Graft Versus Host Disease

Updated: Aug 02, 2017
  • Author: Romeo A Mandanas, MD, FACP; Chief Editor: Mary C Mancini, MD, PhD, MMM  more...
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Overview

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 (see the image below), 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.

Autologous graft versus host disease (GVHD) involv 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.

Signs and symptoms

Presentation in acute GVHD is as follows:

  • A pruritic or painful rash (median onset, day 19 posttransplantation; range, 5-47 days) [2]
  • Pruritus from initially asymptomatic liver involvement, anorexia, weight loss, followed rarely by hepatic coma
  • Diarrhea, intestinal bleeding, cramping abdominal pain, and ileus

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. [3] Manifestations are as follows:

  • Ocular – Burning, irritation, photophobia, and pain from lack of tear secretion
  • Oral and GI – Mouth dryness, sensitivity to acidic or spicy foods, dysphagia, odynophagia, and insidious weight loss
  • Pulmonary – Obstructive lung disease, with symptoms of wheezing, dyspnea, and chronic cough that is usually nonresponsive to bronchodilator therapy
  • Neuromuscular – Generalized or focal weakness, neuropathic pain, vision loss, muscle cramps, myalgia
  • Joints – Arthralgia, arthritis

Physical examination

Skin findings are as follows:

  • Maculopapular exanthema – Red-to-violet lesions that typically first appear on the palms of the hands, soles of the feet, cheeks, neck, ears, and upper trunk, sometimes progressing to involve the whole body; in severe cases, bullae may be observed, and vesicles may form
  • Lichenoid skin lesions or sclerodermatous thickening of the skin, which sometimes causes contractures and limits joint mobility
  • Jaundice from hyperbilirubinemia; patients who subsequently develop pruritus may exhibit excoriations from scratching

Ocular findings may include the following:

  • Acute GVHD – Hemorrhagic conjunctivitis, pseudomembrane formation, and lagophthalmos
  • Chronic GVHD – Keratoconjunctivitis sicca, which may lead to punctate keratopathy

Additional findings are as follows:

  • Oral – Atrophy of the oral mucosa, erythema, and lichenoid lesions of the buccal and labial mucosae in chronic GVHD
  • Pulmonary – Prolonged expiratory breathing phase (wheezes) from bronchiolitis obliterans
  • GI – Diffuse abdominal tenderness with hyperactive bowel sounds may accompany secretory diarrhea of acute GVHD; in severe ileus, the abdomen is silent and appears distended
  • Neuromuscular – Findings of myasthenia gravis, polymyositis, optic neuritis, arthritis may occur in chronic GVHD
  • Vaginitis and vaginal strictures have been described in chronic GVHD

See Presentation for more detail.

Diagnosis

Laboratory study results in GVHD are as follows:

  • CBC – Autoimmune cytopenias (eg, thrombocytopenia, anemia, leukopenia) may be observed with chronic GVHD
  • Liver function tests – Elevation of the alkaline phosphatase level, an early sign of liver involvement by GVHD; hypoalbuminemia is typically due to GVHD-associated intestinal protein leakage and a negative nitrogen balance
  • Serum electrolytes and chemistries (eg, potassium, magnesium, bicarbonate levels) may be altered; massive diarrhea and diminished oral intake can lead to serious electrolyte abnormalities

Other tests

  • Schirmer test – To measure the degree of tear formation by the lacrimal glands in chronic GVHD
  • Pulmonary function tests and arterial blood gas analysis – To identify obstructive pulmonary disease (eg, obliterative bronchiolitis) in chronic GVHD
  • Manometric studies of the esophagus

Imaging studies

  • Hepatic and Doppler sonography
  • Barium swallow study

Procedures

  • Skin punch biopsy
  • Upper GI endoscopy and biopsy in patients with persistent anorexia and vomiting
  • Flexible sigmoidoscopy or colonoscopy with biopsy of sigmoid or colonic lesions in patients with diarrhea
  • Liver biopsy (rarely done, usually only in patients with isolated hepatic findings)

See Workup for more detail.

Management

The criterion standard for primary prophylaxis of acute GVHD is cyclosporine for 6 months and short-course methotrexate in T-cell–replete allogeneic HCT (criterion standard); currently, tacrolimus is often substituted for cyclosporine because of its more potent immunosuppressant capacity and lower risk of nephrotoxicity. Antithymocyte globulin (ATG) is given before HCT in unrelated-donor transplants.

