Training,detraining,and retraining: Two 12-week respiratory muscle training regimens in a child with infantile-onset Pompe disease

1. Introduction

Pompe disease (glycogen storage disease type II, acid maltase deficiency) is a progressive metabolic myopathy resulting from deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). The most severe phenotype is classic infantile-onset Pompe disease (IOPD) which results from a complete or almost complete absence of GAA. Onset is within the first days to weeks of life and signs and symptoms include hypertrophic cardiomyopathy, hypotonia, profound muscle weakness, motor delays, feeding difficulties, and respiratory insufficiency [3, 4]. Without treatment, death due to cardiorespiratory failure occurs by 24 months of age [5].

Relatively few options are available for the treatment of respiratory muscle weakness. The advent of enzyme replacement therapy (ERT) with alglucosidase alfa in 2006 (Myozyme TM ) has improved both overall and ventilator-free survival for children with IOPD [6, 7, 8, 9]. Variability exists in individual response to ERT, and appears to arise from multiple factors such as age at initiation of ERT, disease severity, genotype, and immunologic differences [5, 9, 10]. The first cohort of children with IOPD treated with ERT are now surviving into late adolescence, and implementation of newborn screening (NBS) programs in the US and other countries is reducing diagnostic delay and time to initiation of treatment [11]. Thus, the phenotype of long-term survivors continues to develop. While the need for invasive or noninvasive ventilation has decreased with earlier diagnosis and initiation of treatment [5, 9], respiratory muscle weakness persists in some children with IOPD despite treatment with ERT and may result in hypoventilation, reduced cough strength, and reduced tolerance of physical activity [2, 10, 12, 13, 14, 15].

Our laboratory has pioneered the use of respiratory muscle training (RMT) as a treatment for inspiratory and expiratory muscle weakness in individuals with Pompe disease. RMT is accomplished using hand-held respiratory trainer devices that provide calibrated, individualized, and progressive pressure-threshold resistance against inhalation (inspiratory muscle training [IMT]) and exhalation (expiratory muscle training [EMT]) [16, 17, 18, 19, 20]. We first described the use of a clinical RMT program in two adults with late-onset Pompe disease (LOPD) and severe respiratory muscle weakness [18]. RMT was well-tolerated and large increases in inspiratory and expiratory muscle strength were detected. These observations spurred systematic research to determine the effects of our 12-week RMT regimen using a single-subject experimental design replicated across participants. Participants in this 6-month study, including two childhood survivors of IOPD [2] and eight adults with late-onset Pompe disease (LOPD) [1], completed 12 weeks of RMT and were followed for 3 months of detraining. The primary outcome measures were maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP). These outcomes were assessed at pretest, posttest, and post-detraining, with the magnitude of change estimated using Cohen’s d statistic [21].

From pretest to posttest, all 8 adult participants demonstrated increases in MIP and 7 of 8 showed increases in MEP. Effect size data revealed the magnitude of change to be large to very large using conservative estimates. Across participants, pretest to posttest MIP and MEP increased by 19.6% and 16.1%, respectively. Increases in respiratory strength, particularly in terms of the inspiratory muscles, were generally durable to 3-months detraining [1]. In our two pediatric participants, one child demonstrated negligible to modest increases in MIP/MEP (6% increase in MIP, d = 0.25; 19% increase in MEP, d = 0.87), while the other participant demonstrated very large increases in MIP/MEP (46% increase in MIP, d = 2.40; 83% increase in MEP, d = 4.33). Following three-month RMT withdrawal, both pediatric participants maintained these strength increases and demonstrated maximal MIP and MEP values at follow-up [2].

We now report additional data from one of our pediatric participants who re-enrolled in the study and completed our 12-week RMT regimen for a second time. Although this participant made significant gains in response to training, she continued to demonstrate respiratory muscle weakness, particularly of the inspiratory muscles. Therefore, 4 months after completing the first 12-week RMT regimen, we offered her and her parents the opportunity to re-enroll in the research to determine if additional increases in respiratory muscle strength could be achieved with additional RMT.

