AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Graft versus host disease (GVHD) occurs when immunologically competent cells are introduced into an immunoincompetent host. GVHD refers to both the immunologic insult and the consequences to the organism. The leading cause of GVHD is hematopoietic cell transplantation (HCT), both allogeneic (between 2 individuals) and autologous (from the same individual). Solid organ transplants, blood transfusions, and maternal-fetal transfusions also reportedly cause GVHD.

Acute GVHD occurs within the first 100 days of transplantation and consists of the triad of dermatitis, enteritis, and hepatitis. Chronic GVHD develops after day 100 and consists of an autoimmune syndrome directed toward multiple organs. Because the skin often is the earliest organ affected in GVHD, dermatologists are crucial members of the patient's treatment team.

Acute GVHD usually starts as scattered erythematous macules and papules that involve a greater percentage of total body surface area as the severity of GVHD increases. Erythroderma and bullae may occur in the most severe form of acute GVHD. Chronic GVHD may occur either as a late phase of acute GVHD or as a distinct entity. The skin is the primary organ involved in chronic GVHD, which can manifest as a lichen planus–like eruption or as scleroderma. Despite attempts to manipulate the immune response before, during, and after transplantation, GVHD remains a primary cause of morbidity and mortality after HCT.

GVHD remains the primary cause of morbidity and mortality in hematopoietic cell recipients. Increasingly, HCT is used (rather than last-resort therapies) to treat lymphoreticular malignancies and aplastic anemia (eg, solid tumors, autoimmune disorders). HCT remains a powerful treatment option that offers a true chance for a cure of many malignancies. Introducing hematopoietic cells into an immunoincompetent host with successful marrow engraftment, with maintenance of an antitumor effect (if applicable), and without GVHD is the goal of many investigators.

The diagnosis of GVHD is complicated by the fact that other eruptions, such as engraftment syndrome, autologous GVHD, viral exanthems and drug eruption, can also occur after transplantation and can have similar histopathological finding as GVHD, making clinical correlation both necessary and complex.¹ For example, zoster can occur after a stem cell transplant and can be confused with acute GVHD.²

Related eMedicine articles include Graft Versus Host Disease (pediatric focus) and Graft Versus Host Disease (transplantation focus).

Pathophysiology

In 1966, Billingham described 3 criteria for the development of GVHD that currently remain applicable: (1) the graft must contain immunologically competent cells, (2) the host must appear foreign to the graft, and (3) the host must be incapable of reacting sufficiently against the graft.

The extent of histoincompatibility between donor and host and the residual number of T cells in the graft has a major effect on the incidence of GVHD. Histoincompatibility (major or minor complexes) does not fully account for the pathogenesis of GVHD; recipients of syngeneic or autologous bone marrow transplants can develop GVHD while taking cyclosporin A. The mechanism for cyclosporin A–induced GVHD is not clear, but it probably involves dysregulation of self-tolerance during a critical period during reconstitution of the immune system.

The pathophysiology of GVHD involves the recognition of epithelial target tissues as being foreign by immunocompetent cells, with subsequent induction of an inflammatory response and eventual apoptotic death of the target tissue. This apoptosis occurs regardless of whether the immunoreactive T cells are derived from a nonidentical donor or from the recipient. Implicating any single cell type as the effector cell of GVHD is difficult. Although T cells may orchestrate the initial inflammatory response, many cell types (eg, CD4⁺, CD8⁺ T-cell subsets, natural killer cells) are found at sites of epithelial injury.

Dermatologically, the reaction against the host's keratinocytes is believed to directly influence the phenotype, which ranges from mild erythematous macules to full-blown epidermal necrosis.
 
CXCL10-CXCR3 interactions play an important role in the pathogenesis of acute GVHD in the skin following allogeneic stem cell transplantation.³ 
 
Host T cells affect donor T-cell engraftment and GVHD after reduced-intensity HCT.⁴
 
Regulatory dendritic cells protect against cutaneous chronic GVHD mediated through CD4⁺CD25⁺Foxp3⁺ regulatory T cells.⁵

Frequency

United States

The incidence and severity of GVHD is directly correlated with the degree of major histocompatability complex mismatch. Among recipients of marrow with identical human leukocyte antigens, 40% develop acute GVHD. Among recipients of marrow with 1 antigen mismatch, 60-80% develop acute GVHD. Minor histocompatibility antigen mismatches are correlated with GVHD in adults but not in children.

