Exploring the Interaction Between Obstructive Sleep Apnea and Idiopathic Pulmonary Fibrosis
Article information
Abstract
Recent evidence suggests that the prevalence of obstructive sleep apnea (OSA) is higher in patients with idiopathic pulmonary fibrosis (IPF) than in the general population, and coexistence of OSA and IPF is associated with a poor prognosis. The relationship between OSA and IPF is complicated and may be bidirectional. This review focuses on recent research about the epidemiology, pathophysiologic links, prognosis, and management of the two disorders. Early recognition and intervention may enhance survival rates, hence better screening methods and appropriate treatment should be further investigated.
INTRODUCTION
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by fibrotic processes of unknown etiology. Despite the recent use of antifibrotics to slow the progression of the disease, the 3-year survival rate for IPF remains poor at approximately 70% [1,2], and patients with IPF suffer from many respiratory symptoms and have a poor quality of life. In addition to pharmacologic intervention, current guidelines recommend evaluating and treating comorbidities to enhance treatment outcomes, patients’ symptoms, and quality of life [3].
Obstructive sleep apnea (OSA) is one of the most common sleep disorders, with an estimated global prevalence of 22.6% [4]. Furthermore, the incidence of OSA has been reported to be higher in patients with IPF compared to the general population [5]. Emerging evidence suggests that the relationship between OSA and IPF is bidirectional [6]. These two diseases share some similar pathophysiological mechanisms and would exaggerate each other’s development or progression. OSA exposes the lungs to chronic intermittent hypoxia (CIH) and induces oxidative stress [7,8], which might contribute to the development and aggravation of pulmonary fibrosis [9,10]. On the other hand, as IPF progresses, the decrease in lung volume can lead to structural changes in the upper airway and instability, predisposing the patient to developing OSA [6,11].
The aim of this review is to present current evidence and hypotheses on the relationship between OSA and IPF, as well as to emphasize the clinical importance of this relationship.
PREVALENCE OF OSA IN IPF
The prevalence of OSA varies significantly depending on the diagnostic criteria of OSA, manual scoring of hypopnea events, and the characteristics of study populations. Therefore, obtaining an accurate prevalence of OSA is challenging, and the reported prevalences of OSA in IPF vary across studies, ranging 47.2%–88.8% [12-16]. One recent meta-analysis revealed the prevalence of OSA in IPF as 76.4% [5]. A more recent retrospective study in Korea reported a prevalence of 64.7% for OSA in patients with IPF [17]. On the other hand, the prevalence of OSA in the general population is reported to be approximately 25% [4,18], and previous studies have shown a higher prevalence of OSA in IPF compared to the general population [5]. However, old age and male sex, which are mainly affected populations by IPF, are also prevalent for OSA, so caution is needed for interpretation. In fact, one cohort study in the US reported up to 43.2% in men aged 50 to 70 years [19]. Another cohort study reported a higher prevalence of OSA, 53.4% in adults aged 50 to 80 years [20]. Despite the apparent higher prevalence of OSA in the IPF population compared to the general population, we need additional studies that directly compare the two groups with matching key factors like age, sex, and comorbidities to establish strong evidence.
PATHOPHYSIOLOGIC INTERACTIONS BETWEEN OSA AND IPF
Recent studies have proposed a bidirectional link between IPF and OSA, however, the exact mechanisms are not yet fully understood. The main suggested mechanisms by which OSA impacts IPF include CIH-induced oxidative stress, lung injury caused by mechanical stretch, and microaspiration due to gastroesophageal reflux disease (GERD).
OSA accompanies CIH, which more effectively leads to systemic responses than continuous hypoxia, and it eventually makes patients prone to morbidity and mortality [8]. CIH and subsequent re-oxygenation produce reactive oxygen species (ROS) and oxidative stress [7]. After exposure to CIH, the levels of ROS were elevated in lung tissue from patients with interstitial lung disease (ILD) and animal models of pulmonary fibrosis [21,22]. This ROS induces tissue destruction, inflammation, and fibrosis by activating several related proteins, protein kinases, and transcription factors [8,23]. For example, the level of hypoxia-inducible factor-1α (HIF-1α) in lung tissue, a subunit of HIF-1 (an elemental transcription factor for oxygen homeostasis in the body), significantly increased and worsened pulmonary fibrosis in an animal model [22,24]. Transforming growth factor-β is also increased by ROS and contributes to fibrosis [21,25]. The expression of deoxycytidine kinase also increased in hypoxia which induced epithelial cell proliferation and pulmonary fibrosis [9]. In a recent animal study, these processes of fibrosis induced by oxidative stress from CIH were more exaggerated in older groups, which are major concern groups of OSA and IPF [26].
