Chronic obstructive pulmonary disease (COPD) is defined by airflow limitation and is a complex pathological condition. COPD is associated with an important reduction in physical activity that contributes to the patient's disability and poor health-related quality of life. Pulmonary rehabilitation (PR) is aimed to eliminate or at least attenuate these difficulties.1,2 Therefore, PR has been recommended as an integral part of management for patients with COPD.3,4 However, the responses to PR may vary significantly among individuals. Although there are many studies mentioning changes of FEV1, FVC, FEV1/FVC after PR, in some studies, significant changes in forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC values were not detected after PR.5–8

The diffusing capacity for carbon monoxide (DlCO) is a common and clinically useful test that provides a quantitative measure of gas transfer in the lungs.9 The decrease in DlCO, one of the first signs of disease progression, can point out the arterial O2 desaturation during exercise. For COPD patients with low DlCO values pose a high risk for poor survival.10 Although PR is known to have many effects on functional outcomes of COPD patients, there is not enough information about the diffusion capacity in terms of PR outcome.2 Also in a recent study authors suggest that diffusing capacity was the strongest predictor of exercise capacity in all subjects with COPD.11 Therefore can CO diffusion capacity be used to evaluate which patient will benefit more from PR program? Moreover will there be a significant change in CO diffusion capacity after PR program in patients with COPD?

The aim of our study was to compare the results of PR program on exercise capacity (6mWT) between COPD patients with moderate and severe diffusion defect detected by DlCO. Our secondary aims were comparing the results of the program on arterial blood gas analysis, dyspnea sensation, exercise capacity, quality of life and psychological symptoms between two groups.

We conducted a prospective cohort study to compare the effectiveness of exercise training in COPD patients with moderate and severe diffusion defect. The study was approved by the local institutional review board. Patients included in the study completed an informed written consent form.

In this study we found significant improvement in oxygenation (PaO2), severity of dyspnea, exercise capacity and quality of life parameters in patents with moderate and severe diffusion defect after PR program. Additionally FEV1 and DlCO increased significantly in patients with severe diffusion defect. When comparing changes between groups; improvement in dyspnea sensation was significantly higher in patients with severe diffusion defect.

All studies about effects of pulmonary rehabilitation on lung function have investigated FEV1, FVC, FEV1/FVC and blood gas analysis. There are few studies conducted on investigating the effect of PR program on different DlCO groups.21,22 COPD is characterized by high morbidity and mortality. It remains unknown which aspect of lung function carries the most prognostic information. In a study of 604 COPD patients which were clinically stable it was concluded that DlCO was the most powerful predictor of survival.23 In another study in patients with COPD it was emphasized that FEV1, IC and DlCO were higher predictive regarding exercise capacity and DlCO was the strongest predictor.11 In a 5-year follow up study it was found that decline in 12-minute walk test was mainly explained by deterioration in DlCO and this measurements at baseline were the most important predictors of declining exercise capacity in COPD patients.24

Single measurements of DlCO in patients with COPD have shown that a reduced value in early disease is associated with accelerated decline in FEV1 and in advanced disease it predicts exercise capacity and mortality. In population studies a reduced DlCO predicts all-cause mortality more strongly than a reduced FEV1. It also stated that repeated measurements of CO transfer in individuals were needed to increase the present poor knowledge of the natural history of the contribution of alveolar disease to the progression of COPD.25 In a study performed in heavy smokers lower diffusing capacity was found to be directly correlated with decline FEV1/FVC ratio and a greater progression of CT – quantified emphysema.26 Mohsenifar et al. demonstrated that patients with reduced DlCO, particularly when <20% of predicted, were more likely to have reduced PaO2 at rest and were more likely to require supplemental oxygen with low levels of activity. They pointed out DlCO was useful in evaluating whether supplemental oxygen is required for exercise.27 In our study, consistent with the other studies, FEV1, FEV1/FVC, PaO2, SaO2, exercise capacity and quality of life scores were significantly lower in patients with severe diffusion defect before pulmonary rehabilitation.

Pulmonary rehabilitation has emerged as a recommended standard of care for patients with chronic lung disease.1,28 It has been demonstrated to improve exercise capacity, reduce symptoms of dyspnea and increase health-related quality of life.28,32 Pulmonary function tests showed different results after pulmonary rehabilitation in previous studies. In most of them, significant changes in FEV1, FVC and FEV1/FVC values5–8 were not detected. Because rehabilitation is a multicomponent intervention the results are controversial. In a study of 24 patients with COPD who carried out at least half an hour of pranayama breathing exercises for 3 months, despite significant increase in PEF values, there was no significant increase in FEV1 and FVC.33 Cecily et al. had observed that as well as FEV1 and FVC the value of PEFR (peak expiratory flow rate) significantly had increased in 100 patients with COPD.34 Shebl et al. concluded that FEV1 increased only in severe COPD but FVC and FEV1/FVC ratio was increased in the medium and severe COPD after the supervised two- month home based exercise program. However, these increases were not statistically significant.35 In a study comparing differences of improvement by gender, FEV1 and FVC increased in both; however they were greater in males after pulmonary rehabilitation program.36 When 225 patients were assessed according to severity of COPD; FEV1 increased significantly in stage 3 and 4, VC (vital capacity) increased significantly to 2.3 and 4, TLC (total lung capacity) decreased significantly only in stage 3, RV (residual volume) were significantly decreased in stage 3 and 4 after pulmonary rehabilitation program.37 Unlike other studies, after pulmonary rehabilitation for 3 years, there was not a significant fall in FEV1 at the end of the 3rd year.38

