Asthma rehabilitation at high vs. low altitude: randomized parallel-group trial

Asthma is a major global health problem affecting over 300 million people worldwide with increasing prevalence in developing countries [1]. Asthma causes respiratory symptoms (mainly cough, dyspnea), limitation of activity and exacerbations that may require emergency treatment [1].

The current Global Initiative for Asthma (GINA) has outlined that patients with asthma should be managed, according to their level of asthma control, which includes symptoms during the day, symptoms during the night, use of reliever medication, limitation of daily activity, pulmonary function and exacerbations [1].

Many patients with asthma can be adequately controlled with bronchodilators in combination with inhaled corticosteroids. However, some asthma patient suffer from refractory disease despite medical therapy [2] and even controlled patients have to be prepared for flare-ups. Besides the pharmacological treatment, rehabilitation programs might be beneficial for asthma patients. The GINA guidelines state to advice all patients with chronic airflow disease for rehabilitation, whereas high altitude treatment has evidence level C [1].

Rehabilitation contains not only physical training and breathing exercises but also education, including smoking cessation [3, 4] aiming to deliver a profound insight into the disease and the ability to adequately react on exacerbations [5].

For decades, asthma patients have been sent to altitude clinics aiming to improve asthma control [6, 7]. At high altitude there is less allergen exposure [8, 9], e.g. house dust mites do not exist > 1600 m above sea level (asl). A factor that might also mitigate a potential beneficial effect of altitude exposure on asthma control is the dry and generally less polluted air resulting in less inflammation [10, 11] and improved respiratory function [12]. In addition, the decreased air density at altitude leads to reduced airway resistance [13], which might additionally help to increase exercise capacity for asthmatics at altitude. The mountain environment may also signify less psychosocial stress for many patients having the opportunity to leave their everyday environment behind and enjoy a pleasant stay at altitude. Stress is associated with reduced sensitivity to endogenous glucocorticosteroids and chronic psychological stress has been associated with asthma exacerbation, whereas stress reduction seems to improve asthma control [14, 15].

Kyrgyzstan is a lower middle- income country with less access to advanced drug therapies [16]. Thus, allergen avoidance along with an intense asthma education and rehabilitation program is potentially of even greater importance in order to avoid disease exacerbations or chronification due to low asthma control.

As in the Swiss Alps, since many years asthma patients have been taken to Tuja Ashu, a high-altitude clinic located at 3100 m asl in the mountain area of the Kyrgyz Republic to improve asthma control. However, randomized controlled trials, which compare the effect of asthma rehabilitation at high compared to low altitude are completely lacking. Whether the reported positive effect of asthma rehabilitation at Alpine resorts is due to hypobaric hypoxic environment at altitude with less allergen exposure or due to the comprehensive rehabilitation program, including patient education and exercise or both is not clear to date.

We aimed to study a specific in-patient asthma rehabilitation program and its effectiveness on asthma control and investigated the effects of performing the rehabilitation at the Tuja Ashu high altitude clinic (HA), 3100 m, in comparison to the same program performed at low altitude in Bishkek (LA), 760 m. We hypothesized that a 3-week rehabilitation at high altitude improves PEF-variability and ACQ compared to a low altitude 3-week rehabilitation. Additionally, we hypothesized the effects would be sustained at 3 months follow-up.

Of 159 eligible patients 50 were included in the study: 25 per group with one patient in each group not receiving the intervention (one for professional and one family reasons), see study flow chart Fig. 1. Therefore, the analysis was performed per protocol on data from all participants undergoing rehabilitation. Baseline characteristics are shown in Table 1.

This is the first randomized controlled trial which investigated the additional effect of undergoing a 3-week rehabilitation program at HA (3100 m) vs. LA (760 m) on asthma control in patients with uncontrolled asthma. We found that a comprehensive 3-week rehabilitation program including education, endurance training, muscle- and breathing exercise significantly improved asthma control both at low and high altitude. The effect of the rehabilitation at HA was not superior compared to the same rehabilitation program at LA in ameliorating asthma control as assessed by the ACQ and PEF-variability. Nevertheless, rehabilitation at HA was well tolerated and led to a better improvement of exercise capacity (STS) and airway inflammation assessed by FeNO. In addition, regression analysis revealed that the overall improvement in PEF-variability from baseline to 3 weeks was better in the HA vs. LA-group when controlling for relevant confounders such as age, gender and the baseline absolute PEF. Thus suggesting that patients with a higher baseline PEF-variability may benefit more from a rehabilitation at altitude.

