Draft

234  Overlap Syndrome Evidence Review

234.1 Summary

  • Overlap syndrome (OSA-COPD) evidence review
  • 123: Malhotra A, Schwartz AR, Schneider H, et al. Research priorities in pathophysiology for sleep-disordered breathing in patients with chronic obstructive pulmonary disease. An official American Thoracic Society research statement. Am J Respir Crit Care Med 2018; 197: 289–299.
  • Adler D, Bailly S, Benmerad M, Joyeux-Faure M, Jullian-Desayes I, Soccal PM, et al. (2020) Clinical presentation and comorbidities of obstructive sleep apnea-COPD overlap syndrome. PLoS ONE 15(7): e0235331. https://doi.org/10.1371/journal.pone.0235331https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347183/pdf/pone.0235331.pdf
  • Pathogenesis of obstructive sleep apnea in individuals with the COPD + OSA Overlap syndrome versus OSA alonePhysiological Reports. 2020;8:e14371. https://doi.org/10.14814/phy2.14371
  • Non-apnea related hypoventilation in COPD[ ] retool this one – frame this as additive to the deleterious consequences of hypoxemia/hypercapnia. Ie – what are the consequences
  • Weitzenblum E, Chaouat A, Kessler R, Canuet M: Overlap syndrome.Obstructive sleep apnea in patients with chronic obstructive pulmonarydisease. Proc Am Thorac Soc 2008, 5:237–241.
  • Resta O, Foschino Barbaro MP, Brindicci C, Nocerino MC, Caratozzolo G, Carbonara M. Hypercapnia in overlap syndrome: possible determinant factors. Sleep Breath 2002;6:11–18https://pubmed.ncbi.nlm.nih.gov/11917259/
  • https://doi.org/10.1016/j.smrv.2016.10.004Diagnostic accuracy of the Berlin questionnaire, STOP-BANG, STOP, and Epworth sleepiness scale in detecting obstructive sleep apnea: A bivariate meta-analysis
  • Overlap syndrome epidemiology
  • Untreated OSA and COPD: societal effects
  • Increased risk of pulmonary hypertension cor pulmonale
  • OVS vs OHS

