Graft Versus Host Disease

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Practice Essentials

Graft versus host disease (GVHD) is an immune-mediated disease resulting from a complex interaction between donor and recipient adaptive immunity.[1] Acute GVHD describes a distinctive syndrome of dermatitis, hepatitis, and enteritis developing within 100 days after allogeneic hematopoietic-cell transplantation (HCT). Chronic GVHD describes a more diverse syndrome developing after day 100. In addition to allogeneic HCT, procedures associated with high risk of GVHD include transplantation of solid organs containing lymphoid tissue and transfusion of unirradiated blood products

Essential update: A new biomarker for treatment-resistant and fatal GVHD

Vander Lugt and colleagues found that plasma levels of the biomarker suppression of tumorigenicity 2 (ST2) at the initiation of therapy can help predict the risk of therapy-resistant GVHD and 6-month mortality. Compared with patients with low ST2 values at the start of treatment, those with high ST2 values were 2.3 times as likely to have treatment-resistant GVHD and were 3.7 times as likely to die within 6 months. Patients with low ST2 values had significantly lower mortality without relapse than those with high ST2 values, regardless of their GVHD grade.[2]

Signs and symptoms

Presentation in acute GVHD is as follows:

Diarrhea in acute GHVD is green, mucoid, watery, and mixed with exfoliated cells forming fecal casts. Voluminous secretory diarrhea may persist despite cessation of oral intake.

Upper GI enteric GVHD occurs in approximately 13% of patients who receive HLA-identical transplants and manifests as anorexia and dyspepsia without diarrhea. It is most common in older patients.

Chronic GVHD may be an extension of acute GVHD, may occur de novo in patients who never have clinical evidence of acute GVHD, or may emerge after a quiescent interval after acute GVHD resolves.[4] Manifestations are as follows:

Physical examination

Skin findings are as follows:

Ocular findings may include the following:

Additional findings are as follows:

See Clinical Presentation for more detail.

Diagnosis

Laboratory study results in GVHD are as follows:

Other tests

Imaging studies

See Workup for more detail.

Management

The criterion standard for primary prophylaxis of acute GVHD is cyclosporin A for 6 months and short-course methotrexate in T-cell–replete allogeneic HCT (criterion standard); tacrolimus is often substituted for cyclosporine, especially in unrelated-donor transplantation. Prednisone may be added. Antithymocyte globulin (ATG) can be given before HCT.

Primary therapy for acute GVHD is as follows:

Secondary therapy for acute GVHD is as follows:

Primary therapy for chronic GVHD is as follows:

Secondary therapy for chronic GVHD is as follows:

See Treatment and Medication for more detail.

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Autologous graft versus host disease (GVHD) involving the skin of a patient's arm appeared shortly after signs of engraftment appeared. The patient ha....

Background

Barnes and Loutit first described (in mice) what is now known as graft versus host disease (GVHD) as a syndrome called secondary disease to differentiate it from primary disease of radiation sickness. Mice that were given allogeneic spleen cells after irradiation developed fatal secondary disease (skin abnormalities and diarrhea), which was a result of introducing immunologically competent cells into an immunoincompetent host.

Human GVHD occurs after allogeneic stem-cell transplantation, with features similar to those observed in animal studies. Acute GVHD describes a distinctive syndrome of dermatitis, hepatitis, and enteritis developing within 100 days of allogeneic hematopoietic-cell transplantation (HCT). Chronic GVHD describes a more diverse syndrome developing after day 100.

Pathophysiology

Several criteria, as first described by Billingham in 1966,[9] are traditionally required to diagnose GVHD, including the following:

Certain patient groups are at risk for GVHD, as outlined in Table 1.

Table 1. Procedures Associated with a High Risk of GVHD*


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Current understanding of the biology of GVHD includes the occurrence of autologous GVHD and transfusion-associated GVHD. The former suggests that inappropriate recognition of host self-antigens may occur, and the latter is an example of GVHD in an individual who is immunocompetent (see image below).


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Autologous graft versus host disease (GVHD) involving the skin of a patient's arm appeared shortly after signs of engraftment appeared. The patient ha....

