Abstract
Graft-versus-host disease (GVHD) is an important complication after hematopoietic stem cell transplantation (HSCT) in children, and is second only to disease relapse as a cause of death in this population. This chapter reviews the pathophysiology, incidence, clinical features, classification, and treatment of acute and chronic variants of this condition. Unique aspects of acute and chronic GVHD in the pediatric population are highlighted. Lastly, knowledge gaps and potential directions for further research are addressed.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Hill GR, Ferrara JL. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood. 2000;95(9):2754–9.
Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet (London, England). 2009;373(9674):1550–61.
Billingham R. The biology of graft-versus-host reactions. Harvey Lect. 1966–1967;62:21–78.
Hymes SR, Alousi AM, Cowen EW. Graft-versus-host disease: Part I. Pathogenesis and clinical manifestations of graft-versus-host disease. J Am Acad Dermatol. 2012;66(4):515 e1–18; quiz 33–4
Cooke KR, Luznik L, Sarantopoulos S, Hakim FT, Jagasia M, Fowler DH, et al. The biology of chronic graft-versus-host disease: a task force report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2017;23(2):211–34. Epub 2016.
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 diagnosis and staging working group report. Biol Blood Marrow Transplant. 2015;21(3):389–401. e1
Lee SE, Yoon JH, Shin SH, Park G, Min CK. Skin graft-versus-host disease following autologous stem cell transplantation for multiple myeloma. Immune Netw. 2013;13(3):107–10.
Green T, Hind J. Graft-versus-host disease in paediatric solid organ transplantation: a review of the literature. Pediatr Transplant. 2016;20(5):607–18.
Shin CR, Nathan J, Alonso M, Yazigi N, Kocoshis S, Tiao G, et al. Incidence of acute and chronic graft-versus-host disease and donor T-cell chimerism after small bowel or combined organ transplantation. J Pediatr Surg. 2011;46(9):1732–8.
Andres AM, Santamaria ML, Ramos E, Sarria J, Molina M, Hernandez F, et al. Graft-vs-host disease after small bowel transplantation in children. J Pediatr Surg. 2010;45(2):330–6; discussion 6.
Sharma A, Armstrong AE, Posner MP, Kimball PM, Cotterell AH, King AL, et al. Graft-versus-host disease after solid organ transplantation: a single center experience and review of literature. Ann Transplant. 2012;17(4):133–9.
Davies SM, Wang D, Wang T, Arora M, Ringden O, Anasetti C, et al. Recent decrease in acute graft-versus-host disease in children with leukemia receiving unrelated donor bone marrow transplants. Biol Blood Marrow Transplant. 2009;15(3):360–6.
Woolfrey AE, Anasetti C, Storer B, Doney K, Milner LA, Sievers EL, et al. Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children. Blood. 2002;99(6):2002–8.
Jacobsohn DA. Acute graft-versus-host disease in children. Bone Marrow Transplant. 2008;41(2):215–21.
Harris AC, Ferrara JL, Levine JE. Advances in predicting acute GVHD. Br J Haematol. 2013;160(3):288–302.
Faraci M, Caviglia I, Biral E, Morreale G, Giardino S, Garbarino L, et al. Acute graft-versus-host disease in pediatric allogeneic hematopoietic stem cell transplantation. Single-center experience during 10 yr. Pediatr Transplant. 2012;16(8):887–93.
Eisner MD, August CS. Impact of donor and recipient characteristics on the development of acute and chronic graft-versus-host disease following pediatric bone marrow transplantation. Bone Marrow Transplant. 1995;15(5):663–8.
Martin P, Bleyzac N, Souillet G, Galambrun C, Bertrand Y, Maire PH, et al. Clinical and pharmacological risk factors for acute graft-versus-host disease after paediatric bone marrow transplantation from matched-sibling or unrelated donors. Bone Marrow Transplant. 2003;32(9):881–7.
Zecca M, Prete A, Rondelli R, Lanino E, Balduzzi A, Messina C, et al. Chronic graft-versus-host disease in children: incidence, risk factors, and impact on outcome. Blood. 2002;100(4):1192–200.
Atkinson K, Horowitz MM, Gale RP, van Bekkum DW, Gluckman E, Good RA, et al. Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation. Blood. 1990;75(12):2459–64.