For many years, asthma patients are taken to HA in order to improve their asthma control in a presumptively cleaner environment with less allergen exposure. The effect of training at altitude (1600 m asl) on asthma control was investigated in a prospective, uncontrolled study by Rijssenbeek-Nouwens and coworkers [7], which showed that sensitized and unsensitized patients improved their ACQ score by 1.4 and 1.5 after 12 weeks. However, as this study was lacking a low-altitude control group, it remains unclear whether the favorable effect was due to altitude exposure or the educational and exercise training per se.

In the present randomized trial, we could not show an additive effect of providing the rehabilitation at HA vs. LA on our primary outcome. This extends data from a previous non-randomized study suggesting that that allergen avoidance during HA sojourns improved bronchial hyperresponsiveness in adolescents with severe asthma [6]. Additional benefits of HA than mere allergen reduction have been postulated such as dryer, thinner and cleaner air, less fungi and an increased vitamin-D production due to increased exposure to sunlight [8].

In our study, the vast majority of participants (92%) had atopic asthma, but the improvements found with the rehabilitation at HA were similar as with the same program performed at LA. Nevertheless, we found a significantly greater reduction of FeNO in patients undergoing HA- vs. LA rehabilitation. This may point towards less airway inflammation in the HA-group. The findings are especially remarkable as FeNO measurements were performed at 760 m on the day after return from HA presumably when patients were already re-exposed to some allergens and other noxious stimuli. Our data are in line with previous reports of beneficial effects of HA rehabilitation in adults and children on FeNO and asthma control in both, allergic and non-allergic asthmatics according to nonrandomized studies [7, 11, 22].

Several randomized trials showed a positive impact of physical exercise and training on asthma control [5, 23‐25] and maximal performance but no improvements in lung function [26]. Our study confirmed that a 3-week comprehensive rehabilitation program at both low and high altitude was highly effective to render sustained improvements in asthma control, quality of life and exercise capacity directly after the rehabilitation and up to 3 months.

We could show that exercise capacity assessed by the 6MWD and the STS improved significantly with our comprehensive 3-week rehabilitation program and the improvements were maintained up to 3 months follow-up, potentially due to the continuation of daily exercise according to the programs instruction in this highly motivated asthma collective. The improvement in exercise capacity found in both our groups where slightly smaller compared to other studies, assumedly because the rehabilitation lasted 3 weeks compared to 12 weeks [7]. Another study with a 12-week rehabilitation program at low altitude increased the exercise capacity in terms of the VO₂ max and the total treadmill time [27]. Whereas the improvements in 6MWD were similar in the group that trained at HA vs. LA, we found a better improvement of the STS test in the HA vs. LA-group. This may point towards a higher effect of training at HA on exercise performance after return to LA. Such beneficial effects of altitude training have been previously described for many athletes and HA-training has been incorporated in training plans due to its increase in hemoglobin and thus oxygen transport [28]. Of interest, the additive effect of HA rehabilitation on the STS were maintained up to 3 months and might be at least partly explained by a significant increase in hemoglobin in the HA-group.

The significant improvement of asthma specific quality of life reflects an important effect of rehabilitation that was achieved to a similar degree in the HA and LA group. Also all sub scores of the AQLQ improved after the rehabilitation and remained at this level at 3 months follow up in both groups without difference between groups.

The program was well tolerated by patients at both locations, expect one patient at altitude who suffered from mild AMS (headache), no adverse events occurred. Intrinsically, it was not possible to blind investigators and patients to the intervention, and thus other factors than altitude and rehabilitation such as being away from home or factors concerning comfort might have played a role in the outcomes. However, this would be the case with any rehabilitation program all over the world. Among the participants of our study, there were no current smokers. Thus, our results may not be transferable to smoking asthmatics. The current study population revealed a relatively low and thus favorable daily PEF-variability and it may well be that the effect of a rehabilitation program including education and training would have been different, potentially even better, in a more compromised asthma collective. Despite these limitations, this study is of particular importance because of its robust design as a randomize trial.

In the present randomized trial, we could show that a 3-week comprehensive asthma rehabilitation program including a clear action plan, peak flow diary, patient education, respiratory exercises, force and endurance training is highly effective in sustainably improving asthma control in terms of the Co-primary outcome asthma-related quality of life (ACQ) and PEF-variability, but also exercise performance and this positive effect was irrespective of the altitude is the rehabilitation program was performed.