Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Physical function and quality of life in patients with chronic GvHD: a summary of preclinical and clinical studies and a call for exercise intervention trials in patients

Abstract

Allogeneic hematopoietic stem cell transplant, to reconstitute the hematopoietic and immune status of patients undergoing myeloablative therapy for hematologic disorders, has been of great benefit in minimizing or eradicating disease and extending survival. Patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) are subject to many comorbidities among which the most significant, affecting quality of life (QoL) and survival, are acute GvHD (aGvHD) and chronic GvHD (cGvHD), resulting from donor lymphocytes reacting to and damaging host tissues. Physical activity and exercise have clearly been shown, in both children and adults, to enhance fitness, improve symptomatology and QoL, reduce disease progression and extend survival for many diseases including malignancies. In some cases, vigorous exercise has been shown to be equal to or more effective than pharmacologic therapy. This review addresses how cGvHD affects patients’ physical function and physical domain of QoL, and the potential benefits of exercise interventions along with recommendations for relevant research and evaluation targeted at incorporating this strategy as soon as possible after allo-HSCT and ideally, as soon as possible upon diagnosis of the condition leading to allo-HSCT.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Fraser CJ, Bhatia S, Ness K, Carter A, Francisco L, Arora M et al. Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: A report from the Bone Marrow Transplant Survivor Study. Blood 2006; 108: 2867–2873.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Ferrara JL, Levine JE, Reddy P, Holler E . Graft-versus-host disease. Lancet 2009; 373: 1550–1561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Martin PJ, Counts GW, Appelbaum FR, Lee SJ, Sanders JE, Deeg HJ et al. Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation. J Clin Oncol 2010; 28: 1011–1016.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol 2011; 29: 2230–2239.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Savani BN, Koklanaris EK, Le Q, Shenoy A, Goodman S, Barrett AJ . Prolonged chronic graft-versus-host disease is a risk factor for thyroid failure in long-term survivors after matched sibling donor stem cell transplantation for hematologic malignancies. Biol Blood Marrow Transplant 2009; 15: 377–381.

    PubMed  PubMed Central  Google Scholar 

  6. Montero A, Savani BN, Shenoy A, Read EJ, Carter CS, Leitman SF et al. T-cell depleted peripheral blood stem cell allotransplantation with T-cell add-back for patients with hematological malignancies: effect of chronic GVHD on outcome. Biol Blood Marrow Transplant 2006; 12: 1318–1325.

    PubMed  Google Scholar 

  7. Garnett C, Apperley JF, Pavlů J . Treatment and management of graft-versus-host disease: improving response and survival. Ther Adv Hematol 2013; 4: 366–378.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Fiuza-Luces C, Garatachea N, Berger NA, Lucia A . Exercise is the real polypill. Physiology (Bethesda) 2013; 28: 330–358.

    CAS  Google Scholar 

  9. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-host Disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.

    Article  PubMed  Google Scholar 

  10. Couriel D, Carpenter PA, Cutler C, Bolaños-Meade J, Treister NS, Gea-Banacloche J et al. Ancillary therapy and supportive care of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working. Biol Blood Marrow Transplant 2006; 12: 375–396.

    PubMed  Google Scholar 

  11. Martin PJ, Weisdorf D, Przepiorka D, Hirschfeld S, Farrell A, Rizzo JD et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. Design of Clinical Trials Working Group report. Biol Blood Marrow Transplant 2006; 12: 491–505.

    PubMed  Google Scholar 

  12. Pavletic SZ, Martin P, Lee SJ, Mitchell S, Jacobsohn D, Cowen EW et al. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant 2006; 12: 252–266.

    PubMed  Google Scholar 

  13. Schultz KR, Miklos DB, Fowler D, Cooke K, Shizuru J, Zorn E et al. Toward biomarkers for chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-host Disease: III. Biomarker Working Group Report. Biol Blood Marrow Transplant 2006; 12: 126–137.

    PubMed  Google Scholar 

  14. Shulman HM, Kleiner D, Lee SJ, Morton T, Pavletic SZ, Farmer E et al. Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant 2006; 12: 31–47.

    PubMed  Google Scholar 

  15. Pidala J, Vogelsang G, Martin P, Chai X, Storer B, Pavletic S et al. Overlap subtype of chronic graft-versus-host disease is associated with an adverse prognosis, functional impairment, and inferior patient-reported outcomes: A Chronic Graft-versus-Host Disease Consortium study. Haematologica 2012; 97: 451–458.