International

International statistics are in accordance with those in the United States.

Mortality/Morbidity

Patients with acute GVHD are at risk for sepsis, electrolyte disturbances secondary to diarrhea, elevated liver enzyme levels, bilirubinemia, and hepatorenal syndrome.

Patients with chronic GVHD are at risk for joint contractures secondary to sclerodermatous skin changes, skin atrophy with ulceration, esophageal strictures, lichen planus–like lesions of mucosa and skin, keratoconjunctivitis sicca, and global immune impairment.

Acute and chronic GVHD appear to inhibit recurrence of malignancies, suggesting a graft-versus-leukemia effect in patients who receive HCT as treatment for a hematopoietic malignancy.

• Acute GVHD is a primary or contributory cause of death in 15-40% of patients who develop GVHD. Mortality resulting from acute GVHD is directly related to severity; the more severe and extensive the involvement, the greater the risk of mortality. Overwhelming sepsis is the primary cause of death in patients with acute GVHD.
• Chronic GVHD occurs in 15-50% of patients who survive 3 months after transplantation. Chronic GVHD most commonly occurs as a transition from acute GVHD, but it can occur de novo in 20-30% of patients. Low-grade liver disease occurs in most patients with GVHD but rarely leads to cirrhosis. The primary cause of morbidity and mortality is global immune function impairment (as evidenced by increased nonspecific suppressor T cells, decreased immunoglobulin synthesis, production of a number of autoantibodies).

  Bronchiolitis obliterans contributes to mortality; sepsis remains the common denominator in patients who die with chronic GVHD. Skin changes of lichen planus, with corresponding fully developed lichen planus–like changes seen with skin biopsy, are correlated with an increased risk of death regardless of other factors (eg, original neoplasm, sex, age).

• Graft-versus-leukemia effect: Patients who undergo HCT after total body irradiation as treatment for lymphoreticular malignancies demonstrate decreased malignancy relapse rates when they develop GVHD. Patients who receive syngeneic marrow are 2.5 times more likely to develop malignancy recurrence than patients who receive allogeneic marrow. Whether the decrease in leukemic relapses associated with GVHD outweighs the mortality associated with GVHD is not clear. Active investigations are exploring approaches to maintaining graft-versus-leukemia effect while inhibiting GVHD.

Race

No racial predilection exists for GVHD.

Sex

The incidence of GVHD decreases for sex-matched donors and recipients versus sex-mismatched donors and recipients.

• Donor parity is associated with an increased risk of acute GVHD.
• Male and female recipients of sex-matched, nulliparous, hematopoietic stem cells have equal risk for developing GVHD.

Age

The risk for GVHD increases with the age of the marrow recipient. The approximate incidence of acute stage 3 or 4 GVHD increases with age. Age-related risks are as follows:

• Patients younger than 20 years - 20% risk
• Patients aged 45-50 years - 30% risk
• Patients older than 50 years - 80% risk

CLINICAL

Section 3 of 11  

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History

The type of transplant, pretransplantation ablative therapy, marrow preparation, and concurrent medications can affect the presentation of GVHD. Acute GVHD occurs 10-30 days after transplantation, whereas chronic GVHD occurs after day 100. Chronic GVHD usually evolves from acute GVHD but may occur de novo in 20-30% of patients.

