Graft-vs-Host Disease

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The number of allogeneic bone marrow and stem cell transplants is increasing worldwide. Graft-versus-host disease (GvHD) is a serious complication of this type of transplant. The incidence of acute GvHD varies widely, ranging from 10-80% depending on risk factors.[1]GvHD is a prominent cause of death in bone marrow and stem cell recipients and has important implications on immunosuppressive medications.[2]

There are three requirements for GvHD, set out by Billingham in 1966:[2]

  • Graft contains immunologically functioning cells (discovered later to be T cells).
  • The recipient expresses antigens that are not found in the donor.
  • The recipient is unable to mount an immune response sufficient to eliminate the transplanted cells.

Immunosuppressed patients who receive white blood cells from another person.[2]

The T cells from the donor respond to proteins on host cells, the most important being the human leukocyte antigens (HLAs). There are two major classes of HLA important in GvHD:

  • Class I HLA proteins - (A, B and C) expressed on almost all nucleated cells.
  • Class II HLA proteins - (DR, DQ and DP) mainly found on haematopoietic cells - eg, B cells, dendritic cells and monocytes. Class II protein expression can be induced in certain states - eg, inflammation.

Acute GvHD relates to the degree of HLA mismatch; thus, it is usual to try to match donors and recipients for these proteins, especially HLA-A, -B, -C and DRB1. It is important to appreciate that some patients can tolerate certain levels of mismatch and that other factors are also involved, as 40% of patients who receive an HLA-matched transplant will still develop acute GvHD, probably resulting from other genetic differences.

  • Risk most probably relates to polymorphisms in cytokines that are involved in GvHD - eg, tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ).[2, 3]
  • Mismatched donors.
  • Unrelated donors.
  • Having a donor of a different sex (possible risk).
  • Reduced-intensity conditioning (ie using less chemotherapy and radiation to prevent graft rejection and to allow a donor transplant to become established) is a risk factor for developing both late-onset acute GvHD and overlap syndrome.[2]
  • Older age and history of acute GvHD are risk factors for developing chronic GvHD.[2]

Historically, GvHD was divided into four broad clinical groups depending on the time of onset of clinical features. These were acute (within the first 100 days following transplant), late-onset acute (acute features presenting after 100 days), overlap syndrome (features of both acute and chronic GvHD) and chronic GvHD (classically after 100 days).[1, 2] However, it is becoming increasingly apparent that chronic GvHD can also occur early on; thus, classification is now based on clinical presentation rather than time of onset.

This has led to the following classifications:

  • Acute GvHD - usually presents with skin and/or liver and or gut involvement.
  • Chronic GvHD - classical and overlap syndrome.

The diagnosis is clinical and usually one of exclusion; however, biopsy of affected tissues may be helpful in unclear cases.[1]

Acute GvHD

Development of acute GvHD is directly related to the level of HLA mismatch and it represents an exaggerated but normal inflammatory response to donor lymphocytes.


  • Skin (>80%) - usually the first organ:
    • Maculopapular rash - pruritic; may start on the palms and soles but can also involve the whole body with scalp sparing; may lead to blistering and ulceration. In severe cases, a picture resembling toxic-epidermal necrolysis can occur.
  • Gastrointestinal (~50%):
    • Diarrhoea is most common; however, vomiting, abdominal pain and anorexia may occur. Mucosal ulceration, which can lead to massive bleeding is associated with a poor prognosis.
  • Liver (~50%):
    • Cholestasis with hyperbilirubinaemia.

Acute GvHD may also present as culture-negative fever.

Grading for acute GvHD is also recommended, as it relates to prognosis. Various systems are available but the modified Seattle Glucksberg criteria are recommended.[1] These divide acute GvHD into four stages based on the extent of involvement of the skin, liver and gastrointestinal tract (GIT):[4]

  • Stage I (skin rash over <25% of body, bilirubin 26-60 μmol/L, gut fluid loss 500-1000 ml/day).
  • Stage II (25-50% of skin involved; bilirubin 61-137 μmol/L, gut fluid loss 1000-1500 ml/day).
  • Stage III (>50% of skin involved or erythroderma; bilirubin 138-257 μmol/L, gut fluid loss >1500 ml/day).
  • Stage IV (bullae desquamation of skin; bilirubin >257 μmol/L, gut fluid loss >2500 ml/day or ileus).

Chronic GvHD[5]

This is an important entity and a major cause of late non-relapse death after haematopoietic cell transplantation.[5]

Two subcategories are recognised:

  • Classic - clinical features of chronic GvHD are seen.
  • Overlap - both features of acute and chronic GvHD are recognised.

