AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

The occurrence of an immunologically mediated and injurious set of reactions by cells genetically disparate to their host, otherwise known as graft versus host disease (GVHD), is a phenomenon that has been described as the age of bone marrow and solid organ transplantation has emerged. In 1955, Barnes and Loutit first described GVHD in mice. Simonsen introduced the term graft-versus-host reaction in 1958 to describe the direction of the immunological damage caused by introduction of immunologically competent cells into an immunocompromised host. In 1966, Billingham proposed 3 conditions required for the development of GVHD, as follows: (1) the graft must contain immunologically competent cells, (2) the host must possess important transplant alloantigens that are lacking in the donor graft so that the host appears foreign to the graft, and (3) the host itself must be incapable of mounting an effective immunologic reaction against the graft.

According to the accepted definition, the immunologic assault itself and its consequences are referred to as GVHD. In both experimental and clinical scenarios, acute GVHD describes a syndrome consisting of dermatitis, enteritis, and hepatitis occurring within the first 100 days, but typically within 30-40 days, following a bone marrow transplant (BMT). Chronic GVHD usually develops after 100 days and describes an autoimmunelike syndrome consisting of impairment of multiple organs or organ systems.

Pathophysiology

GVHD can develop in the course of (1) BMT or peripheral blood progenitor (hematopoietic stem cell) transplantation, (2) transfusion of unirradiated blood products (transfusion-associated GVHD) especially in immunodeficient individuals, or (3) solid organ transplantation involving organs containing lymphoid tissue. GVHD from passive transmission of immunocompetent maternal cells has also been described in immunodeficient neonates.

The immunopathologic characteristics of acute GVHD has often been separated into different phases (1 through 3), which describes the creation of a suitable host environment with the conditioning regimens intended to remove particular host cell populations, and immune-based sensitizing and efferent (effector) phases (see Image 1).

During phase 1, tissue injured by chemotherapy and irradiation releases proinflammatory cytokines such as tumor necrosis factor (TNF) alpha and interleukin (IL) -1, which subsequently increases expression of adhesion molecules, major histocompatibility complex (MHC) molecules, and costimulatory molecules.

In phase 2, donor T lymphocytes are responsible for triggering GVHD and proliferate after activation by the aforementioned recipient antigens expressed on host cells. Antigen-presenting cells, such as dendritic cells or macrophages, present the antigen to CD4⁺ T cells, that recognize antigens in association with human leukocyte antigen (HLA) class II molecules. IL-1 produced by monocytes and other factors stimulates the T helper cells. The T helper cells, in turn, release compounds such as interleukin 2 (IL-2) and interferon (IFN)-g, the latter which enhances the expression of MHC class II on epithelial cells and macrophages, further stimulating the activation of T cells and NK cells.

IL-2 activates cytotoxic CD8-positive T cells, which react with MHC class II-positive targets. In addition, natural killer (NK) cells and macrophages appear to participate in the development of GVHD, althoughtheir roles are not well defined. Among the variables determining the extent to which GVHD develops are the types and properties of the transplanted T cells, the degree of MHC antigen mismatching, and the degree of interactions between T cells and the endothelial cells.

The final phase (3) of acute GVHD, is where immune effector cells and cytokines enact end-organ damage and contribute to a possible loss of self-tolerance. This injury is clinically manifested as the symptoms seen in GVHD and may be a contributing factor to the development of chronic GVHD.

As mentioned before, chronic GVHD develops after day 100 from transplantation and, like acute GVHD, appears dependent on alloreactivity for it to develop. Chronic GVHD has features similar to naturally occurring autoimmune disease with a wider range of involved organs. Clinical manifestations can include sclerodermatous lesions, liver failure, autoantibody production, and immune complex disease (including glomerulonephritis). Host-recipient differences in MHC antigens or minor histocompatibility antigens can lead to this syndrome, albeit with slightly different kinetics. Alterations in thymic function with decreased thymopoiesis likely contribute to this syndrome with a breakdown of normal self-tolerance mechanisms. The donor CD4⁺ T-cell population is necessary for human chronic GVHD to develop with a shift toward the Th2 phenotype being the predominant subpopulation, although the latter issue remains poorly defined.