• GVHD may be associated with different types of transplants.
• GVHD has been reported after solid organ transplantation (especially that involving the liver) and after the transfer of immunocompetent maternal cells to a relatively immunosuppressed fetal recipient.
• Whalen et al noted in 2005⁶ that 15 days after a patient received a liver transplant, rash and pancytopenia were the first manifestations of acute GVHD. Similarly, in 2006, Smith et al⁷ noted an eruption associated with acute GVHD in a patient immediately after lung transplantation.
• • The incidence of GVHD is higher in recipients of allogeneic hematopoietic cells than in patients receiving syngeneic or autologous hematopoietic cells. The greatest incidence occurs in patients in whom bone marrow is used as the source of hematopoietic cells.
  • Peripheral blood stem cells (PBSCs) are increasingly used for autologous grafting. Allogeneic grafting increases the risk of chronic GVHD in patients in whom PBSCs are used.
  • Cord blood stem cells (CBSCs) currently are being evaluated as a source for transplantation. Patients who receive CBSCs appear to have a decreased risk of developing GVHD. However, hematopoietic recovery is delayed. The immunologic immaturity of CBSCs may lessen the risk of GVHD.
  • Incidence of GVHD in allogeneic recipients increases with the degree of mismatch of major histocompatibility antigens, but GVHD still occurs in matched donor-recipients regardless of the source of the stem cells (eg, marrow, PBSCs, CBSCs).
  • Patients receiving autologous hematopoietic cells are at risk for GVHD, especially if they receive cyclosporin and/or interferon gamma around the time of transplantation. Patients who develop GVHD after autologous or syngeneic cell transplantation tend to develop mild disease.
  • Transfusion-associated GVHD in an immunocompetent individual following cardiac surgery was noted by Serefhanoglu et al in 2005.⁸ It has also been noted after transfusions of other varieties.
• Regimens used to ablate marrow (eg, cyclophosphamide, busulfan, and etoposide in various combinations, with or without total body irradiation) should be considered when GVHD is diagnosed.⁹
• • Do not mistake hyperpigmentation of palms and soles that cyclophosphamide and busulfan can cause for early GVHD.
  • Busulfan has been associated with a widespread bullous eruption.
  • Etoposide has been associated with hypersensitivity reactions.
  • Characteristic histopathologic findings are present that can help the physician differentiate busulfan and etoposide reactions from GVHD.
• Various sorting mechanisms remove putative GVHD effector cells from donor marrow before transplantation but do not significantly reduce rates of GVHD.
• After HCT, patients usually take multiple medications. Eruptions related to these medications can have a clinical presentation similar to that of GVHD. The timing and administration of all medications is important when a diagnosis of GVHD is considered.
• Human herpesvirus type 6 reactivation is significantly associated with the occurrence of GVHD, as is co-infection with Epstein-Barr virus.¹⁰

Physical

Acute GVHD consists of tender erythematous macules that may coalesce over time. Patients with chronic GVHD exhibit skin changes that resemble either lichen planus or scleroderma, sometimes simultaneously or sequentially.

• Acute GVHD is observed 10-30 days after transplantation.
• • Eruptions usually begin as faint, tender erythematous macules on any part of the body, though they usually affect the palms and soles first.
  • When erythematous macules form on the trunk or limbs, erythema preferentially forms around the hair follicle.
  • As the disease progresses, more erythematous macules form and may coalesce to form confluent erythema. The erythematous macules may evolve into papules.
  • In the most severe cases, subepidermal bullae form, the disease resembles toxic epidermal necrolysis.
  • A staging system for the skin involvement in acute GVHD has been outlined, as follows:
  • • Stage 1 - Involvement of less than 25% of the body surface
    • Stage 2 - Involvement of 25-50% of the body surface
    • Stage 3 - Involvement of 50-100% of the body surface (erythroderma)
    • Stage 4 - Vesicles and bullae
  • Some patients develop stage 1 GVHD that responds to therapy and never progresses further. Other patients develop a fulminant form that quickly evolves from erythroderma to a lichen planus–like eruption.
  • Patients with chronic GVHD may have alopecia, nail dystrophy, and thickening of the skin (hyperkeratosis).
  • Patients are at increased risk for a variety of bacterial, viral, and fungal infections.
• Chronic GVHD evolves from acute GVHD in 70-90% of patients.
• • The risk of chronic GVHD increases with the severity of acute GVHD.
  • Patients with stage 3 or stage 4 acute GVHD are more likely to develop chronic GVHD than patients with stage 1 or stage 2 acute GVHD.
  • As erythema subsides in acute GVHD, violaceous lichenified papules arise; these lesions are indistinguishable from those of lichen planus.
  • Typical lacy, white patches on the buccal mucosa of lichen planus are often present.
  • Lichenoid papules have a predilection for flexural surfaces.
  • Sclerodermatous changes are seen in patients with chronic GVHD.
  • Some patients have few, scattered sclerodermatous plaques. Other patients develop widespread disease that results in ulcerations, joint contractures, and esophageal dysmotility.
• The degree of liver and gastrointestinal tract involvement in acute GVHD affects patient outcome. Evidence of liver and/or gastrointestinal tract GVHD without skin involvement is rare.
• In 2006, Zenz et al¹¹ noted an autologous GVHD-like syndrome that followed an alemtuzumab-containing conditioning regimen and autologous stem cell transplantation to treat chronic lymphocytic leukemia.
• Kuskonmaz et al¹² noted fatal GVHD mimicking contact dermatitis in an infant who underwent 5/6 HLA-matched bone marrow transplantation from his mother for malignant infantile osteopetrosis. The initial rash on day 32 of life simulated diaper rash. The rash evolved into a belt-shaped rash, and then the child developed hyperkeratotic nodules on the hand.
• Because of the complex immune status of patients with GVHD, other eruptions that can mimic GVHD must remain under consideration. Drug reactions are the most common in this regard, but other eruptions are also mimics of GVHD. In 2006, Ozdemir and Molldrem¹³ reported a hookworm infection of the sigmoid colon mimicking GVHD in an immunosuppressed patient following allogeneic stem cell transplantation who had received a donor lymphocyte infusion for refractory acute promyelocytic leukemia.
• In 2007, Nakagiri et al¹⁴ noted thymoma-associated GVHD-like erythroderma.
• Sclerodermatous GVHD has a broad clinical spectrum and presents therapeutic challenges.¹⁵
• Grover disease after bone marrow transplantation has been associated with GVHD.¹⁶

