Approximately 10%-20% of children suffering hematological malignancies or refractory solid tumors need hematopoietic stem cell transplantation (HSCT), which includes both bone marrow transplantation (BMT) and peripheral blood stem cell transplantation. Patients who undergo HSCT are at risk of suffering treatment-related complications mostly associated with the immune system (19). Graft-versus-host disease (GVHD), infections, and delay in immune cell recovery are the major sources of HSCT comorbidities as well as major limiting factors to consolidate transplant success (19,22).
The health benefits of regular exercise training in cancer patients or survivors including adult inpatients receiving HSCT are promising and include increases in hemoglobin levels (7), improved physical fitness (4,5,7), improved vigor (6), and fatigue stabilization (6). In outpatient children with acute lymphoblastic or myeloid leukemia who received HSCT, an 8-wk supervised exercise intervention induced a significant improvement in functional capacity and quality of life (26). Kim and Kim (16) reported that in-room (bed) exercise during hospitalization of adults for HSCT increased total lymphocyte count without deteriorating cellular subpopulations (CD3+, CD4+, and CD8+ or CD4+/CD8+ ratio) (16).
Intervention studies examining the effects of regular exercise training on the immune system in pediatric cancer patients or survivors are scarce. It is known that bed rest aggravates the already low functional capacity as well as the muscle atrophy induced by immunosuppressive therapy in children receiving HSCT (21). A preliminary report by Shore and Shepard (28) showed that a 12-wk aerobic exercise training program decreased CD3+, CD4+, and CD8+ counts in three children with acute lymphoblastic leukemia receiving chemotherapy; however, the training-induced changes were not of sufficient magnitude to be a health concern. More recently, Ladha et al. (17) reported no deleterious acute effect of a single 30-min bout of aerobic exercise on immune parameters in children receiving maintenance therapy against acute lymphoblastic leukemia. Although these studies concerned children being treated for cancer, the findings cannot be extrapolated to children while undergoing HSCT hospitalization.
The purpose of the present controlled trial was to assess the effect of a ∼3-wk exercise intervention performed during inpatient stay for HSCT on immune cell recovery, that is, blood counts of leukocytes, monocytes, and lymphocytes and main lymphocyte subpopulations (T lymphocytes, natural killer cells (NK), NK T, CD4+, and CD8+) and dendritic cells. We also assessed the effect of this intervention on patients' body mass, body mass index (BMI), and estimated fat-free mass because body composition seems to be affected in patients undergoing HSCT and has a prognostic value in this population (8,10,18).
MATERIALS AND METHODS
A preliminary screening for children selection was performed in the medical database of the Onco-Hematology Department at Children's Hospital Universitario Niño Jesús (Madrid, Spain). The children were eligible for participating in the study if they met the following criteria: (i) being a pediatric patient (<16 yr) with high-risk cancer needing HSCT; (ii) receiving manipulated allogeneic HSCT and nonmyeloablative conditioning therapy in the aforementioned hospital; (iii) receiving the same type of medical treatment (conditioning regimen), including antibiotic prophylaxis if needed; (iv) no evidence of cardiac or pulmonary failure associated with treatment; and (v) being in an isolated unit during the neutropenic phase of their hospital stay with high-efficiency particulate air (HEPA) filter and room positive pressure.
Before entering the study, one parent or legal guardian provided written informed consent. The study procedures were explained verbally to all children, and all gave verbal consent to participate in the study. The research protocol was approved by the institutional review board of Children's Hospital Universitario Niño Jesús. In addition, the treating oncologist's approval was required before a child entered the training group.
Intervention and control groups.
Because of the low number of hospitalized children with cancer, it was not possible to perform a randomized controlled trial. Instead, we performed a controlled trial using a "historical" control group whose medical conditions were comparable to those of the intervention group. Because the groups were closely matched, we believe that lack of randomization in group assignment did not materially affect the results.
