- Serum Cytokines as Potential Biomarkers for Diagnosis and Monitoring of Sleep Disorders: A Cross-Sectional and Longitudinal Study
Serum levels of IL-6, TNF-α, IL-1β, IL-10, and CRP
Abstract
Background: Sleep disorders, particularly Obstructive Sleep Apnea (OSA) and Insomnia Disorder (ID), are associated with systemic inflammation. However, the diagnostic and monitoring utility of specific cytokine profiles remains unclear.
Objective: To identify distinct serum cytokine signatures in OSA and ID compared to healthy controls (HC) at baseline and to evaluate longitudinal changes in these biomarkers following standard treatment.
Methods: In this pilot study, 75 cases (25 OSA, 25 ID, 25 HC) were enrolled. Serum levels of IL-6, TNF-α, IL-1β, IL-10, and CRP were measured at baseline using multiplex immunoassay. All patients underwent polysomnography and clinical assessment. The OSA and ID cohorts were re-evaluated after 3 months of treatment (CPAP for OSA, CBT-I for ID) with repeat cytokine analysis.
Results: At baseline, the OSA group showed significantly elevated levels of IL-6 (p<0.001), TNF-α (p=0.003), and CRP (p<0.001) compared to HC. The ID group had elevated IL-6 (p=0.01) and IL-1β (p=0.02) but not CRP. A combined panel of IL-6, TNF-α, and IL-1β differentiated OSA from ID with an AUC of 0.87 (95% CI: 0.78-0.96). Longitudinally, CPAP therapy in adherent patients (>4 hrs/night) led to a significant reduction in IL-6 (p=0.004) and CRP (p=0.008), correlating with apnea-hypopnea index (AHI) improvement (r=0.65, p=0.002). CBT-I in ID led to a reduction in IL-1β (p=0.03), which correlated with improved sleep efficiency (r=-0.52, p=0.02).
Conclusion: This pilot study identifies disorder-specific inflammatory profiles in OSA and ID. Serum IL-6 and CRP are promising biomarkers for OSA severity and treatment response, while IL-1β may be salient to insomnia pathophysiology. These findings support the role of cytokines as complementary objective tools for diagnosis and monitoring in sleep medicine.
References
2. Kapur VK, Auckley DH, Chowdhuri S, et al. Clinical Practice Guideline for Diagnostic Testing for Adult Obstructive Sleep Apnea: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017;13(3):479-504.
3. Irwin MR. Sleep and inflammation: partners in sickness and in health. Nat Rev Immunol. 2019;19(11):702-15.
4. Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab. 2010;24(5):775-84.
5. Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation. 2005;112(17):2660-7.
6. Irwin MR, Olmstead R, Carroll JE. Sleep Disturbance, Sleep Duration, and Inflammation: A Systematic Review and Meta-Analysis of Cohort Studies and Experimental Sleep Deprivation. Biol Psychiatry. 2016;80(1):40-52.
7. Bøggild H, Vestergaard CH, Lundbye-Christensen S, et al. Insomnia and risk of cardio-metabolic disease: a systematic review. Eur Heart J. 2022;43(Supplement_2).
8. Vgontzas AN, Zoumakis E, Lin HM, et al. Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor-alpha antagonist. J Clin Endocrinol Metab. 2004;89(9):4409-13.
9. Liukkonen T, Räsänen P, Ruokonen A, et al. C-reactive protein levels and sleep disturbances: observations based on the Northern Finland 1966 Birth Cohort study. Psychosom Med. 2007;69(8):756-61.
10. Hoyos CM, Drager LF, Patel SR. OSA and cardiometabolic risk: What's the bottom line? Respirology. 2017;22(3):420-9.
11. American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.
12. Edinger JD, Arnedt JT, Bertisch SM, et al. Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2021;17(2):263-98.
13. Buysse DJ, Ancoli-Israel S, Edinger JD, Lichstein KL, Morin CM. Recommendations for a standard research assessment of insomnia. Sleep. 2006;29(9):1155-73.
14. Berry RB, Brooks R, Gamaldo CE, et al. for the American Academy of Sleep Medicine. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications. Version 2.6. Darien, IL: American Academy of Sleep Medicine; 2020.
15. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193-213.
16. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540-5.
17. Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001;2(4):297-307.
18. Morin CM, Bootzin RR, Buysse DJ, et al. Psychological and behavioral treatment of insomnia:update of the recent evidence (1998-2004). Sleep. 2006;29(11):1398-414.
19. Elshal MF, McCoy JP. Multiplex bead array assays: performance evaluation and comparison of sensitivity to ELISA. Methods. 2006;38(4):317-23.
20. Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automated high-sensitivity C-reactive protein assay. Clin Chem. 1999;45(12):2136-41.
21. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143(1):29-36.
22. Arnardottir ES, Mackiewicz M, Gislason T, Teff KL, Pack AI. Molecular signatures of obstructive sleep apnea in adults: a review and perspective. Sleep. 2009;32(4):447-70.
23. Lavie L. Oxidative stress in obstructive sleep apnea and intermittent hypoxia--revisited--the bad ugly and good: implications to the heart and brain. Sleep Med Rev. 2015;20:27-45.
24. Irwin MR, Opp MR. Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity. Neuropsychopharmacology. 2017;42(1):129-55.
25. Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab. 2000;85(3):1151-8.
26. Festa A, D'Agostino R Jr, Williams K, et al. The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord. 2001;25(10):1407-15.
27. Hoyos CM, Drager LF, Patel SR. OSA and cardiometabolic risk: What's the bottom line? Respirology. 2017;22(3):420-9.
28. Nadeem R, Molnar J, Madbouly EM, et al. Serum inflammatory markers in obstructive sleep apnea: a meta-analysis. J Clin Sleep Med. 2013;9(10):1003-12.
29. Fernandez-Mendoza J, Shea S, Vgontzas AN, et al. Insomnia and incident depression: role of objective sleep duration and natural history. J Sleep Res. 2015;24(4):390-8.
30. Prather AA, Vogelzangs N, Penninx BW. Sleep duration, insomnia, and markers of systemic inflammation: results from the Netherlands Study of Depression and Anxiety (NESDA). J Psychiatr Res. 2015;60:95-102.
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