    PubMed  PubMed Central  Google Scholar 

  16. Hymes SR, Turner ML, Champlin RE, Couriel DR . Cutaneous manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2006; 12: 1101–1113.

    PubMed  Google Scholar 

  17. Chu Y-W, Gress RE . Murine models of chronic graft-versus-host disease: insights and unresolved issues. Biol Blood Marrow Transplant 2008; 14: 365–378.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Schroeder MA, DiPersio JF . Mouse models of graft-versus-host disease: advances and limitations. Dis Model Mech 2011; 4: 318–333.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang C, Todorov I, Zhang Z, Liu Y, Kandeel F, Forman S et al. Donor CD4+ T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations. Blood 2006; 107: 2993–3001.

    CAS  PubMed  Google Scholar 

  20. Wu T, Young JS, Johnston H, Ni X, Deng R, Racine J et al. Thymic damage, impaired negative selection, and development of chronic graft-versus-host disease caused by donor CD4+ and CD8+ T cells. J Immunol 2013; 191: 488–499.

    CAS  PubMed  Google Scholar 

  21. Srinivasan M, Flynn R, Price A, Ranger A, Browning JL, Taylor PA et al. Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans. Blood 2012; 119: 1570–1580.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Sato M, Tokuda N, Fukumoto T, Mano T, Sato T, Ueyama Y . Immunohistopathological study of the oral lichenoid lesions of chronic GVHD. J Oral Pathol Med 2006; 35: 33–36.

    CAS  PubMed  Google Scholar 

  23. Imanguli MM, Swaim WD, League SC, Gress RE, Pavletic SZ, Hakim FT . Increased T-bet+cytotoxic effectors and type i interferon-mediated processes in chronic graft-versus-host disease of the oral mucosa. Blood 2009; 113: 3620–3630.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Panoskaltsis-Mortari A, Tram K V, Price AP, Wendt CH, Blazar BR . A new murine model for bronchiolitis obliterans post-bone marrow transplant. Am J Respir Crit Care Med 2007; 176: 713–723.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Briones J, Novelli S, Sierra J . T-cell costimulatory molecules in acute-graft-versus host disease: therapeutic implications. Bone Marrow Res 2011; 2011: 1–7.

    Google Scholar 

  26. Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. New Engl J Med 2011; 365: 2055–2066.

    CAS  PubMed  Google Scholar 

  27. Brüggen MC, Klein I, Greinix H, Bauer W, Kuzmina Z, Rabitsch W et al. Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease. Blood 2014; 123: 290–299.

    PubMed  Google Scholar 

  28. Matsuoka K, Kim HT, McDonough S, Bascug G, Warshauer B, Koreth J et al. Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation. J Clin Invest 2010; 120: 1479–1493.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Corre E, Carmagnat M, Busson M, de Latour RP, Robin M, Ribaud P et al. Long-term immune deficiency after allogeneic stem cell transplantation: B-cell deficiency is associated with late infections. Haematologica 2010; 95: 1025–1029.

    PubMed  PubMed Central  Google Scholar 

  30. Kim SJ, Lee JW, Jung CW, Min CK, Cho B, Shin HJ et al. Weekly rituximab followed by monthly rituximab treatment for steroid-refractory chronic graft-versus-host disease: results from a prospective, multicenter, phase II study. Haematologica 2010; 95: 1935–1942.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kuzmina Z, Greinix HT, Weigl R, Körmöczi U, Rottal A, Frantal S et al. Significant differences in B-cell subpopulations characterize patients with chronic graft-versus-host disease-associated dysgammaglobulinemia. Blood 2011; 117: 2265–2274.

    CAS  PubMed  Google Scholar 

  32. Kuzmina Z, Krenn K, Petkov V, Körmöczi U, Weigl R, Rottal A et al. CD19(+)CD21(low) B cells and patients at risk for NIH-defined chronic graft-versus-host disease with bronchiolitis obliterans syndrome. Blood 2013; 121: 1886–1895.