The exercise program was performed during 2007-2008. A total of 14 children met the aforementioned criteria to participate in the intervention study. Of these, nine patients entered the study. Two of them had very severe medical complications at the start of the training program, before HSCT (one patient had respiratory insufficiency, and the other child suffered bacteremia for Staphilococus hominis and urinary infection by Escherichia coli with a high fever). The oncologist did not recommend these children to enroll in any type of exercise program. Thus, we reported data from seven children (5 boys and 2 girls; age (mean ± SD) = 8 ± 4 yr) in the intervention group.
During the intervention phase of the study, a researcher blinded to the immune and anthropometric results of the intervention group was in charge of gathering the control inpatients from medical records (corresponding to the period January to December 2006) of the same hospital. Children were selected as controls if we obtained their parents' consent to use their child's data for research purposes, if they met all the eligibility criteria (see previous section), and if there were available data on the same immune and anthropometric parameters at the same time points used for the exercise group. A control group of 13 children (9 boys and 4 girls; age = 7 ± 3 yr) met all inclusion criteria. Characteristics of study participants are shown in Table 1. They were all treated by the same medical staff (physicians and nurses) of the onco-hematology department. This staff has not changed since year 2005.
Transplantation Protocol and Hospitalization
The HSCT protocol and the study design are presented in Figure 1. The training protocol started at the beginning of the conditioning phase (pretransplant) and lasted until the end of the neutropenic phase (i.e., mean of ∼3 wk). Patients were closely supervised and clinically evaluated on a daily basis. During hospitalization, prophylactic therapy was given to all patients with acyclovir to prevent herpes simplex virus and cytomegalovirus reactivation infection and with cyclosporine and methotrexate to prevent GVHD. The conditioning regimen preceding HSCT included the following drugs in all patients: thiotepa (daily), fludarabine (daily), dexamethasone (daily), and busulphan (for 2 d). Standard prophylactic antibiotics were administered if the absolute neutrophil count was <0.5 × 109 L−1 and fever >38°C developed and were maintained until neutropenia resolved. The neutropenic phase ended with neutrophil engraftment, which was defined to occur the first day that absolute neutrophil count was higher than 0.5 × 109 L−1.
FIGURE 1-Scheme of t...Image Tools
We prepared six cytometry tubes with six monoclonal antibodies marked with six different fluorochromes to study leukocyte subpopulations in patients' peripheral (venous) blood. We incubated 100 μL of blood in each tube during 20 min at room temperature in the dark and treated red blood cells with a 1-mL lysis solution for 10 min. The different white blood cell population counts (leukocytes, monocytes, and lymphocytes) were measured with a hematology analyzer (Advia 120 Hematology System; Bayer Corporation, Tarrytown, NY). The different lymphocyte subpopulations (lymphocytes T (CD45+ CD3+ CD56−), NK (CD45+ CD3− CD56+), NKT (CD45+ CD3+ CD56+), CD4+ (CD3+ CD4+ CD8−), and CD8+ (CD3+ CD4− CD8+)) and dendritic cells (CD45+ lineage HLA-DRhigh) were assessed by flow cytometry (FACS Canto II flow cytometer; BD Bioscience, Franklin Lakes, NJ). The cell count of each of the lymphocyte subpopulations was calculated by multiplying total leukocyte count by the percentage of each subpopulation.
All immunological variables were assessed before (before the conditioning regimen) and after HSCT (+15 and +30 d post-HSCT, respectively) (Fig. 1).
We measured standing height to the nearest 0.1 cm with a clinical stadiometer (Asimed T2, Barcelona, Spain) while children were standing barefoot. We determined body mass to the nearest 0.05 kg using a balance scale (Ano Sayol S.L., Barcelona, Spain) with the subjects in their underwear. We calculated body mass index (BMI) as weight height (kg·m−2). We estimated children's fat-free mass (FFM) from the following equation (1): FFM = body mass − fat mass (FM), where FM = 4.95 body density (BD) × body mass. Children's BD was in turn estimated from skinfold thickness at the triceps, biceps, subscapular, and suprailiac area at the left side of the body according to the criteria described by Lohman et al. (20) using different equations depending on children's age and gender: BD = 1.169 − 0.0788log Σ 4 skinfolds and BD = 1.2063 − 0.0999log Σ 4 skinfolds (for boys and girls, respectively, aged ≤12 yr) (1) and BD = 1.1533 − 0.0643log Σ 4 skinfolds and BD = 1.1369 − 0.0598log Σ 4 skinfolds (for boys and girls, respectively, aged ≥13 yr) (9).
