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Physical Activity in Pediatric Pulmonary Arterial Hypertension Measured by Accelerometry: A Candidate Clinical Endpoint

Zijlstra WM, Ploegstra MJ, Vissia-Kazemier T, Roofthooft MT, du Marchie Sarvaas G, Bartelds B, Rackowitz A, van den Heuvel F, Hillege HL, Plasqui G, Berger RM. Am J Respir Crit Care Med. 2017 Feb 8. doi: 10.1164/rccm.201608-1576OC. [Epub ahead of print]

Article Summary:

Background: Although the six-minute walk distance is well established as a clinically relevant endpoint for adults with pulmonary arterial hypertension (PAH), this endpoint is less applicable to infants and children who may be unable to participate in such testing. Thus, there is a critical need to develop and validate means of assessing activity levels in younger populations that can be applied to clinical trial design. Accelerometry has previously been used in adults and children to measure physical activity, but whether accelerometry correlates with disease severity and outcomes in pediatric PAH remains unknown.

Methods and Results: Children with PAH were recruited from the Dutch National Network for Pediatric Pulmonary Hypertension. These subjects were age- and sex-matched to controls without hemodynamically relevant cardiac disease recruited from the Beatrix Children’s Hospital outpatient Cardiology Clinic, with 2 controls to every 1 pulmonary hypertension patient. Children were asked to wear the ActiGraph wGT3X accelerometer for 7 days on the right hip during all awake time. Vector magnitude counts per minute were defined as the primary accelerometer outcome, and physical activity intensity was defined as the secondary accelerometer outcome. Physical activity measures were then correlated with patient characteristics, WHO functional class, six minute walk distance (for children aged 7 years or older), serum NT-pro BNP levels, and pulmonary hypertension medication use.

Twenty-nine children with PAH and 60 age- and sex-matched control children completed the accelerometry study. PAH subjects included 4 children (14%) under 5 years of age, and 3 children (10%) with Down syndrome; most children were WHO functional class II or III. Six minute walk distance was unavailable in 9 PAH children (31%) due to young age or developmental disorder. Average wear time per day was similar between PAH and control children, and there was no significant day-to-day variance in vector magnitude counts.

Average vector magnitude counts per minute were significantly lower in children with PAH compared to controls. Additionally, children with PAH were significantly less likely to engage in moderate or vigorous physical activity. Time spent in moderate or vigorous physical activity inversely correlated with WHO functional class in all children. Vector magnitude counts also correlated inversely with WHO functional class in univariate analysis, but lost significance when corrected for age and diagnosis. In a post hoc Cox regression analysis, lower vector magnitude counts were associated with a shorter time to PAH-related hospitalization, and less time spent in higher activity levels was associated with worse outcome.

Conclusions: Accelerometry is a feasible measure of physical activity, even in young children with PAH who would otherwise be incapable of completing classic measures such as six-minute walk distance. Physical activity levels measured by accelerometry are significantly decreased among children with PAH. Activity correlated well with clinical disease severity markers, and may correlate with outcomes. Additional validation in larger studies may help to identify age-related normal values for activity. Finally, use of accelerometry for tracking individual activity levels in response to changes in therapy may be beneficial for assessing treatment effects. Accelerometry should be considered as a clinically meaningful endpoint in pediatric PAH, and may be useful to implement in future trial design as an adjunct to six-minute walk testing, particularly for younger children or those with developmental disabilities.

