Reduced Physical Activity Patterns in Patients with Thalassemia Compared to Healthy Controls

Background: Patients with Thal (Thalassemia) are presumed to be inactive for many of the same reasons as healthy adults, though there are limited published data to support this claim. The primary aim of this study was to compare physical activity patterns in subjects with Thal to healthy controls as well as to explore the effects of transfusion therapy on physical activity in transfusion dependent patients with Thal. Methods: 37 Thal (23 Thal major, 14 Thal intermedia, 21 Female, 27.3±10.1 years) and 30 healthy controls (17 Female, 28.0 ± 13.7 years) wore an ActiGraph accelerometer for one to two weeks. Results: Thal subjects recorded a significantly fewer total number of steps per day and lower total energy expenditure compared to healthy controls (p=0.001). None of the adult Thal subjects met the recommended 10,000 steps/day as opposed to 27% of healthy adult controls (p=0.004). Thal spent significantly less time in moderate (p=0.03) to vigorous (p=0.005) activities and more time in sedentary activity (p=0.006). Conclusion: It is now clear that Thal spend significantly less time in physically demanding activities than age-matched healthy controls, a result that has long been assumed though not previously documented. Further research is needed to define an appropriate physical activity regimen best suited for patients with Thal while examining its effect on mental and physical health. J O U R N A L O F H E M A T O L O G Y A N D O N C O L O G Y R E S E A R C H ISSN NO: 2372-6601 Research DOI : 10.14302/issn.2372-6601.jhor-15-776 Corresponding author: Ellen B. Fung, PhD RD CCD, Department of Hematology, UCSF Benioff Children's Hospital, Oakland, 747 52 Street, Oakland, CA 94609, Phone: 510-428-3885 x 4939, Fax: 510-450-5877 , efung@mail.cho.org


Introduction
The 2008 Physical Activity Guidelines for Americans state that adults should participate in a minimum of 30 minutes of moderate level of physical activity per day, children a minimum of 60 minutes.
Less than half of US adults meet this recommendation and it is estimated that fewer than 30% of adolescents participate in an hour per day of physical activity 1 .
Patients with Thal are presumed to be inactive for many of the same reasons as healthy adults, though there are limited published data to support these claims.
Additionally, there are a number of other factors that may contribute to inactivity in Thal. Chronically low hemoglobin (Hb) levels, either in non-transfusion dependent patients or prior to-transfusion have been associated with reduced exercise performance 2,3 . Along with reduced hemoglobin, pain 4 , depression 5,6 , and particularly for children, overprotective parenting can result in reduced physical activity for many patients with Thal. Additionally, patients with Thal major have various complications, which may inhibit or otherwise hamper participation in moderate to vigorous physical activity including iron overload associated cardiomyopathy, hepatitis, diabetes, osteoporosis and hypothyroidism.
While a small number of patients suffer from these co-morbidities, a larger percentage of relatively healthy patients, maintained on optimal chronic transfusion and chelation regimens could benefit from a regular low-intensity physical-activity program. In non-Thal populations, regular physical activity has been shown to decrease depression and improve mood 7 , school performance 8,9,10 , glucose tolerance 11,12,13 , weight maintenance 14 , body composition 15 and bone health 16,17,18 .
There is a paucity of published literature examining physical activity patterns in hemoglobinopathies. Poor exercise performance and overall less activity have been observed in both adults and adolescent patients with sickle-cell disease 19,20 . Very few studies have examined physical activity in patients with Thal, and those that have focused primarily on the effect of iron overload on physical activity 2 . Thalassemic patients with heart failure and increased myocardial iron had reduced exercise tolerance compared to β-thalassemic patients without heart failure 21 . In general, those living with chronic illnesses that limit physical endurance have been shown to display lower levels of daily activity 22 .
However, daily physical activity patterns amongst Thal patients, in particular, has yet to be explored. The primary aims of this study were to compare physical activity patterns in subjects with Thal to healthy controls, as well as to explore the effects of transfusion therapy on physical activity in transfusion dependent patients with Thal. Thal subjects were found to be significantly less active compared to age-matched healthy controls using a variety of measures, a result that has long been assumed though not previously documented.

Materials and Methods
A prospective case-control study design was used to evaluate physical activity among patients with Thal relative to healthy controls. Thal subjects and controls were asked to wear an ActiGraph (GT3X) accelerometer for week-long intervals, which measured their physical activity frequency and intensity. Twenty of the Thal patients included herein were also enrolled in a randomized trial testing the effect of vibration therapy on bone health 23 Figure 2.  ^Hours of evening sleep recorded during the week(s) when the Actigraph was worn to assess physical activity.
Missing and unreliable data was obtained from many of the younger Thal and healthy control subjects, therefore summary statistics are only presented for the adult cohorts. Average number of hours of evening sleep was also estimated by each subject during the first week the actigraph was worn using the validated Block Physical Activity Survey.
Activities were categorized in the validated physical activity survey based on their metabolic expenditure levels  Table 4. Physical activity patterns and energy expenditure assessed by ActiGraph in subjects with Thal prior to and following red blood cell transfusion.* Thal youth (<18 years) spent significantly less time in light, moderate, vigorous and very vigorous activity and more time in sedentary activity compared to healthy controls (<18).

Pre-Transfusion n=20
Post-Transfusion n=20 * Subjects were asked to begin recording ActiGraph data one week prior to the day of transfusion, and again immediately following transfusion for an additional week of data collection.
Three subjects were missing post-transfusion data and therefore were not included in the analysis above.
^ For subjects who were considered more "Active" which included those categorized as either "non-office workers", "students" or "unemployed", n=12.

Discussion
This is the first study to have measured the activities of daily living in Thal subjects using ActiGraph This study was limited in its sample size, particularly for the cohort of transfused subjects. Consequently, our assessment of the effect of transfusion therapy on physical activity patterns may be imprecise. We were also limited by the inability to match occupational status in the case and control subjects. However, if anything, this worked to our disadvantage in that the Thal group participated in more physically demanding jobs, where one might expect overall energy expenditure to be higher. Moreover, given we did not assess pain or mood in this study, we were limited by the inferences we could draw linking physical activity to overall quality of life.
Additionally, we found it interesting that measured activity (by ActiGraph) and those by selfreport did not corroborate, particularly for the Thal subjects. Perhaps subjects with Thal perceive themselves to be more active, or desire to be more active than they currently are. Whatever the etiology, this topic requires further exploration in future research.

Conclusion
In conclusion, Thal subjects recorded significantly less total number of steps per day compared to healthy controls. Additionally, substantial differences in daily activity patterns were observed, with Thal subjects taking part in less vigorous activities and more sedentary activities. These findings suggest a substantial degradation in overall physical activity as a result of the various ailments associated with Thal. This provides needed grounding to the common perception that Thal patients exhibit significantly less exercise than their healthy counterparts. Further research is needed following Thal patients in a physical activity regimen best suited to their needs while examining any changes in mental and physical health.
well as Catherine Gariepy for her initial assistance and enthusiasm for the project, Elizabeth Scott, who assisted with data management and quality control of the ActiGraph data and Ginny Gildengorin, PhD who provided statistical support and expertise during the data analysis phase.

Financial Support
This