Anthropometry was assessed before (prior to the conditioning regimen) and 30 d post-HSCT (Fig. 1). Because of logistic problems, it was not possible to assess these parameters 15 d post-HSCT.
Training Intervention in Each Isolated Room
The intervention group trained from the beginning of the conditioning regimen until neutrophil engraftment, that is, the end of the neutropenic phase (Fig. 1). A mean of ∼22 training sessions would have been completed by each child if they all had a 100% adherence to the training program. The total number of planned training sessions was not the same for all children (range = 17-23) as there were individual variations in the duration of the neutropenic phase.
We used a combined (aerobic + resistance) training design on the basis of our previous experience with children (outpatients, <16 yr of age) who received HSCT within the previous 12-month period (26). Due to the unique setting characteristics (with each patient living in his room and within an isolation unit with HEPA and positive room pressure during the entire neutropenic phase), group training was not possible. Thus, each training session was individually supervised (one fitness instructor per patient). During the neutropenic phase, all training equipment (including cycle ergometers) was sterilized before each training session, and the instructors wore face masks during the sessions.
The training program for the exercise group was planned to include five weekly ∼50-min sessions, that is, three sessions including aerobic exercises only and two sessions including both aerobic and resistance exercises. Only those exercises such as bench (chest) press that had to be performed in the supine position were performed while children were lying in bed. All sessions started and ended with articular motion (hip, knees, and shoulders) and stretching exercises involving all major muscle groups at the start and end of session, respectively. Aerobic training corresponded to low- to moderate-intensity cycle ergometry (Rhyno Magnetic H490; BH Fitness Proaction, Victoria, Spain), averaging a total mean duration of 25-30 min per session and ranging from 10 to 40 min per session, depending on the physical status of each child. When needed, participants took short 1- to 2-min rest periods during the aerobic part of the sessions to allow completion of the target total training time. All participants wore a portable heart rate monitor (Xtrainer Plus; Polar Electro OY, Kempele, Finland) during the sessions to allow maintaining aerobic exercise intensity between 50% and 70% of age-predicted maximum heart rate, depending on the physical status of each child.
Patients also performed twice a week strength exercises engaging the major muscle groups (arm curl, elbow extension, bench press, leg extension, half squat, abdominals, supine bridge, and rowing). They performed one set of 12-15 repetitions per exercise. As for loads, we used (i) their own body weight (e.g., for abdominal crunches); (ii) Therabands (usually for the youngest children) with resistance gradually increasing over the program, that is, from low (yellow color) to medium (red) or high resistance (green); (iii) 1.5- to 3-kg barbells (for the oldest ones); or (iv) both body weight and barbells (e.g., for half squats by the end of the program). A session was cancelled if a child had fever >38°C, hemorrhage, severe muscle pain, or extreme fatigue.
To assess the effect of the training intervention on immune and anthropometric variables, we used a two-factor (group (exercise and control) × time (pre-HSCT, +15, or +30 d post-HSCT)) ANCOVA with repeated measures for time. The analyses were adjusted for multiple comparison (14). Age was initially introduced in the model as a covariate. For each variable, we reported the P value corresponding to the main group (between-patient) and time (within-patient) interaction (group × time) effects. Since there was no interaction between sex, training, and any of the outcome variables (all P > 0.2), all the analyses were performed for boys and girls together, and sex was included in the model as a covariate.