234.2 Slide outline

234.2.1 Slide 1

  • Overlap syndrome (OSA-COPD) evidence review ### Slide 2
  • 123: Malhotra A, Schwartz AR, Schneider H, et al. Research priorities in pathophysiology for sleep-disordered breathing in patients with chronic obstructive pulmonary disease. An official American Thoracic Society research statement. Am J Respir Crit Care Med 2018; 197: 289–299.
  • ”Overlap syndrome” – where does this term come from?
  • No definitive evidence of increased incidence beyond what is expected by two common conditions. (26, 27) – most evidence only pertains to mild COPD though
  • Both conditions are increasing – right? – due to aging population, historical smoking trends, obesity
  • However, the traditional definition of OSA (based on AHI) may not adequately capture the disordered breathing in COPD, particularly as increased upper airways resistance, hypoventilation, (+/- REM hypoxemia) and sleep fragmentation may occur independent of hypopneas and apneas. [citation 20]
  • This disorder sleep, in turn, can worsen daytime HRQOL – increased time in bed, more naps
  • Pathophysiology: smoking, rostral fluid shift, upper airway muscle weakness, inhaled corticosteroids.
  • Loss of drive to breath -> increased airflow resistance, decreased load compensation > hypoventilation. While not causing apnea, this may lead to systemic effects where similarly severe OSA (by AHI) would not -> thus, the COPD ‘enables’ deleterious effects of OSA (normal gas exchange can occur in healthy individuals, but can’t in COPD due to unmasking of some of the ways that the body compensates
  • Emphysema: protective due to traction that occurs with dynamic hyperinflation. ### Slide 3
  • Adler D, Bailly S, Benmerad M, Joyeux-Faure M, Jullian-Desayes I, Soccal PM, et al. (2020) Clinical presentation and comorbidities of obstructive sleep apnea-COPD overlap syndrome. PLoS ONE 15(7): e0235331. https://doi.org/10.1371/journal.pone.0235331https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347183/pdf/pone.0235331.pdf
  • OVS: less snoring, morning headaches, and EDS including sleepiness while driving.
  • More common nocturia.
  • OVS has more comorbidities (HLD, HTN, Stroke, CAD/MI, PVD, CHF) – largely mediated by increased smoking.
  • Leads to more profound hypoxemia, higher Risk of pHTN and right heart failure.
  • Description of pathophysiology:
  • However: Overlap syndrome is actually a mix of separate pathophysiology: OSA, CSA, worsening airflow obstruction, hypoventilation, oxygen desaturation, and sleep fragmentation. - often a conflation of SDB and ‘OSA’, though there are some shared pathophysiologic constraints.
  • NREM: increased upper airway resistance, impaired load compensation, blunted chemosensitivity
  • REM: propensity for upper airway collapse and hypovenlation related to skeletal muscle atonia (loss of rib cage intercostal muscle contribution to ventilation.
  • Likely have different manifestations in COPD vs OSA. ### Slide 4
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  • Pathogenesis of obstructive sleep apnea in individuals with the COPD + OSA Overlap syndrome versus OSA alonePhysiological Reports. 2020;8:e14371. https://doi.org/10.14814/phy2.14371
  • OSA pathogenicity:
  • Anatomic factors: upper airway collapsibility (may stiffen when lung is hyper-inflated, but emphysema loss of elastic recoil may lessen this – hard to know a priori)
  • Neurologic / Physiologic factors: upper airway muscle response (worsened by ICS? Smoking?), respiratory-related arousability from sleep (may be lower in OVS due to frequent awakenings in the absence of upper airway collapse), control of breathing (respiratory drive generally increased)
  • Matched OSA (n15) to OVS (n15; most with moderate obstruction) on gender, age, BMI. Exclude: narcotics, sedatives, supp O2, recent exacerbation, BMI over 36, active smoking, heavy EtOH
  • PSG to determine Veupnea, Vpassive and Pcrit, Varousal/ArTh, Loop gain
  • “Consistent differences in key OSA traits were not observed between OVS and OSA alone.”. OVS: lower sleep efficiency, REM SpO2
  • Reduced upper airway response in those with air trapping; increased loop gain in those with worse airflow obstruction (contrary to expection; perhaps mediated by hypoxemia?). Somewhat lower arousal threshold – perhaps explains how hypercapnia can occur?
  • No difference in collapsibility: perhaps this is selection – if you have to have dx of OSA, then by definition the airway must be collapsable ### Slide 10
  • Non-apnea related hypoventilation in COPD[ ] retool this one – frame this as additive to the deleterious consequences of hypoxemia/hypercapnia. Ie – what are the consequences
  • Sleep disordered breathing in COPD has many non-apnea components – for examples ~30% decreased in Ve during REM sleep may be enough to significantly increase PaCO2, even after have left REM
  • Because patients with COPD have increased physiological dead space, the rapid shallow breathing that normally accompanies bursts of eye movements in REM sleep produces an even greater decrease in alveolar ventilation than in healthy subject. This can account for virtually all the hypoxaemia observed in REM sleep in patients with COPD.54
  • Significant hypoventilation during sleep is common in advanced COPD and was reported in 43% of 54 subjects with advanced COPD by O’Donoghue et al. 56
  • Compensatory renal retention of bicarbonate may then lead to impairment of ventilatory control and maintenance of daytime hypercapnia 55.
  • COPD - non-OSA sleep disordered breathing prevalence? (e.g. CSA, hypoventilation, sleep fragmentation). Overlap syndrome is actually a mix of separate pathophysiology: OSA, CSA, worsening airflow obstruction, hypoventilation, oxygen desaturation, and sleep fragmentation.
