The present study investigated the effect of exercise training under the support of NPV for patients with severe RLD. This study was designed in a prospective controlled setting. The between group difference in Δ6MWD, the primary end point, reached statistical difference in favor of the NPV-exercise group. An improvement in SGRQ was also seen in the NPV-exercise group compared with the control group.
Although exercise training PR programs can improve exercise capacity and HRQoL in patients with RLD for those with severe disease , it tends to be intolerable. The patients enrolled for PR training in the present study (FVC 32.5 ± 11.7% predicted) appeared to be more severe than those in previous reports (FVC 48–68% predicted) [7–9]. Almost none of the patients were able to perform functional exercise tasks because of severe ventilation impairment accompanied with muscle weakness and deconditioning. Muscle weakness can be overcome by ventilation support as demonstrated by Borel et al . With the assistance of NPV, all patients in the study group well tolerated the exercise PR program, and they also achieved even better results (difference in 6MWT between groups 66.6 m) than those demonstrated in earlier reports (35.0–46.3 m) [7, 8]. This difference is greater than the minimal clinical important difference (MCID) for COPD (54 m)  and that for idiopathic pulmonary fibrosis (24–45 m) . Nevertheless, our patients comprised a heterogeneous group of patients with different diseases, for most of which the MCID has not been defined. Whether the improvement in exercise capacity reaches clinical significance needs further study to confirm.
Ventilation support by using NPPV can unload ventilator muscles, leading to a reduction in breathing work and dyspnea sensation . This unloading has also been demonstrated to improve peripheral muscle oxygenation in the absence of changes in systemic oxygen delivery in patients with advanced COPD during high-intensity exercise, probably due to redistribution of cardiac output to appendicular muscles . This will not only allow a greater intensity of exercise but also allow it to be sustained for longer periods to achieve a training effect . Although not proven directly, NPV may also benefit patients with severe RLD through similar mechanisms such that patients may be able to tolerate exercise training to an extent of adequate intensity. Increased peripheral muscle oxygenation may also contribute to a better training efficacy. Although more data is necessary to support this theory, this concept may be a rationale to introduce NPV during exercise training for patients with RLD with less severity, or even other respiratory diseases such as COPD.
The present study showed that an NPV-assisted exercise program remarkably improved health-related quality of life (HRQoL), as demonstrated by the SGRQ scores. Patients in the NPV-exercise group had clinically significant decreases in total and almost all components of the scores, e.g. symptoms, activity and impact. This is consistent with most previous reports observing the effects of exercise training on HRQoL in a range of RLD using the Chronic Respiratory Disease Questionnaire [8, 9] or the SGRQ . Both resting and post-exercise dyspnea sensation, determined by the Borg score, also improved. This improvement was not associated with changes of muscle power or O2 saturation. Interestingly, we observed a significant increase in pulmonary function, including FEV1 and FVC, after 12 weeks of training. Importantly, the increase in FVC (2.5% predicted) reached the recently defined minimal clinical important difference for IPF , in which the small changes of 2–6% were thought to be clinically important. This was not seen in previous reports on exercise training for RLD patients [8, 9]. Further study is needed to see whether this improvement in pulmonary function has clinical significance. Of note, Smith et al. reported their experience of treating kyphotic patients with nocturnal non-invasive ventilation, either with an individually constructed cuirass shell and a negative pressure pump or nasal intermittent positive pressure ventilation, long-term use of which resulted in a significant increase in FEV1 and FVC . As the between group difference in FVC in the present study, albeit with a trend, was not statistically significant, further studies enrolling more patients is necessary to confirm our observations.
The present study did not include a group of NPV without endurance training. It is therefore not conclusive whether the study group got benefits from NPV and/or exercise training. Guzun et al. recently reported that physical training at mild intensity, even below the level expected for a physiological training effect, can induce comparable changes in skeletal muscles oxidative energy metabolism in patients with COPD and sedentary healthy subjects . Thus it is interesting to conduct a study to explore the pure effect of NPV or NPV with physical activity of mild intensity.
A limitation of the study is the non-randomized design. This is dictated by the fact that few patients were willing to be randomized in such kind of intervention. Nevertheless, the baseline characteristics were similar between the two groups such that a skewed population in each group, although cannot be completely excluded, became less likely. In addition, there is heterogeneity of patients. Subgroup analysis revealed that NPV-exercise training benefited both ILD and CWD patients in HRQoL. Whereas this training improved exercise capacity and pulmonary functions in ILD patients, it only had a trend of improvement (exercise capacity) or no effects (pulmonary functions) in CWD patients. Whether this training has clinically relevant effects on exercise capacity in these patients needs to be confirmed in a larger scale of study.