GVHD is an immune-mediated disease resulting from a complex interaction between donor and recipient adaptive immunity.[1] The main effectors are donor T cells, which are activated in the presence of co-stimulatory molecules by a storm of proinflammatory cytokines[11] (see image below). The successful use of B cell targeted therapy like rituximab in chronic GVHD has sparked an interest in defining the role of B cells in the pathophysiology of GVHD.[12]


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Interactive factors involved in the pathogenesis of graft versus host disease (GVHD.) Courtesy of Romeo A. Mandanas, MD, FACP.

Chronic GVHD is a syndrome that mimics the autoimmune diseases. Donor T cells play an important role in its development, but humoral immunity is also implicated. The targets of attack may include host non-HLA antigens like minor histocompatibility antigens. In some studies, host dendritic cells may also be at play. A close relationship exists between the development of chronic GVHD and a helpful graft-versus-tumor/leukemia effect.[4]

Frequency

United States

Autologous GVHD occasionally occurs after autologous or syngeneic HCT (7-10%). Tissue damage caused by high-dose chemotherapy or secondary cytokine production may expose cryptic self-antigens, which the immune system may newly recognize only after HCT. Mild and usually self-limited episodes of dermal GVHD or even hepatic and GI abnormalities have been described. GVHD-like symptoms and findings can also be induced in autologous recipients after the administration (and withdrawal) of cyclosporin (CSP) and interleukin (IL)-2.[13]

Transfusion-associated GVHD occurs 4-30 days after transfusion and resembles hyperacute GVHD after allogeneic HCT. Marrow aplasia is a frequent and often fatal complication. This serious complication of transfusion can be prevented by irradiating blood products with at least 2500 cGy before transfusion in individuals at risk. In Japan (where inbred populations share common haplotypes), marrow aplasia is estimated to occur in 1 in 500 open-heart operations in individuals who are immunocompetent.

The occurrence of acute GVHD in patients who receive marrow from HLA-identical siblings varies widely depending on several recognized risk factors. About 19-66% of recipients are affected, depending on their age, on donor-recipient sex matching, and on donor parity. The incidence of GVHD increases with HLA-nonidentical marrow donors who are related or in HLA-matched unrelated donors, with rates of 70-90%.[14]

Chronic GVHD is observed in 33% of HLA-identical sibling transplantations, in 49% of HLA-identical related transplantations, in 64% of matched unrelated donor transplantations. The rate could be as high as 80% in 1-antigen HLA-nonidentical unrelated transplantations.[4]

The source of donor graft affects the incidence of GVHD. Although acute GVHD does not differ significantly among recipients of HLA-identical sibling bone marrow (BM) versus peripheral blood stem cells (PBSC), the cumulative incidence of chronic GVHD (and extensive GVHD) is higher in those who received PBSC (73% vs. 55%).[15, 16] Cumulative incidence of Grades III-IV acute and extensive chronic GVHD is much lesser in unrelated cord blood recipients than in either recipients of HLA-identical sibling BM or PBSC transplants.[17]

Mortality/Morbidity

Epidemiology

Frequency

United States

Autologous GVHD occasionally occurs after autologous or syngeneic HCT (7-10%). Tissue damage caused by high-dose chemotherapy or secondary cytokine production may expose cryptic self-antigens, which the immune system may newly recognize only after HCT. Mild and usually self-limited episodes of dermal GVHD or even hepatic and GI abnormalities have been described. GVHD-like symptoms and findings can also be induced in autologous recipients after the administration (and withdrawal) of cyclosporin (CSP) and interleukin (IL)-2.[13]

Transfusion-associated GVHD occurs 4-30 days after transfusion and resembles hyperacute GVHD after allogeneic HCT. Marrow aplasia is a frequent and often fatal complication. This serious complication of transfusion can be prevented by irradiating blood products with at least 2500 cGy before transfusion in individuals at risk. In Japan (where inbred populations share common haplotypes), marrow aplasia is estimated to occur in 1 in 500 open-heart operations in individuals who are immunocompetent.