  • Circadian variation in spirometry – FEV1 and FVC change 30%, more than in healthy individuals (37-39) – also, REM hypoventilation is increased compared to normal subjects (?due to skeletal muscle weakness and changes in control center?) – resulting in hypoxemia and hypercapnia (30-34)
  • thus, there are non-OSA components to the OVS that obstructions may have additive effects on. ### Slide 11
  • Weitzenblum E, Chaouat A, Kessler R, Canuet M: Overlap syndrome.Obstructive sleep apnea in patients with chronic obstructive pulmonarydisease. Proc Am Thorac Soc 2008, 5:237–241.
  • [x]Overlap syndrome: Coined by David Flenley to refer to the cooccurance of OSA and any chronic respiratory disease (Flenley DC. Sleep in chronic obstructive lung disease. Clin Chest Med 1985;6:51–61.) but has since come to refer to COPD-OSA.
  • Most other info from this source has ben superseded. ### Slide 12
  • Resta O, Foschino Barbaro MP, Brindicci C, Nocerino MC, Caratozzolo G, Carbonara M. Hypercapnia in overlap syndrome: possible determinant factors. Sleep Breath 2002;6:11–18https://pubmed.ncbi.nlm.nih.gov/11917259/
  • Overlap patients vs OSA patients: higher PaCO2 (44.59 vs. 39.22 mm Hg; p < 0.01), similar AHI (40.46 vs. 41.59/h).
  • Overlap patients vs COPD patients: higher PaCO2 value (44.59 vs. 39.63 mm Hg; p < 0.005), less severe obstructive impairment (FEV 162.93 vs. 47.31%; FEV1 /FVC ratio 66.71 vs. 59.25%; p < 0.005)
  • Confounder: Obesity -> OSA; while severe COPD -> cachexia (another feature, in addition to tracheal traction, that may be protective); smoking may be a risk factor for poor control of OSA.
  • Obesity in COPD outside of OSA?
  • Smoking and OSA? [citation 33]
  • “In the Wisconsin Sleep Cohort Study it was found that an AHI of at least 5/hour was three times more likely in current smokers than in never-smokers. Heavy smokers (≥40 cigarettes/d) had an OR of 6.74 for AHI of at least 5/hour” [32]. ### Slide 13
  • https://doi.org/10.1016/j.smrv.2016.10.004Diagnostic accuracy of the Berlin questionnaire, STOP-BANG, STOP, and Epworth sleepiness scale in detecting obstructive sleep apnea: A bivariate meta-analysis ### Slide 14
  • Overlap syndrome epidemiology
  • Key source: CHEST 2017; 152(6):1318-1326
  • Frequency: Thus based on established prevalence figures, both disorders should coexist in about 1% of the adult general population, with even higher figures likely depending on the definitions used for diagnosis. Phenotypically, emphysema seems protective while chronic bronchitis predisposing. Overall, the relationship has been unclear whether COPD predisposes to OSA or vice versa.
  • When OSA present, associated with deeper desaturations than non-COPD matched controls – associated with increased risk of cor pulmonale. The oxygen desaturation index provides a measure of intermittent hypoxemia, which is particularly important in the generation of systemic inflammation,52 and appears to be superior to the AHI in predicting cardiovascular comorbidity ### Slide 15
  • Untreated OSA and COPD: societal effects
  • OSA and COPD exist in roughly the expected overlapping proportion if they were independent
  • Connaughton JJ, Catterall JR, Elton RA, Stradling JR, Douglas NJ. Do sleep studies contribute to the management of patients with severe chronic obstructive pulmonary disease? Am. Rev. Respir. Dis. 1988; 138: 341–344.
  • Sanders MH, Newman AB, Haggerty CL, Redline S, Lebowitz M, Samet J, O’Connor GT, Punjiba NM, Shahar E, Sleep Heart Health Study. Sleep and sleep-disordered breathing in adults with predominantly mild obstructive airway disease. Am. J. Respir. Crit. Care Med. 2003; 167: 7–14.
  • However, patients who have OSA+COPD develop hypercapnia, pulmonary hypertension, and cor pulmonale more often than patients with COPD only (OSA is an effect modifier?)
  • Bradley TD, Rutherford R, Grossman RF, Lue F, Zamel N, Moldofsky H, Phillipson EA. Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome. Am. Rev. Respir. Dis. 1985; 131: 835–839. ### Slide 16
  • Increased risk of pulmonary hypertension cor pulmonale
  • Intermittent hypoxemia -> pulmonary vascular resistance increase -> increased RV afterload -> more RV hypertrophy than severity matched COPD alone
  • Sharma B, Neilan TG, Kwong RY, Mandry D, Owens RL, McSharry D, et al. Evaluation of right ventricular remodeling using cardiac magnetic resonance imaging in co-existent chronic obstructive pulmonary disease and obstructive sleep apnea. COPD 2013;10 4–10.
  • Additionally, OVS patients develop daytime hypercapnia at a lower BMI and AHI than patients with OSA alone (as well as increased nocturnal hypoxemia compared to COPD alone) -> more frequent pulmonary hypertension than either
    1. Sajkov D, Wang T, Saunders NA, Bune AJ, Neill AM, Douglas Mcevoy R. Daytime pulmonary hemodynamics in patients with obstructive sleep apnea without lung disease. Am J Respir Crit Care Med 1999;159: 1518–1526
  • Only associative? [ ] review these ### Slide 17
  • OVS vs OHS
  • https://link.springer.com/content/pdf/10.1186/1465-9921-14-132.pdf
  • ““
  • In subjects with chronic hypercapnia, there is an increased blood bicarbonate concentration, which may inhibit the ventilatory response to CO2 and decreases mouth occlusion pressure response during wakefulness and sleep [50]. When normocapnic, overlap patients can however have a normal or even enhanced ventilatory response to CO2 [51]. This is in contrast to the data on decreased hypercapnic (HCVR) and hypoxic (HVR) ventilatory response in OHS, as compared to obese, non-hypercapnic subjects [52].“
  • 23 Bradley TD, Rutherford A, Lue F, Moldofsky H, Grossmann RF, Zamel N, Phillipson EA: Role of diffuse airway obstruction in the hypercapnia of obstructive apnea. Am Rev Respir Dis 1986, 134:920–924.
