230  OSA Asthma Lit Review

230.1 Summary

• OSA Asthma Literature Review
• Direct methods influencing reactivity – possible?
• Morrison JF, Pearson SB, Dean HG Parasympathetic nervous system in nocturnal asthma BMJ 1988 29614279https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2545890/
• Desjardin JA, Sutarik JM, Suh , BY , et al. Influence of sleep on pulmonary capillary volume in normal and asthmatic subjects Am J Respir Crit Care Med 1995 1521938, 7599823https://pubmed.ncbi.nlm.nih.gov/7599823/
• Ahmed T, Marchette B Hypoxia enhances nonspecific bronchial reactivity Am Rev Respir Dis 198513283944, 3931524https://pubmed.ncbi.nlm.nih.gov/3931524/
• OSA -> bronchial reactiveness: more direct evidence of connection
• OSA – inflammation connection: Proof of Concept Based on Two Illustrative Cytokines. Kheirandish-Gozal L, Gozal D Int J Mol Sci. 2019 Jan 22; 20(3):.
• Phenotypes: (GINA) – Global Initiative for Asthma . Global Strategy for Asthma Management and Prevention: Online Appendix 2020. (2020) Available online at: www.ginasthma.org (accessed September 8, 2020). [Ref list]
• Mechanisms
• Taillé C, Rouvel-Tallec A, Stoica M, Danel C, Dehoux M, Marin-Esteban V, Pretolani M, Aubier M, d’Ortho MP. Obstructive sleep apnoea modulates airway inflammation and remodelling in severe asthma. PLoS One. 2016;11:e0150042. https://doi.org/10.1371/journal.pone.0150042.
• Other unreviewed articles
• 45. Teodorescu M, Barnet JH, Hagen EW, Palta M, Young TB, Peppard PE. Association between asthma and risk of developing obstructive sleep apneahttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334115/

