Exercise training for lung transplant candidates and recipients: a systematic review

Exercise capacity: pre-transplant

Seven of the nine studies reported improvements in exercise capacity following completion of an exercise programme prior to lung transplantation. Of these studies, two were inpatient (3–6 weeks) and five were outpatient programmes (8–12 weeks), with no observable benefit of one approach over the other. The 6MWT is commonly used in pre- and post-operative evaluation and has proven beneficial in determining the effect of therapeutic interventions, due to its prognostic value [6, 52]. It has also been found to correlate with V_O2peak in candidates for lung transplantation [53]. The improvements presented in the seven studies all exceeded the MCID for 6MWT distance for patients with chronic lung disease, which have been reported as >30 m for COPD [49], >22–37 m for ILD [50], and 33 m for pulmonary hypertension [51]. Currently, evidence for the MCID in cystic fibrosis is lacking. Despite this, direct causation cannot be confirmed, due to the lack of a no-treatment control group in eight of the nine studies.

The RCT comparing interval and continuous training did not confer any benefit of one approach over the other, in terms of functional or maximal exercise capacity [42]. This finding agrees with that of Beauchamp et al. [54], where interval and continuous training were deemed comparable in patients with COPD. However, interval training was associated with lower training symptoms and therefore may be used as alternative, more tolerable method of training [42]. Of the two studies showing no improvement in 6MWT distance, the intervention implemented by Li et al. [45] was significantly longer (∼16 weeks) compared to other pre-transplant studies (3–12 weeks) in this review [18–20, 42–44]. Therefore, this longer time period may have resulted in greater disease progression and risk for exacerbation. It is also important to note that a criterion for lung transplant listing is a survival prognosis of less than 2 years, therefore maintenance of 6MWT distance pre-transplantation could be considered a positive finding, as functional deterioration can occur rapidly during the waiting period. Indeed, the pilot study by Singer et al. [21] was the first to introduce home-based tele-rehabilitation prior to lung transplantation, and demonstrated maintenance of 6MWT distance, although this could also be due to the small sample size (n=15). Overall, the intervention [21] was well received and safe, hence, further investigation in the form of an RCT should be conducted to determine the true effect of this novel intervention, that could confer similar benefits to supervised exercise training, but without the financial and logistical demands.

The above findings confirm and expand those reported in the review by Hoffman et al. [10], in which a significant improvement in 6MWT distance was found in four of the six studies included. Since the review by Hoffman et al. [10], more observational studies have added to the evidence base; however, RCTs are still lacking. A possible reason for the lack of RCTs in this population is that as exercise-based pulmonary rehabilitation has become a well-recognised treatment in patients with chronic respiratory diseases [55–57], obtaining a non-exercising control group is difficult and potentially unethical.

Exercise capacity: post-transplant

All 12 studies conducted post-transplantation reported an improvement in at least one measure of exercise capacity. However as only one study compared exercise training to a non-exercising control group [22], it is difficult to draw definite conclusions. Nevertheless, in this study [22] the improvement in 6MWT distance was significantly higher in the intervention group than the control group, both at 12 weeks and 1 year. This study scored well on the quality assessment, providing robust evidence that exercise training has a beneficial effect on functional exercise capacity, which reflects the capacity required to undertake activities of daily living [58]. However, this evidence is restricted to the participant age range of 40–65 years highlighting a need for future RCT's in younger lung transplant recipients [22]. It should be highlighted that the control group in the study by Langer et al. [22] demonstrated an improvement of 132 m over the 12-week intervention period. Thus, the natural course of recovery from lung transplantation can result in clinically significant increases in 6MWT distance, even when additional exercise training is not undertaken. This supports the fact that although all single-arm studies showed significant enhancements in 6MWT distance, definite cause and effect cannot be determined.

Langer et al. [22] found no significant improvement in maximal exercise capacity (V_O2peak (% predicted) or PWR (% predicted)) immediately post-intervention. Despite this, V_O2peak (% predicted) was 71% in the exercise training group at 12 weeks and 78% at 1 year, which exceeds the values commonly reported in the first year following lung transplant of 40–60% of predicted normal values [59, 60]. The higher V_O2peak (% predicted) values shown in this study may be due to only patients with an uncomplicated post-operative period being included. Therefore, this does not represent patients having a prolonged hospital stay, who are likely to exhibit lower exercise capacity as a result of prolonged deconditioning. In recipients 12–18 months post-transplant, Stiebellehner et al. [48] demonstrated significant improvements in V_O2peak after aerobic training; however, these values were still limited to 65% predicted. It is noted that prior to initiating the exercise programme, patients were followed for 6 weeks and showed no significant change in V_O2peak and PWR. The comparison between the control and intervention period improves the internal validity of this cohort study, by attempting to differentiate the effect of the training intervention from natural recovery.

Both inpatient and outpatient exercise training significantly improved V_O2peak in recipients 4.5±3.2 years following transplant [23]. Thus, exercise training is beneficial in the long-term and short-term management of lung transplant recipients. It is known that chronic exercise limitation following lung transplant is predominantly due to impaired oxidative capacity of skeletal muscle which is exacerbated by immunosuppressive medications [11], thus optimising peripheral muscle function is an important goal of exercise training [61]. Gloeckl et al. [30] concluded that WBVT may be used as a complimentary therapy to exercise training, demonstrating further enhancements in exercise capacity. This is thought to be due to the mechanical vibration eliciting neuromuscular adaptations.