The occurrence of acute GVHD in patients who receive marrow from HLA-identical siblings varies widely depending on several recognized risk factors. About 19-66% of recipients are affected, depending on their age, on donor-recipient sex matching, and on donor parity. The incidence of GVHD increases with HLA-nonidentical marrow donors who are related or in HLA-matched unrelated donors, with rates of 70-90%.[14]

Chronic GVHD is observed in 33% of HLA-identical sibling transplantations, in 49% of HLA-identical related transplantations, in 64% of matched unrelated donor transplantations. The rate could be as high as 80% in 1-antigen HLA-nonidentical unrelated transplantations.[4]

The source of donor graft affects the incidence of GVHD. Although acute GVHD does not differ significantly among recipients of HLA-identical sibling bone marrow (BM) versus peripheral blood stem cells (PBSC), the cumulative incidence of chronic GVHD (and extensive GVHD) is higher in those who received PBSC (73% vs. 55%).[15, 16] Cumulative incidence of Grades III-IV acute and extensive chronic GVHD is much lesser in unrelated cord blood recipients than in either recipients of HLA-identical sibling BM or PBSC transplants.[17]

Mortality/Morbidity

History

Patients at risk for acute GVHD and chronic GVHD are those undergoing allogeneic HCT.

Acute GVHD

Chronic GVHD

Physical

Acute GVHD is a clinicopathologic syndrome involving the skin, liver, and gut. Staging and grading is important in determining the management and prognosis and for comparing the results of immunosuppressive prophylaxis.

Table 2. Clinical Staging of Acute GVHD


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Table 3. Clinical Grading of Acute GVHD


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Chronic GVHD has manifestations similar to those of systemic progressive sclerosis, systemic lupus erythematosus, lichen planus, Sjögren syndrome, eosinophilic fasciitis, rheumatoid arthritis, and primary biliary cirrhosis. The median day of diagnosis in HLA-identical sibling recipients is 201 days after transplant; diagnosis is earlier in patients receiving marrow from HLA-nonidentical related or unrelated donors (159 or 133 d, respectively). Staging and classification helps in predicting the patient's prognosis.

Table 4. Clinicopathologic Classification of Chronic GVHD


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Different screening studies have been used to diagnose and stage chronic GVHD.

Table 5. Screening Studies for GVHD by Organ or System


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Causes

Important factors in determining occurrence and severity of GVHD are listed below.

Donor-host factors

Stem-cell source

Immune modulation

High-dose chemotherapy and radiation therapy

Laboratory Studies

Imaging Studies

Other Tests

Procedures

Histologic Findings

Characteristic findings on histologic examination of skin (eg, eosinophilic bodies), liver (eg, necrosis of the bile duct), and gut (eg, crypt-cell degeneration) soon after transplantation may be difficult to distinguish from the effects of the conditioning chemoradiotherapy. Serial biopsy and observation help establish the diagnosis and severity of acute GVHD.

On histology, mononuclear-cell infiltration and inflammation of affected epithelium is more subtle in chronic GVHD than in acute GVHD. Dermal fibrosis and inflammation of sweat glands can be used to distinguish chronic GVHD of skin from acute GVHD. Fibrosis of the submucosa and serosa is observed when chronic GVHD involves the GI tract. See the image below.


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Acute graft versus host disease (GVHD). Hematoxylin and eosin–stained tissue shows dyskeratosis of individual keratinocytes and patchy vacuolization o....

Medical Care

Acute GVHD

Chronic GVHD

Surgical Care

Surgical consultations are required mainly for the insertion of central venous access devices, such as Infuse-A-Port devices and pheresis catheters.

Consultations

Diet

Activity

Encourage patients who are receiving corticosteroid therapy to maintain an active lifestyle and to participate in a mild-to-moderate exercise program.

Medication Summary

Therapy includes immunosuppressive agents, antimetabolite and/or chemotherapeutic agents, antibodies and/or Igs, immunomodulating agents, and photoactive agents.

Methylprednisolone (Solu-Medrol)

Clinical Context:  Synthetic analog of naturally occurring glucocorticoids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Greater anti-inflammatory potency than that of prednisolone and less likely than prednisolone to induce sodium and water retention.