Eapen M, Horowitz MM, Klein JP, Champlin RE, Loberiza FR Jr, Ringden O, et al. Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol. 2004;22(24):4872–80.
Couriel D, Caldera H, Champlin R, Komanduri K. Acute graft-versus-host disease: pathophysiology, clinical manifestations, and management. Cancer. 2004;101(9):1936–46.
Tucunduva L, Volt F, Cunha R, Locatelli F, Zecca M, Yesilipek A, et al. Combined cord blood and bone marrow transplantation from the same human leucocyte antigen-identical sibling donor for children with malignant and non-malignant diseases. Br J Haematol. 2015;169(1):103–10.
Giebel S, Giorgiani G, Martinetti M, Zecca M, Maccario R, Salvaneschi L, et al. Low incidence of severe acute graft-versus-host disease in children given haematopoietic stem cell transplantation from unrelated donors prospectively matched for HLA class I and II alleles with high-resolution molecular typing. Bone Marrow Transplant. 2003;31(11):987–93.
Rocha V, Wagner JE Jr, Sobocinski KA, Klein JP, Zhang MJ, Horowitz MM, et al. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med. 2000;342(25):1846–54.
Wagner JE, Kernan NA, Steinbuch M, Broxmeyer HE, Gluckman E. Allogeneic sibling umbilical-cord-blood transplantation in children with malignant and non-malignant disease. Lancet (London, England). 1995;346(8969):214–9.
Meisel R, Laws HJ, Balzer S, Bernbeck B, Kramm C, Schonberger S, et al. Comparable long-term survival after bone marrow versus peripheral blood progenitor cell transplantation from matched unrelated donors in children with hematologic malignancies. Biol Blood Marrow Transplant. 2007;13(11):1338–45.
Arai S, Arora M, Wang T, Spellman SR, He W, Couriel DR, et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2015;21(2):266–74.
Storb R, Prentice RL, Sullivan KM, Shulman HM, Deeg HJ, Doney KC, et al. Predictive factors in chronic graft-versus-host disease in patients with aplastic anemia treated by marrow transplantation from HLA-identical siblings. Ann Intern Med. 1983;98(4):461–6.
Sullivan KM, Shulman HM, Storb R, Weiden PL, Witherspoon RP, McDonald GB, et al. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood. 1981;57(2):267–76.
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(12):945–56.
Treister NS, Woo S-B, O’Holleran EW, Lehmann LE, Parsons SK, Guinan EC. Oral chronic graft-versus-host disease in pediatric patients after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11(9):721–31.
Gilman AL, Schultz KR, Goldman FD, Sale GE, Krailo MD, Chen Z, et al. Randomized trial of hydroxychloroquine for newly diagnosed chronic graft-versus-host disease in children: a Children’s Oncology Group study. Biol Blood Marrow Transplant. 2012;18(1):84–91.
Huang JT, Duncan CN, Boyer D, Khosravi H, Lehmann LE, Saavedra A. Nail dystrophy, edema, and eosinophilia: harbingers of severe chronic GVHD of the skin in children. Bone Marrow Transplant. 2014;49(12):1521–7.
Brazzelli V, Grasso V, Muzio F, Moggio E, Zecca M, Locatelli F, et al. Narrowband ultraviolet B phototherapy in the treatment of cutaneous graft-versus-host disease in oncohaematological paediatric patients. Br J Dermatol. 2010;162(2):404–9.
Skin signs of other systemic diseases. In: Paller A, Mancini A, editor. Hurwitz clinical pediatric dermatology. 4th ed. London: Elsevier; 2011. p. 562–79.
Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;27(9):893–8.
Schmid I, Stachel D, Pagel P, Albert MH. Incidence, predisposing factors, and outcome of engraftment syndrome in pediatric allogeneic stem cell transplant recipients. Biol Blood Marrow Transplant. 2008;14(4):438–44.
Nishio N, Yagasaki H, Takahashi Y, Hama A, Muramatsu H, Tanaka M, et al. Engraftment syndrome following allogeneic hematopoietic stem cell transplantation in children. Pediatr Transplant. 2009;13(7):831–7.
Bolognia JL, Cooper DL, Glusac EJ. Toxic erythema of chemotherapy: a useful clinical term. J Am Acad Dermatol. 2008;59(3):524–9.
