOS) have a high prevalence of sleep disorders. Metformin is an antidiabetic drug that may have a role in treatment of the manifestations of PCOS. The aim of this study was to assess the presence of sleep disorders in adolescent girls with PCOS and to study the effects of using metformin on sleep disorders in these girls. METHODS This study was carried out on 90 adolescent girls aging from 12 to 18 years who were divided into 3 equal groups: control untreated group, untreated PCOS group, and PCOS + metformin group. Body weight, height, body mass index, hirsutism score, fasting and postprandial blood glucose, fasting serum insulin, Homeostatic Model Assessment (HOMA) index, sleep disturbances scale, and Epworth sleepiness scale were measured. RESULTS Metformin administration resulted in significant decrease in the body weight, body mass index, hirsutism score, fasting and postprandial blood glucose, fasting serum insulin, HOMA index, sleep disturbances scale, and Epworth sleepiness scale compared to the untreated PCOS group. CONCLUSION Metformin can reduce the incidence of sleep disorders and excessive daytime sleepiness in adolescent girls with PCOS.
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Affiliation(s)
| | | | - Mohammed K Aly
- Pediatric Department, Faculty of Medicine, Benha University, Benha, Egypt.
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44
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Young P. Genetische Diagnostik von Schlafstörungen. SOMNOLOGIE 2014. [DOI: 10.1007/s11818-014-0687-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Intracranial hypertension associated with obstructive sleep apnea: a discussion of potential etiologic factors. Med Hypotheses 2014; 83:792-7. [PMID: 25456788 DOI: 10.1016/j.mehy.2014.10.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2014] [Revised: 09/07/2014] [Accepted: 10/14/2014] [Indexed: 01/02/2023]
Abstract
Obstructive sleep apnea has been shown to increase intracranial pressure, and to be a secondary cause of intracranial hypertension. There are a few theories that attempt to explain this relationship, however there is little data, and even less recognition among physicians that this actually occurs. This paper discusses multiple pieces of data, from anatomical correlates to biochemical information involving neuro-excitotoxicity, as well as hematologic factors and issues surrounding brain edema and blood-brain barrier dysfunction. A complex paradigm for how obstructive sleep apnea may lead to increased intracranial pressure is thus proposed. In addition, suggestions are made for how obstructive sleep apnea must as a result be managed differently in the setting of idiopathic intracranial hypertension.
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Wu Y, Cao C, Wu Y, Zhang C, Zhu C, Ying S, Chen Z, Shen H, Li W. TNF-α-308G/A polymorphism contributes to obstructive sleep apnea syndrome risk: evidence based on 10 case-control studies. PLoS One 2014; 9:e106183. [PMID: 25192323 PMCID: PMC4156295 DOI: 10.1371/journal.pone.0106183] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 07/28/2014] [Indexed: 01/16/2023] Open
Abstract
Objective The aim of our study was to investigate the association between the TNF-α-308G/A polymorphism and obstructive sleep apnea syndrome (OSAS). Method The Medline, Web of Science, EMBASE, Chinese National Knowledge Infrastructure (CNKI), and Cochrane Central Register of Controlled Trials were searched. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to study TNF-α-308G/A polymorphism and risk of OSAS. Result 10 case-control studies were included in our meta-analysis. The results from our study showed that the TNF-α-308G/A polymorphism was significantly associated with risk of OSAS (A vs. G: OR = 1.67, 95% CI = 1.43–1.95). In the subgroup analysis by ethnicity, the statistical similar results were observed both in European (A vs. G: OR = 1.68, 95% CI = 1.35–2.08) and Asian population (A vs. G: OR = 2.02, 95% CI = 1.50–2.71). When stratified by age, a significantly increased risk was observed in adult carries A allele compared with G allele (OR = 1.79, 95% CI = 1.50–2.13), whereas no association was found in children (OR = 1.09, 95% CI = 0.70–1.69). Conclusion Our study suggested that the TNF-α- 308G/A polymorphism contributed to the susceptibility to the risk of OSAS. Additional well-designed large studies are needed to validate our findings.
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Affiliation(s)
- Yanping Wu
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chao Cao
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Department of Respiratory Medicine, Affiliated Hospital of School of Medicine, Ningbo University, Ningbo, China
| | - Yinfang Wu
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chao Zhang
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chen Zhu
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Songmin Ying
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhihua Chen
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Huahao Shen
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wen Li
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Carreras A, Almendros I, Farré R. Potential role of bone marrow mesenchymal stem cells in obstructive sleep apnea. Int J Stem Cells 2014; 4:43-9. [PMID: 24298333 DOI: 10.15283/ijsc.2011.4.1.43] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2011] [Indexed: 01/18/2023] Open
Abstract
Obstructive sleep apnea syndrome (OSA) is a prevalent disease caused by increased collapsibility of the upper airway. OSA induces oxidative stress, inflammation and endothelial dysfunction, with important clinical consequences such as neurocognitive alterations and cardiovascular diseases. Although it has been shown that bone marrow-derived stem cells play a protective and reparative function in several diseases involving inflammatory processes and endothelial dysfunction, the data currently available on the potential role of adult stem cells in OSA are scarce. The present review presents recent data on the potential role of bone marrow-derived mesenchymal stem cells (MSC) in OSA. The results obtained in animal models that realistically mimic the events characterizing this sleep breathing disorder strongly support the notion that MSC are mobilized in circulating blood and then activated to play an anti-inflammatory role in OSA.
