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Pediatric Graft Versus Host Disease Treatment & Management

  • Author: Phillip Ruiz, Jr, MD, PhD; Chief Editor: Harumi Jyonouchi, MD  more...
Updated: Oct 07, 2015

Medical Care

Prevention and treatment of acute graft versus host disease

Successful therapeutic intervention of life-threatening graft versus host disease (GVHD) is possible, although the consequence can be the development of fatal opportunistic infections. Therefore, the best approach to manage GVHD should be its prevention. Effective prevention against GVHD includes the use of histocompatible donor and recipient combinations.[16, 17, 18]

Primary prophylaxis

Interference of T-cell activation/function using immunosuppressive therapy: The calcineurin inhibitors (cyclosporine and tacrolimus) are the principal drugs used to prevent GVHD. They are not found to be very effective and have additional toxicity that reduces their use. Corticosteroids can also interfere with T-cell activation and function but are uncommonly used in prophylactic regimens because they seem to increase mortality from infection. Over the last few years, great attention has been focused on the potential of regulatory T cells (Tregs) for inhibiting the division, expansion and differentiation of donor T cells specific for host antigens. However, the potential use of this approach in humans is still not established.

Removal of T cells by T–cell depletion ex vivo or T-cell depletion in vivo. The in vivo host lymphocyte depletion has the advantage of reducing the risk of graft rejection, but both techniques are associated with a reduction in graft-versus-leukemia (GVL) effects and a concomitant increase in risk of leukemia relapse.

  • T–cell depletion ex vivo: Removing T cells from the graft is very effective in preventing GVHD without affecting the graft survival, disease-free survival, and treatment-related mortality rates. The number of infused T cells should not exceed 5 × 10 4 cells/kg of recipient body weight. This procedure increases a risk of graft rejection.
  • T-cell depletion in vivo: Adding T-cell antibodies to the conventional conditioning regimen has the following 2 side effects: (1) it can reduce the host response, which improves engraftment, and (2) it affects mature donor T cells in the graft. This can be accomplished with such agents as alemtuzumab (Campath) or antithymocyte globulin (ATG). These long-lived agents can be directly administered to the patient, a tactic that depletes host and donor-derived T cells. Alternatively, the T cells (in the donor bone marrow) can be eliminated in vitro using monoclonal antibodies and using physical methods such as elutriation, or using immunotoxins.

Inhibition of T-cell proliferation. Drugs often used for this therapy include methotrexate and mycophenolate (MMF). Methotrexate has been the primary drug in this indication for decades, and, although effective, it is also associated with delayed engraftment, mucositis, and transplant-associated toxicity. MMF inhibits T-cell purine salvage pathways and appears to have less toxicity than methotrexate and can be used with a calcineurin inhibitor.[19]

Interference of cytokine function (although this approach is relatively new and still experimental). Moreover, agents such as corticosteroids definitely reduce inflammatory cytokine levels, but, as noted above, for the most part they have not been helpful in GVHD prophylaxis.

Removal of host antigen-presenting cells (APCs) using extracorporeal photopheresis (ECP).[20] ECP is pheresis of approximately 5 × 109 leukocytes that are treated with a photoactive compound 8-methoxypsoralen and ultraviolet A light and re-infused to the patients. This therapy induces lymphocytes undergoing apoptosis. Those apoptotic cells are taken up by host APCs, thereby triggering certain tolerance mechanisms, which results in lower incidence of GVHD.

Increase in host immune activity using reduced-intensity conditioning regimens. This was defined as a conditioning regimen in which the dosage of chemotherapy and/or total body irradiation (TBI) was reduced to 50%. These changes may result in less toxicity and less severe GVHD due to the persistence of host T cells.

Housing the patient in a pathogen-poor protected environment can be very helpful to reduce the risk of infections.



Many different therapies have been used in the treatment of acute GVHD. Unfortunately, control of GVHD does not translate into improved survival in many patients because of the subsequent development of opportunistic infections.

