The number of allogeneic bone marrow and stem cell transplants is increasing worldwide. Yet as our knowledge of immunosuppression and transplantation increases, graft-vs-host disease (GVHD) is still a prominent cause of death and has important implications on immunosuppressive medications.¹

There are three requirements for GVHD, set out by Billingham in 1966:¹

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

Who is at risk?

Immunosuppressed patients who receive white blood cells from another person.¹

Pathophysiology¹

The T cells from the donor respond to proteins on host cells, the most important being the human leukocyte antigens (HLAs), which in one way or another are essentially expressed on all nucleated cells. There are two major classes of HLA important in graft-vs-host disease (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, e.g. B cells, dendritic cells and monocytes.

Class II protein expression can be induced in certain states, e.g. 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 factors

• Risk most probably relates to polymorphisms in cytokines that are involved in graft-vs-host disease (GVHD), e.g. tumour necrosis factor-α and interferon-γ.^1,2
• Mismatched donors.
• Unrelated donors.
• Having a donor of a different sex (possible risk).
• Reduced-intensity conditioning (i.e. 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.¹
• Older age and history of acute GVHD are risk factors for developing chronic GVHD.¹

Clinical syndromes

There are four broad clinical groups: acute graft-vs-host disease (GVHD) (within 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

Acute GVHD, late-onset acute GVHD and overlap syndrome¹

These all represent acute GVHD but the timing of acute and late-onset acute varies. 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.

Presentation

• Skin (>80%) - usually the first organ
  • Maculopapular rash - pruritic; involves whole body with scalp sparing; may lead to blistering and ulceration.
• Gastrointestinal (~50%)
  • Diarrhoea is most common; but 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.

Chronic GVHD¹

This is an important entity and a major cause of late non-relapse death after hematopoietic cell transplantation.

Presentation

Three patterns are recognised:

1. Progressive - active or acute GVHD becoming prolonged and merging into the chronic form.
2. Quiescent - acute GVHD resolves completely and then is followed by chronic GVHD.
3. De novo.

• Skin and nails - dyspigmentation, new alopecia, lichen planus-like eruptions, poikiloderma or sclerotic features, nail dystrophy/loss
• Mouth - xerostomia, ulcers, sclerosis limiting mouth opening, lichen-type changes on mucosa
• Eyes - dry eyes, Sjögren's syndrome, cicatrical conjunctivitis
• Muscles and joints - joint stiffness, fasciitis and myositis
• Genitalia - mostly in women; sclerosis of vagina and ulcerations
• Gastrointestinal - anorexia, weight loss, oesophageal web or strictures
• Liver - jaundice and raised transaminases
• Lungs - restrictive or obstructive defects on lung function tets, bronchiolitis obliterans, effusions
• Heart - pericarditis
• Bone marrow - thrombocytopenia, anaemia and neutropenia
• Kidneys - nephrotic syndrome

Investigations

These should be directed according to the symptom/sign at presentation. For example:

• Blood tests in the presence of liver involvement - including hepatitic screen if appropriate.
• Abdominal X-ray (AXR)- in acute graft-vs-host disease (GVHD) there can be luminal dilatation and air fluid levels indicating an ileus.
• CT scan of the abdomen - small bowel wall thickening described as "ribbon sign".

Differential diagnosis

Diagnosis will depend on biopsy of involved tissue but other tests may be warranted and you should be guided by the mode of presentation - for example:

• Liver involvement - the diagnosis of liver disease being caused by graft-vs-host disease (GVHD) is one of exclusion. The differential includes: veno-occlusive disease - adverse medication effects toxicity and sepsis.
• Drug toxicity
• Viral infections

Management

Steroids and calcineurin inhibitors form a large part of therapy.^1,3 Calcineurin is an enzyme critical in T-cell activation, and is the target of inhibitors such as tacrolimus and ciclosporin.