  • 50 Radwan L, Maszczyk Z, Koziorowski A, Koziej M, Cieslicki J, Sliwinski P, Zielinski J: Control of breathing in obstructive sleep apnoea and in patients with the overlap syndrome. Eur Respir J 1995, 8:542–545
  • 51 Verbraecken J, De Backer W, Willemen M, De Cock W, Wittesaele W, Van de Heyning P: Chronic CO2 drive in patients with obstructive sleep apnea and effect of CPAP. Respir Physiol 1995, 101:279–287.
  • 52 Zwillich CW, Sutton FD, Pierson DJ, Greagh EM, Weil JV: Decreased hypoxic ventilatory drive in the obesity hypoventilation syndrome. Am J Med 1975, 59:343–348. ### Slide 18
  • COPD-OSA - impacts
  • Consequences: more nocturnal hypoxemia, more oxidative stress and inflammation (citation?), increased risk of exacerbations, increased risk of death
  • Compared to OSA? Or Compared to COPD?
  • In particular: increased risk of readmission after respiratory failure [124] that may be improved by CPAP [125]
  • 124 Adler D, Pepin JL, Dupuis-Lozeron E, et al. Comorbidities and subgroups of patients surviving severe acute hypercapnic respiratory failure in the intensive care unit. Am J Respir Crit Care Med 2017; 196: 200–207.
  • 125 Marin JM, Soriano JB, Carrizo SJ, et al. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med 2010; 182: 325–331
  • Have worse nocturnal oxygen desaturation than either disease alone [ citation 3 - https://pubmed.ncbi.nlm.nih.gov/12502472/]
  • More exacerbations and higher motality than COPD alone [ citations 2 - https://pubmed.ncbi.nlm.nih.gov/28169105/, 6 - https://pubmed.ncbi.nlm.nih.gov/19484281/ elevated economic burden,7 - https://pubmed.ncbi.nlm.nih.gov/20378728/] ### Slide 19
  • OSA+COPD profound nocturnal hypoxemia -> higher risk of pulmonary hypertension and cor pulmonale: Citations 13-16
  • [ ]15. McNicholas WT. COPD-OSA Overlap Syndrome: Evolving Evidence Regarding Epidemiology, Clinical Consequences, and Management. Chest. 2017; 152(6):1318–26. https://doi.org/10.1016/j.chest.2017. 04.160 PMID: 28442310
  • [x ] 16. McNicholas WT. Does Associated Chronic Obstructive Pulmonary Disease Increase Morbidity and Mortality in Obstructive Sleep Apnea?: American Thoracic Society; 2019 ### Slide 20
  • Krachman SL, Tiwari R, Vega ME, Yu D, Soler X, Jaffe F, et al.; COPDGene Investigators. Effect of emphysema severity on the apnea-hypopnea index in smokers with obstructive sleep apnea. Ann Am Thorac Soc 2016;13:1129–1135
  • Goal: influence of lung inflation on AHI
  • N51 smokers from COPDGene who had been referred for suspected OSA; quantified for emphysema and gas trapping on CT
  • Inverse correlation between AHI and percent emphysema and CT-derived gas trapping
  • Critique: influence of selection bias introduced by the referral? ### Slide 21
  • Kendzerska T, Leung RS, Aaron SD, Ayas N, Sandoz JS, Gershon AS; Canadian Respiratory Research Network. Cardiovascular outcomes and all-cause mortality in patients with obstructive sleep apnea and chronic obstructive pulmonary disease (overlap syndrome). Ann Am Thorac Soc 2019;16:71–81.
  • Academic hosp in Toronto – EMR linked to provincial services administrative data. Demographic variables and PSG available but not PFTs.
  • To what degree are AHI and Nocturnal hypoxemia influence (hospitalization for MI, stroke, CHF) (cardiovascular resvascularization) (mortality)
  • Physician diagnosed COPD considered as effect modifier (though no spiro – thus no severity info and probable high rate of misclassification)
  • In adjusted model (taking comorbidities into consideration), no added CV risk for those with OSA on top of COPD
  • editorial – “The growing number of reports on this topic provide evidence of increased cardiovascular morbidity and mortality in patients with OSA-COPD overlap when compared with either disorder alone, and furthermore point to hypoxemia as the most important pathophysiological factor in this relationship.” ### Slide 22
  • Putcha N, Crainiceanu C, Norato G, Samet J, Quan SF, Gottlieb DJ, et al. Influence of lung function and sleep-disordered breathing on all-cause mortality. a community-based study. Am J Respir Crit Care Med 2016;194:1007–1014.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067819/
  • Sleep heart health study; participants had spirometry, HSAT recorded. Death from any cause primary end-point.
  • Multivariable model (proportional hazards); comorbidities, smoking status taking as covariates.
  • 6163 patients.
  • No excess mortality attributable to AHI and FEV1 beyond the individual deleterious effects (in fact, relatively protective). ### Slide 23
  • Adler D, Bailly S, Benmerad M, Joyeux-Faure M, Jullian-Desayes I, Soccal PM, et al. (2020) Clinical presentation and comorbidities of obstructive sleep apnea-COPD overlap syndrome.PLoS ONE 15(7): e0235331. https://doi.org/10.1371/journal.pone.0235331
  • French National Sleep Apnea Registry 1997-2017; univariable and multivariable logic regressions comparing OVS to OSA.
  • AHI over 15 required; either PSG or HSAT. All had spirometry to be included.
  • N 14368 with OSA, 2098 with OVS (unmatched)
  • Note: this is primarily comparisons of OSA vs overlap, not overlap vs COPD
  • OVS patients have more comorbidities (higher likelihood of CAD, CHF, Stroke, DM – synergistic deleterious effect on cardiovascular comorbidities. (strong effect modification for CHF, CAD, peripheral neuropathy; not so much for HTN and stroke)
  • Great nocturnal hypoxemia, greater proportion presenting with elevated PaCO2 during the day. ### Slide 24
  • Management (and thus, inference of disease attributable risk) is harder because these patients have been excluded from most trials
  • Daytime CO2 + O2 tensions improved in overlap syndrome when treated with CPAP; not with O2