We hypothesized that: 1) additional increases in inspiratory and expiratory strength would be achieved with additional RMT, 2) respiratory strength increases would be at least large in magnitude ( d ⩾ 1.00), and 3) peak MIP and MEP values over this participant’s entire participation would be achieved at posttest following the second course of RMT.

2. Materials and methods

The study was approved by the Duke University Institutional Review Board, and written informed consent was obtained from the participant’s parents after explaining the purpose and procedures of the study. This study was part of a larger investigation into the effects of RMT on respiratory muscle strength in participants with Pompe disease. Data from 2 participants with IOPD and 8 adults with LOPD were previously published [1, 2].

This report details the response of one of the 2 participants with IOPD following completion of a second 12-week regimen of RMT (RMT #2). The participant was recruited through the Duke Pompe Disease Clinical and Research Program. Inclusion criteria included confirmed diagnosis of Pompe disease via enzyme activity showing deficient GAA activity (skin fibroblasts, muscle, or dried blood spot assay) and mutation analysis showing two GAA gene mutations; ability to participate in an intensive RMT program; and ability to maintain a consistent amount of non-research related physical activity over the course of the study. Exclusion criteria included inability to perform the research protocol; medical problems that precluded meaningful study participation; inability to perform high-effort respiratory tasks; and profound respiratory weakness that would prevent RMT at the minimum pressure-threshold resistance offered by commercially available, FDA-approved RMT devices.

Participant demographic data at baseline for RMT #1 and #2 are provided in Table 1. In both 12-week RMT regimens, the participant was prescribed 9,000 total RMT repetitions (4,500 IMT and 4,500 EMT). During RMT #2, the participant reported completion of 4350 IMT repetitions and 4350 EMT repetitions for an overall total of 8700 RMT repetitions, representing self-reported adherence of 97% to the prescribed RMT program. On average, she completed her home therapy program approximately 5 days per week and both IMT and EMT were completed with a mean percent accuracy of 99% per self-report. Neither the participant nor her caregivers reported pain or other adverse side effects associated with RMT.

4. Discussion

Although ERT prolongs ventilator-free survival [7, 8], some children demonstrate progressive respiratory muscle weakness [10, 12, 13, 14, 15]. Therefore, a simple, low-cost, largely home-based training program that can effect substantial changes in respiratory muscle strength in conjunction with ERT holds great appeal. Our results in a child with IOPD support our hypotheses that a second course of our intensive 12-week RMT regimen would result in additional increases in inspiratory and expiratory strength that were at least large in magnitude ( d ⩾ 1.00) and that peak MIP and MEP values over this participant’s entire participation would be achieved at posttest following the second course of RMT. Following the two RMT regimens, her MIP improved from 36% of predicted to 46% of predicted, and her MEP increased from 60% of predicted to 96% of predicted for gender and age. Both RMT #1 and RMT #2 were associated with very large effect sizes based on Cohen’s d statistic. However, when comparing the results from RMT #2 to RMT #1, the response to training was less robust based on percent change of MIP and MEP.

Despite the progressive myopathy and respiratory muscle weakness associated with Pompe disease, even when treated with ERT, increases in respiratory str-ength associated with RMT appeared to be relatively persistent following withdrawal of training in this participant. Peak MIP and MEP values were noted at post-detraining assessment in RMT #1, indicating no evidence of detraining following 3 months of RMT withdrawal in the first experiment. As expected, MIP and MEP declined (by 1% and 9%, respectively) after 7 months of detraining between the two RMT regimens. However, this represents retention of 45% of the gains in MIP and 67% of the gains in MEP realized during RMT #1. In contrast to the first RMT regimen, small declines in MIP and MEP (6% and 3%, respectively) were observed after 3 months of RMT withdrawal in RMT #2, though effect sizes remained large for MIP and very large for MEP at post-detraining. These data suggest RMT may effect durable increases in respiratory muscle strength, even in the setting of progressive neuromuscular disease [31].

