eMedicine Specialties > Transplantation > Complications

Graft Versus Host Disease

Author: Romeo A Mandanas, MD, FACP, Director, Western Oklahoma Bone Marrow Transplant Program, Site Research Leader, Cancer Care Associates-Oklahoma City
Contributor Information and Disclosures

Updated: Aug 20, 2008

Introduction

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 1966,¹ 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 in Table 1.

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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. Image 4 shows the interactive factors involved in the pathogenesis of GVHD.

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.

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.

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%.

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.

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%). 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.

Mortality/Morbidity

• 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.
• 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%.

Clinical

History

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

• Acute GVHD
  • Acute GVHD may initially appear as a pruritic or painful rash (median onset, day 19 posttransplantation; range, 5-47 d).
  • A hyperacute form of GVHD has been described as including fever, generalized erythroderma, and desquamation developing 7-14 days after transplantation.
  • After the skin, the next most frequently involved target of GVHD is the liver, where the disease causes asymptomatic elevation of bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase levels similar to those observed with cholestatic jaundice. Pruritus ensues, with hyperbilirubinemia. Hepatic coma is rare.
  • Acute GVHD may involve the distal small bowel and colon, resulting in diarrhea, intestinal bleeding, cramping abdominal pain, and ileus. The diarrhea is green, mucoid, watery, and mixed with exfoliated cells forming fecal casts. Voluminous secretory diarrhea may persist despite cessation of oral intake. Approximately 13% of patients who receive HLA-identical transplants may present with upper-GI enteric GVHD manifesting as anorexia and dyspepsia without diarrhea. This is most common in older patients.
  • Acute GVHD also has been associated with increased risk of infectious and noninfectious pneumonia and sterile effusions, hemorrhagic cystitis with infective agents, thrombocytopenia, and anemia. Hemolytic-uremic syndrome (thrombotic microangiopathy) has been observed in patients given CSP A who developed severe GVHD.
• Chronic GVHD
  • Chronic GVHD is viewed as an extension of acute GVHD. However, it also may occur de novo in patients who never have clinical evidence of acute GVHD, or it may emerge after a quiescent interval after acute GVHD resolves.
  • Ocular manifestations may include burning, irritation, photophobia, and pain due to a lack of tear secretion.
  • Oral and GI manifestations include dryness, sensitivity to acidic or spicy foods, and increasing pain after day 100 (chronic GVHD). Chronic GVHD may affect the esophagus, resulting in symptoms of dysphagia, odynophagia, and insidious weight loss.
  • Obstructive lung disease, with symptoms of wheezing, dyspnea, and chronic cough that is usually nonresponsive to bronchodilator therapy, is a clinical feature of chronic GVHD.
  • Neuromuscular manifestations include weakness, neuropathic pain, and muscle cramps.

Physical

• Skin (maculopapular exanthema) findings
  • Lesions are red to violet and typically first appear on the palms of the hands, soles of the feet, cheeks, neck, ears, and upper trunk. They can progress to involve the whole body.
  • In severe cases, bullae may be observed, and vesicles may form.
  • Chronic GVHD can lead to lichenoid skin lesions or sclerodermatous thickening of the skin, which sometimes causes contractures and limits joint mobility.
• Hepatic findings: Hyperbilirubinemia can manifest as jaundice, cause pruritus, and lead to excoriations from the patient's scratching. Portal hypertension, cirrhosis, and death from hepatic failure are rare.
• Ocular findings: Acute GVHD may also cause hemorrhagic conjunctivitis, pseudomembrane formation, and lagophthalmos. These complications worsen the prognosis. With chronic GVHD, keratoconjunctivitis sicca is common. Because of the dryness, punctate keratopathy (minimal or severe erosions of the cornea) may ensue.
• Oral findings: Atrophy of the oral mucosa, erythema, and lichenoid lesions of the buccal and labial mucosae are significantly correlated with chronic GVHD.
• Pulmonary findings: Bronchiolitis obliterans causes prolonged expiratory breathing phase (wheezes).
• GI findings: 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: Findings of autoimmune phenomenon of myasthenia gravis or polymyositis are sometimes observed in chronic GVHD.
• Other findings: Vaginitis and vaginal strictures have been described in chronic GVHD. Autoimmune thrombocytopenia and anemia have also been described with chronic GVHD.
• 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

  Stage	Skin Findings	Liver Findings (Bilirubin level, mg/dL)	Gut Findings
  +	Maculopapular rash on <25% of body surface	2-3	Diarrhea 500-1000 mL/d or persistent nausea
  ++	Maculopapular rash on 25-50% of body surface	3-6	Diarrhea 1000-1500 mL/d
  +++	Generalized erythroderma	6-15	Diarrhea >1500 mL/d
  ++++	Desquamation and bullae	>15	Pain with or without ileus