  • Fletcher EC, Schaaf JW, Miller J, Fletcher JG. Long-term cardiopulmonary sequelae in patients with sleep apnea and chronic lung disease. Am. Rev. Respir. Dis. 1987; 135: 525–533. ### Slide 25
  • A large portion of the morbidity and mortality of patients with COPD occurs through cardiovascular effects – either due to confounding causes (smoking), or direct pathophysiologic interplay ( citations?)
  • Mechanisms: “In terms of intermediary mechanisms, OSA and COPD share an increased burden of systemic inflammation via the activation of transcriptional factors (nuclear factor kappa B and hypoxia-inducible factor 1), oxidative stress, sympathetic overactivity and endothelial dysfunction [17–19].”
  • Consequences of OVS – summarized from:Verbraecken and McNicholas: Respiratory mechanics and ventilatory control in overlap syndrome and obesity hypoventilation. Respiratory Research 2013 14:132.doi:10.1186/1465-9921-14-132 https://link.springer.com/content/pdf/10.1186/1465-9921-14-132.pdf
  • Additive risk when both are present: more hypoxemia, worse sleep quality
  • Severe OSA (due to insufficient ventilation, temporal v/q mismatch), OHS, and OVS can all have some degree of hypoxemia between apneic events
  • Impaired CO2 Responsiveness, which manifests as a tendency to develop hypercapnia.
  • Influence of obesity as a confounder for this has not been adequately excluded.
  • Tendency toward development of pulmonary hypertension:
  • In COPD alone, pHTN does not occur until hypoxemia develops [77]
  • Yet, in OVS – higher rates of pHTN are seen (9% OSA, 36% overlap in [54]); even when obstruction is mild-moderate ([3])
  • Cor Pulmonale: “Overlap was also associated with a markedly higher right ventricular mass index and right ventricular remodelling index compared to a COPD-only group [79].” ### Slide 27
  • Consequences of OVS – summarized from:Verbraecken and McNicholas: Respiratory mechanics and ventilatory control in overlap syndrome and obesity hypoventilation. Respiratory Research 2013 14:132.doi:10.1186/1465-9921-14-132 https://link.springer.com/content/pdf/10.1186/1465-9921-14-132.pdf
  • “Kwon et al. reported that increased severity of hyperinflation, which is the ratio of inspiratory capacity to total lung capacity (IC/TLC), is associated with worse sleep efficiency in overlap, independent of apnea and nocturnal hypoxemia [56,57].”
  • Argues that it may be not OSA mechanisms that are responsible for symptoms worsening.
  • Minute ventilation decreases with increasing depth of sleep in healthy individuals; this is mediated by decreased HCVR [64, 65]. With the addition of apneas, acute hypercapnia causing increased ventilation occurs. In OVS (or OHS) – if mechanical impairment is such that ventilation can’t compensate OR the HCVR becomes blunted, then hypercapnia develops [51,66,67].
  • [ ]What factors are known to explain why some become hypercapnic and some don’t?
  • Event severity and frequency “However, a correlation between hypercapnia and the frequency and duration of respiratory events during the night could not be observed [72,73].”
    1. Degree of ventilatory limitation
    1. Resetting of chemoreceptor set points (LTF?)
    1. “Finally, also constitutional or genetic factors may be responsible for lowered HCVR in hypercapnic patients [75].” ### Slide 28
  • Additive effect of OSA to Obesity/COPDFrom: https://jcsm.aasm.org/doi/10.5664/jcsm.9506
  • “Sleep [apnea] can further exacerbate the dysfunction as it leads to reduced respiratory motor neuron output, increased upper airway resistance (ie, obstructive sleep apnea, OSA), and diminished chemoreceptor sensitivity.”
  • “Patients who have both obesity and obstructive airways disease contributing to their hypoventilation are often excluded from clinical trials—patients with a forced expiratory ratio < 0.7 are excluded from OHS trials,7–9 while the presence of obesity or OSA often results in exclusion in long-term BPAP trials in pure COPD” ### Slide 29
  • 58 Schreiber A, Surbone S, Malovini A, et al. The effect of continuous positive airway pressure on pulmonary function may depend on the basal level of forced expiratory volume in 1 second. J Thorac Dis 2018; 10: 6819–6827
  • Importantly, PAP is reported to improve daytime blood gases and reduce mortality, morbidity and exacerbation rates in patients with overlap syndrome [57, 58].’
  • Reduced all cause mortality (at 9.4 yrs) and time to COPD exacerbation. ### Slide 30
  • 57 Marin JM, Soriano JB, Carrizo SJ, et al. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med 2010; 182: 325–331.
  • “Clinical cohort studies indicate that exacerbation rate and mortality is reduced in subjects compliant with PAP treatment”
  • Prospective cohort in spain. Clasified by COPD w/o OSA, COPD w OSA not on CPAP, and COPD w OSA on CPAP. ~200 patients each
  • K-M curves / proportional hazard for mortality and time w/o exacerbation.
  • Higher comorbidity burden in OVS; increased mortality and exacerbations in the untreated OVS group compared to COPD and treated OVS.
  • Critique: receipt not randomized, CPAP likely marker for are healthcare behaviors. ### Slide 31
  • Machado MC, Vollmer WM, Togeiro SM, Bilderback AL, Oliveira MV, Leitão FS,Queiroga F Jr, Lorenzi-Filho G, Krishnan JA: CPAP and survival inmoderate-to-severe obstructive sleep apnoea syndrome and hypoxaemicCOPD. Eur Respir J 2010, 35(1):132–137.
  • Machado et al DOI: 10.1183/09031936.00192008 , CPAP treated with 71% survival vs 26% in untreated in LTOT COPD clinic in Brazil. Adjusted HR 0.19 (0.08-0.48)
  • Implausibly large treatment effect. – also, not large enough for that many predictors?
  • All needed oxygen for more than 6 months.