In OSA, resistive inspiration against a closed upper airway is repeated multiple times and may cause alveolar traction injury in peripheral lung [27]. During inspiration, the lung compliance is relatively low, so it becomes more predisposed to tractional injury [27,28]. Tractional injury has been proposed as a key pathogenic mechanism that leads to alveolar epithelial injuries and fibrosis in IPF [27].
Moreover, OSA is known to be associated with an increased prevalence of GERD [29]. One study reported that OSA causes gastroesophageal reflux by inducing frequent transient lower esophageal sphincter relaxation [30]. GERD, also very common in IPF, has been raised as having a major role in pathogenesis of IPF. One study investigated the prevalence of GERD between OSA and non-OSA individuals with fibrotic ILD, and there was no difference between the two groups, nor was OSA a risk factor for GERD in fibrotic ILD [31]. However, given the cross-sectional nature of this study, a longitudinal cohort study is necessary to determine the causative relationship among these three diseases.
The exact mechanism by which IPF affects OSA is also still unclear. One hypothesis is that a reduction in lung volume from progression of IPF may increase resistance of pharynx due to decreased traction on the upper airway, and as a result, it may reduce upper airway instability and provoke collapse [32]. This instability aggravates especially during REM sleep, as skeletal muscle atonia occurs and functional residual capacity is further reduced [6,33]. Skeletal muscle dysfunction in patients with IPF is also common, and it may also contribute to upper airway collapse, but further study is required.
The low respiratory arousal threshold, which means numerous arousals even by minimal stimulations and leads to sleep fragmentation, is an important contributor to the pathogenesis of OSA. Sleep fragmentation prevents progression from shallow stages to deeper sleep stages, and prevents the stabilization of respiratory drive and synchronization with pharyngeal dilatator muscles [5]. Similarly, in patients with IPF, sleep fragmentation and shallow sleep stages are common [16]. This predisposition may relate to development of OSA, but further research is required.
THE IMPACT OF OSA ON QUALITY OF LIFE, PROGNOSIS, AND SURVIVAL IN IPF
Patients with IPF commonly suffer from decreased quality of life due to sleep. One study found that patients with IPF experience poor sleep quality, as measured by their self-reported Pittsburgh Sleep Quality Index. This poor sleep quality was also correlated with a lower health-related quality of life to the Short-Form 36 Health Survey (SF-36) [34]. A later study demonstrated that quality of life was notably reduced in patients with IPF or sarcoidosis, especially in the domains related to physical health and the level of independence [35]. In addition, the presence of OSA further reduced the quality of life in patients with IPF. One study in 2021 showed that patients with IPF and OSA exhibited more significant functional impairments in questionnaire assessments, particularly in the domains of general health component of the SF-36 [36]. Another study with newly diagnosed IPF found that those with OSA and nocturnal hypoxemia had a poorer health-related quality of life, as measured by the St. George’s Respiratory Questionnaire when compared with those without OSA [37].
Patients with IPF and OSA showed poor prognosis in terms of mortality and clinical deterioration, compared to IPF without OSA [38]. Particularly, intermittent desaturations during sleep seem to be associated with poorer survival. In a study of 31 patients with IPF, maximum difference in SpO2 between wakefulness and sleep was correlated with survival, dyspnea, estimated right ventricular systolic pressure, and inversely correlated with diffusing capacity [39]. This intermittent hypoxemia has also been linked to a poor prognosis for IPF with OSA, possibly due to a predisposition to the development of pulmonary hypertension (PH) [40]. The exact mechanism of development of PH in IPF is not well understood, but nocturnal hypoxemia in IPF was associated with advanced PH and right ventricular dysfunction [41]. OSA in patients with IPF additionally contributes to nocturnal hypoxemia and promotes pulmonary hypoxic vasoconstriction and the development of PH [42]. One recent study that analyzed the cardiopulmonary exercise test results of IPF without and with sleep related breathing disorders (SRBD) showed that pulmonary vascular limitations are significantly worse in the SRBD subgroup [43].