    CAS  PubMed  Google Scholar 

  33. Sarantopoulos S, Stevenson KE, Kim HT, Cutler CS, Bhuiya NS, Schowalter M et al. Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. Blood 2009; 113: 3865–3874.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Clark WB, Brown-Gentry KD, Crawford DC, Fan KH, Snavely J, Chen H et al. Genetic variation in recipient B-cell activating factor modulates phenotype of GVHD. Blood 2011; 118: 1140–1144.

    CAS  PubMed  Google Scholar 

  35. Fujii H, Cuvelier G, She K, Aslanian S, Shimizu H, Kariminia A et al. Biomarkers in newly diagnosed pediatric-extensive chronic graft-versus-host disease: a report from the Children’s Oncology Group. Blood 2008; 111: 3276–3285.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Sarantopoulos S, Stevenson KE, Kim HT, Bhuiya NS, Cutler CS, Soiffer RJ et al. High levels of B-cell activating factor in patients with active chronic graft-versus-host disease. Clin Cancer Res 2007; 13: 6107–6114.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Sarantopoulos S, Stevenson KE, Kim HT, Washel WS, Bhuiya NS, Cutler CS et al. Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease. Blood 2011; 117: 2275–2283.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. She K, Gilman AL, Aslanian S, Shimizu H, Krailo M, Chen Z et al. Altered toll-like receptor 9 responses in circulating B cells at the onset of extensive chronic graft-versus-host disease. Biol Blood Marrow Transplant 2007; 13: 386–397.

    CAS  PubMed  Google Scholar 

  39. Flynn R, Du J, Veenstra RG, Reichenbach DK, Panoskaltsis-Mortari A, Taylor PA et al. Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood 2014; 123: 3988–3998.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Patriarca F, Skert C, Sperotto A, Zaja F, Falleti E, Mestroni R et al. The development of autoantibodies after allogeneic stem cell transplantation is related with chronic graft-vs-host disease and immune recovery. Exp Hematol 2006; 34: 389–396.

    CAS  PubMed  Google Scholar 

  41. Svegliati S, Olivieri A, Campelli N, Luchetti M, Poloni A, Trappolini S et al. Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease. Blood 2007; 110: 237–241.

    CAS  PubMed  Google Scholar 

  42. Clave E, Busson M, Douay C, De Latour RP, Berrou J, Rabian C et al. Acute graft-versus-host disease transiently impairs thymic output in young patients after allogeneic hematopoietic stem cell transplantation. Blood 2009; 113: 6477–6484.

    CAS  PubMed  Google Scholar 

  43. Hillebrandt S, Wasmuth HE, Weiskirchen R, Hellerbrand C, Keppeler H, Werth A et al. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nat Genet 2005; 37: 835–843.

    CAS  PubMed  Google Scholar 

  44. Zhou L, Askew D, Wu C, Gilliam AC . Cutaneous gene expression by DNA microarray in murine sclerodermatous graft-versus-host disease, a model for human scleroderma. J Invest Dermatol 2007; 127: 281–292.

    CAS  PubMed  Google Scholar 

  45. Joseph RW, Couriel DR, Komanduri KV . Chronic graft-versus-host disease after allogeneic stem cell transplantation: challenges in prevention, science and supportive care. J Support Oncol 6: 361–372.

  46. Banovic T, MacDonald KPA, Morris ES, Rowe V, Kuns R, Don A et al. TGF-beta in allogeneic stem cell transplantation: friend or foe? Blood 2005; 106: 2206–2214.

    CAS  PubMed  Google Scholar 

  47. Nishimori H, Maeda Y, Teshima T, Sugiyama H, Kobayashi K, Yamasuji Y et al. Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17. Blood 2012; 119: 285–295.

    CAS  PubMed  Google Scholar 

  48. Mays JW, Fassil H, Edwards DA, Pavletic SZ, Bassim CW . Oral chronic graft-versus-host disease: current pathogenesis, therapy, and research. Oral Dis 2013; 19: 327–346.

    CAS  PubMed  Google Scholar 

  49. Buchanan DR, O’Mara AM, Kelaghan JW, Sgambati M, McCaskill-Stevens W, Minasian L . Challenges and recommendations for advancing the state-of-the-science of quality of life assessment in symptom management trials. Cancer 2007; 110: 1621–1628.

    PubMed  Google Scholar 

  50. Herzberg PY, Heussner P, Mumm FHA, Horak M, Hilgendorf I, von Harsdorf S et al. Validation of the human activity profile questionnaire in patients after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2010; 16: 1707–1717.