Prednisone (Sterapred)

Clinical Context:  Synthetic analog of naturally occurring glucocorticoids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability.

Cyclosporine (Sandimmune, Neoral)

Clinical Context:  Cyclic polypeptide. Suppresses some humoral immunity and more so cell-mediated immune reactions. Dosages for children and adults based on ideal body weight. Sandimmune and Neoral not bioequivalent.

Sirolimus (Rapamune)

Clinical Context:  Inhibits lymphocyte proliferation by interfering with signal-transduction pathways. Binds to immunophilin FKBP to block action of mammalian target of rapamycin (mTOR). Approved by Food and Drug Administration for prophylaxis of organ rejection in patients receiving allogeneic renal allografts. Prolonged survival of allografts (kidney, heart, skin, islet, small bowel, pancreaticoduodenal, bone marrow) in mice, rats, pigs, and primates. Reversed acute rejection of heart and kidney allografts in rats and prolonged graft survival in presensitized rats. Immunosuppressive effect may last up to 6 mo after discontinuation. Tolerization effect is alloantigen specific. Also used for treatment of GVHD and for prophylaxis in combination with tacrolimus and/or MTX.

Tacrolimus (Prograf)

Clinical Context:  Previously known as FK506. Macrolide immunosuppressant produced by Streptomyces tsukubaensis. Prolonged host and transplant survival in animal models. Adults should receive doses at low end of dosing range. Concomitant adrenal corticosteroid therapy recommended early after transplantation.

Mycophenolate mofetil (CellCept)

Clinical Context:  The 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent. Inhibits purine synthesis and proliferation of human lymphocytes. Prolonged survival of allogeneic transplants in animal models.

Class Summary

Corticosteroids are the mainstay for treatment of GVHD. Corticosteroids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli. Complications associated with glucocorticoid therapy depend on the dose and duration of treatment. A risk-benefit decision is made to determine the dose, duration, and frequency (daily or intermittent) of treatment.

The lowest possible dose of corticosteroid is used to control the condition and then gradually reduced when possible. Most patients undergoing allogeneic stem-cell transplantation are receiving prophylaxis for GVHD with CSP or tacrolimus in combination with methotrexate (MTX) and/or prednisone. Acute GVHD is treated with IV methylprednisolone for as long as 14 days. Subsequent tapering of the dose or switching to an oral agent is continued over several weeks to months. Chronic GVHD is treated with oral prednisone alone or in combination with CSP. If the response is positive, it is continued and tapered over 6-9 months.

Thalidomide (Thalomid)

Clinical Context:  Immunologic effects vary substantially in different conditions but may be related to suppression of excessive TNF-alpha production and downmodulation of selected cell-surface adhesion molecules involved in leukocyte migration.

Class Summary

Thalidomide exerts an immunologic effect. Its effectiveness is thought to be due to suppression of excessive TNF-alpha production and downmodulation of selected cell-surface adhesion molecules involved in leukocyte migration.

8-MOP, methoxsalen, 8-methoxypsoralen (Oxsoralen)

Clinical Context:  Naturally occurring photoactive substance that acts as photosensitizer. Subsequent exposure to UVA can cause cell injury. PO dose reaches skin by blood, and UVA penetrates well into skin. If sufficient cell injury occurs in skin, inflammatory reaction occurs. Most obvious manifestation is erythema, which may not begin for several h and peaks at 48-72 h. Over days to weeks, inflammation followed by repair manifested by increased melanization of epidermis and thickening of stratum corneum.

Exact mechanism of action with epidermal melanocytes and keratinocytes not known. Best-known biochemical reaction is with DNA. On photoactivation, conjugates and forms covalent bonds with DNA, which leads to formation of monofunctional (addition to single strand of DNA) and bifunctional adducts (cross-linking of psoralen to both strands of DNA).

Class Summary

Methoxsalen, a psoralen, and PUVA may be beneficial in treating cutaneous lesions of GVHD and may improve survival in some patients with steroid-resistant GVHD.