230.2 Slide outline

230.2.1 Slide 1

• OSA Asthma Literature Review ### Slide 2
• Direct methods influencing reactivity – possible?
• https://jcsm.aasm.org/doi/full/10.5664/jcsm.27397
• Vagal tone: Muller maneuver -> more vagal tone -> airway muscarinic receptors -> bronchoconstriction -> nocturnal asthma
• Laryngeal stimulation -> parasympathetic activation that includes trachea / bronchi
• Negative intrathoracic efforts -> increased thoracic blood volume
• CIH/Hypoxia -> increased bronchial reactivity to methacholine challenge and 65
• Also – more remodeling
• Increased local inflammation from trauma/snoring
• Increased systemic inflammation (elevated CRP in dose-response)
• Treatments: Oral steroids increase risk of OSA (M. Yigla, N. Tov, A. Solomonov, A.H.E. Rubin, D. HarlevDifficult-to-control asthma and ohstructive sleep apnea J Asthma, 40 (2003), pp. 865-871),
• ICS maybe too M. Teodorescu, F.B. Consens, W.F. Bria, M.J. Coffey, M.S. McMorris, K.J. Weatherwax, et al. Predictors of habitual snoring and obstructive sleep apnea risk in patients with asthma Chest, 135 (2009), pp. 1125-1132
• OSA (in dose response to increase AHI) increases markers seen with neutrophil-predominant asthma such as IL-8
• Taillé C, Rouvel-Tallec A, Stoica M, Danel C, Dehoux M, Marin-Esteban V, et al. Obstructive sleep apnoea modulates airway inflammation and remodelling in severe asthma. PLoS One 2016;11:e0150042.
• Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010;181:315-23. ### Slide 3
• Morrison JF, Pearson SB, Dean HG Parasympathetic nervous system in nocturnal asthma BMJ 1988 29614279https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2545890/
• 10 patients wiwth asthma & diurnal variation to PEF 20%+
• Atropine and 4am and 4pm
• AM: 260->390 l/min
• PM: 400->440 l/min
• Implication: vagal (cholinergic) mechanisms are part of pathophysiology of nocturnal asthma
• (note: inhaled LAMAs mostly effect large airways, vs intravenous uniform effect throughout the bronchial tree) ### Slide 4
• Desjardin JA, Sutarik JM, Suh , BY , et al. Influence of sleep on pulmonary capillary volume in normal and asthmatic subjects Am J Respir Crit Care Med 1995 1521938, 7599823https://pubmed.ncbi.nlm.nih.gov/7599823/
• 5 health subjects; 15 patients with asthma
• Spirometry performed pre- and post-
• 10/15 patients had FEV1 drop by more than 15%; they had an increase in DLCo (corresponding to an increase in capillary blood volume) by 15.7% +/- 16.6%
• Implication: during sleep, the intrathoracic blood volume incresaes ### Slide 5
• Ahmed T, Marchette B Hypoxia enhances nonspecific bronchial reactivity Am Rev Respir Dis 198513283944, 3931524https://pubmed.ncbi.nlm.nih.gov/3931524/
• 11 sheep – specific lung resistance determined by plethysmography before and after exposure to air (sham) or 13% O2; +/- cromolyn pretreatment
• Hypoxia -> increased reactivity to both histamine and carbachol triggers
• Cromyln reduces impact
• Human replications:
• https://thorax.bmj.com/content/52/5/453.abstract stable mild/mod asthmatic patients; methacholine provocation. Hypoxia worsens, hyperoxia does not improve
• https://www.atsjournals.org/doi/abs/10.1164/ajrccm/138.4.789 10 asthmatics. No change to compliance or resistance. Increase plasma catecholamines and response to methacholine. ### Slide 6
• OSA -> bronchial reactiveness: more direct evidence of connection
• Obstructive sleep apnea syndrome and bronchial hyperreactivity. Lin CC, Lin CY. Lung. 1995; 173(2):117-26. ### Slide 7
• OSA – inflammation connection: Proof of Concept Based on Two Illustrative Cytokines. Kheirandish-Gozal L, Gozal D Int J Mol Sci. 2019 Jan 22; 20(3):.
• Narrative review: Epidemiologic correlation between OSAS and neurocognitive, cardiopulmonary, and metabolic adverse outcomes – how?
• Obesity also a low-grade inflammatory condition; difficult to disentangle the effects
• TNF-alpha: pro-inflammatory cytokine, promotes sleep depth. Levels modestly increased in OSAS – though less than other cytokines.
• IL-6 – levels correlate with incident metabolic syndrome, atherosclerosis, etc. – plausible mediator of OSAS effects
• Levels decrease with CPAP
• Effects of these mediators depends on genetic and environmental milieu; in the future, levels of these mediators might be able to differentiate patients at risk of end-organ morbidity from sleep apnea ### Slide 8
• Phenotypes: (GINA) – Global Initiative for Asthma . Global Strategy for Asthma Management and Prevention: Online Appendix 2020. (2020) Available online at: www.ginasthma.org (accessed September 8, 2020). [Ref list]
• Allergic asthma – elevated IgE, FeNO elevated, Th2 response
• Non-allergic asthma – neutrophilic, (or eosinophils??), less ICS responsive
• Late-onset asthma – more common in women, symptoms start as adult. More often non-allergic
• Asthma with persistent flow limitation – longstanding asthma causes airway remodeling
• Asthma with obesity – little eosinophilic airway inflammation but still severe symptoms ### Slide 9
• Mechanisms
• From https://www.atsjournals.org/doi/full/10.1164/rccm.201810-1838TR
• Non-Th2 mediated inflammation mediates the features of disease in more than half of patients with persistent disease, and portends a poor response to corticosteroids. Higher risk higher sputum neutrophils