Parker TL, Cooper DL, Seropian SE, Bolognia JL. Toxic erythema of chemotherapy following i.v. BU plus fludarabine for allogeneic PBSC transplant. Bone Marrow Transplant. 2013;48(5):646–50.
Sheu J, Hawryluk EB, Guo D, London WB, Huang JT. Voriconazole phototoxicity in children: a retrospective review. J Am Acad Dermatol. 2015;72(2):314–20.
Graft-versus-host disease (GVHD). In: Brinster NK, Liu V, Hafeez DA, McKee PH, editors. Dermatopathology: high-yield pathology. Philadelphia: Elsevier; 2011. p. 42–3.
Other non-neoplastic diseases. In: Rapini RP, Rapini RP, editors. Practical dermatopathology. 2nd ed. Beijing: Elsevier; 2012. p. 239–5.
Byun HJ, Yang JI, Kim BK, Cho KH. Clinical differentiation of acute cutaneous graft-versus-host disease from drug hypersensitivity reactions. J Am Acad Dermatol. 2011;65(4):726–32.
Drijkoningen M, De Wolf-Peeters C, Tricot G, Degreef H, Desmet V. Drug-induced skin reactions and acute cutaneous graft-versus-host reaction: a comparative immunohistochemical study. Blut. 1988;56(2):69–73.
Firoz BF, Lee SJ, Nghiem P, Qureshi AA. Role of skin biopsy to confirm suspected acute graft-vs-host disease: results of decision analysis. Arch Dermatol. 2006;142(2):175–82.
Kohler S, Hendrickson MR, Chao NJ, Smoller BR. Value of skin biopsies in assessing prognosis and progression of acute graft-versus-host disease. Am J Surg Pathol. 1997;21(9):988–96.
Marra DE, McKee PH, Nghiem P. Tissue eosinophils and the perils of using skin biopsy specimens to distinguish between drug hypersensitivity and cutaneous graft-versus-host disease. J Am Acad Dermatol. 2004;51(4):543–6.
Zhou Y, Barnett MJ, Rivers JK. Clinical significance of skin biopsies in the diagnosis and management of graft-vs-host disease in early postallogeneic bone marrow transplantation. Arch Dermatol. 2000;136(6):717–21.
Shulman HM, Cardona DM, Greenson JK, Hingorani S, Horn T, Huber E, et al. NIH Consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. The 2014 Pathology Working Group Report. Biol Blood Marrow Transplant. 2015;21(4):589–603.
Jacobsohn DA, Schechter T, Seshadri R, Thormann K, Duerst R, Kletzel M. Eosinophilia correlates with the presence or development of chronic graft-versus-host disease in children. Transplantation. 2004;77(7):1096–100.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15(6):825–8.
Harris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, et al. International, Multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the Mount Sinai acute GVHD international consortium. Biol Blood Marrow Transplant. 2016;22(1):4–10.
Dignan FL, Clark A, Amrolia P, Cornish J, Jackson G, Mahendra P, et al. Diagnosis and management of acute graft-versus-host disease. Br J Haematol. 2012;158(1):30–45.
Van Lint MT, Uderzo C, Locasciulli A, Majolino I, Scime R, Locatelli F, et al. Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation. Blood. 1998;92(7):2288–93.
MacMillan ML, Weisdorf DJ, Wagner JE, DeFor TE, Burns LJ, Ramsay NK, et al. Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems. Biol Blood Marrow Transplant. 2002;8(7):387–94.
Ball LM, Bernardo ME, Roelofs H, van Tol MJ, Contoli B, Zwaginga JJ, et al. Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III-IV acute graft-versus-host disease. Br J Haematol. 2013;163(4):501–9.
Cragg L, Blazar BR, Defor T, Kolatker N, Miller W, Kersey J, et al. A randomized trial comparing prednisone with antithymocyte globulin/prednisone as an initial systemic therapy for moderately severe acute graft-versus-host disease. Biol Blood Marrow Transplant. 2000;6(4a):441–7.
Teachey DT, Bickert B, Bunin N. Daclizumab for children with corticosteroid refractory graft-versus-host disease. Bone Marrow Transplant. 2006;37(1):95–9.