Pentostatin (Nipent)

Clinical Context:  Inhibits adenosine deaminase resulting in deoxyadenosine and deoxyadenosine 5+-triphosphate accumulation that may inhibit DNA or RNA synthesis causing cell death.

Methotrexate (Rheumatrex)

Clinical Context:  Formerly amethopterin. Antimetabolite used to treat certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. Interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues (eg, malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, cells of urinary bladder) generally most sensitive to this effect. May impair malignant growth without irreversible damage to healthy tissues when cellular proliferation in malignant tissues is greater than that of most healthy tissues. Preservative formulation contains benzol alcohol and must not be used for intrathecal or high-dose therapy.

Azathioprine (Imuran)

Clinical Context:  Imidazolyl derivative of 6-mercaptopurine. Many of its biologic effects similar to those of the parent compound. Suppresses hypersensitivities of cell-mediated type and variably alters antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity suppressed more than antibody responses. Considered slow-acting drug, and effects may persist after discontinuation.

Denileukin diftitox (Ontak)

Clinical Context:  Molecule in which diphtheria toxin and receptor-binding domain of human IL-2 fused. Fusion protein selectively delivers cytotoxic activity of diphtheria toxin to targeted cells. Used only in T-cell lymphoma in which malignant cells express CD25 component of IL-2 receptor. Binds to the IL-2 receptor (measured by CD25). Internalized by receptor-mediated endocytosis, and inhibits protein synthesis by translocating active portion of diphtheria toxin into cytosol. This, in turn, causes cell death.

Class Summary

These agents inhibit cell growth and proliferation.

MTX is used to treat certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. A short-course MTX is administered for the prophylaxis of acute GVHD. It is used in combination with CSP or tacrolimus.

Azathioprine is an antimetabolite that suppresses cell-mediated hypersensitivities and causes variable alterations in antibody production. It is used in combination with steroids and CSP to treat chronic GVHD.

Newer antineoplastic treatments include novel fusion proteins carrying a toxin or chemotherapeutic agents are engulfed into target cells, delivering a highly toxic molecule and leading to cell death.

Infliximab (Remicade)

Clinical Context:  Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-α and inhibits its binding to TNF-α receptor. Reduces infiltration of inflammatory cells and TNF-α production in inflamed areas.

Rituximab (Rituxan)

Clinical Context:  Antibody genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on surface of normal and malignant B lymphocytes. Antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy- chain variable region sequences and human constant region sequences.

Daclizumab (Zenapax)

Clinical Context:  Humanized monoclonal antibody that specifically binds to and blocks interleukin-2 (IL-2) receptor on surface of activated T cells.

Class Summary

These agents are monoclonal antibody directed against specific antigens found on surface of normal and/or malignant cells. They may also be directed against specific molecules to render them inactive.

Antithymocyte globulin-equine (Atgam)

Clinical Context:  Ig-containing immunosuppressive agent. Immunosuppressive action generally similar to that of other antilymphocyte preparations. May differ qualitatively and/or quantitatively in extent of specific effects, partly because of factors such as source of antigenic material, animal used to produce antiserum, and method of production.

Intravenous immune globulin, human (Sandoglobulin, Gammagard, Gammar-P, Gamunex)

Clinical Context:  Sterile, highly purified polyvalent antibody product containing, in concentrated form, all IgG antibodies that regularly occur in donor population. Do not mix with other medications or fluids; administer in separate infusion line.

Muromonab-CD3 (Orthoclone OKT3)

Clinical Context:  Murine monoclonal antibody to CD3 antigen of human T cells, which functions as immunosuppressant. Monoclonal antibody preparation; therefore, homogeneous, reproducible antibody product with consistent, measurable reactivity to human T cells. Reverses graft rejection, probably by blocking function of T cells, which play major role in acute allograft rejection. In in-vitro cytolytic assays, blocked generation and function of effector cells. Binding to T lymphocytes results in early activation of T cells, which leads to cytokine release then blockage of T-cell functions. After termination, T-cell function usually returns to normal within 1 wk.