    PubMed  Google Scholar 

  51. Pidala J, Anasetti C, Jim H . Quality of life after allogeneic hematopoietic cell transplantation. Blood 2009; 114: 7–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Arai S, Jagasia M, Storer B, Chai X, Pidala J, Cutler C et al. Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH consensus criteria. Blood 2011; 118: 4242–4249.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Baird K, Steinberg SM, Grkovic L, Pulanic D, Cowen EW, Mitchell SA et al. National Institutes of Health chronic graft-versus-host disease staging in severely affected patients: organ and global scoring correlate with established indicators of disease severity and prognosis. Biol Blood Marrow Transplant 2013; 19: 632–639.

    PubMed  PubMed Central  Google Scholar 

  54. Bhatia S, Francisco L, Carter A, Sun CL, Scott Baker K, Gurney JG et al. Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: Report from the Bone Marrow Transplant Survivor study. Blood 2007; 110: 3784–3792.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Heinonen H, Volin L, Zevon MA, Uutela A, Barrick C, Ruutu T . Stress among allogeneic bone marrow transplantation patients. Patient Educ Couns 2005; 56: 62–71.

    PubMed  Google Scholar 

  56. Kopp M, Holzner B, Meraner V, Sperner-Unterweger B, Kemmler G, Nguyen-Van-Tam DP et al. Quality of life in adult hematopoietic cell transplant patients at least 5 yr after treatment: a comparison with healthy controls. Eur J Haematol 2005; 74: 304–308.

    Article  PubMed  Google Scholar 

  57. La Nasa G, Caocci G, Efficace F, Dessì C, Vacca A, Piras E et al. Long-term health-related quality of life evaluated more than 20 years after hematopoietic stem cell transplantation for thalassemia. Blood 2013; 122: 2262–2270.

    CAS  PubMed  Google Scholar 

  58. Lee SJ . Flowers MED. Recognizing and managing chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program 2008; 2008: 134–141.

    Google Scholar 

  59. Lee SJ, Kim HT, Ho VT, Cutler C, Alyea EP, Soiffer RJ et al. Quality of life associated with acute and chronic graft-versus-host disease. Bone Marrow Transplant 2006; 38: 305–310.

    CAS  PubMed  Google Scholar 

  60. Messerer D, Engel J, Hasford J, Schaich M, Ehninger G, Sauerland C et al. Impact of different post-remission strategies on quality of life in patients with acute myeloid leukemia. Haematologica 2008; 93: 826–833.

    PubMed  Google Scholar 

  61. Mitchell SA, Leidy NK, Mooney KH, Dudley WN, Beck SL, LaStayo PC et al. Determinants of functional performance in long-term survivors of allogeneic hematopoietic stem cell transplantation with chronic graft-versus-host disease (cGVHD). Bone Marrow Transplant 2010; 45: 762–769.

    CAS  PubMed  Google Scholar 

  62. Mo X-D, Xu L-P, Liu D-H, Chen Y-H, Han W, Zhang X-H et al. Patients receiving HLA-haploidentical/partially matched related allo-HSCT can achieve desirable health-related QoL that is comparable to that of patients receiving HLA-identical sibling allo-HSCT. Bone Marrow Transplantation 2012; 47: 1201–1205.

    PubMed  Google Scholar 

  63. Mo X, Xu L, Liu D, Chen Y, Zhang X, Chen H et al. Health related quality of life among patients with chronic graft-versus-host disease in China. Chin Med J (Engl) 2013; 126: 3048–3052.

    Google Scholar 

  64. Pidala J, Kim J, Anasetti C, Nishihori T, Betts B, Field T et al. The global severity of chronic graft-versus-host disease, determined by National Institutes of Health consensus criteria, is associated with overall survival and non-relapse mortality. Haematologica 2011; 96: 1678–1684.

    PubMed  PubMed Central  Google Scholar 

  65. Pidala J, Kurland B, Chai X, Majhail N, Weisdorf DJ, Pavletic S et al. Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. Blood 2011; 117: 4651–4657.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Pidala J, Kurland BF, Chai X, Vogelsang G, Weisdorf DJ, Pavletic S et al. Sensitivity of changes in chronic graft-versus-host disease activity to changes in patient-reported quality of life: results from the chronic graft-versus-host disease consortium. Haematologica 2011; 96: 1528–1535.