• 6 -Teodorescu M, Broytman O, Curran-Everett D, Sorkness RL, Crisafi G, Bleecker ER, et al.; National Institutes of Health, National Heart, Lung and Blood Institute Severe Asthma Research Program (SARP) Investigators. Obstructive sleep apnea risk, asthma burden, and lower airway inflammation in adults in the Severe Asthma Research Program (SARP) II. J Allergy Clin Immunol Pract 2015;3:566–575.e1.)
• higher IL-8 and MMP
• 18 - Taillé C, Rouvel-Tallec A, Stoica M, Danel C, Dehoux M, Marin-Esteban V, et al. Obstructive sleep apnoea modulates airway inflammation and remodelling in severe asthma. PLoS One 2016;11:e0150042.)
• “Once established, OSA, through its features, notably chronic intermittent hypoxia, has been shown to shift the airway inflammatory profile away from T-helper cell type 2 (Th2) pathways, which leads to lung remodeling and airway dysfunction, in a pattern that is less responsive to ICS therapy. Without addressing OSA, achieving asthma control would likely require a step-up in ICS dose and repeated steroid bursts, further raising the risk for or the severity of OSA with its consequences for asthma, accelerating this vicious cycle and translating into irreversible airway dysfunction.” ### Slide 10
• Taillé C, Rouvel-Tallec A, Stoica M, Danel C, Dehoux M, Marin-Esteban V, Pretolani M, Aubier M, d’Ortho MP. Obstructive sleep apnoea modulates airway inflammation and remodelling in severe asthma. PLoS One. 2016;11:e0150042. https://doi.org/10.1371/journal.pone.0150042.
• Overnight polygraphy performed on patients with severe asthma and nocturnal symptoms/apneas/fatigue. 27/55 had sleep apnea
• Collectected; PMNs higher in OSA than non-OSA patients. Increased IL-8 and MMP-9, lower IL-5. Bronchoscopy w TBBx done in 31 – RBM thickness (usually associated with eospinphilic inflammation and airway obstruction -?ICS responsiveness pattern) negatively correlated with AHI.
• Groups did not differ by age, sex, BMI, lung function, asthma ctrl, or asthma treatment.
• Hypopneas more common than Apneas on the sleep studies. ### Slide 11
• Other unreviewed articles
• Snoring - Longitudinal study of risk factors for habitual snoring in a general adult population: the Busselton Health Study.Knuiman M, James A, Divitini M, Bartholomew H. Chest. 2006 Dec; 130(6):1779-83. ### Slide 12
• 45. Teodorescu M, Barnet JH, Hagen EW, Palta M, Young TB, Peppard PE. Association between asthma and risk of developing obstructive sleep apneahttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334115/
• Asthma increases the risk of new incident- In an analysis of the Wisconsin Sleep Cohort where Wisconsin state employees underwent overnight polysomnography at 4 year intervals between 1988 and 2013,
• Asthma is associated with subsequent incidence of OSA (RR 1.39) and asthma was associated with subsequent incidence of OSAS (RR 2.72) ### Slide 13
• Teodorescu M, Broytman O, Curran-Everett D, Sorkness RL, Crisafi G, Bleecker ER, et al.; National Institutes of Health, National Heart, Lung and Blood Institute Severe Asthma Research Program (SARP) Investigators. Obstructive sleep apnea risk, asthma burden, and lower airway inflammation in adults in the Severe Asthma Research Program (SARP) II. J Allergy Clin Immunol Pract 2015;3:566–575.e1
• Methodology: n94 w severe asthma, n161 with nonsevere asthma, n146 normal controls (n125 with no methacholine responsiveness). All completed sleep quality, SA-SDQ and PSQI (measures sleep quality), and clinical assessments (not PSG/HSAT), and induced sputum in a subset
• Asthmatic of all severity had worse sleep; SA-SDQ (validated, self-administers, measures risk of OSA) correlated with worse symptoms, more PMNs neutrophilic airway inflammation.
• Severe asthma patients have poor sleep quality, excessive sleepiness, worse QoL
• SA-SDQ associated with: day symptoms, night symptoms, beta-agonist use, probably healthcare utilization, poor asthma qol, and count of PMNs in sputum in a dose dependent manor, independent of obesity, age, gender, and race. No association with Spirometric parameters.
• Note: independence of these findings from obesity suggests that it’s the OSA, not just obesity, that explains the link. ### Slide 14
• Asthma-OSA associated with daytime sleepiness, poor asthma control, and reduced quality of life: 110-114; 116 (economic burdens)
• 110 - Kim MY, Jo EJ, Kang SY, et al. Obstructive sleep apnea is associated with reduced quality of life in adult patients with asthma. Ann Allergy Asthma Immunol 2013; 110: 253–257.
• [x ] 114 Teodorescu M, Polomis DA, Hall SV, et al. Association of obstructive sleep apnea risk with asthma control in adults. Chest 2010; 138: 543–550.
• 116 Becerra MB, Becerra BJ, Teodorescu M. Healthcare burden of obstructive sleep apnea and obesity among asthma hospitalizations: results from the U.S.-based Nationwide Inpatient Sample. Respir Med 2016; 117: 230–236 ### Slide 15
• Becerra MB, Becerra BJ, Teodorescu M. Healthcare burden of obstructive sleep apnea and obesity among asthma hospitalizations: results from the U.S.-based Nationwide Inpatient Sample. Respir Med 2016; 117: 230–236
• https://pubmed.ncbi.nlm.nih.gov/27492536/
• Nationwide inpatient sample 2009-2011
• ICD code identification for primary hospitalization for asthma. N179,789; secondary diagnosis codes for OSA and obesity
• Outcome: length of stay, total charges
• Regression controlling for: hospital characteristics, age, sex, race, household income by ZIP, comorbidity index, and permutations of OSA and obesity.