Alemtuzumab (Campath)

Clinical Context:  Monoclonal antibody against CD52, antigen found on B-cells, T-cells, and almost all chronic lymphocytic leukemia (CLL) cells. Binds to CD52 receptor of lymphocytes, which slows proliferation of leukocytes.

Class Summary

Antithymocyte globulin-equine (Equine, Atgam) is an Ig-containing immunosuppressive agent that principally inhibits cell-mediated immune responses and inhibits humoral immune response to an extent.

IVIG (human) is a sterile, highly purified polyvalent antibody product containing, in concentrated form, all the IgG antibodies that regularly occur in the donor population.

Muromonab-CD3 is a murine monoclonal antibody to the CD3 antigen of human T cells that functions as an immunosuppressant. It is thought to reverse graft rejection by blocking the function of T cells that play a major role in acute allograft rejection.

Newer monoclonal antibodies directed against particular targets such as cytokines or antigens on cells that may have a role in GVHD initiation and propagation include alemtuzumab, daclizumab, infliximab, and other agents being investigated.

Etanercept (Enbrel)

Clinical Context:  A dimeric fusion protein made up of the extracellular ligand-binding portion of tumor necrosis factor receptor linked to the Fc portion of human IgG1. It binds specifically to TNF and blocks its interaction with cell surface TNF receptors. TNF is a naturally occurring cytokine involved in normal inflammatory and immune responses. It is also implicated in mediating GVHD both through amplification of donor immune response to host tissues as well as direct toxicity to target organs.

Class Summary

Preclinical studies have shown the importance of tumor necrosis factor-α (TNF α) as an effector of experimental GVHD. TNF inhibition can be accomplished by either antibodies against soluble and membrane-bound TNF α or by competitive binding using soluble TNF α receptors (such as etanercept) to render the molecule inactive.

Further Inpatient Care

Deterrence/Prevention

Complications

Prognosis

Author

Romeo A Mandanas, MD, FACP, Research Site Leader, Integris Cancer Institute of Oklahoma

Disclosure: Nothing to disclose.

Specialty Editors

Antoni Ribas, MD, Assistant Professor of Medicine, Division of Hematology-Oncology, University of California at Los Angeles Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Marcel E Conrad, MD, Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Disclosure: No financial interests None None

Chief Editor

Mary C Mancini, MD, PhD, Professor and Chief of Cardiothoracic Surgery, Department of Surgery, Louisiana State University School of Medicine in Shreveport

Disclosure: Nothing to disclose.

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Autologous graft versus host disease (GVHD) involving the skin of a patient's arm appeared shortly after signs of engraftment appeared. The patient had undergone autologous peripheral blood stem-cell transplantation to treat ovarian cancer. Courtesy of Romeo A. Mandanas, MD, FACP.

Autologous graft versus host disease (GVHD) involving the skin of a patient's arm appeared shortly after signs of engraftment appeared. The patient had undergone autologous peripheral blood stem-cell transplantation to treat ovarian cancer. Courtesy of Romeo A. Mandanas, MD, FACP.

Interactive factors involved in the pathogenesis of graft versus host disease (GVHD.) Courtesy of Romeo A. Mandanas, MD, FACP.

Acute graft versus host disease (GVHD) involving desquamating skin lesions in a patient after allogeneic bone marrow transplantation for myelodysplasia. Courtesy of Romeo A. Mandanas, MD, FACP.

This boy developed stage III skin involvement with acute graft versus host disease (GVHD) despite of receiving prophylaxis with cyclosporin A. The donor was his HLA-matched sister; the sex disparity increased the risk for acute GVHD. Courtesy of Mustafa S. Suterwala, MD.

Same boy as in previous image progressed to grade IV graft versus host disease (GVHD). High-dose cyclosporin A and methylprednisolone had been administered intravenously. He later died from chronic pulmonary disease due to chronic GVHD. Courtesy of Mustafa S. Suterwala, MD.

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

Acute graft versus host disease (GVHD). Hematoxylin and eosin–stained tissue shows dyskeratosis of individual keratinocytes and patchy vacuolization of the basement membrane. Moderate superficial dermal and perivascular lymphocytic infiltrate are also observed. Courtesy of Melanie K. Kuechler, MD.