We applied a Mann-Whitney's U test to compare between the two groups the duration (in days) of the conditioning phase, neutropenic phase, and severe myelosupression as well as the number of erythrocyte and platelet concentrate transfusions needed. To assess the efficacy of the training program in improving children's fitness, we compared indicators of aerobic (resting heart rate) (25) and muscle fitness (resistance loads) between the start and the end of the intervention using a Mann-Whitney's U test.
All statistical analyses were performed using the Statistical Package for the Social Sciences for Windows (Version 16.0; SPSS Inc., Chicago, IL), the level of significance was set to ≤0.05, and all data are expressed as mean ± SD, unless otherwise indicated.
There were no protocol deviations from the study as planned. The final number of participants included as valid study participants in the intervention group, that is, with a 100% return for follow-up over the assessment period (pre-HSCT and up to +30 d post-HSCT), equaled seven.
We observed no significant differences (P > 0.05) between groups in main transplant characteristics (Table 2).
Only one study participant (in the control group) received no antibiotic prophylaxis. As for transplant-related toxicities, all but one control subject (92%) had one or more of such toxicities, including oropharyngeal mucositis (n = 3), intestinal mucositis (n = 3), liver toxicity (n = 7), diarrhea (n = 6), and cyclosporine-induced hypertension (n = 1). In the exercise group, five patients (71% of total) had transplant toxicities, including oropharyngeal mucositis (n = 2), kidney (n = 2) and liver toxicity (n = 2), diarrhea (n = 2), and cyclosporine-induced hypertension (n = 1). Six (46%) and two (29%) children in the control and exercise group, respectively, had acute GVHD after HSCT. In the control group, seven patients (54%) had no fever during hospitalization, and the rest of the control patients had fever during 1 (n = 3), 2 (n = 2), or 4 d (n = 1). In the exercise group, two children (15%) had no fever during hospitalization, whereas the rest of children had fever during 1 (n = 2), 4 (n = 2), or 9 d (n = 1).
The training characteristics for each child in the exercise group are shown in Table 3. Mean adherence to training was high (i.e., >90%), and we observed no major adverse effect or health problems induced by exercise during or after the training sessions. Reasons for lacking one or more sessions were lack of motivation (one patient), coincidence with transplant day (n = 1), feeling bad or weak (n = 3), fever (n = 2), and diarrhea (n = 1). One patient in the intervention group was missing the lower part of a leg and thus performed one-legged cycle ergometry and strength exercises. The training program improved children's functional capacity, that is, increase over the intervention period in (i) aerobic fitness, as reflected by significant decreases in resting heart rate, and (ii) muscle strength, as reflected by significantly augmenting resistance loads (Table 4).
Mean levels of anthropometric variables by group are shown in Table 5. There were no differences between groups before HSCT. We observed no significant group (between-patient) effect for any of the variables (all P > 0.1). We found a significant effect of the interaction group × time for all anthropometric variables (weight, BMI, body fat, and fat-free mass), indicating an increase over the hospitalization period only in the intervention group. The effect of the interaction group × time on fat-free mass became nonsignificant after adjusting for multiple comparisons. All the anthropometric variables tended to slightly decrease from pretransplant to posttransplant conditions in the control group.
Immune cell recovery.
Mean levels of white blood cell subpopulations by group are shown in Table 6. There were no differences between groups before transplantation. We observed no significant group (between-patient) effect for any of the variables (all P > 0.1). We only found a time (within-patient) effect for lymphocytes T, CD4+, and dendritic cells, which became nonsignificant after adjustment for multiple comparisons. Further, we only observed a significant effect of the interaction group × time, that is, an effect actually attributable to the exercise intervention versus the control condition, for dendritic cells (P = 0.045), which also became nonsignificant after adjustment for multiple comparisons. The dendritic cell count decreased from pretransplant to +15 d posttransplant in both groups and thereafter remained stable, yet the posttransplant decrease was more abrupt in the control group.
The main finding of our study was that, overall, moderate-intensity exercise training (19 sessions on average, including both aerobic and light resistance exercises) during inpatient stay for HSCT did not affect immune cell recovery in very young children with high-risk cancer. Further, this intervention contributed to increase patient's body mass and BMI, an effect that was partly mediated by an increase in fat-free mass.