Clinical features[5]
Chronic GvHD has a mixed picture; the first signs are commonly in the buccal mucosa. Guidelines highlight diagnostic features which, if present, confirm the diagnosis and distinctive features which may suggest chronic GvHD but warrant further investigations - eg, biopsy. Chronic GvHD can result in multiple clinical features involving multiple sites - eg, eyes, GIT, liver, lungs, heart, bone marrow, and kidneys.

The British Committee for Standards in Haematology (BCSH) and the British Society for Blood and Bone Marrow Transplantation (BSBMT) proposed diagnostic and distinctive features of chronic GvHD to help make the diagnosis:

  • Diagnostic features - for example, skin poikiloderma and lichen planus, lichen-type changes on mucous membranes (such as the mouth or genitals), fasciitis and joint contractures.
  • Distinctive features - for example, dyspigmentation, new alopecia, nail dystrophy, xerostomia, mucoceles, ulceration of the mouth, keratoconjunctivitis sicca and myositis.

Classification of chronic GvHD[5]

It is recommended that all patients be scored initially at three months post-transplant and every three months thereafter if they are diagnosed with GvHD. There are two aspects to the scoring, resulting in a classification of mild, moderate and severe chronic GvHD:

  • The effect of involvement of any organ or site on daily living is scored: 0 - no involvement, 1 - mild involvement but no impairment of daily living, 2 - moderate involvement with significant impairment of daily living and 3 - severe impairment with major disability.
  • Based on the above:
    • Mild chronic GvHD - involvement of one or two organs (but not lung involvement) with a score of 1.
    • Moderate chronic GvHD - involvement of three organs with a score of 1 or one organ with a a score of 2 or pulmonary GvHD with a score of 1.
    • Severe chronic GvHD - major disability in any region or site or pulmonary involvement with a score of 2 or 3.

These should be directed according to the presentation - for example:

  • Blood tests in the presence of liver involvement - including hepatitis screen if appropriate.
  • Abdominal X-ray (AXR) - in acute GvHD there can be luminal dilatation and air fluid levels indicating an ileus.
  • CT scan of the abdomen - small bowel wall thickening described as the 'ribbon sign'.
  • Endoscopy and/or colonoscopy in those with GIT disease.

The differential diagnosis depends on the presenting features and includes:

  • Skin disease - drug reactions, viral exanthems, engraftment syndrome, adverse effects from chemotherapy or radiation.
  • GIT disease - drug reactions, viral or bacterial infections of the gut.
  • Liver disease - veno-occlusive disease, drug toxicity, viral infections and sepsis.

The diagnosis is clinical and management should not be delayed for a biopsy. Patients should be managed by specialist transplant physicians and usually a multidisciplinary approach is undertaken. Organ-specific illnesses may warrant additional specialist expertise - for example, dermatologists, hepatologists, gastroenterologists, etc.

GvHD does have the benfit of anti-tumour activity and thus treatment has to achieve a fine balance so that the level of suppression is not so great that the underlying disease increases.[6]

Randomised clinical trials in the treatment of GvHD are lacking but steroids and calcineurin inhibitors form a large part of therapy.[2, 7] Calcineurin is an enzyme critical in T-cell activation and is the target of inhibitors such as tacrolimus and ciclosporin which are used as prophylactic agents.

Acute GvHD[1]

  • Stage I: topical steroids for skin involvement (if resistant, give topical tacrolimus); optimise prophylaxis with calcineurin inhibitors (usually ciclosporin); consider antihistamines and analgesia for symptom relief.
  • Stage II-IV: intravenous (IV) methylprednisolone (higher dose in grades III-IV than II); optimise prophylaxis with calcineurin inhibitors; consider non-absorbable steroids (eg, budesonide for intestinal involvement) to reduce the dose of systemic steroids. If patients fail to respond then second-line agents may be necessary - such as extracorporeal photopheresis (where the patient's white blood cells are collected and treated with 8-methoxypsoralen (a DNA intercalating agent which leads to cell apoptosis) and then returned to the patient), anti-TNF-α antibodies, mammalian target of rapamycin (mTOR) inhibitors, mycophenolate mofetil, or interleukin-2 receptor antibodies. Third-line agents include alemtuzumab, pentostatin, mesenchymal stem cells and methotrexate.