Autologous graft versus host disease (GVHD) involving the skin of a patient's arm appeared shortly after signs of engraftment appeared. The patient had undergone autologous peripheral blood stem-cell transplantation to treat ovarian cancer. Courtesy of Romeo A. Mandanas, MD, FACP.

Acute graft versus host disease (GVHD) involving desquamating skin lesions in a patient after allogeneic bone marrow transplantation for myelodysplasia. 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 be a result of GVHD. Courtesy of Romeo A. Mandanas, MD, FACP.

Interactive factors involved in the pathogenesis of graft versus host disease (GVHD.) Courtesy of Romeo A. Mandanas, MD, FACP.

This boy developed stage III skin involvement with acute graft versus host disease (GVHD) despite of receiving prophylaxis with cyclosporin A. The donor was his HLA-matched sister; the sex disparity increased the risk for acute GVHD. Courtesy of Mustafa S. Suterwala, MD.

Same boy as in previous image progressed to grade IV graft versus host disease (GVHD). High-dose cyclosporin A and methylprednisolone had been administered intravenously. He later died from chronic pulmonary disease due to chronic GVHD. Courtesy of Mustafa S. Suterwala, MD.

Acute graft versus host disease (GVHD). Hematoxylin and eosin–stained tissue shows dyskeratosis of individual keratinocytes and patchy vacuolization of the basement membrane. Moderate superficial dermal and perivascular lymphocytic infiltrate are also observed. Courtesy of Melanie K. Kuechler, MD.

ProcedureGroups at High Risk
Allogeneic HCTPatients receiving no GVHD prophylaxis

Older patients

Recipients of HLA-nonidentical stem cells

Recipients of graft from allosensitized donors

Recipients of grafts from unrelated donors

Solid-organ transplantation (organs containing lymphoid tissue)Recipients of small-bowel transplants
Transfusion of unirradiated blood productsNeonates and fetuses

Patients with congenital immunodeficiency syndromes

Patients receiving immunosuppressive chemoradiotherapy

Patients receiving directed blood donations from partially HLA-identical, HLA-homologous donors

*Modified from Ferrara and Deeg, 1991.[10]

HLA = Human leukocyte antigen.

StageSkin FindingsLiver Findings (Bilirubin level, mg/dL)Gut Findings
+Maculopapular rash on < 25% of body surface2-3Diarrhea 500-1000 mL/d or persistent nausea
++Maculopapular rash on 25-50% of body surface3-6Diarrhea 1000-1500 mL/d
+++Generalized erythroderma6-15Diarrhea >1500 mL/d
++++Desquamation and bullae>15Pain with or without ileus
Overall GradeStage
SkinLiverGutFunctional Impairment
0 (None)0000
I (Mild)+ to ++000
II (Moderate)+ to ++++++
III (Severe)++ to +++++ to +++++ to +++++
IV (Life-threatening)++ to ++++++ to ++++++ to +++++++
ClassificationClinicopathology
LimitedLocalized skin involvement and/or hepatic dysfunction due to chronic GVHD
ExtensiveGeneralized skin involvement or localized skin involvement and/or hepatic dysfunction due to chronic GVHD, plus 1 of the following:

- Liver histology showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis

- Involvement of the eye (Schirmer test with < 5-mm wetting)

- Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy

- Involvement of any other target organ

Organ or SystemClinical FindingsScreening Studies
SkinDyspigmentation, xerosis, erythema, scleroderma, onychodystrophy, alopeciaSkin biopsy with a 3-mm punch-biopsy sample from the back and forearm areas
MouthLichen planus, xerostomiaOral biopsy with sample from lower lip
EyesSicca, keratitisSchirmer test
LiverJaundiceAlkaline phosphatase, AST, bilirubin determinations
LungsObstructive and/or restrictive lung diseasePulmonary function studies, arterial blood gas analysis
VaginaSicca, atrophyGynecologic evaluation
GI (nutrition)Protein and calorie deficiencyWeight, measurement of muscle and/or fat stores
Multiple (clinical performance)Contractures, debilityDetermination of Karnofsky score and Lansky play index