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Affiliation(s)
- Alba Carreras
- Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona-IDIBAPS, Barcelona ; CIBER de Enfermedades Respiratorias (CIBERES), Bunyola, Spain
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Tan HL, Kheirandish-Gozal L, Gozal D. The promise of translational and personalised approaches for paediatric obstructive sleep apnoea: an 'Omics' perspective. Thorax 2014; 69:474-80. [PMID: 24550060 DOI: 10.1136/thoraxjnl-2013-204640] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Obstructive sleep apnoea (OSA) can result in significant morbidities including the cardiovascular, metabolic and neurocognitive systems. These effects are purportedly mediated via activation of inflammatory cascades and the induction of oxidative stress, ultimately resulting in cellular injury and dysfunction. While great advances have been made in sleep medicine research in the past decades, there are still wide gaps in our knowledge concerning the exact underlying pathophysiological mechanisms of OSA and consequences. Without resolving these issues, the reasons why patients with a similar severity of OSA can have markedly different clinical presentation and end-organ morbidity, that is, phenotype, will continue to remain elusive. This review aims to highlight the recent exciting discoveries in genotype-phenotype interactions, epigenetics, genomics and proteomics related to OSA. Just as PCR revolutionised the field of genetics, the potential power of 'Omics' promises to transform the field of sleep medicine, and provide critical insights into the downstream pathological cascades inherent to OSA, thereby enabling personalised diagnosis and management for this highly prevalent sleep disorder.
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Affiliation(s)
- Hui-Leng Tan
- Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, , London, UK
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49
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Zhang SXL, Wang Y, Gozal D. Pathological consequences of intermittent hypoxia in the central nervous system. Compr Physiol 2013; 2:1767-77. [PMID: 23723023 DOI: 10.1002/cphy.c100060] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Intermittent hypoxia (IH) is a frequent occurrence in clinical settings. In the last decades, evidence has emerged implicating the gas exchange alterations and sleep disruption associated with those disorders in the high prevalence of cognitive and behavioral deficits afflicting these patients. In an effort to better characterize the role of IH, and to identify potential mechanisms of IH-induced central nervous system (CNS) dysfunction, a large number of rodent models have been recently developed. The cumulative evidence confirms that IH indeed induces a heterotopic pattern of injury in the brain, particularly affecting cortical, subcortical, and hippocampal regions, ultimately leading to neuronal apoptosis and activation of microglia. These IH-induced deleterious processes exhibit substantial variability across the lifespan, are under substantial modulatory influences of diet, physical or intellectual activity, and genetic factors, and preferentially recruit oxidative stress and inflammatory pathways.
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Affiliation(s)
- Shelley X L Zhang
- Department of Pediatrics, University of Chicago, Chicago, Illinois, USA
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Israel LP, Benharoch D, Gopas J, Goldbart AD. A pro-inflammatory role for nuclear factor kappa B in childhood obstructive sleep apnea syndrome. Sleep 2013; 36:1947-55. [PMID: 24293770 DOI: 10.5665/sleep.3236] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
STUDY OBJECTIVES Childhood obstructive sleep apnea syndrome (OSAS) is associated with an elevation of inflammatory markers such as C-reactive protein (CRP) that correlates with specific morbidities and subsides following intervention. In adults, OSAS is associated with activation of the transcription factor nuclear factor kappa B (NF-kB). We explored the mechanisms underlying NF-kB activation, based on the hypothesis that specific NF-kB signaling is activated in children with OSAS. DESIGN Adenoid and tonsillar tissues from children with OSAS and matched controls were immunostained against NF-kB classical (p65 and p50) and alternative (RelB and p52) pathway subunits, and NF-kB-dependent cytokines: interleukin (IL)- 1α, IL-1β, tumor necrosis factor-α, and IL-8). Serum CRP levels were measured in all subjects. NF-kB induction was evaluated by a luciferase-NF-kB reporter assay in L428 cells constitutively expressing NF-kB and in Jurkat cells with inducible NF-kB expression. p65 translocation to the nucleus, reflecting NF-kB activation, was measured in cells expressing fluorescent NF-kB-p65-GFP (green fluorescent protein). SETTING Sleep research laboratory. PATIENTS OR PARTICIPANTS Twenty-five children with OSAS and 24 without OSAS. INTERVENTIONS N/A. MEASUREMENTS AND RESULTS Higher expression of IL-1α and classical NF-kB subunits p65 and p50 was observed in adenoids and tonsils of children with OSAS. Patient serum induced NF-kB activity, as measured by a luciferase-NF-kB reporter assay and by induction of p65 nuclear translocation in cells permanently transfected with GFP-p65 plasmid. IL-1β showed increased epithelial expression in OSAS tissues. CONCLUSIONS Nuclear factor kappa B is locally and systemically activated in children with obstructive sleep apnea syndrome. This observation may motivate the search for new anti-inflammatory strategies for controlling nuclear factor kappa B activation in obstructive sleep apnea syndrome.
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Affiliation(s)
- Lee P Israel
- Department of Microbiology and Immunology ; Pediatric Pulmonary and Sleep Research Laboratory
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