eMedicine Specialties > Dermatology > Allergy & Immunology

Graft Versus Host Disease

Author: Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice
Coauthor(s): Melanie K Kuechle, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Washington School of Medicine
Contributor Information and Disclosures

Updated: Mar 14, 2008

Introduction

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

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.

More on Graft Versus Host Disease

Overview: Graft Versus Host Disease
Differential Diagnoses & Workup: Graft Versus Host Disease
Treatment & Medication: Graft Versus Host Disease
Follow-up: Graft Versus Host Disease
Multimedia: Graft Versus Host Disease
References
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Further Reading

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Keywords

GVHD, graft-versus-host disease, allogenic hematopoietic cell transplantation, HCT, autologous hematopoietic cell transplantation, solid organ transplants, blood transfusions, maternal-fetal transfusions, graft-versus-leukemia reaction, graft versus leukemia reaction, peripheral blood stem cells, PBSCs, cord blood stem cells, CBSCs

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Contributor Information and Disclosures

Author

Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice
Noah S Scheinfeld, MD, JD, FAAD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Optigenex Consulting fee Independent contractor

Coauthor(s)

Melanie K Kuechle, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Washington School of Medicine
Melanie K Kuechle, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Medical Editor

Evan R Farmer, MD, Professor of Dermatology, Johns Hopkins University School of Medicine, Clinical Professor of Pathology, Virginia Commonwealth University School of Medicine; Consulting Staff, Department of Dermatology, Johns Hopkins Hospital, VCU Health Services
Evan R Farmer, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, American Medical Association, American Society of Dermatopathology, and International Society of Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey
Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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