• Found that while both obesity and OSA increase healthcare costs and length of stay associated with asthma exacerbations, OSA is a strong correlate and the presence of both is associated with a multiplicative increase in healthcare costs (+28.5% fem, 24.9% male) and LOS. (1.19 and 1.24 for males and females) ### Slide 16
• Kim MY, Jo EJ, Kang SY, et al. Obstructive sleep apnea is associated with reduced quality of life in adult patients with asthma. Ann Allergy Asthma Immunol 2013; 110: 253–257
• https://pubmed.ncbi.nlm.nih.gov/23535088/
• Asthma clinic in Seoul with persistent asthma and PFTs supporting the dx
• Completed OSA screening (Berlin), asthma control (ACT), asthma QOL questionarires
• High Risk vs Low risk for OSA groups compared; regression controlling for BMIk, smoking status, comorbidities?
• High risk OSA low QOL, same FENO and ACT
• Note: polysomnography not performed. Eh, not sure this is usable without it as data less robust supporting its predictive value. ### Slide 17
• Greenberg-Dotan S, Reuveni H, Tal A, Oksenberg A, Cohen A, Shaya FT, Tarasiuk A, Scharf SM. Increased prevalence of obstructive lung disease in patients with obstructive sleep apnea. Sleep Breath. 2014;18:69–75. https://doi.org/10.1007/s11325-013-0850-3.
• HMO in Israel
• Patients 40-89 with PSG (AHI>5), n1497; control group (n1497) randomly selected from HMO database – matched on age, gender, location, and PCP. Not matched on BMI
• Comorbidities assessed by diagnostic codes
• RR 2.2 for asthma (for OSA vs no OSA); COPD rate also elevated.
• Limitation: since BMI not matched, not clear if this is obesity or OSA mediating the relationship. ### Slide 18
• Asthma co-occurrence and severity
• “The prevalence of OSA in adult asthma patients is estimated at 50% in this meta-analysis and the odds of having OSA is 2.64 times higher in asthma patients than in the non-asthma patients.” https://www.nature.com/articles/s41598-017-04446-6
• Meta-analysis of 26 studies, n7675 patients
• Kong DL, Qin Z, Shen H, et al. Association of obstructive sleep apnea with asthma: a meta-analysis. Sci Rep 2017; 7: 4088.
• Overall, the risk of OSA appears to be approximately doubled in asthmatic populations and asthma severity, female gender, obesity, and gastroesophageal reflux (GER) are important positive moderators of this risk. (from https://doi.org/10.1016/j.smrv.2013.04.004)
• See table on next page ### Slide 19
• Shen TC, Lin CL, Wei CC, Chen CH, Tu CY, Hsia TC, et al. Risk of obstructive sleep apnea in adult patients with asthma: a population-based cohort study in Taiwan. PLoS One 2015;10:e0128461.
• Taiwanese health insurance data: 38840 newly diagnosed patients with Asthma 2000-2010; compared to 4 matched patients (gender, age, index year)
• Risk of incident OSA; cox proportional hazard model
• aHR 1.81 (23.8 in those visiting ER more than once per year)
• HR 1.33 for ICS treatment.
• Is this due to increased health contact? Also had higher comorbidities such as HTN, Rhinitis, GERD, Obesity. Adjustment for these only partially explained (2.5 ->1.8) ### Slide 20
• TODO: No text extracted from this slide. ### Slide 21
• The prevalence of sleep impairments and predictors of sleep quality among patients with asthma. Braido F, Baiardini I, Ferrando M, Scichilone N, Santus P, Petrone A, Di Marco F, Corsico AG, Zanforlin A, Milanese M, Steinhilber G, Bonavia M, Pirina P, Micheletto C, D’Amato M, Lacedonia D, Benassi F, Propati A, Ruggeri P, Tursi F, Bocchino ML, Patella V, Canonica GW, Blasi F J Asthma. 2021 Apr; 58(4):481-487.
• 30 centers in Italy; filled out PSQI (Pittsburgh Sleep Quality Index), ACT, T5SS (rhinitis symptoms), SA-SDQ, Gerd Impact Scale
• 1150 patients with asthma filled out questionaires
• No difference in sleep quality between w/ and w/o rhinitis, but Rhinasthma score was independently associated.
• Uncontrolled asthma (by ACT) -> 3.3 OR for poor sleep quality.
• Interestingly, SASDQ was not- seems to be a common thread that sleep is generally poor in asthma, but not exclusively because of OSA. ### Slide 22
• SA-SDQ in asthma?
• Original study: Douglass AB, Bornstein R, Nino-Murcia G, et al. The Sleep Disorders Questionnaire. I: Creation and multivariate structure of SDQ. Sleep 1994;17:160-7.
• Its eight symptom items asked about loud snoring disruptive to the bed partner, pauses in breathing during sleep, sudden gasping arousals from sleep, worsening of snoring while supine or after alcohol, nocturnal sweating and nasal congestion, and history of hypertension
• • thus, one would expect that it is specific to upper airway pathology – but is it? Additionally, it predicts OSAS, not OSA (can be good or bad)
• “This instrument has high diagnostic value in comparison to other sleep apnea screening instruments (45). Although the SA-SDQ has not been validated specifically in asthma patients, the scale does predict PSG-diagnosed OSA well in other samples (46, 47).
• Does not appear that this has been validated in asthma; concerning for the validity of the hRQOL studies; discuss in paper.. ### Slide 23
• Haven’t reviewed these:
• Other Epidemiologic links From https://www.atsjournals.org/doi/full/10.1164/rccm.201810-1838TR
• “worse daytime and nighttime asthma symptoms, bronchodilator use, FEV1 decline in time, increased exacerbations, and reduced quality of life have been documented in patients with asthma (6–8, 61–64),”