First-line treatment

Steroids in conjunction with cyclosporine or tacrolimus are considered standard therapy. Treatment is required for established grades II-IV GVHD and often consists of continuation of original immunosuppressive agents used for GVHD prophylaxis and the addition of methylprednisolone at 2 mg/kg/d in divided doses for 10-14 days or until GVHD is controlled, followed by steroid taper. Patients who have not received cyclosporine or tacrolimus as part of their GVHD prophylaxis may benefit by combining it with corticosteroids. Combination triple therapy with cyclosporine, prednisone, and antithymocyte globulin has been found to be equally efficacious but more toxic in children. Successful treatment of GVHD with this initial intervention is only seen in about 25-40% of patients after donor transplantation; thus, 60-75% of patients with clinically significant GVHD require therapy in addition to corticosteroids.

Steroid-refractory GVHD

For steroid-refractory GVHD, rituximab along with other sporadically tried drugs have been studied. ATG has activity in steroid refractory GVHD, especially in the skin. Overall responses are seen in 20-60% of patients, but overall survival has not improved, and 1-year mortality rates approach 90%. One other form of antibody therapy that has been used is the anti-IL-2 receptor (IL-2R) monoclonal antibody, daclizumab. However, in a phase III trial of primary GVHD therapy, increased mortality from a combination of infection and relapse was noted. Denileukin diftitox (Ontak) is an engineered toxin that combines the IL-2 molecule to the diphtheria toxin. This drug was also developed to eliminate the IL-2R expressing cells. Daclizumab was withdrawn from the United States market in 2009 and denileukin was discontinued from the market in January 2014.

A 2011 study noted that in patients with chronic GVHD refractory to glucocorticoid therapy, daily low-dose subcutaneous interleukin-2 was found to increase regulatory T cells in vivo, suppress clinical manifestations, and permit glucocorticoid tapering by a mean of 60%.[21]

Cytokine blockade

This has been attempted with blocking actions of IL-1 by preventing it binding to IL-1 receptor either by soluble IL-1 receptor or by IL-1 receptor antagonist, anakinra [Kineret]. This approach has not been extensively pursued. The anti-TNF alpha antibody infliximab (Remicade) has been effective in steroid-resistant GVHD but with increased subsequent infection. To date, it has shown benefit over steroids alone.

Cytotoxic therapy

MMF and the inosine monophosphate dehydrogenase (IMPDH) inhibitor, pentostatin, are cytotoxic reagents tried on acute GVHD. The latter drug appears to be highly active in acute GVHD in a single institution experience. The response rate was approximately 65%, but long-term survival was only 26%. Several small studies of MMF have shown therapeutic efficacy in the range of 40-70%, with survival rates ranging from 16-37%. As with other reagents, opportunistic infections mandate careful dosing.

Newer therapies

A murine monoclonal antibody against CD147, which is a neurothelion member of the immunoglobulin superfamily and up-regulated on activated B cells and T cells, induced 50% response in steroid-resistant acute GVHD. Moderate-to-severe myalgia occurred in 28-60% of cases and was dose limiting. Visilizumab is a humanized anti-CD3 antibody that selectively induces apoptosis of activated T-cells. A phase I study demonstrated that all patients affected by severe acute GVHD and treated with visilizumab improved. However, posttransplant lymphoproliferative disease (PTLD) was a major concern. Also, extracorporeal photopheresis has been used to treat resistant, acute GVHD; the patients who responded had a significantly better outcome.

Prevention and treatment of chronic graft versus host disease

The best prophylaxis against chronic GVHD is prevention of acute GVHD because de novo chronic GVHD is less common compared with incidence in patients with acute GVHD. Limited chronic GVHD may spontaneously resolve without specific therapy. Treatment of extensive chronic GVHD involves oral prednisone, which may be used simultaneously or on an alternate day schedule with cyclosporine or tacrolimus. Azathioprine may be used as a corticosteroid-sparing agent.