Frequency

United States

Incidence and frequency of acute GVHD in transplanted or transfused populations is related to the presence of several risk factors, as follows:

• Histocompatibility: The most important factor correlating with incidence and severity of GVHD is the degree of HLA disparity. With HLA-identical siblings used as bone marrow donors, incidence of moderate-to-severe acute GVHD ranges from less than 10% to 60%, depending on prophylaxis and other risk factors. Incidence of grades II-IV acute GVHD increases to 70-75% with one HLA antigen mismatch and up to 90% with 2-3 HLA antigen mismatch. Incidence of grades II-IV GVHD of up to 70% have been reported in unrelated donors; a difference was noted between those receiving marrow from an HLA-identical donor or from an HLA-mismatched donor.
• Graft cell composition: T-cell depletion of the bone marrow decreases risk of GVHD; however, an increased risk of graft failure is associated with leukemic relapse due to a loss of a graft versus leukemia effect. Umbilical cord blood cells, when used for hematopoietic cell transplantation, cause reduced incidence of GVHD, while the same is not true of peripheral blood stem cells.
• Age and sex: Older patients have a significantly higher risk of acute GVHD, with an incidence of approximately 20% in the pediatric population and rising to 30% in patients aged 20-50 years and to 70% in patients aged 51-62 years. An increased risk of GVHD exists in recipients of gender-mismatched marrow, possibly because of HLA association with the Y chromosome.
• Microenvironment: Host environment is important for the development of GVHD. Patients with aplastic anemia who are undergoing BMT and are treated with antibiotics, are treated with skin and gut decontamination, and are placed in a protective environment with laminar airflow units have reduced incidence of GVHD.
• Chronic GVHD develops in 30-50% of long-term survivors after BMT. HLA disparity, prior acute GVHD, older age, and viral infections (especially herpesvirus group) are associated with increased risk of chronic GVHD. Chronic GVHD also is known to occur at a higher rate in survivors of transplant for aplastic anemia.

Mortality/Morbidity

The survival rate is 90% in grade 0-I, 60% in grade II-III, and 0 in grade IV. Fatality mainly results from infections, hemorrhages, and hepatic failure. Acute GVHD has an antileukemic effect.

Sex

Increased risk of GVHD exists in recipients of sex-mismatched marrow, possibly because of HLA association with the Y chromosome.