• 7.Teodorescu M, Polomis DA, Gangnon RE, Fedie JE, Consens FB, Chervin RD, et al. Asthma control and its relationship with obstructive sleep apnea (OSA) in older adults. Sleep Disord 2013;2013:251567.Crossref, Medline, Google Scholar
• 62.Teodorescu M, Polomis DA, Teodorescu MC, Gangnon RE, Peterson AG, Consens FB, et al. Association of obstructive sleep apnea risk or diagnosis with daytime asthma in adults. J Asthma 2012;49:620–628.Crossref, Medline, Google Scholar
• 63.Wang TY, Lo YL, Lin SM, Huang CD, Chung FT, Lin HC, et al. Obstructive sleep apnoea accelerates FEV1 decline in asthmatic patients. BMC Pulm Med 2017;17:55.Crossref, Medline, Google Scholar
• 64.Wang Y, Liu K, Hu K, Yang J, Li Z, Nie M, et al. Impact of obstructive sleep apnea on severe asthma exacerbations. Sleep Med 2016;26:1–5.Crossref, Medline, Google Scholar
• 60. Tay TR, Radhakrishna N, Hore-Lacy F, Smith C, Hoy R, Dabscheck E, et al. Comorbidities in difficult asthma are independent risk factors for frequent exacerbations, poor control and diminished quality of life. Respirology (Carlton, Vic) 2016;21:1384-90.
• From Randerath ERJ 2017 https://doi.org/10.1183/13993003.02616-2017
• 111 Luyster FS, Teodorescu M, Bleecker E, et al. Sleep quality and asthma control and quality of life in non-severe and severe asthma. Sleep Breath 2012; 16: 1129–1137.
• 113 Teodorescu M, Consens FB, Bria WF, et al. Correlates of daytime sleepiness in patients with asthma. Sleep Med 2006; 7: 607–613.
• Julien, J. Y. et al. Prevalence of obstructive sleep apnea-hypopnea in severe versus moderate asthma. J Allergy Clin Immunol. 124, 371–6 (2009). ### Slide 24
• Yii ACA, Tan JHY, Lapperre TS, Chan AKW, Low SY, Ong TH, et al. Longterm future risk of severe exacerbations: distinct 5-year trajectories of problematic asthma. Allergy 2017;72:1398-405.
• Singapore Gen Hosp (2011, derivation) (2012-3, validation), generated a scoring system to predict long term risk of exacerbations.
• Used univariate based method to select scores
• A clinical risk score composed of ≥2 severe exacerbations in the past year (+2 points), history of near‐fatal asthma (+1 point), body mass index ≥25kg/m2 (+1 point), obstructive sleep apnea (+1 point), gastroesophageal reflux (+1 point), and depression (+1 point)
• area under the receiver operating characteristic curve: 0.84, sensitivity 72.2%, specificity 81.1% using cutoff ≥3 points for persistent frequent ### Slide 25
• https://doi.org/10.1016/j.jaci.2009.05.016Prevalence of obstructive sleep apnea–hypopnea in severe versus moderate asthma
• Is prevalence and severity of OSA higher in more severe asthma?
• Nonsmokers, controls recruited through community advertisements
• PSG on n26 with severe asthma; 26 with mod asthma, and 26 with controls (matched BMI)
• Presence of OSA: 50% (severe), 23% (moderate), 12% (controls) using Wisconsin criteria
• Dose response seen in: Sleep efficiency, no of awakenings, no. of arousals, AHI.
• No correlations seen between OSA severity and measures of asthma severity (FEV1, QOL scores) ### Slide 26
• Asthma-Obesity-Rhinitis-GERD: confounds direct effects assessment.
• https://doi.org/10.1016/j.jaip.2021.09.003
• Obesity -> Asthma (weight gain precedes increased asthma incidence) ### Slide 27
• Risk factors of frequent exacerbations in difficult-to-treat asthma. Ten Brinke A, Sterk PJ, Masclee AA, Spinhoven P, Schmidt JT, Zwinderman AH, Rabe KF, Bel EHhttps://erj.ersjournals.com/content/26/5/812
• Leiden Med Center; consecutively recruited from outpatient clinic at 10 regions in western Netherlands. Included if 3+ exacerbations per year (n39) compared to 1 exacerbation per year (n24).
• ENT+sinus assessment for nasal disease, 24h pH probe, spiro. OSA assess by either prior PSG (not routine testing) or report of apneas.
• Univariate (corr for age, asthma duration): Severe sinus disease (OR 3.7); GERD (OR 4.9); Psychological dysfunction (OR 10.8); recurrent respiratory infections (OR 6.9); OSA (OR 3.4)
• Multivariate: Only sinus disease and psychological dysfunction (OR 5.5 and 11.7) were independently associated.
• • this is probably underpowered, given small event count and several independent predictors. Take w grain of salt. ### Slide 28
• 55. Dixon AE, Clerisme-Beaty EM, Sugar EA, Cohen RI, Lang JE, Brown ED,et al. Effects of obstructive sleep apnea and gastroesophageal reflux disease onasthma control in obesity. J Asthma 2011;48:707-13.
• Inadequately control moderate to severe Asthma patients
• All received trial of reflux treatment; sleep testing
• Reflux -> worse with higher BMI; very common
• pH was similar between the groups w obesity and OSA vs not
• reflux. Symptoms and diagnosis of OSA were more common in the obese and associated with worse asthma control. ### Slide 29
• Lim KG, Morgenthaler TI, Katzka DA. Sleep and nocturnal gastroesophagealreflux: an update. Chest 2018;154:963-71.
• Controversey about whether OSA and nocturnal reflux are causally linked or merely share risk factors.
• Though GERD improves with CPAP treatment – whether or not OSA is present.
• Ing AJ, Ngu MC, Breslin AB. Obstructive sleep apnea and gastroesophageal reflux. Am J Med. 2000;108(suppl 4a):120S-125S. ### Slide 30
• Teodorescu M, Polomis DA, Hall SV, et al. Association of obstructive sleep apnea risk with asthma control in adults. Chest 2010; 138: 543–550.
• University of Wisc 2007-2009l clinics; mostly white