    PubMed  PubMed Central  Google Scholar 

  67. Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, Hansen JA et al. Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood 2004; 104: 3501–3506.

    CAS  PubMed  Google Scholar 

  68. Wong FL, Francisco L, Togawa K, Bosworth A, Gonzales M, Hanby C et al. Long-term recovery after hematopoietic cell transplantation: predictors of quality-of-life concerns. Blood 2010; 115: 2508–2519.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Le RQ, Bevans M, Savani BN, Mitchell SA, Stringaris K, Koklanaris E et al. Favorable outcomes in patients surviving 5 or more years after allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Biol Blood Marrow Transplant 2010; 16: 1162–1170.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. El-Jawahri A, Pidala J, Inamoto Y, Chai X, Khera N, Wood WA et al. Impact of age on quality of life, functional status, and survival in patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant 2014; 20: 1341–1348.

    PubMed  PubMed Central  Google Scholar 

  71. Pidala J, Chai X, Kurland BF, Inamoto Y, Flowers MED, Palmer J et al. Analysis of gastrointestinal and hepatic chronic grant-versus-host disease manifestations on major outcomes: a chronic grant-versus-host disease consortium study. Biol Blood Marrow Transplant 2013; 19: 784–791.

    PubMed  PubMed Central  Google Scholar 

  72. Carlson LE, Smith D, Russell J, Fibich C, Whittaker T . Individualized exercise program for the treatment of severe fatigue in patients after allogeneic hematopoietic stem-cell transplant: a pilot study. Bone Marrow Transplantation 2006; 37: 945–954.

    CAS  PubMed  Google Scholar 

  73. DeFor TE, Burns LJ, Gold EMA, Weisdorf DJ . A randomized trial of the effect of a walking regimen on the functional status of 100 adult allogeneic donor hematopoietic cell transplant patients. Biol Blood Marrow Transplant 2007; 13: 948–955.

    PubMed  Google Scholar 

  74. Dimeo F, Schwartz S, Wesel N, Voigt A, Thiel E . Effects of an endurance and resistance exercise program on persistent cancer-related fatigue after treatment. Ann Oncol 2008; 19: 1495–1499.

    CAS  PubMed  Google Scholar 

  75. Khera N, Storer B, Flowers MED, Carpenter PA, Inamoto Y, Sandmaier BM et al. Nonmalignant late effects and compromised functional status in survivors of hematopoietic cell transplantation. J Clin Oncol 2012; 30: 71–77.

    PubMed  Google Scholar 

  76. Syrjala KL, Langer SL, Abrams JR, Storer BE, Martin PJ . Late effects of hematopoietic cell transplantation among 10-year adult survivors compared with case-matched controls. J Clin Oncol 2005; 23: 6596–6606.

    PubMed  Google Scholar 

  77. Kovalszki A, Schumaker GL, Klein A, Terrin N, White AC . Reduced respiratory and skeletal muscle strength in survivors of sibling or unrelated donor hematopoietic stem cell transplantation. Bone Marrow Transplant 2008; 41: 965–969.

    CAS  PubMed  Google Scholar 

  78. Acquadro C, Berzon R, Dubois D, Leidy NK, Marquis P, Revicki D et al. Incorporating the patient’s perspective into drug development and communication: an ad hoc task force report of the patient-reported outcomes (PRO) Harmonization Group meeting at the food and drug administration, February 16, 2001. Value Health 2003; 6: 522–531.

    PubMed  Google Scholar 

  79. Lee S k, Cook EF, Soiffer R, Antin JH . Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2002; 8: 444–452.

    PubMed  Google Scholar 

  80. Waters RL, Lunsford BR, Perry J, Byrd R . Energy-speed relationship of walking: standard tables. J Orthop Res 1988; 6: 215–222.

    CAS  PubMed  Google Scholar 

  81. Pidala J, Chai X, Martin P, Inamoto Y, Cutler C, Palmer J et al. Hand grip strength and 2-minute walk test in chronic graft-versus-host disease assessment: analysis from the chronic GVHD consortium. Biol Blood Marrow Transplant 2013; 19: 967–972.