Expert commentary:
Pediatric pulmonary hypertension (PH) has been long-recognized as poorly understood and relatively understudied, with many persistent challenges regarding understanding basic disease mechanisms, short- and long-term outcomes, and optimal treatment strategies. (1-3) Despite the growing armamentarium and availability of PH-targeted drug therapies in adults, data from multicenter randomized clinical trials remain extremely limited in the pediatric setting. As a result, drug therapies are often used in children based largely or exclusively on the results of studies in adults with pulmonary arterial hypertension (PAH), with minimal direct evidence that supports efficacy in pediatric PAH. The need for more data on how to best optimize our approaches towards the evaluation and care of children with PAH has recently been expressed, but perhaps one of the major challenges is the uncertainty regarding how to best monitor disease progression or response to therapy in pediatric PAH.(3-5) The lack of sufficient and validated study endpoints remains a major gap in how care providers, pharmaceutical companies and regulator agencies can best define standards for clinical trials in children. (5)

Thus, more research is required to improve understanding of the natural history, basic mechanisms of disease, and optimal treatment of many pediatric PH-related disorders. Limitations to performing adequate studies of the pediatric population include the wide diversity of associated conditions and co-morbidities that challenge our characterization of pediatric PH and its classification, challenges in obtaining informed consent, the relatively small numbers of PAH patients at each center, the scarcity of multi-disciplinary pediatric PH programs, the lack of a national PH network, and suboptimal communication between PH scientists and clinicians. (4) There is clearly a need to better define the natural history of pediatric PAH, to develop new strategies to identify patients at-risk for development of PH, and to develop and test novel biomarkers, drugs and devices to diagnose, monitor and treat children with PH.

A major gap limiting our ability to improve outcomes of children with PAH is the lack of efficacy endpoints or surrogate measures that are capable of reproducibly and reliably reflecting changes in pulmonary arterial pressure in response to a therapeutic intervention that is being assessed in pediatric clinical trials.(4,5) Children are often too young and developmentally unable to perform standard cardiopulmonary exercise testing and the use of several metrics are not as accurate for reflecting clinical status in children as in adults, such as 6 minute walk distance (6 MWD). Additionally, the use of cardiac catheterization to directly and frequently measure pulmonary vascular resistance index (PVRI) is invasive, requires anesthesia, and has additional risks for complications. As a result, PVRI as a direct measure for outcomes of clinical trials and assessments of disease progression is limited.

Impaired exercise tolerance is a prominent feature of PAH and contributes significantly to reduced quality of life. Assessing exercise capacity is an integral part of the clinical evaluation of PAH in adults and the use of the six-minute walk distance (6MWD) is the most common primary endpoint in adult PAH clinical trials.  Importantly, the six-minute walk test (6MWT) and other existing exercise performance tests that are readily applied in adult studies are not reliable and applicable for young children, especially in young infants or children with developmental disabilities.

Thus, to address this critical and unmet medical need in children with PAH, Zijlstra and colleagues studied measures of physical activity (PA) by accelerometry as a potential metric for assessing clinical status. (6). Actigraphy is a mobile device that directly, reproducibly and non-invasively measures physical activity that can be readily assessed in the ambulatory setting and may provide a novel, simple and inexpensive approach. (7-9).  Early reports have supported its potential use in adults with PAH (10,11), but the role of actigraphy in children with PAH has been uncertain. In this report if a small cohort of children with PAH, PA by actigraphy is strongly associated with WHO functional class and 6MWD, as well as late clinical outcomes. These exciting findings suggest that actigraphy may provide a novel endpoint for assessing clinical course and drug efficacy in children with PAH, especially as related to previously identified, significant outcomes (12), and support the need for further studies to define its applicability and to define its potential use in clinical trials. 
If successful, actigraphy could become a study endpoint and clinical outcomes that would be accepted in children as a clinically-relevant standard for PAH clinical trials. As such, this simple tool has great promise for having a significant regulatory impact that will improve outcomes of the management of children with PAH and advance the public health mission on a broader scale.


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Article summary by: Kara Goss, MD, Assistant Professor of Medicine and Pediatrics, University of Wisconsin.

Expert commentary by: Steve Abman, MD, Professor of Pediatrics and Director of the Pediatric Heart Lung Center, University of Colorado School of Medicine and Children’s Hospital Colorado.

Last Reviewed: June 2017