  • 95 patients diagnosed with OVS; 61 treated+adherent to CPAP, 34 not. Not treated were older, more exacerbations. Multivariable model controlled for spiro, BMI, smoking hx, hosp, CCI, noct hypoxemia. ### Slide 32
  • Krishna suggested revision review:
  • While the cardiovascular and ventilatory control aspects have been highlighted, a third aspect is the direct effect of intermittent hypoxia on airway inflammation and risk of exacerbations. This may be the most relevant to the clinician if OSA treatment can reduce the frequency of exacerbations, degree of dyspnea or other COPD related symptoms.
  • Intermittent hypoxemia – airway inflammation (CRP, IL6 NFKB-TNFalpha, IL-8) and ROS may both contribute to exacerbations. ### Slide 33
  • He BT, Lu G, Xiao SC, et al. Coexistence of OSA may compensate for sleep related reduction in neural respiratory drive in patients with COPD. Thorax 2017;72:256–62.
  • NREM drive to breath assessed by Ve / EMGdi ratio in overlap syndrome against COPD alone, OSA alone, and healthy subjects. (n16,19,14,12 each)
  • Ve decreased 10% in healthy, 24% in COPD, 21% in OSA, and 27% in OVS
  • Drive: decreased in COPD (20-30%), increased in OSA (in response to upper airway resistance), and remained unchanged on OVS (cancelled).
  • Thus, OVS may be protective against sleep hypoventilation?
  • ETCO2 similar between OVS and OSA - either deadspace increased in OVS or apneas/hypopneas were less consequential (traction?) – OVS had mostly hypopneas
  • Critique: no matching for disease or severity symptoms – are these differences in pathophysiology, or reflection of what conditions are often present at the diagnosis of sleep complaints? ### Slide 34
  • Stanchina ML, Welicky LM, Donat W, et al. Impact of CPAP use and age on mortality in patients with combined COPD and obstructive sleep apnea: the overlap syndrome. J Clin Sleep Med 2013;9: 767–72PMID: 23946706
  • 10272 outpatients with OSA or COPD diagnostic codes -> 1,112 COPD and 2284 OSA confirmed; 227 overlap patients.
  • In multivariate analysis / Cox-regression of OVS, CPAP use (HR 0.71 per hour used in the first 1-3 months) and Age (1.14 per decade) independently associated with risk of mortality
  • No independent association with other factors (FEV1, Supplemental O2, active smoking, or comorbidity index) was found.
  • Observational ### Slide 35
  • Adler D, Bailly S, Benmerad M, Joyeux-Faure M, Jullian-Desayes I, Soccal PM, Janssens JP, Sapène M, Grillet Y, Stach B, Tamisier R, Pépin JL. Clinical presentation and comorbidities of obstructive sleep apnea-COPD overlap syndrome. PLoS One. 2020 Jul 9;15(7):e0235331. doi: 10.1371/journal.pone.0235331. PMID: 32645005; PMCID: PMC7347183.
  • National Registry in France, patient referred for suspected SDB. OVS (FEV1/FVC < 0.7, n2098) vs OSA (AHI 15+, FEV1/FVC > 0.7 n14368) alone. (All smokers get spiro as part of their workup, supposedly)
  • Same BMI; More hypercapnia in OVS, lower oxygen
  • More comorbidities of all sorts in OVS group, less sleepiness at the wheel.
  • In regressions: older age (they used fixed cutoff). PVD, alcohol, smoking, age, and male gender all independently associated. For example, HTN and stroke not independently associated.
  • “Associations between COPD and CV in OSA patients; causality needs to be firmly established by incident data and RCTs” ### Slide 36
  • Toraldo DM, De NF, Nicolardi G. Fixed-pressure nCPAP in patients with obstructive sleep apnea (OSA) syndrome and chronic obstructive pulmonary disease (COPD): a 24-month follow-up study. Sleep Breath 2010;14:115–23.PMID: 19756803
  • 12 patients BMI 30+ with diagnosis of COPD not on LTOT; 1 center in Italy. Avg FEV1 60% predicted (moderate obstruction), BMI 34.2, severe OSA (43)
  • Starting auto nCPAP; followed for 2 years. Mean use 5 hours per night. Assessed at 3, 12, and 24 months.
  • All changes occurred within 3 months (excessive normalization of sleepiness): FEV1, FRC, mPAP, CO2, PaO2 (daytime), as well as sleep measures (hypox and AHI)
  • No control group
  • Also reported pre-post hospitalization though the data is not believable. ### Slide 37
  • As previously covered, OVS can lead to hypercapnia. Comparison between OVS and OHS comorbidities paper? ### Slide 38
  • DOI: 10.7759/cureus.3453[ ] cite this with the CHEST review
  • Several observational studies have demonstrated reduced risk of exacerbations and death in patients with overlap syndrome who accept and adhere to CPAP treatment. How much of this effect results from effects of CPAP versus as a marker for health-related behaviors cannot be determined from the existing literature.
  • Also cite: Owens RL, Malhotra A. Sleep-disordered breathing and COPD: the overlap syndrome. Respiratory care. 2010 Oct 1;55(10):1333-46. as a review. ### Slide 39
  • Health-related quality of life in patients with obstructive sleep apnoea and chronic obstructive pulmonary disease (overlap syndrome)C. Mermigkis, doi: 10.1111/j.1742-1241.2006.01213.x
  • 75 patients with COPD, stable outpatient, +snoring but no EDS (ie. would not meet traditional screens)
  • 30 had OSA;
  • Compared to 15 matched (demo, spiro, abg) controls
  • St George’s respiratory questionnaire: OVS > Symptoms, activity and impact scores.
  • Sleep architecture similar; oxygen desaturation similar ### Slide 40
  • CPAP vs BiPAP (or NIV)? JCSM study
  • However, one study that found benefit from NIV in hypercapnic COPD may have included overlap-syndrome patients.108,109
    1. Gay PC. Chronic obstructive pulmonary disease and sleep. Respir Care. 2004; 49(1):39–51. [PubMed: 14733621]
    1. Meecham Jones DJ, Paul EA, Jones PW, Wedzicha JA. Nasal pressure support ventilation plus oxygen compared with oxygen therapy alone in hypercapnic COPD. Am J Respir Crit Care Med. 1995; 152(2):538–544. [PubMed: 7633704] ### Slide 41
