In this population-based, longitudinal study of persons with COPD, we found that disturbed sleep is predictive of exacerbations, respiratory-related emergency utilization, and all-cause mortality. This longitudinal relationship persisted even after controlling for both FEV1 and COPD Severity Score, suggesting that disturbed sleep is playing an independent role as a risk factor for poor outcomes in COPD, rather than simply being a marker of worse disease.
Although sleep disturbance was not related to FEV1
, our findings demonstrated an association between sleep disturbance and both respiratory symptoms and COPD Severity Score, indicating that sleep disturbance is, on balance, associated with severity of disease in COPD. The lack of a relationship between sleep quality and FEV1
that we observed is consistent with the findings of Klink and colleagues [6
]. Although perhaps surprising, and therefore important that the work of Klink and colleagues be replicated, we note that the correlation between dyspnea and FEV1
is often low [50
]. Regardless, the COPD Severity Score, although modestly correlated with FEV1
, is a strong predictor of poor outcomes in COPD, and higher COPD Severity Scores were associated with greater likelihood of disturbed sleep [18
]. Thus, by virtue of an effect-response relationship, our findings suggest that COPD may in fact be contributing to disturbed sleep, which would potentially lower one’s threshold, in the clinic, for suspecting sleep disturbance in COPD patients.
Our findings, however, also support a bi-directionality to the relationship between disturbed sleep and disease severity in COPD. That is, COPD symptoms such as cough and dyspnea may be, in part, responsible for poor sleep quality, yet disturbed sleep may in turn contribute to COPD exacerbations and greater COPD severity. The fact that disturbed sleep was longitudinally predictive of poor COPD-related outcomes, even after rigorously controlling for COPD severity with both FEV1 and COPD Severity Score in multivariate models, supports this concept. This would be consistent with sleep disturbance being part of a vicious circle, whereby COPD contributes to poor sleep, which in turn contributes to worse COPD.
Hypothetically, if there were an interaction between COPD and disturbed sleep, we might expect that sleep disturbance would place subjects with more advanced COPD at higher risk of adverse outcomes. Our sample size limited a robust analysis of this question, but the higher estimates for mortality and respiratory-related emergency utilization associated with sleep disturbance at baseline, comparing subjects with GOLD stages 3–4 to subjects with GOLD stages 1–2, would be consistent with such an interaction. However, a substantially larger sample size adequate to statistically examine an interaction effect would be necessary to conclusively establish such a finding.
There are several theoretical mechanisms by which sleep disturbance could contribute to worsening COPD. It is thought that disturbed sleep, in general populations, may affect memory, learning, and abstract problem solving [51
]. It is also known that verbal memory impairment in COPD patients is associated with poor adherence to medications [1
]. Alternatively, poor sleep quality is also known to affect immune function, and poor immunity may be particularly harmful for patients with COPD in whom infectious etiologies may precipitate COPD exacerbations [3
]. Finally, although we attempted to measure insomnia symptoms rather than sleep-disordered breathing symptoms, it is possible that nocturnal hypoxemia or other nocturnal respiratory factors may have contributed to the observed findings.
In our modeling, we tested whether poor outcomes might have resulted from cognitive dysfunction, depression, or anxiety related to sleep disturbance. Although sleep disturbance was indeed cross-sectionally associated with poor memory, this did not appear to explain the risk for poorer outcomes. As expected, sleep disturbance was cross-sectionally associated with depressive and anxiety symptoms. This study cannot resolve whether such psychological factors were the result or the cause of insomnia symptoms; prior research, however, has shown that insomnia symptoms do strongly predict the subsequent development of depression [43
]. Regardless, the central observation remains that sleep disturbance predicted death and COPD-related emergency utilization even after controlling for depressive or anxiety symptoms, suggesting that these psychological factors do not entirely explain the role of sleep disturbance.
This study has important limitations. The lack of objective sleep-related data, such as that obtained from polysomnography, does not permit us to more fully understand the etiology of the sleep disturbance we characterized; for example, whether it is related, at least in part, to sleep-disturbed breathing or hypoxemia. It is certainly possible that disturbed sleep, as assessed in our study, was a manifestation of nocturnal hypoxemia. Second, although the Medical Outcomes Study sleep scale has been psychometrically validated in a variety of populations, and we conducted our own analysis of performance characteristics, this sleep questionnaire has not been validated against objective measures of sleep quality such as polysomnography data. Nonetheless, these questions have strong face validity by virtue of their consistency with major criteria used for insomnia. Third, the wide confidence intervals in our longitudinal analyses, especially for the outcomes of COPD exacerbations and emergency utilization, limit our ability to accurately estimate the actual magnitude of the association between sleep disturbance and poor outcomes, although the fact that the confidence intervals excluded unity lends credence to the presence of an association between sleep disturbance and poor outcomes in the direction observed. Next, we measured lung function spirometrically but because of the population-based nature of recruitment with in-home assessments, additional measures of pulmonary function were not feasible. We were unable to determine, therefore, whether pulmonary impairments such as air-trapping or reduced diffusing capacity might be associated with sleep disturbance.
Loss to follow-up for the outcomes of COPD exacerbations and emergency utilization is an additional limitation. We attempted to compensate for potential biases by utilizing probability-of-attrition models, but less attrition would have provided greater confidence in these results. Nonetheless, it is reassuring that the mortality analysis reflected similar results, since this analysis did not require subject reassessment and therefore was not subject to follow-up loss. Also, the exacerbation and utilization outcomes were determined by self-report, albeit at subject follow-up. Objective confirmation might have provided more accurate measurement, but the approach of self-report has been shown to be valid and reasonably accurate, especially for emergency utilization services [54
]. Although there is some evidence that older adults may tend to under-report utilization [55
], under-reporting would tend to diminish any observed associations with sleep disturbance, and thus be a conservative bias (that is, biasing toward the null). Furthermore, it is again reassuring that the mortality outcome, which was confirmed through database queries, yielded results similar to the self-reported outcomes.
Our study underscores the potential importance of sleep quality in COPD. Sleep quality was assessed using items which elicited symptoms reflecting major criteria for insomnia, and disturbed sleep as such predicted poorer longitudinal outcomes in COPD, even after controlling for COPD severity. Interventional trials that specifically target insomnia symptoms, either by virtue of COPD control focused specifically on nocturnal symptoms or behavioral therapies targeted at improved sleep hygiene and sleep quality, would appear warranted. Although further investigations are needed to better delineate the causal pathways accounting for the potent adverse risks we observed, this study supports the conclusion that disturbed sleep, assessed in terms of insomnia symptoms, is a potential contributor to poor outcomes in COPD.