• Prevention of graft-vs-host disease (GVHD) - as there is a possibility that acute GVHD can lead to chronic GVHD, treatment is aimed at preventing acute GVHD. Ciclosporin alone is commonly used prior to the transplant and, if patients are unable to tolerate this, then mycophenolate mofetil in combination with tacrolimus can be used. Monoclonal antibodies towards T cells can also be used prior to the transplant, e.g. alemtuzumab or antithymocytic globulin.¹ Although many of these prevent acute GVHD they are also associated with higher rates of graft failure, relapse of malignancy and enhanced infection rates.
• Acute and chronic GVHD - therapy centres around the use of steroids added to existing immunosuppressives which are usually calcineurin inhibitors These are usually combined with methotrexate or mycophenolate mofetil (the latter being more favourable in some centres).¹ Topical steroids can be used if there is only skin involvement but high-dose systemic steroids are needed for more widespread involvement. If the illness is only limited to the skin then psoralen + UVA (PUVA) or extracorporeal photophoresis, 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, can be trialled.^1,3 Response is reduced in severe acute GVHD.¹

Supportive care

The immunosuppressive medications that are necessary in these patients renders them susceptible to a number of other illnesses. Thus, infectious disease prophylaxis and prophylaxis of noninfectious diseases is needed, e.g. fluconazole to prevent fungal infections and possibly aciclovir prophylaxis in certain individuals.¹

GVHD patients also have deficiencies of certain subclasses of IgG immunoglobulins and they should receive routine vaccinations (pneumococcal and haemophilus) along with prophylactic penicillin (if not penicillin-allergic).¹

Along similar lines these patients may not be able to mount a full immune response and 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 for infection. Also adverse effects relating to the prescribed medications should be looked for and corrected promptly.

Other therapies in the research phase

• B-cell depletion - there is evidence suggesting that B cells are also important in the pathogenesis of graft-vs-host disease (GVHD). This has been supported by a good response to B-cell depletion with rituximab preventing GVHD. Further work in this area is continuing.⁴
• High-dose cyclophosphamide - this has been used successfully for prophylaxis but larger trials are needed.⁵
• Sirolimus - this drug is similar to tacrolimus and is undergoing clinical trial testing in combination with tacrolimus.¹
• Etanercept - this leads to blockade of tumour necrosis factor-α, and clinical trials suggest up to 80% complete responses in gastrointestinal tract and skin involvement.

Prognosis

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 falls to 20-35% with second-line agents.⁶ This may improve with the use of mycophenolate mofetil, etanercept and alemtuzumab.⁶

Transfusion-associated graft-vs-host disease

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: immunocompromised, e.g. 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 irradiated blood which protects where radiation acts to inactivate the T cells. Transfusion-associated GVHD has also been described following the transfusion of platelets and granulocytes.

Document references

1. Ferrara JL, Levine JE, Reddy P, et al; Graft-versus-host disease. Lancet. 2009 May 2;373(9674):1550-61. Epub 2009 Mar 11. [abstract]
2. Socie G, Blazar BR; Acute graft-versus-host disease: from the bench to the bedside. Blood. 2009 Nov 12;114(20):4327-36. Epub 2009 Aug 27. [abstract]
3. Penas PF, Zaman S; Many faces of graft-versus-host disease. Australas J Dermatol. 2010 Feb 1;51(1):1-10. [abstract]
4. Alousi AM, Uberti J, Ratanatharathorn V; The role of B cell depleting therapy in graft versus host disease after Leuk Lymphoma. 2010 Feb 8. [abstract]
5. Luznik L, Bolanos-Meade J, Zahurak M, et al; High-dose cyclophosphamide as single agent, short-course prophylaxis of Blood. 2010 Feb 2. [abstract]
6. Landfried K, Wolff D, Holler E; Pathophysiology and management of graft-versus-host disease in the era of Curr Opin Oncol. 2009 Jun;21 Suppl 1:S39-41. [abstract]

Internet and further reading

• e Medicine; Graft Versus Host Disease; Aug 2008.

Acknowledgements