• ACQ ctrl questionair, SA-SDQ (OSA risk - validated Douglass et al. below), chart review for comorbidities. Logistic regressions for not-well controlled asthma by ACT.
• In multivariable models, High OSA risk (OR 2.87), GERD (3.0), Nasal Polyps (2.37) and Psychiatric disease (1.79) independently associated.
• Strength: shows independent of other conditions (direct effect)
• Limitation: Again, ”OSA-risk” as a stand in for OSA presence seems dubious, as reverse causation (poor asthma causing some of those symptoms) may explain. ### Slide 31
• Gastroesophageal reflux - OSA
• Associated even when controlling for alcohol intake and BMI - Ing AJ, Ngu MC, Breslin ABO bstructive sleep apnea and gastroesophageal reflux Am J Med2000108Suppl 4a120S5S, 10718464
• Likely due to subatmospheric pressure generated during mueller maneuvers, which favor GERD – although other possible mechanisms exist (Urata M, Fukuno H, Nomura M, et al. Gastric motility and autonomic activity during obstructive sleep apnea Aliment Pharmacol Ther200624Suppl 413240)
• Acid instillation to esophagus -> increased bronchial reactivity Schan CA, Harding SM, Haile JM, et al.Gastroesophageal reflux-induced bronchoconstriction. An intraesophageal acid infusion study using state-of-the-art technology Chest 1994 1067317, 8082350
• Also – micro-aspiration Jack CI, Calverley PM, Donnelly RJ, et al.Simultaneous tracheal and oesophageal pH measurements in asthmatic patients with gastro-oesophageal reflux Thorax 1995 502014, 7701464
• And
• Any direct interventional data to support the connection of CPAP->GERD control->Asthma improvements?
• K.L. Shepherd, A.L. James, A.W. Musk, M.L. Hunter, D.R. Hillman, P.R. Eastwood Gastro-oesophageal reflux symptoms are related to the presence and severity of obstructive sleep apnoea J Sleep Res, 20 (2011), pp. 241-249
• A. Panoutsopoulos, A. Kallianos, K. Kostopoulos, C. Seretis, E. Koufogiorga, A. Protogerou, et al. Effect of CPAP treatment on endothelial function and plasma CRP levels in patients with sleep apnea Med Sci Monit, 18 (2012), pp. CR747-CR751
• M. Petrosyan, E. Perraki, D. Simoes, I. Koutsourelakis, E. Vagiakis, C. Roussos, et al. Exhaled breath markers in patients with obstructive sleep apnoea Sleep Breath, 12 (2008), pp. 207-215
• A.M. Fortuna, R. Miralda, N. Calaf, M. Gonzalez, P. Casan, M. Mayos Airway and alveolar nitric oxide measurements in obstructive sleep apnea syndrome Respir Med, 105 (2011), pp. 630-636 ### Slide 32
• 118. Tawk M, Goodrich S, Kinasewitz G, Orr W. The effect of 1 week ofcontinuous positive airway pressure treatment in obstructive sleep apnea
• 16 p atients, with GERD and OSA.
• Before-after with treatment initiation with OSA
• Improvement in acid contact time. ### Slide 33
• 69. Emilsson ÖI, Bengtsson A, Franklin KA, Torén K, Benediktsdóttir B, Farkhooye A, et al. . Nocturnal gastro-oesophageal reflux, asthma and symptoms of OSA: a longitudinal, general population study. Eur Respirat J. (2013) 41:1347–54. 10.1183/09031936.00052512
• 2640 Nordic countries
• Nocturnal reflux independently increased the risk of new asthma diagnosis.
• Nocturnal reflux ALSO independently increased the risk of OSA – thus not clear that the causal arrow all goes in the OSA -> GERD directions.
• Assessment biases? ### Slide 34
• 64. Orr WC, Elsenbruch S, Harnish MJ, Johnson LF. Proximal migration of esophageal acid perfusions during waking and sleep. Am J Gastroenterol. (2000) 95:37–42. 10.1111/j.1572-0241.2000.01669.x ### Slide 35
• Current opinions for the management of asthma associated with ear, nose and throat comorbiditiesEuropean Respiratory Review 2018 27: 180056; DOI: 10.1183/16000617.0056-2018
• Paradigm: Unified airways (upper and lower); differentiating shared exposure from either postnasal drip or systemic influence.
• [ summarize info below] ### Slide 36
• Tay TR, Hew M. Comorbid “treatable traits” in difficult asthma: current evidence and clinical evaluation. Allergy2018; 73: 1369–1382.
• Contains prevalence estimates for asthma+ ### Slide 37
• Asthma outcomes improve with continuous positive airway pressure for obstructive sleep apnea.Serrano-Pariente J, Plaza V, Soriano JB, Mayos M, López-Viña A, Picado C, Vigil L, CPASMA Trial Group.Allergy. 2017 May; 72(5):802-812.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412857/
• Before-after (3-6 months) of 90 patients with asthma and newly diagnosed OSAS (mod-severe) who were starting CPAP treatment
• Asthma control improved in 38.4% and worsened in 7.1%, mean change less than MCID., though given no control group it is not clear how much of this represents regression to the mean. Similar with decrease in exacerbations.
• “A prospective trial by Serrano-Pariente et al. has shown that the proportion of adult asthmatic patients suffering from uncontrolled asthma decreased from 41.4 to 17.2% in response to C-PAP therapy. Likewise, the percentage of patients experiencing asthma attacks during the course of 6 months decreased from 35.4 to 17.2% following C-PAP treatment” ### Slide 38
• 17. Lafond C, Series F, Lemiere C. Impact of CPAP on asthmatic patients with obstructive sleep apnoea. Eur Respir J 2007;29:307-11.
• Before after 3 months
• 20 subjects – no change in bronchial responsiveness or spirometry.
• Improves qol - again, limited by no control group. ### Slide 39
• 15. Ciftci TU, Ciftci B, Guven SF, Kokturk O, Turktas H. Effect of nasal continuous positive airway pressure in uncontrolled nocturnal asthmatic patients with obstructive sleep apnea syndrome. Respir Med 2005;99:529-34.