SCREENING AND DIAGNOSIS OF OSA IN PATIENTS WITH IPF
Even though OSA is common in IPF, there are no well-validated screening tools for use in IPF. Some questionnaires, such as the STOP-Bang questionnaire, the Epworth Sleepiness Scale (ESS), and the Berlin Questionnaire, have been developed for screening OSA, but previous studies identifying their roles in IPF showed low positive and negative predictive values [13]. Symptoms expressed by patients with IPF are somewhat distinct from those of the general population [6]. Patients with both IPF and OSA frequently reported daytime fatigue, sleep onset, and maintenance insomnia, but excessive daytime sleepiness was less common, and they scored normal on the ESS [44]. One study suggested that the STOP-Bang scores with cut-off scores of <3 points and >6 points for rule-out and rule-in respectively, could improve their predictive value in patients with ILD. Nevertheless, the optimal screening for OSA in patients with IPF has yet to be established, necessitating evaluation with overnight polysomnography (PSG), which is the gold standard diagnostic test for OSA. Even in the absence of OSA, patients with IPF can develop nocturnal hypoxemia as a result of decreased ventilation and deterioration in gas exchange during sleep [10,45]. Therefore, among the four types of sleep studies, type 1 (in-laboratory overnight) PSG remains the gold standard for the diagnosis of OSA in patients with IPF [6].
TREATMENT OF CONCOMITANT OSA AND IPF
Data is limited regarding treatment options for patients with both IPF and OSA, but managing OSA in IPF seems to improve the quality of life and prognosis [36,44,46]. Continuous positive airway pressure (CPAP) therapy remains an effective therapy for concomitant IPF and OSA. There are controversial results regarding mortality rates among patients with IPF coexisting with OSA. A recent retrospective multicenter study of 131 patients with ILD and OSA showed that adherence to CPAP was not related to improvement in all-cause mortality or progression-free survival, even after adjustment for confounding factors [47]. On the other hand, a cohort study of IPF with OSA in Greece revealed that patients with good CPAP compliance showed significantly better overall survival at 24 months after CPAP initiation compared with poor CPAP compliance group [44]. Regarding quality of life, previous studies similarly reported that CPAP therapy improves overall life and sleep quality [36,44,46].
Maintaining compliance with CPAP in patients with IPF is often challenging due to many reasons, such as an irritating cough, claustrophobia, and insomnia. One study suggested that the intensive follow-up by the CPAP clinic staff can be helpful to improve compliance [44]. The major problem, an irritating cough, can be managed with the use of heated, humidified air [46]. Another problem is claustrophobia, which may be attributed to the rapid and shallow breathing patterns of patients with IPF. This can be solved by having an acclimatization period with low CPAP pressures and intense follow-up [46].
CONCLUSION
The interaction between IPF and OSA is complex and significant, affecting both the prognosis and quality of life of patients. The bidirectional relationship between these two conditions, driven by mechanisms such as CIH, mechanical strain on lung tissue, and instability in upper airway, suggests that managing both OSA and IPF is crucial. Despite the lack of well-validated screening tools for OSA in IPF, overnight in-laboratory PSG remains the gold standard for diagnosis. The evidence indicates that treating OSA with CPAP can improve quality of life and potentially increase survival, although compliance with CPAP therapy poses challenges. Intensive follow-up and fine adjustment for individuals to address common issues such as cough and claustrophobia are essential to enhance adherence to CPAP therapy. Further research should focus on optimizing screening and treatment protocols for OSA in IPF patients, with the goal of improving clinical outcomes and quality of life in this population.
Notes
Sang Haak Lee, a contributing editor of Chronobiology in Medicine, was not involved in the editorial evaluation or decision to publish this article. The remaining author has declared no conflicts of interest.
Availability of Data and Material
Data sharing not applicable to this article as no datasets were generated or analyzed during the study.
Author Contributions
Conceptualization: Bora Lee, Sang Haak Lee. Supervision: Sang Haak Lee. Writing—original: Bora Lee. Writing—review & editing: Sang Haak Lee.
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Acknowledgements
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