During wakefulness, ILD patients are known to have a rapid, shallow breathing pattern both at rest and with exercise[8,9]. This is thought to be due to increased intrinsic elastic loading of respiratory muscles and stimulation of peripheral mechanoreceptors[8,10]. Even in the face of severely impaired gas exchange, this respiratory pattern allows ILD patients to maintain ventilation and daytime eucapnia until very advanced stages of disease. During sleep, some investigators have found respiratory frequency, f to be no different to that when awake[11-14]. Others have shown that f falls, but with an attendant increase in tidal volume, so that overall, the increased minute ventilation is preserved during sleep[15].

Not surprisingly, sleep quality is comparatively poorer than that of the normal population. Nocturnal cough, medications, breathing difficulties, hypoxia and obstructive apneas have all been implicated in disrupting sleep in this population. Perez-Padilla et al[14] in 1985, compared 11 ILD patients with age- and sex-matched controls. They reported decreased amounts of rapid eye movement (REM) sleep as well as significant sleep fragmentation in the patient group[14]. Further prospective studies, with particular focus on IPF confirm these findings, and also report increased stage 1 and 2 sleep, reduced slow wave sleep and poorer overall sleep efficiency[13,15-20]. Sleep characteristics in ILD subjects are shown in Table 1.

The symptoms of sleepiness and fatigue often co-exist in ILD patients. Common causative factors include systemic inflammation, treatment side effects, age and comorbidities. Depression and disease-related stressors also affect many. In addition, sleep fragmentation appears to be a substantial contributor, as demonstrated in studies using numerous sleep and health-related quality of life (QoL) questionnaires in ILD subjects. Fatigue is frequently reported, impacting on wellbeing and daytime function[13,21,22]. The Epworth Sleepiness Scale (ESS), and Pittsburgh Sleep Quality Index (PSQI) scores are higher in unselected ILD patients than in normal controls, indicating poorer quality sleep[22-24]. However, in ILD cohorts with polysomnography, the ESS and other tools do not reliably predict severity of sleep-disordered breathing[2,19,25]. The PSQI does appear to correlate with health-related QoL indices, particularly physical function and vitality, highlighting the pervasive influence of sleep fragmentation[22]. Nocturnal hypoxia in ILD patients is also independently associated with a reduction in energy levels, as well as physical and social functioning, as assessed by a variety of QoL instruments[13,21].

Increased periodic limb movements and restless legs syndrome (RLS) have been documented in IPF and scleroderma patients[17,26]. A self-reported study in IPF patients and normal controls, however, did not find any difference in the incidence of RLS[27]. Gastro-oesophageal reflux disease may also play a role in sleep disruption, particularly in high-risk groups including scleroderma patients[26].

Although retrospective analyses of ILD subjects suggest an association between the degree of lung restriction and the risk and severity of sleep disordered breathing, this has not been demonstrated in larger, prospective studies[2,17,19,20,25,29]. The only correlation between measured lung volumes and PSG parameters, reported by Mermigkis et al[20], was in total lung capacity and REM sleep apnoea hypopnoea index (AHI). Kolilekas et al[2] found an association between overall AHI and peak VO₂ on exercise testing, but this may simply reflect poorer daytime function and more deconditioning in those with more fragmented sleep.

In the general OSA literature, recent attention has been turned towards the inherent characteristics that predispose individuals to sleep disordered breathing. The two key components believed to underscore the pathogenesis of OSA are increased upper airway collapsibility and enhanced ventilatory control system instability[30]. It is useful to consider these processes in the ILD population.

Upper airway collapsibility: It is generally believed that restrictive lung disease leads to increased upper airway collapsibility through reduced caudal traction on these structures[31,32]. The inability to demonstrate a relationship between lung function parameters and AHI seems to refute this theory. One limitation with all reported data, however, is the assessment of lung function in the upright position only. There may be more robust associations between supine measurements and SDB, but this is yet to be investigated in ILD subjects. Increased body mass index (BMI) is associated with deposition of adipose tissue around upper airway structures, enhancing collapsibility. BMI correlates with AHI in some, but not all studies of ILD subjects, suggesting that other mechanisms are important[2,18-20,25].