CLINICAL

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History

• Acute GVHD: The clinical presentation is often a triad of dermatitis, hepatitis, and gastroenteritis, although symptoms may occur alone or in different combinations. Other tissues that may be involved include mucous membrane, conjunctiva, exocrine glands, bronchial tree, and urinary bladder.
• • Skin: Maculopapular rash may present with the onset occurring within 5-47 days after transplantation. Pruritus involving the palms and soles may precede the rash. In the early stage, the rash is confined to the nape of the neck, shoulder, palms, or soles. It may be confluent and involve the entire integument. In severe cases, bullous lesions similar to third-degree burns may develop.
  • Liver: The liver is the second most common organ involved. GVHD first manifests as elevated liver transaminases levels. Cholestatic jaundice is common, but hepatic failure with encephalopathy is unusual. Hepatic and gastrointestinal involvement manifest with or following skin involvement.
  • Gastrointestinal: GVHD of the distal bowel and colon results in profuse diarrhea; intestinal bleeding; cramping, abdominal pain; and paralytic ileus. Diarrhea is greenish mucoid, watery, and secretory in nature. Upper gastrointestinal involvement without enteric manifestation has been described in 13% of adults. Common symptoms are anorexia, nausea, vomiting, and dyspepsia.
  • Grading: Acute GVHD is graded in 5 steps from 0-IV based on involvement of the skin, liver, and gastrointestinal tract. Grade 0 indicates no clinical evidence of disease. Grades I-IV are graded functionally. Grade I indicates rash on less than 50% of skin and no gut or liver involvement. Grade II indicates rash covering more than 50% of skin, bilirubin 2-3 mg/dL, diarrhea 10-15 mL/kg/d, or persistent nausea. Grade III or IV indicates generalized erythroderma with bullous formation, bilirubin greater than 3 mg/dL, or diarrhea more than 16 mL/kg/d.
• Chronic GVHD: This is a more pleiotropic syndrome that develops after day 100. The syndrome resembles autoimmune systemic collagen vascular disease with protean manifestations, involving essentially every organ.
• • Systemic manifestations include recurrent infections with immunodeficiency, weight loss, sicca syndrome, and failure to thrive (children) or debility and weight loss (adults).
  • Chronic GVHD can present with 2 forms of skin involvement. An early phase resembles lichen planus; these lesions may be sparse and transitory, ranging from papules to more typical lesions. Poikiloderma can be present in the later phase, which is extrapigmentation of the skin demonstrating a variety of shades and associated with telangiectasia in the affected area.
  • Hair manifestations present as alopecia.
  • The mouth may present with sicca syndrome, depapillation of the tongue with variegations, scalloping of lateral margins, lichen planus, oral ulcers, and angular tightness.
  • Joints exhibit decreased range of movements with associated myositis and tendinitis.
  • Manifestations of the eyes include decreased tearing, injected sclera, and conjunctivitis.
  • The liver exhibits cholestasis and cirrhosis.
  • Gastrointestinal presentations include esophageal stricture, malabsorption, and chronic diarrhea.
  • Lungs present with cough, dyspnea, wheezing, rales, pneumothorax, and, finally, bronchiolitis obliterans.
  • Heme manifestations include refractory thrombocytopenia and eosinophilia.
  • Spleen may present with functional asplenia.
• Chronic GVHD has 2 stages.
  • Limited chronic GVHD presents with localized skin involvement, hepatic dysfunction caused by chronic GVHD, or both.
  • Extensive chronic GVHD presents with the following:
    • Generalized skin involvement, or localized skin involvement and/or hepatic dysfunction caused by chronic GVHD plus
    • Liver histologic findings showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis
    • Eye involvement - Schirmer test ( <5 mm wetting)
    • Involvement of minor salivary glands or oral mucosa demonstrated by buccal/labial biopsy
    • Involvement of any other target organ

Physical

See History.

DIFFERENTIALS

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Other Problems to be Considered

Acute GVHD disease

Skin

• Chemoradiotherapy toxicity
• Drug reaction
• Viral exanthema

• Venoocclusive disease
• Viral hepatitis
• Drug toxicity
• Septicemia
• Total parental nutrition complications

• Clostridium difficile
• Gastroenteritis, especially cytomegalovirus
• Chemoradiotherapy

Autoimmune diseases

Gastroenteritis, especially cytomegalovirus

Chemoradiotherapy

WORKUP

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Lab Studies

• The diagnosis of GVHD is established by clinical judgment, imaging studies, laboratory workup, and biopsy results.
• Anemia and thrombocytopenia are observed early in acute GVHD or in chronic GVHD.
• Eosinophilia and Howell-Jolly bodies are observed on peripheral smear in chronic GVHD.
• In hepatic involvement, elevation of transaminases is observed early and followed by an increase in bilirubin and, finally, cholestatic picture with increased alkaline phosphatase and glucose tolerance.

Imaging Studies

• Pulmonary fibrosis resulting from irradiation or chemotherapeutic agents
• Bronchiolitis obliterans on radiograph or CT scan observed in chronic GVHD

Procedures

• Although biopsy is not performed routinely, it can be very helpful to distinguish changes of GVHD from drug toxicity in skin and liver. Biopsy is necessary for confirming the diagnosis of chronic GVHD.
• Upper gastrointestinal endoscopy is currently performed routinely in older patients with nausea, anorexia, and dyspeptic symptoms. This study is useful in grading.

