In this cohort of adults suspected of having COPD, OSA, and the overlap syndrome, we showed that all-cause mortality was highest in patients with the overlap syndrome of COPD and moderate-to-severe OSA. We found that our models that incorporated the measurements of hypoxemic load and all covariates in the clinical model better predicted mortality within 10 years compared to the clinical model adjusted only for demographic/anthropometric covariates and comorbidities in patients with COPD, OSA, and the overlap syndrome.
In previous studies, the mortality of the overlap syndrome was higher than that of OSA or COPD alone [5–7]. In a cohort study of patients referred to an academic hospital in Spain, patients with overlap syndrome had higher all-cause mortality than those with COPD alone (relative risk of 2.23) [5]. Similarly, an analysis of the National Health and Nutrition Examination Survey (NHANES) data showed that all-cause mortality was 2.4 times higher in individuals with overlap syndrome than in those who did not have either disease [6]. In a clinical cohort in Canada, the highest hazard of the composite outcome—hospitalization due to cardiovascular causes or death—was associated with patients having both severe OSA and COPD in untreated individuals (HR of 2.01). Here, we report consistent findings in Asian patients [7]. In our study, the adjusted HR for all-cause mortality in patients with overlap syndrome of COPD and moderate-to-severe OSA was 3.19 compared to those who did not have either disease. Although an inconsistent result has been reported from a cohort of veterans with hospitalizations, its results are difficult to generalize because of potential selection bias as acknowledged by the authors [8].
The mechanisms explaining increased mortality in patients with overlap syndrome are not clearly understood, but hypoxemia may play a major role. In OSA alone, recurrent intermittent hypoxemia occurs because of upper airway narrowing or obstruction at a relatively normal baseline oxygen saturation [13]. In COPD alone, prolonged and profound hypoxemia is presumed to be a consequence of hypoventilation, especially during REM sleep characterized by low tidal volume, and increased ventilation–perfusion mismatch during periods of reduced tidal volume [25]. Moreover, in patients with COPD and low baseline oxygen saturation while awake, a similar degree of hypoventilation is associated with greater desaturation because of the initial position being on the steep part of the oxyhemoglobin dissociation curve [13, 15, 25]. If COPD is accompanied by OSA, intermittent hypoxemia develops from a low baseline saturation, and the depth and duration of hypoxemia become more pronounced. This may promote increased oxidative stress, systemic inflammation, and sympathetic activation, thus contributing to cardiovascular and other comorbidities and mortality [26, 27].
Even in patients with OSA, the importance of hypoxemia has emerged as the AHI is considered to predict their outcomes poorly [14, 28]. The newly proposed PSG indices predicting outcomes of OSA include TS90 [29–32], nadir of hypoxemia [33], area under the oxygen desaturation curve [14], and respiratory event duration [28]. However, there have been few studies on PSG indices predicting mortality in patients with overlap syndrome that show more profound hypoxemia. Recently, a study reported that the greatest hazard of the composite cardiovascular outcome was found in patients with both COPD and nocturnal hypoxemia (TS90 ≥ 10 min), but not with AHI > 30 [7]. Our findings are consistent with those of previous studies. In our study, the extended models incorporating measurements of the hypoxemic load (TS90 and mean SpO2) had higher C-indices than that of the clinical model, which was not adjusted for any indices of PSG. The C-index of the extended model with AHI did not show a significant difference from that of the clinical model. Moreover, our models incorporating measurements of the hypoxemic load consistently better predicted mortality within 10 years than the clinical model in the subcohorts of all 262 patients with OSA and all 94 patients with COPD.
In patients with COPD, the lowest SpO2, TS90, and mean SpO2 predicted mortality well. As discussed above, when OSA coexists with COPD, the degree of desaturation may be more pronounced because of the low starting baseline and sleep-related hypoventilation [13, 15, 25]. We speculate that the importance of the depth of hypoxemia in COPD is explained by its pathophysiology.
There was no statistically significant difference when comparing the C-index of our extended model with AHI and those of the extended models with other PSG measurements of the hypoxemic load. The C-index of the extended model with AHI was not significantly higher than that of the clinical model (0.739 vs. 0.737). Our study might not be adequately powered to compare the predictive capacity of AHI and measurements of the hypoxemic load. Further large-scale longitudinal studies are needed to explore our findings.
Our study has notable strengths in the diagnosis of these diseases. In contrast to the previous studies [6–8], all study patients underwent spirometry and bronchodilator response tests, and COPD was spirometrically diagnosed according to the GOLD guidelines [17]. We divided study patients into two groups—those with moderate-to-severe (AHI ≥15 /h) OSA and those without—because long-term outcomes of mild (5 /h ≤ AHI < 15 /h) OSA are unclear [34, 35].
To appreciate the results of our study appropriately, its limitations must be recognized. First, this study was moderately sized and conducted in a single institution. Second, the oxygen desaturation index and the area under the oxygen desaturation curve were not available in our study. Further studies are required to evaluate the predictive power of these PSG metrics for mortality in patients with COPD and overlap syndrome. Third, because of the retrospective nature of the present study, data on patients’ adherence to PAP and bronchodilators were not available, which could have modifying effects on the risks of adverse outcomes.
In conclusion, patients with the COPD–OSA overlap syndrome had increased all-cause mortality. The measurements of the hypoxemic load and not AHI better predicted mortality within 10 years than the clinical model that was not adjusted for any indices of PSG in patients with COPD, OSA, or the overlap syndrome.