A limitation of our study stems from the small population sample and the fact that we did not randomize group assignment. We believe that the limited sample size is justifiable given the low number of children undergoing HSCT, and the lack of randomization did not significantly influence the results as both groups were closely matched for age and type of treatment. In addition, we did not access dietary intake, and further research is necessary assessing dietary intake during HSCT hospitalization. This is an important consideration as HSCT and its related complications can cause gastrointestinal side effects (e.g., mucositis, diarrhea), leading to poor nutrition in children (25). Future research might determine if increased daily energy expenditure associated with exercise training can increase young children's appetite and energy intake, leading to favorable changes in body composition (increased body mass and BMI) as the ones observed here. Although the present findings do not rule out that nutritional status did not affect some variables, it appears that children's nutrition was sufficient to allow an increase in body mass and strength to occur. Our findings on body composition were limited by the fact that we used estimation equations to assess muscle and fat mass. It is likely that the use of more advanced and accurate techniques to quantify body composition (e.g., dual-energy x-ray absorptiometry) may help to better elucidate the effect of an exercise intervention on the patients' body composition. Unfortunately, because of logistic reasons (patients were confined to their rooms), this option was not possible in the present study. Body mass and BMI per se are nonetheless prognostic indicators of HSCT success (8,10,18). Finally, further research is necessary to determine the effect of exercise interventions during HSCT not only in immune cell subpopulations as we did here but also on immune function, for example, neutrophil oxidative capacity (17), cytolytic activity, or mitogen-induced lymphocyte proliferation (28).
The novelty of our data and the special population studied, made up of very young children (mean age = 7-8 yr) with high-risk cancer, are strong aspects of our study. In addition, we performed an individually supervised training intervention in a difficult, unusual setting, that is, isolated hospital rooms requiring sterilization of all training materials. Uniqueness of training conditions together with the high adherence to the program (in spite of the numerous drug toxicities suffered by the children and their poor functional status) also make the data unique. These aspects give support to the notion that exercise training can be a feasible therapeutic intervention even in the most debilitated and immune-compromised patient groups. Although keeping in mind that the total safety of exercise training during inpatient stay for pediatric HSCT remains to be determined in future trials with much larger population samples, we believe that our intervention is applicable worldwide. Besides the fact that all training materials must be sterilized and caution is needed when prescribing training loads in these very young, weak patients, no expensive equipment is needed, and children have high time availability for training during room isolation. The fact that adherence to training was very high concurs with previous intrahospital training trials in pediatric cancer patients (26,27) and supports the applicability of exercise interventions during hospitalization for cancer treatment. Further, intrahospital settings provide the best possible environment in the event of health problems occurring during training sessions.
The training-induced gains we showed in body mass/BMI over the hospitalization period in the intervention group, associated with an approximately 1-kg gain in fat-free mass, are clinically relevant. These anthropometric parameters have prognostic value after HSCT over a wide range of patients' age (8,10,18). In adult patients who received allogeneic HSCT, a low BMI (<20 kg·m−2) was significantly correlated with increased transplant-related mortality, decreased survival, and relapse-free survival (18). Maintenance of skeletal muscle protein is crucial in immunocompromised children (24), including those receiving HSCT (30). Avoiding losses in body mass during pediatric HSCT is of paramount importance because children undergoing this intervention are at particular high risk of malnutrition (34), and their muscle weakness is further aggravated by transplant-related problems, that is, bed rest and drug toxicities including among others oral intestinal mucositis and diarrhea (8,33). Because of the novelty of our design and the type of population, it is not possible to directly compare the present findings on anthropometric data with those reported in previous research. We recently reported no significant changes in body mass in outpatients who underwent HSCT within the previous 12 months after an 8-wk training program combining aerobic and resistance exercises (27). It is important to note that the physical status was less deteriorated than that in the present subjects, making comparisons difficult. Although there is some controversy (3,35), our findings seem to be in agreement with previous research on adult outpatients showing the overall efficacy of exercise training interventions for preserving patients' muscle mass after HSCT (2,3,11). In a home-based 6-month aerobic and resistance training intervention performed by adults receiving BMT, Coleman et al. (2) found that control patients lost body mass whereas intervention participants increased in body mass and fat-free mass. Similarly, Hayes et al. (11) reported increased fat-free mass in adults who received HSCT after a 3-month intervention of aerobic and resistance training.
