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

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 activity¹. 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, pain⁴, 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 mood⁷, school performance^{8, 9, 10}, glucose tolerance^{11, 12, 13}, weight maintenance¹⁴, body composition¹⁵ 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 activity². Thalassemic patients with heart failure and increased myocardial iron had reduced exercise tolerance compared to β-thalassemic patients without heart failure²¹. In general, those living with chronic illnesses that limit physical endurance have been shown to display lower levels of daily activity²². 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.

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 health²³. The ActiGraph was worn only during non-vibrating periods of the protocol. Additional Thal case subjects were invited to participate from the Children’s Hospital Research Center, Oakland (CHRCO) Hematology outpatient clinic. All case subjects were required to have a Thalassemia diagnosis to participate. They were categorized either as transfusion dependent (TM) if they received red blood cell transfusion therapy on a routine basis, typically every three weeks or a minimum of eight times per year, or non-transfusion dependent (TI) if they were non or intermittently transfused. Healthy controls of Asian or Caucasian decent were recruited from staff, friends and families of staff, and the University of California, Berkeley student body. Exclusion criteria for all subjects consisted of age ≤9 years and pregnancy. The protocol was approved by the Institution Review Board of CHRCO. Participants received information about the nature and purpose of the study and signed informed written consent. Adolescents under the age of 18 signed assent.

The ActiGraph measures frequency and intensity of minute-by-minute body movements in three dimensions: anterior-posterior, medial-lateral, and vertical axis. For highest accuracy, patients wore the ActiGraph on their left hip, close to the body’s center of mass. TM patients wore the ActiGraph for one week prior to and post transfusion. Controls and TI patients were asked to wear the ActiGraph for a complete week, at a pre-scheduled time convenient for them. Valid ActiGraph data was considered to include at least three week days and one weekend day²⁴. All subjects were provided a calendar and asked to record any unusual physical activity patterns (e.g. time on rollercoasters, time off to shower or swim), their bedtime and waking time. Subjects were instructed to wear the ActiGraph only during non-sleeping hours. Readings were recorded throughout waking hours, except when infeasible (e.g. during showering, swimming). After subjects completed their wear-time, ActiGraph data was downloaded and saved using ActiLife version 5.10.0 software (Pensacola,FL).

Forty-three subjects with Thal and 31 healthy controls were initially invited to participate in the study. Three adult Thal subjects (2 Male, 1 Female) either moved or expired prior to consenting to the study. Additionally, three adult male Thal subjects dropped after consenting due to scheduling difficulties. One healthy control was excluded after consenting when it was discovered he had a diagnosis of Thal trait. Therefore, a total of 37 Thal (23 transfusion dependent, 14 non-transfusion dependent or intermittently transfused) and 30 healthy controls were included in the analysis. Data was summarized from the ActiGraph for an average of 7.0 ± 1.6 days for Thal and for 7.9 ± 1.7 days for the healthy control groups. The genotypes of the transfused and non-transfused subgroups are provided in Table 2. There were no significant differences observed between the Thal and healthy control groups in terms of age, gender, height, weight, BMI or race.

Employed Thal subjects, both TM and TI, were more likely to have ‘non-office work’ jobs, which included factory work, traveling sales, retail clerks and other physically demanding jobs. All employed controls were involved in ‘office-work’ type jobs, which primarily consisted of sitting at a desk for most of the workday. Employment status and occupation by group are provided in Table 2.

As expected, TM subjects presented greater pre-transfusion hemoglobin and serum ferritin levels compared to TI subjects (Table 2). However, LIC, reflecting total body iron stores, were similar between TM and TI subjects.

Overall, Thal subjects recorded a significantly fewer total number of steps per day compared to healthy controls (Table 3, p=0.001). This observation was significant for both Thal age groups, adults and adolescents (Figure 1). Further analysis revealed that none of the adult Thal subjects met the recommended number of steps/day (10,000) as opposed to a little over one quarter of the healthy adult control group. Similar trends were observed for the sub-group of Thal adolescents (Table 3).

Figure 1.Total Number of Steps Per Day Assessed by ActiGraph in Patients with Thal (n=37) Compared to Healthy Controls (n=30) divided by Age Group. *Step recommendations for adolescents (12,000 steps/day33) and for adults (10,000 steps/day32)

Thal subjects had a significantly lower total energy expenditure (Kcal/day) measured by ActiGraph (p=0.001), a result which appeared to be driven primarily by the adult sub-group. Though when energy expenditure was calculated from the self-reported Physical Activity Survey Questionnaire, there were no significant differences between groups.

Compared with controls, overall subjects with Thal spent significantly less time in moderate (p=0.03), vigorous (p=0.005) and very vigorous (p=0.02) activity and more time in sedentary activity (p=0.006). However, in sub-group analysis it became clear that there were no significant differences observed between adult controls and adult Thal subjects in most activity intensities, other than the small amount of time spent per day in vigorous activities (p=0.007). The distinctive activity patterns for the adolescent Thal compared to healthy controls are illustrated in Figure 2.

Figure 2.Activity Patterns of Daily Living in Young Subjects with Thal Compared to Young Healthy Controls. 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).

Confirming their increased time spent in sedentary activities, Thal subjects reported engaging in their combined time spent watching TV, surfing the internet, driving and other sitting-type-activities in the Self-Assessment Survey Questionnaire.

There were no differences in total hours of sleep per night for adult Thal subjects compared to healthy controls when subjects estimated their usual sleeping habits in the Survey Questionnaire (Table 3). However, when asked to record actual sleeping and waking time on a calendar, Thal adults spent significantly more total hours sleeping, on average spending 1 more hour asleep each night compared to healthy adult controls (p=0.046).