Causes

GVHD occurs when immunocompetent cells react against an immunocompromised host.

• Removal of T cells from the hematopoietic inoculum can prevent GVHD but at the cost of graft failure and loss of the graft-versus-leukemia reaction.
• The cause of GVHD in patients who receive their own marrow (syngeneic graft) who have received cyclosporin or interferon gamma probably is dysregulation of thymic education of precursor T cells with subsequent loss of self-tolerance.

DIFFERENTIALS

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Other Problems to be Considered

Eruption of lymphocyte recovery
Scleroderma
Viral exanthem

WORKUP

Section 5 of 11  

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Lab Studies

• Liver function studies: Routinely monitor liver enzyme and bilirubin levels to assess the development of hepatic GVHD.
• Serum electrolytes: Monitor electrolyte levels because GVHD of the gastrointestinal tract can lead to severe diarrhea.
• Blood and stool cultures: Perform cultures periodically because immunosuppressed recipients of hematopoietic stem cell are at risk for opportunistic infections.

Imaging Studies

• No specific imaging studies aid the diagnosis of GVHD.

Histologic Findings

Skin biopsy with routine hematoxylin and eosin staining is the primary tool for evaluating suspected GVHD skin eruptions.¹⁷

A grading system describes the histologic changes of acute GVHD as follows:

• Grade 0 - Normal skin or changes not consistent with GVHD
• Grade 1 - Basal vacuolization of the dermal-epidermal junction
• Grade 2 - Basal vacuolization, necrotic epidermal cells, and lymphocytic infiltrate in superficial dermis (see Media File 1)
• Grade 3 - Changes of grade 2 plus clefting at the basement membrane
• Grade 4 - Changes of grade 2 plus bullae formation

Chronic GVHD exhibits basement membrane changes similar to those of acute GVHD (eg, vacuolar changes, necrotic epidermal cells, presence of lymphocytes). In addition, chronic disease can result in features such as thickened epidermis (acanthosis), thickened granular layer (hypergranulosis), thickened stratum corneum (hyperkeratosis), and rete ridges with a pointed or sawtooth appearance.

Horn et al reported that the lichen planus–like histologic changes (acanthosis, hypergranulosis, sawtooth rete ridges) believed to represent chronic GVHD occur before the 100th day after transplantation in approximately 15% of patients. In addition, lichen planus–like histologic changes, seen in either the acute or chronic clinical setting of GVHD, portend a poor patient prognosis. Several sequential biopsies are often needed as the rash evolves to establish the diagnosis; histologic changes during the early stage of the disease can be nonspecific.