  Stage	Skin Findings	Liver Findings (Bilirubin level, mg/dL)	Gut Findings
  +	Maculopapular rash on <25% of body surface	2-3	Diarrhea 500-1000 mL/d or persistent nausea
  ++	Maculopapular rash on 25-50% of body surface	3-6	Diarrhea 1000-1500 mL/d
  +++	Generalized erythroderma	6-15	Diarrhea >1500 mL/d
  ++++	Desquamation and bullae	>15	Pain with or without ileus

  Table 3. Clinical Grading of Acute GVHD

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  Table

  Overall Grade	Stage
  	Skin	Liver	Gut	Functional Impairment
  0 (None)	0	0	0	0
  I (Mild)	+ to ++	0	0	0
  II (Moderate)	+ to +++	+	+	+
  III (Severe)	++ to +++	++ to +++	++ to +++	++
  IV (Life-threatening)	++ to ++++	++ to ++++	++ to ++++	+++

  Overall Grade	Stage
  	Skin	Liver	Gut	Functional Impairment
  0 (None)	0	0	0	0
  I (Mild)	+ to ++	0	0	0
  II (Moderate)	+ to +++	+	+	+
  III (Severe)	++ to +++	++ to +++	++ to +++	++
  IV (Life-threatening)	++ to ++++	++ to ++++	++ to ++++	+++

• 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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  Table

  Classification	Clinicopathology
  Limited	Localized skin involvement and/or hepatic dysfunction due to chronic GVHD
  Extensive	Generalized 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

  Classification	Clinicopathology
  Limited	Localized skin involvement and/or hepatic dysfunction due to chronic GVHD
  Extensive	Generalized 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

• 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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  Table

  Organ or System	Clinical Findings	Screening Studies
  Skin	Dyspigmentation, xerosis, erythema, scleroderma, onychodystrophy, alopecia	Skin biopsy with a 3-mm punch-biopsy sample from the back and forearm areas
  Mouth	Lichen planus, xerostomia	Oral biopsy with sample from lower lip
  Eyes	Sicca, keratitis	Schirmer test
  Liver	Jaundice	Alkaline phosphatase, AST, bilirubin determinations
  Lungs	Obstructive and/or restrictive lung disease	Pulmonary function studies, arterial blood gas analysis
  Vagina	Sicca, atrophy	Gynecologic evaluation
  GI (nutrition)	Protein and calorie deficiency	Weight, measurement of muscle and/or fat stores
  Multiple (clinical performance)	Contractures, debility	Determination of Karnofsky score and Lansky play index

  Organ or System	Clinical Findings	Screening Studies
  Skin	Dyspigmentation, xerosis, erythema, scleroderma, onychodystrophy, alopecia	Skin biopsy with a 3-mm punch-biopsy sample from the back and forearm areas
  Mouth	Lichen planus, xerostomia	Oral biopsy with sample from lower lip
  Eyes	Sicca, keratitis	Schirmer test
  Liver	Jaundice	Alkaline phosphatase, AST, bilirubin determinations
  Lungs	Obstructive and/or restrictive lung disease	Pulmonary function studies, arterial blood gas analysis
  Vagina	Sicca, atrophy	Gynecologic evaluation
  GI (nutrition)	Protein and calorie deficiency	Weight, measurement of muscle and/or fat stores
  Multiple (clinical performance)	Contractures, debility	Determination of Karnofsky score and Lansky play index

Causes

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

• Donor-host factors
  • The incidence of GVHD increases with unrelated matched donor transplants compared with related matched transplants.
  • With increasing HLA disparity, the incidence and severity of GVHD increases.
  • Sex mismatching and increasing age of both donor and recipient increase the frequency of GVHD.
• Stem-cell source
  • Cryopreservation of marrow before its infusion apparently reduces the rate of GVHD.
  • Use of umbilical-cord blood rather than marrow may also lower the incidence of GVHD.
  • Allogeneic peripheral blood stem cells (PBSC) may increase the incidence of chronic GVHD and prolong follow-up.
• Immune modulation
  • The efficacy of posttransplantational immunosuppressive prophylaxis affects the development of GVHD.
  • Triple therapy with CSP, short-course methotrexate (MTX), and prednisone lowers the incidence of GVHD compared with double therapy with CSA and MTX alone.
• High-dose chemotherapy and radiation therapy
  • After high-dose chemotherapy, levels of circulating cytokines increase; this is known as a cytokine storm. These cytokines are thought to increase the ability of graft immune cells to recognize host antigens.
  • High-dose chemotherapy can also lead to localized tissue damage, exposing cryptic antigens in certain organs (eg, skin, liver, gut).
  • Conditioning regimens including total-body irradiation are associated with an increased incidence and severity of GVHD compared with chemotherapy alone.
  • Administration of nonmyeloablative but immunosuppressive chemotherapy followed by allogeneic transplants (ie, minidose transplantations, or "transplant-light") decreases the original cytokine storm and tissue damage. This strategy lowers the incidence of GVHD and is aimed at maintaining a graft-versus-tumor effect.

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