Antithymocyte globulin and regulatory T cells are also used in some centres and the current BCSH guidelines acknowledge their use at the discretion of the specialist physician; however, more evidence is required before they can be formally recommended.[1]

Chronic GvHD[5]

  • Supportive therapy - may be required at all stages - eg, antihistamines and analgesia.
  • Mild disease - topical therapy alone may be suitable.
  • Moderate-to-severe disease - systemic therapy with corticosteroids is first-line. Long duration of therapy is necessary and doses may need to be tapered over many months.
  • Prophylaxis - this is achieved with calcineurin inhibitors, of which ciclosporin is first-line. They can be started early and may allow the dose of steroids to be reduced.
  • Second-line agents - various agents have been used and the current guidance is to use the following:
    • Extracorporeal photopheresis (ECP) - for refractory skin, mouth and liver disease.
    • Mammalian target of rapamycin (mTOR) inhibitors - eg, sirolimus.
    • Rituximab - for refractory skin and musculoskeletal disease.
    • Pentostatin - for refractory chronic GvHD.
    • Imantinib - for refractory sclerodermoid skin or lung disease.
  • Several other therapies are currently in the research phase and include antithymocyte globulin, alemtuzumab and mesenchymal stem cells.
  • If one second-line agent fails then another should be tried before moving on to third-line agents
  • Third-line agents - methotrexate, pulsed corticosteroids and mycophenolate mofetil.
  • Organ-specific care may also be needed and examples include the following:[8]
    • Skin disease - all patients on immunosuppressive agents are at risk of skin malignancy so need yearly dermatological review; refer any new lesions to be seen within two weeks by dermatologists; physiotherapy may be required for sclerodermoid disease.
    • GIT disease - GIT presentation can have a wide differential diagnosis so endoscopy and/or colonoscopy with biopsies are required; dietician involvement is also recommended.
    • Eye disease - prolonged systemic steroids may lead to cataracts and patients should be advised to seek help if vision deteriorates; artificial tears and topical steroids may be helpful.
    • Infections - prophylaxis should be considered in all those on immunosuppressives - eg, against Pneumocystis jirovecii, fungi and Streptococcus pneumoniae.
    • Vaccines - avoid all live vaccines; vaccinate against pneumococcus, influenza and Haemophilus influenzae.
    • Long-term steroid risks - check blood pressure and glucose regularly and ensure adequate gastro-protection.

Also be vigilant about infections, as these patients are unable to mount a full immune response and so may not present with the typical signs and symptoms associated with infectious disease. A high index of suspicion is warranted and any potential sites of infection should be checked regularly, with a low threshold to investigate and treat.

Attaining an early response with first-line therapy is crucial to a good outcome. The quoted figures of long-term survival with successful first-line therapy are in the order of 60% which fall to 20-35% with second-line agents. This may improve with the use of mycophenolate mofetil, etanercept and alemtuzumab.

This is one of the most serious blood transfusion-associated complications with mortality rates reaching 90%. Again it relates to the presence of donor T lymphocytes in the transfused blood. It is most susceptible in the following groups of patients: the immunocompromised (eg, those receiving therapy for solid or haematological malignancies) and premature babies. Presentation can be delayed until two weeks following transfusion and includes fever, skin rashes, diarrhoea and hepatitis. Prevention is best and involves irradiating blood to inactivate the T cells. Transfusion-associated GvHD has also been described following the transfusion of platelets and granulocytes.

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Further reading and references

  1. Diagnosis and management of acute graft-versus-host disease, British Committee for Standards in Haematology and the British Society for Blood and Marrow Transplantation (2012)

  2. Ferrara JL, Levine JE, Reddy P, et al; Graft-versus-host disease. Lancet. 2009 May 2373(9674):1550-61. Epub 2009 Mar 11.

  3. Socie G, Blazar BR; Acute graft-versus-host disease: from the bench to the bedside. Blood. 2009 Nov 12114(20):4327-36. Epub 2009 Aug 27.

  4. Hashmi K, Khan B, Ahmed P, et al; Graft versus host disease in allogeneic stem cell transplantation--3 1/2 years J Pak Med Assoc. 2005 Oct55(10):423-7.

  5. Diagnosis and management of chronic graft-versus-host disease, British Committee for Standards in Haematology and the British Society for Blood and Marrow Transplantation (2012)

  6. Jamil MO, Mineishi S; State-of-the-art acute and chronic GVHD treatment. Int J Hematol. 2015 May101(5):452-66. doi: 10.1007/s12185-015-1785-1. Epub 2015 Apr 12.

  7. Penas PF, Zaman S; Many faces of graft-versus-host disease. Australas J Dermatol. 2010 Feb 151(1):1-10.

  8. Organ-specific Management and Supportive Care in Chronic Graft-versus-Host Disease, British Committee for Standards in Haematology and the British Society for Blood and Marrow Transplantation (2012)

  9. Landfried K, Wolff D, Holler E; Pathophysiology and management of graft-versus-host disease in the era of Curr Opin Oncol. 2009 Jun21 Suppl 1:S39-41.