Numerous therapies, including psoralen plus ultraviolet radiation, thalidomide, and clofazimine, have been tried. MMF is an immunosuppressive agent used for prophylaxis for acute GVHD. In the treatment of steroid-refractory chronic GVHD, responses of 90% and 75% in first-line and second-line settings have been reported when MMF is added to standard tacrolimus, cyclosporine, and/or prednisone treatments.[22]

Supportive therapy and symptomatic management is equally important, including ursodeoxycholic acid for cholestasis, artificial tears and saliva for sicca syndrome, physiotherapy to prevent contractures, and immunoglobulin replacement and infection prophylaxis against opportunistic infections.


Surgical Care

Surgical care is restricted to insertion of a central line to aid in parental nutrition and intravenous treatments.



During acute GVHD, persistent diarrhea requires total parenteral nutrition until symptoms have subsided.



Activity is restricted depending on the patient's conditions, and isolation for infection control may be necessary.

Contributor Information and Disclosures

Phillip Ruiz, Jr, MD, PhD Professor of Pathology, Department of Pathology and Surgery, Miller School of Medicine, University of Miami

Phillip Ruiz, Jr, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American Society for Clinical Pathology, American Society of Nephrology, American Society of Transplant Surgeons, American Society of Transplantation, Clinical Immunology Society, Florida Medical Association, New York Academy of Sciences, Pan America Medical Association of Central Florida, Southern Medical Association, United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.


Shoib Sarwar, MD, MPH Fellowship in Cytopathology and Immunopathology, Department of Pathology, Jackson Memorial Hospital, University of Miami Miller School of Medicine

Shoib Sarwar, MD, MPH is a member of the following medical societies: American Medical Association, American Society for Clinical Pathology, American Society of Cytopathology, College of American Pathologists, United States and Canadian Academy of Pathology, American College of Healthcare Executives

Disclosure: Nothing to disclose.

Yaxia Zhang, MD, PhD Resident Physician, Department of Pathology, Jackson Memorial Hospital, University of Miami School of Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter's University Hospital

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.


John Wilson Georgitis, MD Consulting Staff, Lafayette Allergy Services

John Wilson Georgitis, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Chest Physicians, American Lung Association, American Medical Writers Association, and American Thoracic Society

Disclosure: Nothing to disclose.

Mustafa S Suterwala, MD Pediatrics Hospitalist, Pediatrix Medical Group of North Texas; Medical Director, Tiny Tots Clinic, Baylor University Medical Center

Disclosure: Nothing to disclose.

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Pathophysiological pathways and mechanisms of acute GVHD.
This boy developed stage III skin involvement with acute graft versus host disease (GVHD) in spite of receiving prophylaxis with cyclosporin A. The donor was an human leukocyte antigen (HLA)-matched sister; however, the sex disparity increased the risk for acute GVHD. Image courtesy of Mustafa S. Suterwala, MD.
This photo depicts the same boy who has progressed to grade IV graft versus host disease (GVHD). Both cyclosporin A and methylprednisolone had been administered in high dose intravenously. He later died with chronic pulmonary disease caused by chronic GVHD. Image courtesy of Mustafa S. Suterwala, MD.
Autologous graft versus host disease (GVHD) involving the skin of a patient's arm shortly after showing signs of engraftment after an autologous peripheral blood stem cell transplant for ovarian cancer. Image courtesy of Romeo A. Mandanas, MD, FACP.
Acute graft versus host disease (GVHD) involving desquamating skin lesions in a patient following allogeneic bone marrow transplantation for myelodysplasia. Image courtesy of Romeo A. Mandanas, MD, FACP.
Oral mucosal changes in a patient with chronic graft versus host disease (GVHD). Note the skin discoloration (vitiligo), which can result from GVHD. Image courtesy of Romeo A. Mandanas, MD, FACP.
Acute graft versus host disease (GVHD). Hematoxylin-stained and eosin-stained tissue shows dyskeratosis of individual keratinocytes and patchy vacuolization of the basement membrane. A moderate superficial dermal and perivascular lymphocytic infiltrate is also seen in this case. Image courtesy of Melanie K. Kuechler, MD.
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