Discussion:
In this quality improvement project, we successfully introduced a PT evaluation of gross motor skills in school-aged children with CF utilizing the BOT-2. Within a year we completed evaluations in over two-thirds of eligible children. This study is one of the few published gross motor assessments using a standardized tool in school-age children with CF. Prior studies have been very small, although the results were similar to our findings. In an observational study of 14 infants with CF, 27% had motor delays using The Bayley Scales of Infant and Toddler Development® - III Edition(1). In another cross-sectional study examining 12 school aged children with CF, 33% had motor delays using the Movement Assessment Battery for Children 2ndedition (MABC-2)(12).
The most common area of impaired gross motor function was strength. There is CFTR expression in the skeletal muscle of humans(5, 13). Decreased CFTR function in skeletal muscle affects sodium transport and calcium release, which is crucial for a robust muscle contraction(5, 13). In addition, impaired CFTR function impacts ATPase and mitochondria, which is essential for energy production(5). While this quality improvement project was not designed to determine the cause of gross motor delays in this CF cohort, there may be intrinsic CF-related factors leading to skeletal muscle weakness and peripheral muscle atrophy in pwCF(5). We did not identify a difference in gross motor assessments in those receiving CFTR modulators compared to those not eligible. However, relatively few of these children were receiving highly effective modulator therapy (HEMT). Further evaluation of the impact of CFTR modulators on gross motor assessment is indicated now that elexacaftor-tezacaftor-ivacaftor is approved for those down to 2 years of age. A better understanding of how CFTR modulators impact strength and gross motor skills in CF may also help to explain the potentially clinically significant differences seen between genotypes in this cohort given the higher rate of gross motor delays found in those with the F508del/Other mutations (27%) compared to those with F508 homozygous (6%) and Other/Other (9%) genotypes. This is clinically important as skeletal muscle strength impacts exercise capacity, which is a known predictor of survival in CF(14).
The relationship between lung function and gross motors skills is not fully understood. Our data suggests that lower FEV1 and FVC measurements were associated with lower TMC and TMC% scores. It is unknown whether this association is independent or if other factors, such as hospitalizations or presence of comorbidities could be contributing. A study by Wilkes and coworkers highlighted the longitudinal relationship between physical activity and lung health in CF, determining that a greater increase in habitual physical activity was associated with a slower rate of decline in FEV1(2). This, along with the evidence by Nixon and colleagues that children with CF participate in less physical activity than their healthy non-CF peers(4), emphasizes the need for targeted evaluation and interventions in young children with CF to facilitate successful participation in exercise and recreation. If exercise improves lung function, it is possible that optimizing gross motor skills may be one way to improve pulmonary outcomes for children with CF. This would be important for those who are ineligible for or cannot tolerate CFTR modulator therapy.
In our cohort, hospitalizations were also associated with lower TMC scores. We elected to report hospitalizations that lasted 3 days or longer, expecting that brief hospitalizations would have less of an impact on gross motor skills. Gruet and coworkers found that hospitalizations in adults with CF intensified peripheral muscle dysfunction, specifically quadricep strength, which is likely due to disuse and systemic inflammation(15). Decrease in quadricep strength after hospitalization may contribute to decreased gross motor skills. However, a prospective assessment of gross motor delays would better clarify the relationship between physical function, FEV1decline and hospitalizations.
Forty-seven percent of the children in this sample were found to have one or more comorbidities, and those with comorbidities had statistically lower TMC scores compared to those without comorbidities. In this evaluation we compared individuals with any comorbidities to those without. Therefore, it remains unclear the role each separate comorbidity has on gross motor evaluations, due to the infrequency of many of them within this cohort. Understanding the role of individual comorbidities could be helpful in determining the need for specific PT interventions in this population.
Surprisingly, in our sample, we did not observe an association between BMI and gross motor skills given the close association between FEV1 and BMI and prior studies demonstrating this relationship (2, 16-18). Lack of an association may be attributed to fat free mass depletion that can be seen in pwCF with a normal BMI(19, 20). Despite advancements in the nutritional status of many pwCF, a recent study demonstrated high rates of fat-free mass depletion in a cohort of children with CF.
There was also no significant difference in BOT-2 scores between males and females in our sample. This may be related to the age range evaluated (4 to 12 years) as previous studies have demonstrated no gender differences in activity level in prepubescent children with CF but increased activity levels in post-pubescent males compared to females(21). Evaluation with the BOT-2 in the adolescent population may help to better define the relationship between gross motor skills and gender.
Implementation of a 6-week exercise program has been shown to significantly improve pulmonary function, walking distance on 6 minute walk test (6MWT), and scores on the modified Munich fitness test, which assesses flexibility, balance, strength and coordination(22). Similarly, significant improvements in 6MWT, quadricep strength and fat free mass has been demonstrated after an 8-week program(23). A longer-term exercise program has also been shown to be beneficial for children and adolescents with CF by improving motor performance fitness(24). This is very reassuring data to support the implementation of a home program in children with CF, when impairments are identified using a gross motor assessment and exercise testing. As a next step we will be longitudinally evaluating BOT-2 scores in school-aged children in our clinic to determine the impact of a home program on gross motor skill acquisition.
Limitations of these results include that it is a convenience sample and observational with the primary purpose being a quality improvement project to implement gross motor assessments in children with CF. In terms of the BOT-2 assessment tool, it is important to note the TMC is an average of all subsections. For a child that scored high in the body coordination section and low in the strength agility section, they may appear to have average gross motor abilities in evaluating TMC alone. Data from individual sections must therefore be considered when determining the plan of care, PT interventions, and how a child may be functioning in relation to same-age peers. Although associations between gross motor findings and clinical outcomes and demographic characteristics were noted, a causal relationship cannot be established. The strengths of this project include the number of children evaluated, which is the largest published assessment of gross motor skills in children with CF. Additionally, we report novel information on the prevalence of gross motor delays in children with CF including outcomes using the BOT-2 and components of the TMC that were abnormal in this cohort.
The results of this intervention support the need for a PT in the care of children with CF to assess for gross motor delays. This assessment could ultimately lead to earlier detection of delays, improved quality of care, and allows PT to provide individualized recommendations to facilitate participation and success in physical activity from an early age.  If, based on clinic workflow, PT is not embedded within CF clinic or cannot be involved in assessing all children with CF, priority should be given or an outpatient referral to PT should be considered, in those with a history of repeat hospitalizations and co-morbidities, due to the increased rate of gross motor delays in children with these risk factors. More data are needed to understand how motor delays impact health outcomes, and how PT interventions impact clinically meaningful outcomes in children. Longitudinal data are needed to trend changes in gross motor abilities in the CF population and determine risk factors for gross motor delays. Finally, as we enter the era of highly effective CFTR modulator therapies for younger children, it will be important to understand the impact of these therapies on gross motor abilities.
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Table 1: Summary of baseline clinical characteristics (N=72)