    PubMed  PubMed Central  Google Scholar 

  82. Mathiowetz V, Weber K, Volland G, Kashman N . Reliability and validity of grip and pinch strength evaluations. J Hand Surg Am 1984; 9: 222–226.

    CAS  PubMed  Google Scholar 

  83. Carpenter PA . How I conduct a comprehensive chronic graft-versus-host disease assessment. Blood 2011; 118: 2679–2687.

    CAS  PubMed  Google Scholar 

  84. Inamoto Y, Pidala J, Chai X, Kurland BF, Weisdorf D, Flowers MED et al. Assessment of joint and fascia manifestations in chronic graft-versus-host disease. Arthritis Rheumatol 2014; 66: 1044–1052.

    PubMed  PubMed Central  Google Scholar 

  85. Tavares R de CB da S, Silva M de M, Bouzas LF da S, Rodrigues MC, Vigorito AC, Funke V et al. Brazilian workshop model to train investigators in chronic graft-versus-host disease clinical trials according to the 2005-2006 National Institutes of Health recommendations. Rev Bras Hematol Hemoter 2011; 33: 347–352.

    Google Scholar 

  86. Inamoto Y, Chai X, Kurland BF, Cutler C, Flowers MED, Palmer JM et al. Validation of measurement scales in ocular graft-versus-host disease. Ophthalmology 2012; 119: 487–493.

    PubMed  Google Scholar 

  87. Palmer J, Williams K, Inamoto Y, Chai X, Martin PJ, Tomas LS et al. Pulmonary symptoms measured by the national institutes of health lung score predict overall survival, nonrelapse mortality, and patient-reported outcomes in chronic graft-versus-host disease. Biol Blood Marrow Transplant 2014; 20: 337–344.

    PubMed  Google Scholar 

  88. Chiodi S, Spinelli S, Ravera G, Petti AR, Van Lint MT, Lamparelli T et al. Quality of life in 244 recipients of allogeneic bone marrow transplantation. Br J Haematol 2000; 110: 614–619.

    CAS  PubMed  Google Scholar 

  89. Johansen KL, Painter P, Kent-Braun JA, Ng AV, Carey S, Da Silva M et al. Validation of questionnaires to estimate physical activity and functioning in end-stage renal disease. Kidney Int 2001; 59: 1121–1127.

    CAS  PubMed  Google Scholar 

  90. McHorney CA, Ware JE, Raczek AE . The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs Med Care 1993; 31: 247–263.

    CAS  PubMed  Google Scholar 

  91. McQuellon RP, Russell GB, Cella DF, Craven BL, Brady M, Bonomi A et al. Quality of life measurement in bone marrow transplantation: development of the functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) scale. Bone Marrow Transplant 1997; 19: 357–368.

    CAS  PubMed  Google Scholar 

  92. Fiuza-Luces C, Garatachea N, Simpson RJ, Berger NA, Ramírez M, Lucia A . Understanding graft-versus-host disease. Preliminary findings regarding the effects of exercise in affected patients. Exerc Immunol Rev 2015; 21: 80–112.

    PubMed  Google Scholar 

  93. Fiuza-Luces C, Gonzalez-Murillo A, Soares-Miranda L, Martinez Palacio J, Colmenero I, Casco F et al. Effects of exercise interventions in graft-versus-host disease models. Cell Transplant 2013; 22: 2409–2420.

    PubMed  Google Scholar 

  94. Koch LG, Britton SL . Aerobic metabolism underlies complexity and capacity. J Physiol 2008; 586: 83–95.

    CAS  PubMed  Google Scholar 

  95. Wisløff U, Najjar SM, Ellingsen O, Haram PM, Swoap S, Al-Share Q et al. Cardiovascular risk factors emerge after artificial selection for low aerobic capacity. Science 2005; 307: 418–420.

    PubMed  Google Scholar 

  96. Walsh NP, Gleeson M, Shephard RJ, Gleeson M, Woods JA, Bishop NC et al. Position statement part one: Immune function and exercise. Exerc Immunol Rev 2011; 17: 6–63.

    PubMed  Google Scholar 

  97. Kim SD, Kim HS . A series of bed exercises to improve lymphocyte count in allogeneic bone marrow transplantation patients. Eur J Cancer Care (Engl) 2006; 15: 453–457.