• Before and after (2 months)
• Refractory GER despite PPI, asthma, and snoring assessed for OSA
• Started CPAP
• Improves nocturnal symptoms, no change to PFTs.
• No control group. ### Slide 40
• 7.Teodorescu M, Polomis DA, Gangnon RE, Fedie JE, Consens FB, Chervin RD, et al. Asthma control and its relationship with obstructive sleep apnea (OSA) in older adults. Sleep Disord 2013;2013:251567
• “Conversely, continuous positive airway pressure (CPAP) for OSA attenuated risk for worse asthma outcomes and FEV1 decline (7, 62, 64) in older subjects much more than in younger ones (7). “
• Cross section ### Slide 41
• Dissenting studies?
• “It is still uncertain whether treatment of OSA with continuous positive airway pressure (CPAP) might improve asthma control or pulmonary function. Some studies reported positive results [146,147,148] while other studies were negative [149, 150]. One study reported a decreased rate of FEV1 decline in asthmatic patients treated with CPAP [136], but the majority of studies agree on unchanged pulmonary function after CPAP. A recent systematic review pointed out that results of different studies do not allow to document a definite improvement in asthma control, although a positive effect of CPAP treatment seems to occur in patients with severe OSA or poorly controlled asthma [151].”
• review the meta-analysis for the article ### Slide 42
• https://www.resmedjournal.com/article/S0954-6111(18)30261-0/fulltext151 Davies SE, Bishopp A, Wharton S, Turner AM, Mansur AH. Does Continuous Positive Airway Pressure (CPAP) treatment of obstructive sleep apnoea (OSA) improve asthma-related clinical outcomes in patients with co-existing conditions? A systematic review. Respir Med. 2018;143:18–30. ### Slide 43
• OSA treatment
• https://doi.org/10.1016/j.jaip.2021.09.003
• CPAP treatment in patients with OSA and asthma increases asthma QoL
• Observational data suggests in decreases daytime symptoms and increases disease control, but this has not been shown in experimental studies.
• Development of incident asthma? ### Slide 44
• Ng SSS, Chan TO, To KW, Chan KKP, Ngai J, Yip WH, et al. Continuous positive airway pressure for obstructive sleep apnoea does not improve asthma control. Respirology (Carlton, Vic) 2018;23:1055-62
• RCT of severe asthma, assess for OSA. If found, randomize to CPAP vs observation. – no effect on ACT scores at 3 months.
• 101 patients. Hong Kong Prince of Wales Hospital.
• https://clinicaltrials.gov/ct2/show/NCT01383564 ### Slide 45
• Treatment w CPAP
• allegedly shows reduced asthma symptoms, BD use, and improved FEV1 with CPAP: 40. Deslypere G, Dupont L. Principal comorbidities in severe asthma: how to manage and what is their influence on asthma endpoints. EC Pulmonol Respirat Med. (2017) 3:162–174. ### Slide 46
• From https://www.atsjournals.org/doi/full/10.1164/rccm.201810-1838TR
• review these – I’m skeptical.
• From Table 3: ”In quasi-experimental designs, CPAP improved daytime and nighttime symptoms, rescue bronchodilator use, exacerbations, quality of life, and a.m. and p.m. peak inspiratory flow rates (66–69). In addition, some of these effects occurred in a dose-dependent fashion, with the largest improvements in asthma control and asthma-related quality of life noted in patients with moderate–severe persistent asthma or severe OSA diagnosed by respiratory polygraphy (respiratory disturbance index > 30) (69).”
• 69 – reduced proportion of patients with bronchodilator response; no change in FEV1 “A report by Serrano-Pariente and colleagues provides some insights into these relationships (69). A 6-month CPAP treatment for OSA did not impact BMI but it significantly reduced the proportion of subjects who reported nasal symptoms, heartburn, and regurgitation.”
• 68 – no change in methacholine challenge sensitivity.
• 66.Chan CS, Woolcock AJ, Sullivan CE. Nocturnal asthma: role of snoring and obstructive sleep apnea. Am Rev Respir Dis 1988;137:1502–1504.Abstract, Medline, Google Scholar
• 67.Guilleminault C, Quera-Salva MA, Powell N, Riley R, Romaker A, Partinen M, et al. Nocturnal asthma: snoring, small pharynx and nasal CPAP. Eur Respir J 1988;1:902–907.Medline, Google Scholar
• 68.Lafond C, Sériès F, Lemière C. Impact of CPAP on asthmatic patients with obstructive sleep apnoea. Eur Respir J 2007;29:307–311.Crossref, Medline, Google Scholar
• 69.Serrano-Pariente J, Plaza V, Soriano JB, Mayos M, López-Viña A, Picado C, et al.; CPASMA Trial Group. Asthma outcomes improve with continuous positive airway pressure for obstructive sleep apnea. Allergy 2017;72:802–812.Crossref, Medline, Google Scholar ### Slide 47
• Obstructive sleep apnea syndrome and asthma: what are the links?Alkhalil M, Schulman E, Getsy J. J Clin Sleep Med. 2009 Feb 15; 5(1):71-8.
• Allegedly, supports that OSAS treatment improves symptoms, peak flow values, and QoL? ### Slide 48
• Untreated OSA and Asthma: Individual Effects
• Kauppi, P., Bachour, P., Maasilta, P., & Bachour, A. (2016). Long-term CPAP treatment improves asthma control in patients with asthma and obstructive sleep apnoea. Sleep Breath, 20, 1217–1224.
• Wang, T. Y., Lo, Y. L., Lin, S. M., Huang, C. D., Chung, F. T., Lin, H. C., … Kuo, H. P. (2017). Obstructive sleep apnoea accelerates FEV1 decline in asthmatic patients. BMC Pulmonary Medicine, 17, 55.