  • https://jcsm.aasm.org/doi/10.5664/jcsm.9506
  • Prior lit: OHS lit excludes COPD, COPD lit excludes OHS. What to do with both?
  • N 32 stable outpatients with chronic hypercapnic respiratory failure and concurrent obesity and COPD (req: PaCo2 over 45, bmi over 30, FEV1/FVC < 0.7, not on pap). Randomized; single blinded
  • BiPAP-S more effective at reducing PaCO2 than CPAP over 3 months; also increasing FEV1
  • Though no difference in functioning
  • Small driving pressure (6) compared to COPD lit. ### Slide 42
  • Re: Marin study (PMID: 20378728) – “Even when adjusted for COPD severity, comorbid OSA remained a risk factor for death.”
  • In the observational study by Marin, death in the untreated overlap group was most commonly attributed to cardiovascular disease.70
  • Again, CPAP was not provided in a randomized, blinded manner, but markers of both COPD and OSA severity were similar in the CPAP-treated and untreated groups.
  • Platt AB, Kuna ST, Field SH, et al. Adherence to sleep apnea therapy and use of lipid-lowering drugs: a study of the healthy-user effect. Chest. 2010; 137(1):102–108. [PubMed: 19820075]
  • Martha E. Billings, MD, Dennis Auckley, MD, Ruth Benca, MD, Nancy Foldvary-Schaefer, DO, Conrad Iber, MD, Susan Redline, MD, Carol L. Rosen, MD, Phyllis Zee, MD, Vishesh K. Kapur, MD, MPH, Race and Residential Socioeconomics as Predictors of CPAP Adherence, Sleep, Volume 34, Issue 12, 1 December 2011, Pages 1653–1658, https://doi.org/10.5665/sleep.1428
  • Marin 2005 (PMID: 15781100) Also looked at CPAP vs No CPAP (similar methodology, 10y follow-up) in all comers with mortality. Found a 2x increased risk of fatal CV event death compared to those who accepted treatment.
  • Yet, meta-analysis (PMID: 30736888) of 4 RCTs (n1898) followed for 3-5 years RR 0.96 (0.84-1.11) for mortality
  • Same meta-analysis for all cause CV events 6 RCTs (n2188) RR 0.96 (0.76 – 1.21) for CV events. ### Slide 43
  • Pathogenesis of obstructive sleep apnea in individuals with the COPD + OSA Overlap syndrome versus OSA alonePhysiological Reports. 2020;8:e14371. https://doi.org/10.14814/phy2.14371
  • OSA pathogenicity:
  • Anatomic factors: upper airway collapsibility (may stiffen when lung is hyper-inflated, but emphysema loss of elastic recoil may lessen this – hard to know a priori)
  • Neurologic / Physiologic factors: upper airway muscle response (worsened by ICS? Smoking?), respiratory-related arousability from sleep (may be lower in OVS due to frequent awakenings in the absence of upper airway collapse), control of breathing (respiratory drive generally increased)
  • Matched OSA (n15) to OVS (n15; most with moderate obstruction) on gender, age, BMI. Exclude: narcotics, sedatives, supp O2, recent exacerbation, BMI over 36, active smoking, heavy EtOH
  • PSG to determine Veupnea, Vpassive and Pcrit, Varousal/ArTh, Loop gain
  • “Consistent differences in key OSA traits were not observed between OVS and OSA alone.”. OVS: lower sleep efficiency, REM SpO2
  • Reduced upper airway response in those with air trapping; increased loop gain in those with worse airflow obstruction (contrary to expection; perhaps mediated by hypoxemia?). Somewhat lower arousal threshold – perhaps explains how hypercapnia can occur?
  • No difference in collapsibility: perhaps this is selection – if you have to have dx of OSA, then by definition the airway must be collapsable ### Slide 44
  • Differentiating OVS and OHS
  • doi:10.1186/1465-9921-14-132 Cite this article as: Verbraecken and McNicholas: Respiratory mechanics and ventilatory control in overlap syndrome and obesity hypoventilation. Respiratory Research 2013 14:132.
  • https://link.springer.com/content/pdf/10.1186/1465-9921-14-132.pdf ### Slide 45
  • Obesity – Airway disease missed dx
  • Veterans (5000) in PNW - DOI: 10.1378/chest.13-2759
  • BMI category increase reduced likelihood of airflow limitation
  • In each higher category, likelihood of an inappropriate diagnostic label increased as did likelihood of being started (and remaining a year later) on inhalers, inappropriately.
  • Gershon and colleagues studied the healthcare burden of COPD overdiagnosis and demonstrated that individuals with overdiagnosed COPD had 89% higher rates of hospitalizations, 42% higher rates of emergency department visits, and 52% higher rates of ambulatory care visits compared with people without COPD after adjustment for age and sex (10). ### Slide 46
  • Overlap syndrome diagnostic performance
  • Similar to other studies, a large proportion of patients were misdiagnosed as having COPD or left heart failure and likely received inappropriate therapy (including systemic steroids and inhalers)
  • (36). - Collins BF, Ramenofsky D, Au DH, Ma J, Uman JE, Feemster LC. The association of weight with the detection of airflow obstruction and inhaled treatment among patients with a clinical diagnosis of COPD. Chest 2014;146:1513‐1520.
  • “dyspneic obese patients are frequently misdiagnosed with asthma or COPD
  • and treated with inappropriate pharmacologic agents (37).”
  • Sin DD, Jones RL, Man SF. Obesity is a risk factor for dyspnea but not for airflow obstruction. Arch Intern Med 2002;162:1477‐1481. ### Slide 47
  • Sterling et al 2022 AJRCCM - https://www.atsjournals.org/doi/abs/10.1164/rccm.202109-2035OC
  • Proprietary database (https://www.inovalon.com/solutions/insights/) linked to Resmed adherence data
  • Propensity matched Model with comorbidities suggests health outcomes including expenditures, admission rates are lower in patients adherent to PAP
  • Size of reduction comparable to triple inhaler therapy (slightly larger)
  • Pre data is similar; confounding possible though not egregious