Staging

In 2007, Greinix et al¹⁸ reported a single-center pilot validation study of a new chronic GVHD skin scoring system. It combines the percentage of involved body surface area divided into 10 separate anatomic regions, with manifestations of chronic GVHD coded from 0 (normal skin) to 4 (hidebound skin, unmovable sclerosis).

The study used trained physicians who observed 3 times on 2 consecutive days for a total of 192 individual skin assessments. They (1) calculated results; (2) obtained good-to-excellent intraclass correlation coefficients in almost all scores, including erythematous lesions in areas with scores 3 and 4 for all observers; (3) saw moderate-to-good interrater reliability for observers 1 to 4 in lesions with scores 0, 3, and 4, respectively; and (4) noted marked improvement of interrater reliability in all scores and examinations when intraclass correlation coefficients were calculated only for the more experienced observers (1 to 3).

TREATMENT

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Medical Care

Patients recovering from bone marrow transplant are routinely hospitalized in specialized units for weeks after the procedure and continuously monitored for the development of infectious complications secondary to the immunosuppressed status. If the initial outcomes of bone marrow transplantations are successful, patients need close follow-up monitoring of their immunosuppressive regimens and primary tumor status.

Surgical Care

• Patients who develop sclerodermatous changes of chronic GVHD may require surgical release of a contracted joint.
• Patients who develop nonhealing ulcerations secondary to sclerodermatous GVHD may require wound debridement and skin grafting.

Consultations

Subspecialists are often consulted for the management of GVHD. They include hematologists or oncologists, dermatologists, gastroenterologists, physical medicine/rehabilitation specialists, transplantation medicine specialists, and transplantation surgeons.

• Hematologist and oncologist: The most common indication for HCT remains hematologic malignancy. Other indications include treatment of aplastic anemia and, more recently, restoration of marrow after attempts at ablating solid tumors. Most patients who receive HCT are treated primarily by the hematologist or oncologist.
• Dermatologist: A dermatologist may be the best specialist to differentiate the various skin eruptions that can occur in patients who are taking multiple medications and who are at risk for GVHD. Skin biopsy remains the primary tool for differentiating the skin eruptions, and a dermatopathologist with both clinical and dermatopathology training is the best specialist for interpreting the results.
• Gastroenterologist: Patients with GVHD may have hepatic and gastrointestinal mucosal involvement. Input from gastroenterologists is important in treating these complications.
• Physical medicine/rehabilitation specialist: Patients who develop chronic GVHD are at risk for joint contractures and pressure ulcerations.
• Transplantation medicine specialist and transplantation surgeon: Patients who receive solid organ transplants are treated by these specialists. GVHD is rare but has been reported in patients who receive solid organ transplants.

Diet

No specific diet is required in patients with GVHD.

Activity

Activity is permitted as tolerated by the patient.

MEDICATION

Section 7 of 11  

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The best treatment for GVHD is prevention. Prophylaxis for GVHD usually consists of methotrexate (MTX) with or without prednisone, cyclosporine, cyclophosphamide, or tacrolimus. Topical tacrolimus may be helpful for mucosal disease.¹⁹ Marrow T-cell depletion can substantially reduce the incidence and severity of acute GVHD, but these results are offset by an increase in graft failure and recurrent leukemia.

Once the diagnosis of GVHD is established, treatment consists of continuing the original immunosuppressive agent and adding methylprednisolone. Chronic GVHD requires continued immunosuppressive therapy plus other modifying agents, as outlined below. Immune modalities such as treatment with antibodies against the interleukin 2 receptor or antithymocyte globulin are not beneficial in treating acute GVHD.

Halofuginone, a topically applied inhibitor of collagen type I synthesis, is beneficial in patients with sclerodermatous GVHD. Thalidomide has been used for chronic GVHD with reported benefit, but the high rate of adverse effects (including granulocytopenia) precludes its use in many patients.²⁰

Monoclonal antibodies directed either against activated T-cells (daclizumab, visilizumab, murine anti-CD147 monoclonal antibody [ABX-CBL]) or against cytokines (infliximab, etanercept) have had promising preliminary results. Large-scale studies evaluating their effectiveness are not yet available.

Creamer et al²¹ noted eczematoid GVHD that responded to psoralen plus UV-A (PUVA).