    Google Scholar 

  98. Chamorro-Vina C, Ruiz JR, Santana-Sosa E, González Vicent M, Madero L, Pérez M et al. Exercise during hematopoietic stem cell transplant hospitalization in children. Med Sci Sports Exerc 2010; 42: 1045–1053.

    PubMed  Google Scholar 

  99. Ladha AB, Courneya KS, Bell GJ, Field CJ, Grundy P . Effects of acute exercise on neutrophils in pediatric acute lymphoblastic leukemia survivors: a pilot study. J Pediatr Hematol Oncol 2006; 28: 671–677.

    PubMed  Google Scholar 

  100. Fiuza-Luces C, Soares-Miranda L, González-Murillo A, Palacio JM, Colmenero I, Casco F et al. Exercise benefits in chronic graft versus host disease: a murine model study. Med Sci Sports Exerc 2013; 45: 1703–1711.

    CAS  PubMed  Google Scholar 

  101. Kavanagh T, Yacoub MH, Mertens DJ, Kennedy J, Campbell RB, Sawyer P . Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation. Circulation 1988; 77: 162–171.

    CAS  PubMed  Google Scholar 

  102. Mettauer B, Lampert E, Petitjean P, Bogui P, Epailly E, Schnedecker B et al. Persistent exercise intolerance following cardiac transplantation despite normal oxygen transport. Int J Sports Med 1996; 17: 277–286.

    CAS  PubMed  Google Scholar 

  103. Bennett WM, Norman DJ . Action and toxicity of cyclosporine. Annu Rev Med 1986; 37: 215–224.

    CAS  PubMed  Google Scholar 

  104. Mercier JG, Hokanson JF, Brooks GA . Effects of cyclosporine A on skeletal muscle mitochondrial respiration and endurance time in rats. Am J Respir Crit Care Med 1995; 151: 1532–1536.

    CAS  PubMed  Google Scholar 

  105. Allen RD, Staley TA, Sidman CL . Differential cytokine expression in acute and chronic murine graft-versus-host-disease. Eur J Immunol 1993; 23: 333–337.

    CAS  PubMed  Google Scholar 

  106. De Wit D, Van Mechelen M, Zanin C, Doutrelepont JM, Velu T, Gérard C et al. Preferential activation of Th2 cells in chronic graft-versus-host reaction. J Immunol 1993; 150: 361–366.

    CAS  PubMed  Google Scholar 

  107. Fry TJ, Mackall CL . The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J Immunol 2005; 174: 6571–6576.

    CAS  PubMed  Google Scholar 

  108. Ko M-H, Chang C-K, Wu C-L, Hou Y-C, Hong W, Fang S-H . The interactive effect of exercise and immunosuppressant cyclosporin A on immune function in mice. J Sports Sci 2010; 28: 967–973.

    PubMed  Google Scholar 

  109. Fiuza-Luces C, Delmiro A, Soares-Miranda L, González-Murillo Á, Martínez-Palacios J, Ramírez M et al. Exercise training can induce cardiac autophagy at end-stage chronic conditions: Insights from a graft-versus-host-disease mouse model. Brain Behav Immun 2014; 39: 56–60.

    PubMed  Google Scholar 

  110. Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 2007; 13: 619–624.

    CAS  PubMed  Google Scholar 

  111. Taneike M, Yamaguchi O, Nakai A, Hikoso S, Takeda T, Mizote I et al. Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 2010; 6: 600–606.

    CAS  PubMed  Google Scholar 

  112. Van Bilsen M, Smeets PJH, Gilde AJ, Van Der Vusse GJ . Metabolic remodelling of the failing heart: The cardiac burn-out syndrome? Cardiovasc Res 2004; 61: 218–226.

    CAS  PubMed  Google Scholar 

  113. He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 2012; 481: 511–515.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Chen CY, Hsu HC, Lee BC, Lin HJ, Chen YH, Huang HC et al. Exercise training improves cardiac function in infarcted rabbits: Involvement of autophagic function and fatty acid utilization. Eur J Heart Fail 2010; 12: 323–330.

    CAS  PubMed  Google Scholar 

  115. Cui M, Yu H, Wang J, Gao J, Li J . Chronic caloric restriction and exercise improve metabolic conditions of dietary-induced obese mice in autophagy correlated manner without involving ampk. J Diabetes Res 2013; 2013: 852754.