Calore E, Marson P, Pillon M, Tumino M, Tison T, Mainardi C, et al. Treatment of acute graft-versus-host disease in childhood with extracorporeal photochemotherapy/photopheresis: the Padova experience. Biol Blood Marrow Transplant. 2015;21(11):1963–72.
Messina C, Locatelli F, Lanino E, Uderzo C, Zacchello G, Cesaro S, et al. Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell transplantation. Br J Haematol. 2003;122(1):118–27.
Perotti C, Del Fante C, Tinelli C, Viarengo G, Scudeller L, Zecca M, et al. Extracorporeal photochemotherapy in graft-versus-host disease: a longitudinal study on factors influencing the response and survival in pediatric patients. Transfusion. 2010;50(6):1359–69.
Berger M, Albiani R, Sini B, Fagioli F. Extracorporeal photopheresis for graft-versus-host disease: the role of patient, transplant, and classification criteria and hematologic values on outcome-results from a large single-center study. Transfusion. 2015;55(4):736–47.
Levine JE, Paczesny S, Mineishi S, Braun T, Choi SW, Hutchinson RJ, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood. 2008;111(4):2470–5.
Yang J, Cheuk DK, Ha SY, Chiang AK, Lee TL, Ho MH, et al. Infliximab for steroid refractory or dependent gastrointestinal acute graft-versus-host disease in children after allogeneic hematopoietic stem cell transplantation. Pediatr Transplant. 2012;16(7):771–8.
Sleight BS, Chan KW, Braun TM, Serrano A, Gilman AL. Infliximab for GVHD therapy in children. Bone Marrow Transplant. 2007;40(5):473–80.
Prasad VK, Lucas KG, Kleiner GI, Talano JA, Jacobsohn D, Broadwater G, et al. Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study. Biol Blood Marrow Transplant. 2011;17(4):534–41.
Inagaki J, Kodama Y, Fukano R, Noguchi M, Okamura J. Mycophenolate mofetil for treatment of steroid-refractory acute graft-versus-host disease after pediatric hematopoietic stem cell transplantation. Pediatr Transplant. 2015;19(6):652–8.
Inagaki J, Fukano R, Kodama Y, Nishimura M, Shimokawa M, Okamura J. Safety and efficacy of low-dose methotrexate for pediatric patients with steroid-refractory acute graft-versus-host disease after hematopoietic stem cell transplantation. Ann Hematol. 2014;93(4):645–51.
Bolanos-Meade J, Jacobsohn DA, Margolis J, Ogden A, Wientjes MG, Byrd JC, et al. Pentostatin in steroid-refractory acute graft-versus-host disease. J Clin Oncol. 2005;23(12):2661–8.
Kawahara Y, Morimoto A, Masuzawa A, Ikeda T, Hayase T, Kashii Y, et al. Successful treatment with pulse cyclophosphamide of a steroid-refractory hepatitic variant of liver acute graft-vs.-host disease in a child. Pediatr Transplant. 2012;16(7):E315–9.
Mehta P, Kedar A, Graham-Pole J, Skoda-Smith S, Wingard JR. Thalidomide in children undergoing bone marrow transplantation: series at a single institution and review of the literature. Pediatrics. 1999;103(4):e44.
Baird K, Cooke K, Schultz KR. Chronic graft-versus-host disease (GVHD) in children. Pediatr Clin North Am. 2010;57(1):297–322.
Rangarajan HG, Punzalan RC, Camitta BM, Talano JA. The use of novel Therakos Cellex(R) for extracorporeal photopheresis in treatment of graft-versus-host disease in paediatric patients. Br J Haematol. 2013;163(3):357–64.
Salvaneschi L, Perotti C, Zecca M, Bernuzzi S, Viarengo G, Giorgiani G, et al. Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood. Transfusion. 2001;41(10):1299–305.
Kim H, Kim NH, Kang HJ, Lee JW, Kim MS, Park KD, et al. Successful long-term use of imatinib mesylate in pediatric patients with sclerodermatous chronic GVHD. Pediatr Transplant. 2012;16(8):910–2.
Baird K, Comis LE, Joe GO, Steinberg SM, Hakim FT, Rose JJ, et al. Imatinib mesylate for the treatment of steroid-refractory sclerotic-type cutaneous chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21(6):1083–90.