Histologic Findings

Acute GVHD: The skin demonstrates epidermal basal vacuolization, followed by epidermal basal cell apoptotic death with lymphoid infiltration. Eosinophilic bodies may be observed with increased severity. Bullous formation with epidermal separation and necrosis is observed in later stages. Liver tissue undergoing acute GVHD can demonstrate damage to more than 50% of bile ducts with vacuolated cytoplasm, with duct cell nuclear pleomorphism and necrosis of individual cells (apoptosis). There is a lymphocytic infiltrate of portal tracts with endothelialitis (veins with lifting of endothelium from its basement membrane) along with ballooning degeneration of hepatocytes and/or acidophil bodies.

Gastrointestinal biopsy specimens show diffuse edema and mucosal swelling followed by variable crypt cell apoptosis (eg, "exploding" crypts), a mixed chronic and predominantly lymphoplasmacytic infiltrate, and possibly crypt dropout.

Chronic GVHD: Skin biopsy specimens can demonstrate epithelial acanthosis, dyskeratosis, and hyperkeratosis with a mononuclear infiltrate at the dermal-epidermal junction and in adnexal structures. This inflammatory process can evolve to dermal fibrosis and epidermal atrophy. Similarly, a mononuclear infiltrate is seen in the salivary glands on lip biopsy. The liver shows a portal mononuclear infiltrate with damage to the bile ducts and eventually ductopenia, changes that can be seen in the absence of clinical manifestations. Gastrointestinal findings of crypt destruction, increase in lymphoplasmacytic infiltrate with single cell drop out, and fibrosis of lamina propria are observed.

Staging

• Acute GVHD is traditionally graded in 5 stages (0-IV), based on involvement of the skin, liver, and gastrointestinal tract. Grades I-IV are graded functionally.
• • Grade 0 indicates no clinical evidence of disease.
  • Grade I indicates rash on less than 50% of skin and has no gut or liver involvement.
  • Grade II indicates rash covering more than 50% of skin, bilirubin 2-3 mg/dL, diarrhea 10-15 mL/kg/d, or persistent nausea.
  • Grade III or IV indicates generalized erythroderma with bullous formation, bilirubin greater than 3 mg/dL, or diarrhea more than 16 mL/kg/d.
    • Use the "Rule of Nines" or burn chart to determine the range given as total bilirubin. Downgrade one stage if an additional cause of elevated bilirubin level has been documented.
    • Volume of diarrhea applies to adults. For pediatric patients, the volume of diarrhea should be based on body surface area. Gut staging criteria for pediatric patients were not discussed at the consensus conference. Downgrade one stage if an additional cause of diarrhea has been documented.
    • Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.
    • Persistent nausea with histologic evidence of graft-versus-host disease in the stomach or duodenum.
    • Criteria for grading are given as the minimum degree of organ involvement required to confer that grade.
    • Grade IV may also include lesser organ involvement but with extreme decrease in performance status.