There is evidence supporting the beneficial effects of physical exercise in the distribution and function of the cellular components of the immune system in healthy children (31). Up to date, however, the feasibility and the safety of exercise interventions in immunocompromised children as those studied here remain to be determined. Overall, exercise training was shown to be a safe intervention in our inpatients, that is, not compromising immune cell recovery over the hospitalization period. This preliminary finding is promising and clinically relevant, especially when considering that the largest part of the exercise intervention took part during the neutropenic phase, that is, while the absolute neutrophil count was below 0.5 × 109 L−1. Patients were not neutropenic in any of the two previous studies assessing the immune cell acute responses (17) or adaptations to exercise in children with acute lymphoblastic leukemia (28). Both pioneer studies reported no health-threatening effects of exercise on immune cells, which concurs with our results. Our findings are also in agreement with those previously reported by Hayes et al. (12) in adult patients who received HSCT and who were also immunocompromised. They carried out a combined (aerobic + resistance) moderate-intensity exercise training program during the first 3 months posttransplantation that showed no significant effect on immune cell recovery posttransplant. Dimeo et al. (6) reported shorter duration of the neutropenic phase after bed endurance training, and Kim and Kim (16) reported increases in total lymphocyte count with no decreases in lymphocyte subpopulations (CD3+, CD4+, and CD8+ or CD4+/CD8+ ratio). Taken together, these findings support the notion that physical exercise is a promising adjuvant therapeutic intervention during HSCT hospitalization in both children and adults.
We only observed a significant effect of the interaction group × time (which became nonsignificant after adjusting for multiple comparisons) for one of the immune cell populations, that is, dendritic cells. The dendritic cell count decreased from pretransplant to +15 d posttransplant in both groups and thereafter remained stabile with the posttransplant decrease being more abrupt in the control group, that is, −87% versus −63% compared with the intervention group. Whether this finding is of clinical relevance remains to be determined, yet it deserves some attention given the pivotal immune role played by dendritic cells. These cells are the most potent antigen-presenting cells of the immune system (15). They play a central modulator role in allogeneic HSCT (23) and are excellent candidates for immunotherapy in pediatric cancer patients (15). The content of donor's dendritic cells associated with decreased risk of GVHD (32), and dendritic cell recovery at 30 d post-HSCT is associated with the clinical outcome after allogeneic HSCT (29). Ho et al. (13) reported an increase in dendritic cell count after acute (treadmill) exercise that paralleled that of monocytes. Their study showed that exercise is one of the main stressor stimuli able to trigger dendritic cell increases in blood.
In summary, moderate-intensity exercise training during inpatient stay for HSCT (∼3-wk training period) does not negatively affect immune cell recovery in children with high-risk cancer while contributing to increase body mass and BMI. These findings together with the multiple health benefits associated with exercise training in cancer patients support the feasibility of training interventions during hospitalization, including immune-compromised children. Future studies using randomized controlled designs in larger population samples are nonetheless necessary, especially to corroborate the total safety of this type of intervention.
This study was funded by a grant from the Fondo de Investigaciones Sanitarias (grant Nos. P1061183 and PS09/00194), from the Fundación Blas Ponce Para El Niño Oncológico, and from the Spanish Ministry of Education (EX-2007-1124).
The authors state that the results of the present study do not constitute endorsement by the American College of Sports Medicine.
This study was awarded with Segundo Premio Nacional de Investigaion en Medicina del Deporte, Escuela de Medicina del Deporte, Oviedo (Spain).
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