Drug Category: Immunosuppressants

These agents inhibit key factors that mediate immune reactions.

Drug Category: Phototherapeutic agents

These drugs have been proven beneficial for some patients with chronic GVHD. PUVA is used most widely. Success is also reported with extracorporeal photopheresis,²² but access and cost have limited use of this modality. Success with UV-A1 exposure has been reported in a patient with sclerodermatous chronic GVHD.²³

Drug Category: Retinoids

These drugs decrease cohesiveness of abnormal hyperproliferative keratinocytes and may reduce the potential for malignant degeneration. They also modulate keratinocyte differentiation and reduce the risk of skin cancer formation in renal transplant patients. Retinoids may be helpful in managing sclerotic GVHD.

Drug Category: Corticosteroids

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, corticosteroids modify the body's immune response to diverse stimuli.

Drug Category: Immunomodulators

These drugs modify the body's immune response to diverse stimuli.

FOLLOW-UP

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Further Inpatient Care

• Patients who undergo bone marrow transplantation are usually hospitalized until marrow engrafting is established and blood counts are within the reference range.
• Treatment for acute GVHD, which occurs during the transplant recovery phase, is performed on an inpatient basis.
• Patients who develop chronic GVHD sometimes are hospitalized for pulse steroid therapy, but more often they are treated as outpatients.

Further Outpatient Care

• Patients usually require lifelong immunosuppressive therapy.
• Continual monitoring is required.

Transfer

• Immunosuppressed patients with suspected infection (eg, bacterial, viral, fungal) should be transferred to a tertiary care center.

Deterrence/Prevention

• See Treatment.

Prognosis

• Acute GVHD
• • Acute GVHD is the primary or major contributory cause of death in 15-40% of patients who develop GVHD.
  • The primary cause of death in GVHD is overwhelming sepsis.
  • The mortality rate in GVHD is directly related to disease severity. Patients with stage 1 or stage 2 GVHD have a favorable prognosis, whereas those with stage 3 and stage 4 GVHD account for the deaths seen with GVHD.
• Chronic GVHD
• • Patients with mild disease limited to the skin or liver have a favorable prognosis and often do not require treatment.
  • Patients with acute GVHD that directly progresses to chronic GVHD have the highest mortality rates. Acute GVHD patients who develop chronic GVHD after acute GVHD resolves have an intermediate course, whereas patients who develop chronic GVHD without antecedent acute GVHD have the lowest mortality rates.

Patient Education

• Inform patients that GVHD remains a leading cause of morbidity and mortality after HCT.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Failure to clearly inform potential HCT recipients about the risks of developing GVHD and about the treatment strategies used to treat acute and chronic GVHD
• Failure to maintain open and honest doctor-patient communication to prevent false expectations and future misunderstandings by potential HCT recipients
• Prot-Labarthe et al²⁴ noted toxic serum levels of tacrolimus after topical administration in an infant with severe cutaneous GVHD.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Acute graft versus host disease. Tissue stained with hematoxylin and eosin shows dyskeratosis of individual keratinocytes and patchy vacuolization of the basement membrane. A moderate superficial dermal and perivascular lymphocytic infiltrate is also seen. Courtesy of Melanie K. Kuechle, MD.
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Media type:  Photo

Media file 2:  Autologous graft versus host disease involving the skin on a patient's arm shortly after signs of engraftment appeared after autologous peripheral blood stem cell transplantation for ovarian cancer. Courtesy of Romeo A. Mandanas, MD, FACP.
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Media type:  Photo

Media file 3:  Acute graft versus host disease involving desquamating skin lesions in a patient who underwent allogeneic bone marrow transplantation for myelodysplasia. Courtesy of Romeo A. Mandanas, MD, FACP.
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Media type:  Photo

Media file 4:  Oral mucosal changes in a patient with chronic graft versus host disease (GVHD). Note the skin discoloration (vitiligo), which can result from GVHD. Courtesy of Romeo A. Mandanas, MD, FACP.
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Media type:  Photo

Media file 5:  Boy who developed stage 3 skin involvement with acute graft versus host disease (GVHD) despite receiving prophylaxis with cyclosporin A. The donor was a sister matched for human leukocyte antigen. The sex disparity increased the risk of GVHD. Courtesy of Mustafa S. Suterwala, MD.
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Media type:  Photo