Busca A, Saroglia EM, Lanino E, Manfredini L, Uderzo C, Nicolini B, et al. Mycophenolate mofetil (MMF) as therapy for refractory chronic GVHD (cGVHD) in children receiving bone marrow transplantation. Bone Marrow Transplant. 2000;25(10):1067–71.
Jacobsohn DA, Gilman AL, Rademaker A, Browning B, Grimley M, Lehmann L, et al. Evaluation of pentostatin in corticosteroid-refractory chronic graft-versus-host disease in children: a Pediatric Blood and Marrow Transplant Consortium study. Blood. 2009;114(20):4354–60.
Rovelli A, Arrigo C, Nesi F, Balduzzi A, Nicolini B, Locasciulli A, et al. The role of thalidomide in the treatment of refractory chronic graft-versus-host disease following bone marrow transplantation in children. Bone Marrow Transplant. 1998;21(6):577–81.
Goldberg JD, Jacobsohn DA, Margolis J, Chen AR, Anders V, Phelps M, et al. Pentostatin for the treatment of chronic graft-versus-host disease in children. J Pediatric Hematol/Oncol. 2003;25(7):584–8.
Cole CH, Rogers PC, Pritchard S, Phillips G, Chan KW. Thalidomide in the management of chronic graft-versus-host disease in children following bone marrow transplantation. Bone Marrow Transplant. 1994;14(6):937–42.
Couriel DR, Saliba RM, Giralt S, Khouri I, Andersson B, de Lima M, et al. Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant. 2004;10(3):178–85.
Inagaki J, Moritake H, Nishikawa T, Hyakuna N, Okada M, Suenobu S, et al. Long-term morbidity and mortality in children with chronic graft-versus-host disease classified by National Institutes of Health Consensus Criteria after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2015;21(11):1973–80.
Jacobsohn DA, Arora M, Klein JP, Hassebroek A, Flowers ME, Cutler CS, et al. Risk factors associated with increased nonrelapse mortality and with poor overall survival in children with chronic graft-versus-host disease. Blood. 2011;118(16):4472–9.
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(9):1341–8.
Recommended Reading
Baird K, Cooke K, Schultz KR. Chronic graft-versus-host disease (GVHD) in children. Pediatr Clin N Am. 2010;57:297–322.
Cooke KR, Luznik L, Sarantopoulos S, Hakim FT, Jagasia M, Fowler DH, et al. The biology of chronic graft-versus-host disease: a task force report from the National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2017;23(2):211–34. Epub 2016 Oct 3.
Ferrara JLM, Levine JE, Reddy P, Holler E. Graft-versus-host disease. The Lancet. 2009;333:1550–61.
Hymes SR, Alousi AM, Cowen EW. Graft-versus-host disease: Part I. Pathogenesis and clinical manifestations of graft-versus-host disease. J Am Acad Dermatol. 2012;66:515.e1.
Hymes SR, Alousi AM, Cowen EW. Graft-versus-host disease: Part II. Management of cutaneous graft-versus-host disease. J Am Acad Dermatol. 2012;66:535.e2.
Jacobsohn DA. Acute graft-versus-host disease in children. Bone Marrow Transplant. 2008;41(2):215–21.
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21:389–401.
Perotti C, Del Fante C, Tinelli C, Viarengo G, Scudeller L, Zecca M, et al. Extracorporeal photochemotherapy in graft-versus-host disease: a longitudinal study on factors influencing the response and survival in pediatric patients. Transfusion. 2010;50:1359–69.
Acknowledgment
Photographs are courtesy of Jennifer T. Huang, M.D.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG
About this chapter
Cite this chapter
Carlberg, V., Simons, E., Delano, S., Huang, J.T. (2018). Pediatric Graft-Versus-Host Disease. In: Huang, J., Coughlin, C. (eds) Skin Tumors and Reactions to Cancer Therapy in Children. Springer, Cham. https://doi.org/10.1007/978-3-319-66200-8_9
Download citation
DOI: https://doi.org/10.1007/978-3-319-66200-8_9
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-66199-5
Online ISBN: 978-3-319-66200-8
eBook Packages: MedicineMedicine (R0)