Primary therapy for acute GVHD is as follows:

  • For skin GVHD of stage I or II, observation or a trial of topical corticosteroids (eg, triamcinolone 0.1%) may be used
  • For grade II-IV acute GVHD, continuing the original immunosuppressive prophylaxis and adding methylprednisolone (commonly starting at 2 mg/kg/day in 2 divided doses); in patients who respond to initial therapy, the steroid will be tapered weekly thereafter until off 
  • Other therapies are ATG, cyclosporine, sirolimus  [4]  , mycophenolate mofetil (MMF), daclizumab, anti–interleukin-2 (IL-2) receptor, alone or in combination

Secondary therapy for acute GVHD is as follows:

  • ATG or multiple pulses of methylprednisolone (at doses higher than those used in initial therapy)
  • Tacrolimus, for GVHD with cyclosporine resistance or neurotoxicity or nephrotoxicity
  • MMF at 2 g daily, added to the steroid regimen [5]
  • infliximab [6] or etanercept [7]  
  • Psoralen and ultraviolet A irradiation (PUVA), for cutaneous lesions
  • Ruxolitinib 
  • Muromomab-CD3 (Orthoclone OKT3)
  • Humanized anti-Tac antibody to the IL-2 receptor

Primary therapy for chronic GVHD is as follows:

  • Prednisone, 1 mg/kg every day
  • Tacrolimus
  • Cyclosporine, 6 mg given every 12 hours every other day in patients at high risk for GVHD with thrombocytopenia
  • Sirolimus
  • Thalidomide

Secondary therapy for chronic GVHD is as follows:

  • Ibrutinib for adults who failed at least 1 treatment for chronic GVHD [8, 9]
  • MMF, added to standard tacrolimus, cyclosporine, sirolimus, and/or prednisone, for steroid-refractory chronic GVHD
  • Azathioprine, alternating cyclosporine/prednisone, or thalidomide for steroid-refractory chronic GVHD
  • Clofazimine, for treating cutaneous and oral lesions of chronic GVHD and as a steroid-sparing agent
  • PUVA therapy, for refractory cutaneous chronic GVHD
  • Extracorporeal photopheresis (a modification of PUVA treatment) [10]
  • Rituximab, mainly for musculoskeletal and cutaneous chronic GVHD [11]
  • Pentostatin
  • Low-dose (100-cGy) total lymphoid irradiation to thoracoabdominal areas
  • Imatinib [12]

See Treatment and Medication for more detail.

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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. [13] 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.

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Pathophysiology

Several criteria, as first described by Billingham in 1966, [14] are traditionally required to diagnose GVHD, including the following:

  • The graft must contain immunologically competent cells.
  • The host must possess important transplantation alloantigens that are lacking in the donor graft so that the host appears foreign to the graft and can therefore stimulate it antigenically.
  • The host itself must be incapable of mounting an effective immunologic reaction against the graft, or it must at least allow for sufficient time for the latter to manifest its immunologic capabilities (ie, it must have the security of tenure).

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

Table 1. Procedures Associated with a High Risk of GVHD* (Open Table in a new window)

Procedure Groups at High Risk
Allogeneic HCT Patients receiving no GVHD prophylaxis



Older patients



Recipients of HLA-nonidentical stem cells



Recipients of grafts 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 products Neonates 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. [15]



HLA = Human leukocyte antigen.



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).

Autologous graft versus host disease (GVHD) involv 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.

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 [16] (see image below). The successful use of B-cell–targeted therapy such as rituximab in chronic GVHD has sparked an interest in defining the role of B cells in the pathophysiology of GVHD. [17]

Interactive factors involved in the pathogenesis o 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 such as 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. [3]

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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 cyclosporine and interleukin (IL)-2. [18]

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%. [19]

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. [3]

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%). [20, 21] The 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. [22]

Mortality/Morbidity

See the list below:

  • The overall grade of acute GVHD is predictive of the patient's outcome, with the highest rates of mortality in those with grade IV, or severe, GVHD.
  • The response to treatment is also predictive of outcomes in GVHD of grades II-IV. Patients with no response or with progression have a mortality rate as high as 75% compared with 20-25% in those with a complete response. [19]
  • In chronic GVHD, mortality rates are increased in patients with extensive disease, progressive onset, thrombocytopenia, and HLA-nonidentical marrow donors. The overall survival rate is 42%, but patients with progressive onset of chronic GVHD have a survival rate of 10%. [23]
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