PAH patients show clinical characteristics consistent with right-sided heart failure. Although the etiology and mechanisms behind the progress of PAH are unknown, the shortness of breath experienced by patients with PAH is similar to that experienced by patients with other pulmonary diseases. When exercise intensity increases, oxygen consumption for energy metabolism should also increase. Furthermore, respiratory rate and minute ventilation elevate as needed. Because Manes et al.16suggested that survival may be worse for patients who tend to desaturate at a greater extent during exercise and Morris et al.17reported that patients with PAH desaturated during the 6MWT, we aimed to investigate the exercise-induced desaturation during exercise and the severe COPD that may explain this phenomenon.
In advanced COPD patients, ventilation capacity decreases for the following reasons: reduced elastic lung recoil, increased airway narrowing, increased airway resistance, expiratory limitation, and dynamic hyperinflation.18 Furthermore, decreased FEV1, increased reserve volume, sputum accumulation, and large bullae disturb effective gas exchange. Breathlessness and desaturation eventuate from the imbalance between increased ventilatory demand and decreased ventilatory capacity.5 Severity of COPD, as classified by the Global Initiative for Obstructive Lung Disease (GOLD) criteria, correlates with prognosis.19 GOLD grade is determined according to airflow limitation and symptoms such as FEV1, as well as a medical history of acute exacerbation and functional capacity, as evaluated with the modified Medical Research Council dyspnea scale and COPD assessment test. In the study by Golpe et al., patients with a 6MWT score below 395 m or resting SpO2 below 86% showed poor survival probability (AUC = 0.80 and 0.80, respectively).20 Among COPD patients without resting hypoxemia, EID would be considered as the other critical factor. Casanova et al. showed that COPD patients with EID without resting hypoxemia had a higher mortality rate (67% vs. 38% in non-EID patients) and a relative risk of 2.63.21Shogo et al. revealed that EID was a predictive factor for the decline in the functional capacity of patients with COPD.22However, there are some studies that reported the existence of EID in patients with PAH, while there were no studies on the relationship between EID and outcomes. Therefore, the risk assessments suggested by the 2015 ESC/ERS guidelines do not include the occurrence of EID.5
In this study, half of the PAH patients showed EID during the 6MWT, and they showed lower 6MWD and FEV1. Interestingly, functional class—categorized by subjective symptoms—did not influence the occurrence of EID. There was no statistical difference in the distribution of WHO classifications in the EID and non-EID groups. Further, Manes et al. demonstrated that patients in different clinical subgroups showed hemodynamic and survival differences but no WHO functional class differences.16 Therefore, subjective symptoms during daily living or exercise are insufficient to evaluate PAH patients, and PFT and exercise testing with monitoring of oxygen saturation should be evaluated.
Andrianopoulos et al. reported that the sensitivity of a baseline SpO2 ≤ 95% for the prediction of EID was 81.0%, specificity was 49.2%, and positive and negative predictive values were 50.8% and 80.0%, respectively.7 Additionally, they suggested that a DLCO < 50%, an FEV1 < 45%, and a PaO2 < 10 kPa could predict the occurrence of EID. In this study, 6MWD, percentage of predicted 6MWD, percentage of predicted DLCO, percentage of predicted FEV1, and VO2peak were correlated with EID. We suggest that a PSEID predictive scale include these factors, as well as the presence of ILD and sarcopenia. These tests are commonly used for PAH patients. Further, as mentioned in the above results, the predicted accuracy of the PSEID was higher than expected, with 90% sensitivity and specificity. Thus, it would be applicable for clinical use. However, as there is a limit to conducting research on PAH patients in a single center, it is believed that such a “PSEID” needs to be extended to a multi-center study in order to be useful in clinical use.
There was no significant difference regarding the comorbidities in the two groups in this study. However, this could be a statistical error given the small sample size. Four of 10 patients in the EID group were diagnosed with interstitial lung disease (ILD) on chest CT scan. In contrast, none of the 10 non-EID patients had ILD. For the reasons mentioned above, we assume that PAH etiology would not be different between the two groups. PAH with connective tissue disease (CTD) was found in one of 10 patients in the non-EID group and four of 10 patients in the EID group. Four CTD patients showed ILD patterns on chest CT, and they also showed significantly lower DLCO. Considering the correlation between nadir SpO2 and DLCO in the Pearson’s correlation analysis (r = 0.49, p = 0.03), the small sample size might have affected these results.
Casanova et al. demonstrated that the consequences of EID in COPD would suggest a poor prognosis.21However, there is no consensus that the occurrence of EID in PAH patients would increase mortality. In this study, we defined ER visits, re-admission, heart or lung transplantation, and death as events. EID affected the occurrence of events with statistical significance (OR = 13.50, 95% CI 1.20–152.21). Serious events, such as death or lung transplantation surgery, were observed only in the EID group.
Exercise based pulmonary rehabilitation and breathing retraining are effective therapeutic interventions that improve physical performance, shortness of breath, and the quality of life in COPD patients.23However, the effect of rehabilitation on the improvement of desaturation or FEV1 is still controversial because exercise could not restore the destroyed lung parenchyma and airways. In PAH, the safety and effectiveness of exercise training has now been well established. A meta-analysis of 16 trials found the overall risk of adverse events during exercise to be 4.7%.24Another meta-analysis found that exercise training led to improvements in the 6MWD, VO2peak, and peak workload.25Conversely, there is limited evidence on the effect of exercise on pulmonary vascular resistance and right ventricular pump function, and there are currently no studies investigating the effect of exercise on disease progression and survival. Further studies are necessary to investigate the effect of exercise-based rehabilitation on the occurrence of EID and improvements in PFT, particularly FEV1 and DLCO, and on the long-term prognosis.
This study had several limitations. First, we analyzed a small sample of patients. As mentioned, PAH is a very rare disease with a prevalence of 2.5–7.5 per 100,000 persons in Scotland and France.26, 27 Although there is no cohort data regarding PAH in South Korea, it is estimated that there are only 5,000 patients.28 This is considered a low prevalence; however, studies with longer durations including multiple centers are required. Second, this study was designed as a cross-sectional, observational study. Thus, long-term cohort studies are warranted to confirm the influence of EID on the prognosis in PAH patients.