TREATMENT

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Medical Care

• Successful therapeutic intervention of life-threatening 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 following: The first and most important prevention can be accomplished with use of histocompatible donor and recipient combinations.
• Acute GVHD
• • Interference of T-cell activation and function. 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 utility. Corticosteroids can also interfere with T-cell activation and function but are uncommonly used in prophylactic regimens since they seem to increase mortality from infection.
  • A third method is to obstruct T-cell proliferation. Drugs often used for this therapy are methotrexate and mycophenolate (MMF). Methotrexate has been the primary drug in this indication for decades, and, while it is 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.
  • Another method can be an attempt to reduce T-cell numbers. This can be accomplished with such agents as alemtuzumab (Campath) or antithymocyte globulin (ATG). These long-lived agents can be administered directly 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, physical methods such as elutriation, or immunotoxins. 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) and a concomitant increase in relapse.
  • Finally, an attempt can be made to interfere with 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.
  • Possibly housing the patient in a pathogen-poor protected environment can be very helpful to reduce the risk of infections.
• GVHD management
  • Acute GVHD
    • General: A plethora of different therapies has been attempted for the treatment of acute GVHD. Unfortunately, control of GVHD in many patients does not translate into improved survival because of the subsequent development of opportunistic infections.
    • Initial treatment: Treatment is required for established grades II-IV GVHD and often consists of continuing original immunosuppression and adding 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 prednisone. Combination triple therapy with cyclosporine, prednisone, and antithymocyte globulin has been found equally efficacious but more toxic in children. Successfully treated GVHD is unfortunately only seen in about 25-40% of patients after donor transplantation, so that 60-75% of patients with clinically significant GVHD require additional therapy in addition to corticosteroids.
    • 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 approaches 90%. One other form of antibody therapy has been the use of the anti-IL-2 receptor 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 joins the IL-2 molecule to the diphtheria toxin. This drug also attempts to eliminate the IL-2R expressing cells.
    • Cytokine blockade has been attempted with interference with IL-1 either by binding it in serum (eg, soluble IL-1 receptor) or by functional inhibition (IL-1 receptor antagonist anakinra, Kineret). This approach has not been extensively pursued. Infliximab (anti-TNFa antibody; Remicade) has been effective in steroid-resistant GVHD but with increased subsequent infection. To date, it has benefit over steroids alone.
    • Mycophenolate mofetil (MMF, CellCept) and the IMPDH inhibitor pentostatin are cytotoxic therapies tried in 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 activity in the range of 40-70%, with survival rates ranging from 16-37%. As with other reagents, opportunistic infections mandate careful dosing.
• • Chronic GVHD
    • 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 resolve spontaneously without specific therapy.
    • Treatment of extensive chronic GVHD involves oral prednisone, which may be used simultaneously or on an alternate day schedule with cyclosporine. Azathioprine may be used as a corticosteroid-sparing agent.
    • A number of other therapies, including psoralen plus ultraviolet radiation, thalidomide, and clofazimine, have been tried.
    • 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.

Diet

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

Activity

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

MEDICATION

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Drug Category: Immunosuppressive agents

Methotrexate is a folate antagonist and a potent inhibitor of the cell-mediated immune system. Selective inhibitors of T-cell lymphocytes (eg, cyclosporine) suppress early cellular response to antigenic and regulatory stimuli.

Traditionally high-dose steroids were thought to be lympholytic, but recent studies have suggested that steroids may inhibit T-cell proliferation and T-cell dependent immune expression of gene encoding cytokines. They produce nonspecific anti-inflammatory effects and antiadhesion effects that contribute to immune suppression.

FOLLOW-UP

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Further Inpatient Care

• Further inpatient care depends on initial response.
• Maintenance immunosuppression with close monitoring is required.
• Opportunistic infections may become severe and require IV antibiotics and supportive care.

Further Outpatient Care

• Regular follow-up with monitoring of immunosuppressive therapy is needed, as well as vigilance for developing chronic GVHD.

Deterrence/Prevention

• Effective prevention against GVHD includes the following:
• • Use of histocompatible donor and recipients
  • Use of immunosuppressive agents after bone marrow infusion (Most BMT teams currently use cyclosporine plus a brief course of methotrexate as the standard GVHD prophylaxis regime. Adding steroids has been proven beneficial in some trials. Other drugs alone or in combination are tacrolimus, ATG, and sirolimus.)
  • In vitro manipulation of the donor graft, such as marrow T-cell depletion
  • Possibly housing the patient in a pathogen-poor protected environment
• The best prophylaxis against chronic GVHD is prevention of acute GVHD because de novo chronic GVHD is less common compared to incidence in patients with acute GVHD.