Transfused subjects began recording data from their ActiGraph on average 6.0 ± 2.9 days prior to transfusion, and again following, starting to record on average 2.3 ± 2.9 days after their transfusion day (Table 4). There was no significant difference in steps per day when comparing TM subject’s physical activity patterns pre versus post transfusion. Of interest, none of these subjects met the U.S. recommendations for steps per day (10,000 steps/day for adults and 12,000 steps/day for adolescents) prior to their transfusion date, while three subjects met the recommendations post transfusion. Gender, BMI, Hb and serum ferritin were not significant modifiers to step count during the transfusion cycle for these subjects.

Despite the noteworthy trend in overall number of steps taken following a transfusion, results indicated that TM subjects had no significant difference in energy expenditure and time spent in various activity intensities prior to and following their transfusion (Table 4).

This is the first study to have measured the activities of daily living in Thal subjects using ActiGraph technology. The results indicated that when compared to age-matched controls, Thal subjects took significantly fewer total number of steps per day. This result was corroborated with the total energy expenditure, as Thal subjects also had significantly lower total kilocalories expended per day, measured by the ActiGraph, compared to controls.Major differences were recorded in the patterns of the activities in Thal subjects versus controls. Of these, amount of time spent in sedentary and vigorous activities stood out as the most prominent. Unexpectedly, these differences were most notable in Thal youth. Thal youth spent 72% of time in sedentary activity, compared to age-matched control youth (only 56%, Figure 2). It is now clear that physical activity is reduced during activities of daily living in patients with Thal, a result that has long been assumed though not yet documented.

Though no other studies have examined general physical activity patterns among Thal patients, others have explored exercise capacity and performance, focusing on the effects of iron overload and its’ subsequent comorbidities. Mavrogeni et al³⁴ assessed exercise in patients with B-Thal and heart failure using a treadmill protocol. They observed reduced values of exercise indexes associated with myocardial T2*, a magnetic resonance parameter indicating elevated iron concentration in the heart. Sohn and colleagues² also studied the influence of somatic and cardiac iron overload on exercise performance in a large (n=71) TM patient cohort. They found decreased aerobic capacity in Thal patients and concluded that the observed exercise limitation is related to systemic inflammation, degree of anemia and cardiac iron burden. Geordie and colleagues³⁵ examined cardiorespiratory response to exercise on a cycle ergometer in Thal and found a significantly lower peak oxygen consumption during incremental exercise compared to control subjects. Abnormally high heart rate and cardiac output (associated with hypoventilation) were also recorded in Thal subjects during exercise. This study re-tested Thal patients 3 to 8 days after transfusion and found no significant improvement in ventilation or circulation, a result that is consistent with our findings.

The reason for the inactivity observed in patients with Thal in this study may be similar to healthy adults without Thal, though there are limited published data to support these claims. These restrictions may include limited time, lack of motivation, fatigue or lethargy and competing interests. Additionally, they have a myriad of other factors, which may deter from an active lifestyle. One of the most evident reasons is chronic pain, which is increasingly common among Thal patients³⁶. Pain can restrict daily physical activity and dissuade incentives to exercise. Chronic pain can lead to fear of injury: another important reason Thal subjects can be more inactive than their healthy counterparts. Incessant fear of exacerbating their symptoms can lead to a more sedentary lifestyle. Many patients are fearful of cardiomyopathy. Having witnessed fellow patients suffer and on occasion die of heart failure, they find themselves reluctant to stress their hearts with rigorous exercise, whether or not the fear is unfounded. These types of fears may not only come from the patient; parents of Thal children are commonly found to constrain their child’s physical activity.

High rates of depression³⁷ and fatigue found in Thal subjects can also limit a patient’s incentives to stay active. An orthogonal factor to these disincentives to exercise are the set of physical limitations that present with Thalassemia. In particular, Thal subjects have reportedly higher percentage body fat per body weight (that is, they are less lean for body weight)³⁸. Less lean cell mass results in less overall muscle mass to propel and/or sustain an individual during exercise. Lower lean cell mass could equate to fatigue combined with anemia and lead to limited exercise capacity.

Our findings have important implications: they point to potential health benefits for Thal subjects if physical activity levels are increased. A physical activity regimen would be most effective if implemented early on, and in small steps. As with most exercise intervention programs, they are most effective if incorporated when an individual is young, when they can integrate the routine as part of daily schedule. Further, Thal adults more commonly have exercise limiting co-morbidities. For example, a promising potential outcome is increased bone density/strength with a concomitant decreased risk of osteoporosis, a co-morbidity observed in up to 70% of adults with Thal³⁹. A systematic review of the literature on physical activity and bone strength supports the positive association between weight-bearing exercise and the buildup of bone mass in the growing years⁴⁰.

A negative association between Thal and physical activity can carry implications beyond patients’ physical health. Regular physical exercise has been associated with positive mental health benefits⁴¹, and better sleep. Etiology of this includes endorphin release, increase in cortical blood flow, reduced emotional strain, buffer against stress, distraction from negative preoccupations, and increase self-esteem⁴¹. Subjects with Thal slept one hour more per night compared to the controls, though we did not assess the quality of sleep. Recent research suggests that both too much and too little sleep are associated with adverse health outcomes⁴². The optimal amount of sleep appears to be between 6 to 8 hours per night. In this study, a number of patients with Thal slept more than 9 hours per night, which Cappucio and colleagues suggest is can be used as a diagnostic tool related to long-term health consequences. Further research is needed to assess the importance of these mechanisms to improve overall quality of life among those suffering from Thal.

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 self-report 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.

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.

This publication was supported in part by the Cooley’s Anemia Foundation and by the National Center for Advancing Translational Sciences, National Institutes of Health, through the UCSF-CTSI Grant Number UL1 TR000004. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

The authors would like to thank the patients and their families for their time in volunteering for the study, as 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.

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