Media file 6:  Boy in whom graft versus host disease (GVHD), which progressed to stage 4 (same patient as Media File 5). High-dose cyclosporin A and methylprednisolone had been administered intravenously. The patient later died from chronic pulmonary disease resulting from chronic GVHD. Courtesy of Mustafa S. Suterwala, MD.
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Media type:  Photo

Media file 7:  Interaction of factors involved in graft versus host disease (GVHD). Cytokines, such as interleukin-2, tumor necrosis factor-alpha, and gamma interferon, play an important role in the initiation and propagation of GVHD. Courtesy of Romeo A. Mandanas, MD, FACP.
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Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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• References

1. Inaba H, Hale G, Leung W, Woodard P, Burnette K, Handgretinger R, et al. Diagnostic challenge in recurrent skin rash after autologous bone marrow transplantation. J Pediatr Hematol Oncol. Aug 2006;28(8):525-8. [Medline].
2. Fukuno K, Tomonari A, Takahashi S, Ooi J, Takasugi K, Tsukada N, et al. Varicella-zoster virus encephalitis in a patient undergoing unrelated cord blood transplantation for myelodysplastic syndrome-overt leukemia. Int J Hematol. Jul 2006;84(1):79-82. [Medline].
3. Piper KP, Horlock C, Curnow SJ, Arrazi J, Nicholls S, Mahendra P, et al. CXCL10-CXCR3 interactions play an important role in the pathogenesis of acute graft-versus-host disease in the skin following allogeneic stem-cell transplantation. Blood. Dec 2007;110(12):3827-32. [Medline].
4. Hardy NM, Hakim F, Steinberg SM, Krumlauf M, Cvitkovic R, Babb R, et al. Host T cells affect donor T cell engraftment and graft-versus-host disease after reduced-intensity hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. Sep 2007;13(9):1022-30. [Medline].
5. Fujita S, Sato Y, Sato K, Eizumi K, Fukaya T, Kubo M, et al. Regulatory dendritic cells protect against cutaneous chronic graft-versus-host disease mediated through CD4+CD25+Foxp3+ regulatory T cells. Blood. Nov 15 2007;110(10):3793-803. [Medline].
6. Whalen JG, Jukic DM, English JC 3rd. Rash and pancytopenia as initial manifestations of acute graft-versus-host disease after liver transplantation. J Am Acad Dermatol. May 2005;52(5):908-12. [Medline].
7. Smith DM, Agura ED, Ausloos K, Ring WS, Domiati-Saad R, Klintmalm GB. Graft-vs-host disease as a complication of lung transplantation. J Heart Lung Transplant. Sep 2006;25(9):1175-7. [Medline].
8. Serefhanoglu K, Turan H, Saba T, Ozer I, Tosun E, Arslan H. Transfusion-associated graft-versus-host disease in an immunocompetent individual following cardiac surgery. J Natl Med Assoc. Mar 2005;97(3):418-20. [Medline].
9. Aschan J, Carlens S, Hägglund H, Klaesson S, Mattsson J, Remberger M. Improved survival after bone marrow transplantation for early leukemia using busulfan-cyclophosphamide and individualized prophylaxis against graft-versus-host disease: a long-term follow-up. Clin Transplant. Dec 1999;13(6):512-9. [Medline].
10. Hentrich M, Oruzio D, Jäger G, Schlemmer M, Schleuning M, Schiel X, et al. Impact of human herpesvirus-6 after haematopoietic stem cell transplantation. Br J Haematol. Jan 2005;128(1):66-72. [Medline].
11. Zenz T, Ritgen M, Dreger P, Kröber A, Barth TF, Schlenk R, et al. Autologous graft-versus-host disease-like syndrome after an alemtuzumab-containing conditioning regimen and autologous stem cell transplantation for chronic lymphocytic leukemia. Blood. Sep 15 2006;108(6):2127-30. [Medline].
12. Kuskonmaz B, Güçer S, Boztepe G, Cetin M, Uckan D. Atypical skin graft-vs.-host disease following bone marrow transplantation in an infant. Pediatr Transplant. Mar 2007;11(2):214-6. [Medline].
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