Prognosis

• Severe acute GVHD is the important cause of treatment failure after BMT. Survival rates vary from 90% in stage I, 60% in stage II or III, to almost 0% in stage IV. Death often is caused by infections, hemorrhage, and hepatic failure.
• Severe chronic GVHD is associated with a higher mortality rate, mostly because of infection complications. Survivors are often severely disabled. The survival rate after onset of chronic GVHD is approximately 42%. Factors that predict death are progressive presentation (ie, acute GVHD followed by chronic GVHD), lichenoid skin changes on biopsy, and elevated serum bilirubin. A patient with one or more of these factors has a projected 6-year survival rate of 60%.
• Mild chronic GVHD as with mild acute GVHD is associated with improved outcome in patients with leukemia because of graft versus leukemia effect.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Immunization must be performed with caution, especially with live virus vaccine, and Red Book guidelines should be followed.
• Overwhelming bacterial sepsis is not infrequent, and index of suspicion should be high with rapid institution of therapy.
• Patients with chronic GVHD may have functional asplenia, and some facilities administer penicillin prophylaxis.

MULTIMEDIA

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Media file 1:  Pathophysiological pathways and mechanisms of acute GVHD
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Media file 2:  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 HLA-matched sister; however, the sex disparity increased the risk for acute GVHD. Image courtesy of Mustafa S. Suterwala, MD.
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Media file 3:  This photo depicts a boy (the same as in Picture 1) 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.
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Media file 4:  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.
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Media file 5:  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.
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Media file 6:  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.
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Media type:  Photo

Media file 7:  Acute graft versus host disease (GVHD). Hematoxylin- 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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Media type:  Image

REFERENCES

Section 11 of 11

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• Miscellaneous
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• References

• Antin JH. Approaches to graft-vs-host disease. Pediatr Transplantation. 2005;9:71-75.
• Christian A, Wysocki A. Leukocyte migration and graft-versus-host disease. Blood. 2005;11:4191-4199.
• Diaz MA, Vicent MG, Gonzalez ME, et al. Risk assessment and outcome of chronic graft-versus-host disease after allogeneic peripheral blood progenitor cell transplantation in pediatric patients. Bone Marrow Transplant. Jul 26 2004;():[Medline].
• Faraci M, Dallorso S, Morreale G, et al. Surgery for acute graft-versus-host disease of the bowel: description of a pediatric case. J Pediatr Hematol Oncol. Jul 2004;26(7):441-3. [Medline].
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• Graubner UB, Liese J, Belohradsky BH. [Vaccination]. Klin Padiatr. Sep 2001;213 Suppl 1:A77-83. [Medline].
• Guinan EC, Bierer BE. Principles of Bone Marrow and Stem Cell Transplantation. Hematology of Infancy and Childhood. 1998;346-351.
• Klingebiel T, Schlegel PG. GVHD: overview on pathophysiology, incidence, clinical and biological features. Bone Marrow Transplant. Apr 1998;21 Suppl 2:S45-9. [Medline].
• Kollman C, Howe CW, Anasetti C. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood. Oct 1 2001;98(7):2043-51. [Medline].
• Lazarus HM, Vogelsang GB, Rowe JM. Prevention and treatment of acute graft-versus-host disease: the old and the new. A report from the Eastern Cooperative Oncology Group (ECOG). Bone Marrow Transplant. Mar 1997;19(6):577-600. [Medline].
• Mitchell E, Horwitz, K, Sullivan M. Chronic graft-versus-host disease. Blood reviews. 2006;20:15-27.
• Parkman R. Chronic graft-versus-host disease. Curr Opin Hematol. Jan 1998;5(1):22-5. [Medline].
• Ringden O, Deeg HJ. Clinical Spectrum of Graft-Versus-Host Disease. 1997;525-550.
• Simpson D. New developments in the prophylaxis and treatment of graft versus host disease. Expert Opin Pharmacother. Jul 2001;2(7):1109-17. [Medline].

Article Last Updated: Aug 7, 2006