Ventilatory control system instability: In sleep, any rise in arterial CO₂ (such as occurs with an apnoea) will stimulate carotid and medullary chemoreceptors, resulting in a central respiratory motor output response[33]. The direct activation of respiratory pump muscles and upper airway dilator muscles (e.g., genioglossus) restores upper airway patency, and is often accompanied by an arousal. Some individuals with heightened chemo-responsiveness may overshoot the eucapnic range, by overventilating in response to apnoea-induced hypercapnia. The ensuing hypocapnia will then cause a further apnoea, sometimes leading to a cyclical pattern of repetitive apnoeas as the ventilatory system continues to attempt to achieve homeostasis. This ventilatory system instability is believed to be an important contributing factor in many with OSA[34].

Intermittent hypoxia enhances chemo-responsiveness, and is likely to exacerbate ventilatory instability in susceptible individuals[35]. This may at least partly explain the frequent observation in some ILD patients, where repetitive apnoeas are unmasked during REM sleep when hypoxia is most pronounced[20].

As might be expected, daytime hypoxia has been identified as a predictor of night-time desaturation in a number of studies[16,21,36,37]. Severity of lung restriction and degree of desaturation with exercise, on the other hand, do not correlate well with nocturnal hypoxia[1,16,21,37,39]. Respiratory drive during wakefulness, (measured as the change in ventilation in response to changes in PaCO₂), shows a tight negative correlation with the degree of desaturation in both REM and NREM sleep in ILD patients[37], suggesting the innate chemo-responsiveness of the individual will also influence susceptibility to hypoxia. It is possible also that repeated severe episodes of nocturnal desaturation will eventually blunt this responsiveness, further perpetuating the problem as the disease advances.

Although there is widespread practice to provide supplemental oxygen for chronic lung disease patients with significant sleep desaturation, there is very little supportive evidence. In the COPD literature, the survival benefit derived from continuous oxygen therapy has not been demonstrated with overnight supplementation in those with nocturnal hypoxia only[40-42]. There is some suggestion that pulmonary haemodynamics may be improved in COPD patients with long-term nocturnal oxygen[43].

Only two studies have looked at the acute use of nocturnal oxygen in ILD. By eliminating sleep-hypoxia with supplemental oxygen, Shea and co-workers were able to demonstrate a fall in both f and minute ventilation compared with awake values, approximating those of normal controls[44]. Vazquez studied ILD subjects at 2240 m above sea-level, breathing air or oxygen on two separate nights[45]. Not surprisingly, all were hypoxic at rest (mean PaO₂ 51 mmHg). With the addition of low-flow oxygen during sleep, heart rate and f were reduced and oxygenation improved. Sleep architecture, efficiency and arousal index were not significantly altered. To date, there have been no studies to address whether sleep quality or haemodynamics may improve with long-term use in ILD.

Serum Endothelin-1 (ET-1), a vasoactive peptide believed to be important in the pathogenesis of pulmonary hypertension, has been measured in ILD patients during sleep, in a novel study by Trakada and colleagues[50]. During wakefulness, ET-1 was significantly higher in those with elevated pulmonary pressures. During sleep, ET-1 rose acutely in all patients during episodes of desaturation below 90%, and correlated with simultaneously measured PaO₂ concentrations and pulmonary arterial pressures. This very interesting research highlights a putative mechanistic pathway in the evolution of pulmonary vascular disease in ILD patients.

In summary, there is increasing evidence that nocturnal desaturation is not a benign phenomenon in ILD patients. In a large proportion, NOD occurs transiently and repeatedly throughout sleep, both with and without associated apnoeas. This may promote development of pulmonary hypertension, and is independently associated with higher mortality. Mechanisms of SDB and NOD are illustrated in Figure 2.

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Figure 2 Mechanisms of sleep-related pathology in interstitial lung disease. BMI: Body mass index; VQ: Ventilation-perfusion; ET-1: Endothelin-1.