230.3 Learning objectives

• OSA Asthma Literature Review
• Direct methods influencing reactivity – possible?
• Morrison JF, Pearson SB, Dean HG Parasympathetic nervous system in nocturnal asthma BMJ 1988 29614279https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2545890/
• Desjardin JA, Sutarik JM, Suh , BY , et al. Influence of sleep on pulmonary capillary volume in normal and asthmatic subjects Am J Respir Crit Care Med 1995 1521938, 7599823https://pubmed.ncbi.nlm.nih.gov/7599823/
• Ahmed T, Marchette B Hypoxia enhances nonspecific bronchial reactivity Am Rev Respir Dis 198513283944, 3931524https://pubmed.ncbi.nlm.nih.gov/3931524/

230.4 Bottom line / summary

• OSA Asthma Literature Review
• Direct methods influencing reactivity – possible?
• Morrison JF, Pearson SB, Dean HG Parasympathetic nervous system in nocturnal asthma BMJ 1988 29614279https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2545890/
• Desjardin JA, Sutarik JM, Suh , BY , et al. Influence of sleep on pulmonary capillary volume in normal and asthmatic subjects Am J Respir Crit Care Med 1995 1521938, 7599823https://pubmed.ncbi.nlm.nih.gov/7599823/
• Ahmed T, Marchette B Hypoxia enhances nonspecific bronchial reactivity Am Rev Respir Dis 198513283944, 3931524https://pubmed.ncbi.nlm.nih.gov/3931524/

230.5 Approach

1. TODO: Outline the initial assessment or decision point.
2. TODO: Outline the next diagnostic or management step.
3. TODO: Outline follow-up or escalation criteria.

230.6 Red flags / when to escalate

• TODO: List red flags that require urgent escalation.

230.7 Common pitfalls

• TODO: Capture common errors or missed steps.

230.8 References

TODO: Add landmark references or guideline citations.

230.9 Slides and assets

• Presentations/OSA Asthma Lit Review.pptx

230.10 Source materials

• Presentations/OSA Asthma Lit Review.pptx