    PubMed  PubMed Central  Google Scholar 

  116. Willis MS, Min JN, Wang S, Mcdonough H, Lockyer P, Wadosky KM et al. Carboxyl terminus of Hsp70-interacting protein (CHIP) is required to modulate cardiac hypertrophy and attenuate autophagy during exercise. Cell Biochem Funct 2013; 31: 724–735.

    CAS  PubMed  Google Scholar 

  117. De Lisio M, Kaczor JJ, Phan N, Tarnopolsky MA, Boreham DR, Parise G . Exercise training enhances the skeletal muscle response to radiation-induced oxidative stress. Muscle Nerve 2011; 43: 58–64.

    CAS  PubMed  Google Scholar 

  118. Serra-Rexach JA, Bustamante-Ara N, Hierro Villarán M, González Gil P, Sanz Ibáñez MJ, Blanco Sanz N et al. Short-term, light- to moderate-intensity exercise training improves leg muscle strength in the oldest old: A randomized controlled trial. J Am Geriatr Soc 2011; 59: 594–602.

    PubMed  Google Scholar 

  119. Fleck SJ, Bustamante-Ara N, Ortiz J, Vidán M-T, Lucia A, Serra-Rexach JA . Activity in GEriatric acute CARe (AGECAR): rationale, design and methods. BMC Geriatr 2012; 12: p 28.

    PubMed  PubMed Central  Google Scholar 

  120. Del Valle MF, Pérez M, Santana-Sosa E, Fiuza-Luces C, Bustamante-Ara N, Gallardo C et al. Does resistance training improve the functional capacity and well being of very young anorexic patients? A randomized controlled trial. J Adolesc Health 2010; 46: 352–358.

    PubMed  Google Scholar 

  121. Santana-Sosa E, Gonzalez-Saiz L, Groeneveld IF, Villa-Asensi JR, Barrio Gómez de Aguero MI, Fleck SJ et al. Benefits of combining inspiratory muscle with ‘whole muscle’ training in children with cystic fibrosis: a randomised controlled trial. Br J Sports Med 2013; 48: 1513–1517.

    PubMed  Google Scholar 

  122. San Juan AF, Chamorro-Vina C, Moral S, Fernandez Del Valle M, Madero L, Ramírez M et al. Benefits of intrahospital exercise training after pediatric bone marrow transplantation. Int J Sports Med 2008; 29: 439–446.

    CAS  PubMed  Google Scholar 

  123. Wolin KY, Ruiz JR, Tuchman H, Lucia A . Exercise in adult and pediatric hematological cancer survivors: an intervention review. Leukemia 2010; 24: 1113–1120.

    CAS  PubMed  Google Scholar 

  124. Schmitz KH, Courneya KS, Matthews C, Demark-Wahnefried W, Galvão DA, Pinto BM et al. American college of sports medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc 2010; 42: 1409–1426.

    PubMed  Google Scholar 

  125. Beissner KL, Collins JE, Holmes H . Muscle force and range of motion as predictors of function in older adults. Phys Ther 2000; 80: 556–563.

    CAS  PubMed  Google Scholar 

  126. Ware JE Jr, Kosinski M, Dewey JE . How to Score Version 2 of the SF-36 Health Survey (Standard & Acute forms), 2nd Ed. Quality Metric Incorporated, Lincoln, RI, 2001.

    Google Scholar 

Download references

Acknowledgements

This work was supported, in part, by PI07/0907 and PI10/02802 to MR; PI12/0094, Instituto de Salud Carlos III (Spain) and P2015UEM49 Universidad Europea and co-funded by Fondo de Investigaciones Sanitarias and FEDER (Spain) to AL; Sara Borell PhD Contract CD14/00005, Institute de Salud Carlos III (Spain) to CF-L; USA NASA Grant NNJ1 0ZSA003N to RS; and Ellison Medical Foundation and USA NIH Grants P50 CA150964 and U54CA163060 to NB.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N A Berger.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fiuza-Luces, C., Simpson, R., Ramírez, M. et al. Physical function and quality of life in patients with chronic GvHD: a summary of preclinical and clinical studies and a call for exercise intervention trials in patients. Bone Marrow Transplant 51, 13–26 (2016). https://doi.org/10.1038/bmt.2015.195

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2015.195

This article is cited by

Search

Quick links