234.3 Learning objectives

  • Overlap syndrome (OSA-COPD) evidence review
  • 123: Malhotra A, Schwartz AR, Schneider H, et al. Research priorities in pathophysiology for sleep-disordered breathing in patients with chronic obstructive pulmonary disease. An official American Thoracic Society research statement. Am J Respir Crit Care Med 2018; 197: 289–299.
  • Adler D, Bailly S, Benmerad M, Joyeux-Faure M, Jullian-Desayes I, Soccal PM, et al. (2020) Clinical presentation and comorbidities of obstructive sleep apnea-COPD overlap syndrome. PLoS ONE 15(7): e0235331. https://doi.org/10.1371/journal.pone.0235331https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347183/pdf/pone.0235331.pdf
  • Pathogenesis of obstructive sleep apnea in individuals with the COPD + OSA Overlap syndrome versus OSA alonePhysiological Reports. 2020;8:e14371. https://doi.org/10.14814/phy2.14371
  • Non-apnea related hypoventilation in COPD[ ] retool this one – frame this as additive to the deleterious consequences of hypoxemia/hypercapnia. Ie – what are the consequences

234.4 Bottom line / summary

  • Overlap syndrome (OSA-COPD) evidence review
  • 123: Malhotra A, Schwartz AR, Schneider H, et al. Research priorities in pathophysiology for sleep-disordered breathing in patients with chronic obstructive pulmonary disease. An official American Thoracic Society research statement. Am J Respir Crit Care Med 2018; 197: 289–299.
  • Adler D, Bailly S, Benmerad M, Joyeux-Faure M, Jullian-Desayes I, Soccal PM, et al. (2020) Clinical presentation and comorbidities of obstructive sleep apnea-COPD overlap syndrome. PLoS ONE 15(7): e0235331. https://doi.org/10.1371/journal.pone.0235331https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347183/pdf/pone.0235331.pdf
  • Pathogenesis of obstructive sleep apnea in individuals with the COPD + OSA Overlap syndrome versus OSA alonePhysiological Reports. 2020;8:e14371. https://doi.org/10.14814/phy2.14371
  • Non-apnea related hypoventilation in COPD[ ] retool this one – frame this as additive to the deleterious consequences of hypoxemia/hypercapnia. Ie – what are the consequences

234.5 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.

234.6 Red flags / when to escalate

  • TODO: List red flags that require urgent escalation.

234.7 Common pitfalls

  • TODO: Capture common errors or missed steps.

234.8 References

TODO: Add landmark references or guideline citations.

234.9 Slides and assets

234.10 Source materials