The previous systematic review looking at exercise training interventions post-transplantation [16] showed a positive effect on exercise capacity (maximal or functional) in four studies. This review expands significantly on those findings, with 12 studies exhibiting improvements in at least one measure of exercise capacity. In addition to strengthening the evidence base, this review includes studies examining the effect of different modes, doses and settings of exercise training on exercise capacity.

Quality of life: pre- and post-transplant

The most common measure of QoL was the SF-36 questionnaire, which is a global measure of HRQoL [62]. Prior to transplantation, improvements in SF-36 PCS scores ranged from 2 to 4 points and MCS from 2 to 10 points. Currently, the interpretation of changes in SF-36 scores is challenging, as the MCID for lung transplant candidates has not yet been defined. General recommendations for the tool suggest a MCID of four points [2], and a study conducted in IPF patients proposed a MCID of >2–4 units for PCS and MCS scores [63].

Notably, interval training was associated with a significant improvement in SF-36 MCS scores over time, which may be partly attributed to the lower training symptoms (dyspnoea and leg fatigue) associated with this mode of training [42, 64]. Although Li et al. [45] found no improvement in QoL scores, measures reflecting physical function (SF-36 PCS, SGRQ activity domain) were better preserved than other HRQoL measures (e.g. SF-36 MCS). Comparison of HRQoL in lung transplant candidates to normative populations has typically shown greatest impairment in physical function rather than mental health domains [37], highlighting the importance of maintaining or improving this aspect.

After transplant, Langer et al. [22] found no significant difference in HADS scores between the exercise training and control group. This may be related to low baseline scores indicative of sub-clinical levels of anxiety (intervention=5.0±3.4 versus control=7.1±4.1) and depression (3.8±3.4 versus 4.5±3.5) [65]. As such, there was little scope for improvement in this outcome domain, particularly in the intervention group. This is supported by the significant improvement in HADS scores reported by Candemir et al. [25], in which baseline scores were 10±1 and 9±1 for anxiety and depression, respectively.

The improvements in the SF-36 PCS and MCS scores following exercise training [24, 26] well exceeded the estimated MCID (>2–3 units) proposed for lung transplant recipients [66]. A multi-centre study [67] exploring the trajectory of QoL from pre-transplant to 1 year post-transplant without exercise training, reported significant gains in PCS score (+10.9), demonstrating a natural course of physical QoL improvement. This is likely due to marked improvements in pulmonary function, resulting in reduced symptom burden and enhancing the ability to complete everyday activities. However, in this observational study MCS remained unchanged. This indicates that exercise training has a beneficial impact on this QoL component, as improvements in this domain were evident in studies implementing exercise training [24, 26]. Since the review by Wickerson et al. [16] which incorporated one study evaluating QoL, further studies have shown a beneficial impact of exercise training on QoL [22, 24–26, 30], adding to this preliminary evidence. Besides survival, improving QoL is one of the key objectives of lung transplantation, hence interventions that can enhance QoL following the procedure are of great importance.

Clinical outcomes

The evidence pertaining to exercise training and post-transplant clinical outcomes is sparse. Since the last systematic review [10] however, a quasi-experimental study has concluded that pulmonary rehabilitation conducted before lung transplantation halved the risk of mortality and reduced the risk of prolonged ICU and hospital stay [17]. This study [17] is limited by its design, as lack of randomisation may have led to potential selection bias. Additionally, the study [17] only included those with IPF, so findings cannot be extrapolated to all transplant patients.

Safety of exercise training

Limited studies (38%) report data on safety; however, in those that did, no adverse events related to exercise training were reported. This highlights the inconsistent and inadequate reporting of safety in exercise training trials in lung transplant patients, a population that has an increased risk for complications and comorbidities.

Strengths and weaknesses of this review

To our knowledge, this is the first systematic review to synthesise the effects of exercise training in both lung transplant candidates and post-transplant recipients. The review was conducted in a rigorous manner in accordance with PRISMA guidelines [32]. Specific search terms were used to identify appropriate articles and bias was minimised through independent screening by two investigators, using pre-defined criteria. Limitations to this review include the lack of RCTs (five out of 21 studies) and absence of a comparator group or a priori sample size calculations in most studies. As such, it was not possible to perform a meta-analysis due to multiple sources of heterogeneity, including type of exercise training intervention, study design and outcome measures. Additionally, participants across studies varied in underlying respiratory disease and age. Currently, there is little evidence on the effect of exercise training on clinical outcomes; however, the single study included does show a survival benefit [17]. Additional research is needed to establish the efficacy of home-based exercise training interventions. Future studies implementing exercise training should ensure consistent reporting of safety outcomes (e.g. adverse events), as this information is important for decision making by regulators, policy makers and health-care professionals. Findings should be interpreted with caution due to the single-arm study designs implemented in most studies, limiting the ability to establish definite cause and effect. Nevertheless, the review represents the best available overview of the current evidence base for exercise training pre- and post-lung transplantation.