The accumulation of glycogen in skeletal muscle is known to cause weakness and hypotonia leading to delayed achievement of gross motor milestones and a unique set of persistent motor impairments in children with IOPD, despite treatment with ERT [4, 6]. In addition to residual muscle weakness, reduced endurance as well as persistent gait and posture disturbances have been described [4]. Though skeletal muscle weakness is likely the largest contributing factor to chronic mobility impairments in IOPD, the cardiorespiratory system also plays a role in exercise endurance [32]. Therefore, the exploratory outcome measures included in the study protocol examined gross motor function before and after RMT.

Although improvements in this participant’s performance on the 6MWT and time to walk 10 meters were noted during both 6-month experiments, their association with RMT-induced respiratory muscle strength increases is unclear. The expiratory muscles aid non-ventilatory motor function with contributions to trunk stability and mobility [33], representing a plausible mechanism by which RMT could impact motor performance. Overall, the explanation for gross motor improvements is likely multifactorial, including increases in respiratory muscle strength, maturation, progress from ongoing physical therapy, modifications in assistive equipment used for mobility, and possibly participant effort.

Cough effectiveness has implications for airway protection, airway clearance, and overall pulmonary health. Voluntary PCF values 270 L/min increase the risk for ineffective cough during respiratory illness and may necessitate use of airway clearance and secretion management techniques [34]. Reduced PCF is common in individuals with Pompe disease, and cough strength appears more severely compromised in children with IOPD than other disease phenotypes [35]. The physiological relationship between RMT-induced changes in respiratory strength and cough strength are perhaps more straightforward, given that a strong correlation between both inspiratory and expiratory muscle strength and PCF has been demonstrated in adults and children with Pompe disease [35] as well as other types of neuromuscular disease [36, 37]. Our participant’s results align with these findings, with increases in PCF from pretest to posttest evident in both experiments.

There are few additional data regarding RMT in children with Pompe disease. Smith and colleagues found little benefit from IMT in a group of 9 children with Pompe disease and chronic respiratory insufficiency [38]. However, 5 of the 9 participants in the study required full-time mechanical ventilation and thus demonstrated greater respiratory involvement at baseline than our participants.

We know of no studies that have investigated the benefits of additional RMT after a period of withdrawal. In fact, the effects of retraining or periodic training have not been studied in any form of exercise in individuals with neuromuscular disease. However, the exercise literature reports benefit from retraining with both aerobic and resistance-based exercise in healthy adults. Many studies report periodic detraining supports long-term muscle adaptation [39, 40].

Alternative explanations for our findings must be considered. Considering that the participant was receiving ERT, one such explanation is that the observed respiratory strength increases were the result of drug treatment rather than RMT. However, this explanation appears unlikely due to the magnitude of respiratory strength increases observed with ERT when combined with RMT versus with ERT alone [41]. Another alternative explanation of our findings is the possibility that observed increases in MIP and MEP were due to learning effects. To control for learning effects, our study protocol was designed to obtain repeated measures of MIP and MEP during multiple test sessions, produced with minimal variability.

The limitations of this study include the case report of a single participant with lack of replication of retraining results in other participants. The effort-dependent nature of our primary dependent variables (MIP, MEP) and our exploratory outcome measures (6MWT, TFTs, PCF) is also a limitation; future research should explore the use of non-volitional measures of respiratory strength (electrical/magnetic phrenic nerve stimulation), as well as supplementary volitional measures (sniff nasal inspiratory pressure). An additional limitation is the use of self-reported adherence data; the results would be strengthened if the treatment dose (number of repetitions attempted, number of successful repetitions, and frequency of exercise) was quantified with objective measurements. Clearly, replication of the study protocol in additional children with IOPD is needed to establish safety, make preliminary estimates of treatment effect, and explore factors associated with treatment response, such as overall disease severity or baseline respiratory muscle involvement. The addition of a control condition would also strengthen future findings in this area.

In summary, RMT appears to be a promising adjunctive treatment for respiratory muscle weakness in children with IOPD, with cumulative benefit from retraining observed in one participant. Though much additional research is needed, this study suggests that children with Pompe disease may be able to safely participate in multiple intensive RMT regimens and demonstrate measurable increases in respiratory strength.