Changes in arterial blood gas were evaluated less and the results vary in previous studies. In some of the studies PaO2, PaCO2 and SaO2 did not change6,29 but in some other studies both PaO2 and SaO2 increased significantly after pulmonary rehabilitation.21–39 A study that assessed blood gas analysis according to severity of COPD showed that PaO2 increased significantly with stage 3 and 4, PaCO2 decreased significantly in stage 4 diseases after PR.37 There are few studies evaluating changes in diffusing capacity after PR. In a previous study conducted in our clinic there was a significant increase in DlCO level after 8 week outpatient rehabilitation program in 44 patients with COPD.21

Zanini et al. divided moderate to severe COPD patients (n: 75) into two groups depending on the change in 6MWT (responders >30m and no responders ≤30m). They showed that FEV1<50% pred. and TLCO<50% pred. were independent predictors of PR efficacy. They also found that complex COPD patients with poor lung function got more benefit from PR.39 Sixty patients were stratified into subgroups according to airway obstruction (FEV(1)>= or <50% predicted), pulmonary hyperinflation (TLC>or < or =120% predicted), BMI value (BMI > or < or =25), cardiovascular (CV) comorbidity, and resting PaO(2) (PaO(2)>= or <60mmHg) levels, suggesting that subjects with poorer exercise capacity or quality of life had greater room for improvement.40 An observational study, which included 102 COPD patients who followed PR showed that patients with worse disease status (i.e. a combination of lower FEV1, more hyperinflation, lower exercise capacity and worse quadriceps force) improved most in endurance exercise capacity.41 Our results were similar to the results of these studies; although it did not reach statistical difference, there was an improvement in the exercise capacity of the patients with severe diffusion defect when comparing with the patients having moderate diffusion defect. It is possible that the improvement in 6MWT partially reflects the gain in DLCO and lung function or simply reflects the fact that subjects with worse COPD have more room for improvement than those with mild COPD. It may also indicate that emphysematous COPD subjects have a better chance of improvement from rehabilitation than chronic bronchitis. In addition, PaO2 and O2 saturation values were significantly increased in both groups with a little difference in favor of the patients with severe diffusion defect. In COPD patients, exercise capacity may decrease as a result of exercise intolerance, ventilation and gas exchange impairment, cardiac failure and pulmonary muscle dysfunction or combination of them. Hypoxia due to gas exchange dysfunction may directly or indirectly decrease exercise tolerance.20 DlCO which is a good predictor of gas exchange dysfunction can also predict exercise restriction perfectly.11 Older textbooks suggest that thickening of the alveolar-capillary membrane (in interstitial lung disease) and loss of alveolar membrane surface area (in emphysema) are the primary causes of a low DLCO.42 However, new experimental data suggest that diseases that influence the DLCO do so by reducing the volume of red blood cells in the pulmonary capillaries.43 In healthy adults total volume of blood in lungs is less than 150ml at rest.43 Diseases which reduce alveolar-capillary surface area cause a reduction in the blood volume in the lungs. The blood volume in the pulmonary capillaries and the DLCO are increased during exercise.42 Therefore, we hypotheses that the increase in DLCO after PR may be due to the recruitment of pulmonary capillaries after exercise.

Patients with severe diffusion defects usually avoid exercise in daily life. However, PR program including aerobic and reinforcement exercise combination may improve their muscle power, exercise performance and quality of life, and may give them the courage to compete with their dyspnea symptom.44 Improvement in DlCO and FEV1 in this group of patients may reflect the success in muscle exercise as a result of recruitment of pulmonary capillaries. Also by breathing exercises it is possible that the exercise may reverse some dead space ventilation, and make new areas of alveolar more available to gas exchange.

Seventy-four stable COPD patients were grouped according to MMRC dyspnea scale and evaluated after PR. There was an improvement in 6-minute walking test and SGRQ only in the patients with dyspnea score: grade 1/2 and grade 3/4 while the improvement in grade 5 patients was very limited. The authors suggested that baseline state is a poor predictor of response to rehabilitation.45 Despite that, in our study, baseline DlCO levels were good predictors for better PR outcome. Although the MMRC and BORG scores were higher in patients with severe diffusion defect, these scores significantly decreased after PR. Also walking distance within group 2 (not statistically significant between groups) was increased significantly after PR. When the two groups were compared in terms of MMRC and BORG dyspnea score changes, the augmentation of MMRC and BORG score was significantly higher in patients with severe diffusion defect. Additionally, anxiety score was the only parameter decreased in patients with moderate diffusion defect whereas both anxiety score and depression score were decreased in patients with severe diffusion defect.

We concluded that pulmonary rehabilitation improves oxygenation, severity of dyspnea, exercise capacity and quality of life in patents with COPD independent of carbon monoxide diffusion capacity levels. Furthermore pulmonary rehabilitation may improve DlCO and FEV1 values in COPD patients with severe diffusion defect. However long-term follow up studies are needed to have the best results from rehabilitation programs.

The authors have no declarations of interest to report.

The authors have no conflict of interest.