Graft versus Host Disease

A 34-year-old woman received a small bowel, pancreas and abdominal wall transplant.

Despite the operation being technically very difficult and prolonged, she initially recovered well after the procedure and her transplanted bowel started to work. However, after a few days she started developing respiratory complications eventually requiring re-intubation despite antibiotics. She went on to develop multi-organ dysfunction requiring vasopressor support and renal replacement therapy. Antifungals and co-trimoxazole were added, with no additional benefit noted.

A skin rash started to develop, which raised the suspicion of Graft versus Host Disease (GvHD). A diagnostic test was performed (chimerism of peripheral blood leucocytes), and it confirmed the diagnosis of GvHD.

Doses of immunosuppressants such as tacrolimus, mycophenolate mofetil were increased and steroids were started too.

An experimental therapy of mesenchymal stem cells infusion was also employed, but she continued to deteriorate further and she eventually died after a prolonged admission on ICU.

Graft versus Host Disease – what it is, how to diagnose it, how to treat it

Enrico Sorrentino


Graft versus Host Disease is a pathologic entity that arose with the introduction of bone marrow transplantation as a therapy for patients with haematological malignancies, and it is due to the donor’s T lymphocytes triggering an immune response against the host.  Although less frequently, GvHD can manifest itself after solid organ transplantation, depending on the amount of lymphoid tissue present in the organ. Most of the literature available derives from haematological conditions, but most of it is applicable to solid organ transplantation as well.

The small bowel, in particular, contains very large amounts of lymphoid tissue, and for this reason, small bowel transplant carries a significant risk of developing GvHD. Its risk is in fact estimated at about 5-6%, significantly higher than that seen with after the transplant of other organs (about 1%). Its mortality can however be quite high, up to 50% in some studies.


GvHD was traditionally classified as acute or chronic, depending on whether it arose less or more than 100 days after the transplant. However, this classification has become obsolete as acute GVHD can arise after more than 100 days. More recently an NIH consensus conference classified it in acute or chronic based on the clinical manifestations rather than the time of onset, with chronic GVHD being characterised by a mainly cutaneous involvement. An overlap syndrome is also recognised.

Another important classification is the severity of the disease. Grading is very important as it helps predict survival and consequently, choose the correct treatment.

The original grading system was developed by Glucksberg, and it is still partly in use. It involves grading severity from stage 0 to 4 for each of the organs involved, and then integrating all the scores with a ’clinical performance’ score to derive a global stage.


Skin: Area covered by rash

Liver: bilirubin (mmol/l)

GI: diarrhoea (ml/day)










Generalised erythroderma




Generalised with bullae


>2000 or Severe abdominal pain or ileus

More recently, the IBMTR consensus conference in 1997 eliminated the need of assessing for clinical performance to grade the disease:

Overall grade

























Mortality ranges from 27% in patients with grade I GVHD to 92% in patients with grade IV disease.


The pathophysiology of GVHD is commonly divided in three phases.

In the first phase, either the underlying malignancy or the therapies cause tissue damage, and this leads to the release of cytokines (TNF-α, IL-1) that activate the antigen presenting cells.

In the second phase, transplanted T lymphocytes interact with antigen presenting cells, which become activated and start producing IL-2 and IFN-γ, leading to further activation of the T cells.

In the third phase, there is a complex cascade of several immune mediators, which leads to diffuse immune activation and end organ damage.

Risk factors include splenectomy, older age, use of a female donor for a male recipient.

Presentation and diagnosis

GVHD can virtually target any organ, but the common initial symptoms are the following:

  • Skin: pruritic or painful rash
  • Liver: cholestasis, hepatic failure
  • Bowel: diarrhoea, intestinal bleeding, cramping abdominal pain, ileus

Subsequently, it can go on to involve the lungs as well, with a clinical and histopathological picture that can range from acute lung injury to interstitial pneumonia. The bone marrow can also be affected, causing aplasia.

The diagnosis of GvHD is mainly clinical, being based on the presence of the characteristic cutaneous, gastrointestinal and hepatic symptoms. There is however a rather broad differential diagnosis, as phenomena such as diarrhoea can be due to several other causes in the immunocompromised/oncological patient. In particular, CMV reactivation, chemo and radiotherapy effect and drug reactions can mimic most of the clinical manifestations of GVHD.

In the case of this specific patient, the diagnosis was particularly challenging as the presenting feature was ARDS, which is much more commonly caused by sepsis and diffuse pneumonia in the immunocompromised patient.

Biopsies can be of help, and although there is no pathognomonic lesion, a picture of apoptosis of epithelial cells surrounded by a lymphocytic infiltrate is quite characteristic.

Several biomarkers have been proposed, such as ST2 (a member of the IL-1 receptor family), a panel of different cytokines, or the expression of CD30 on peripheral T cells.

More recently, it has become possible to amplify the DNA of circulating lymphocytes in order to determine if a large proportion of them belongs to the donor (a condition called chimerism). Some degree of chimerism is normally present after solid organ transplant and can be beneficial to graft survival, but when massively present it has been associated with development of GvHD and its early detection can be of help in the diagnosis of GvHD.


There is no common standard for GVHD prophylaxis, but in haematology it is common to use a baseline immunosuppressing agent, such as cyclosporin, to try and prevent it. This of course does not apply anyway to solid organ transplantation, where more intense immunosuppression is mandated anyway to prevent rejection of the graft.

Some authors advocate reducing immunosuppression in the early stages of GvHD in the hope of tipping the balance in favour of the host’s immune system, but this is not reflected in current guidelines and most clinicians prefer increasing immunosuppression instead.

The therapy depends on the grading. For grade I disease, treatment is normally with topical steroids only. Grade 2 disease requires starting oral steroids, and for grade 3 and 4 intravenous methylprednisolone is required.

If there is no response, second line therapies include traditional immunosuppressants such as mycophenolate mofetil and sirolimus, as well as monoclonal antibodies against the IL-2 receptor. Good results have also been achieved with etanercept, a soluble TNF-α receptor inhibitor, which significantly increases the chances of as complete response when compared to steroids alone. Another intriguing second line treatment is extracorporeal photopheresis, where the patient’s leukocytes are isolated, treated with psoralene, irradiated with UVA and then returned to the patient. This induces apoptosis of the leukocytes and their phagocytosis. Positive results have been so far mostly anecdotal, but the therapy has a good safety profile and lacks many of the side effects of traditional immunosuppressive therapy, such as nephrotoxicity and bone marrow suppression.

Third line therapies include methotrexate, pentostatin (an adenosine deaminase inhibitor), alemtuzumab (anti CD52 inhibitor) and mesenchymal stem cells. Mesenchymal stem cells are a promising new third line therapy whose mechanism of action is still unclear, but they have shown remarkable efficacy in early phase trials. However, patients with pulmonary involvement seem to be less responsive to it.

Discussion: GvHD in the Intensive Care Unit – a difficult guest to handle

This clinical case presented two major challenges: 1) a difficult timely diagnosis 2) a difficult therapeutic decision.

While GvHD in the context of solid organ transplantation is a well-recognised entity, the symptoms and signs can be very aspecific and conditions such as bacterial sepsis and opportunistic infections such as Cytomegalovirus and Pneumocystis jirovecii can mimic it. Also, in this case the rash appeared quite late in the course of the disease, and the organs more traditionally targeted were, at least initially, spared.

Matters are complicated further by the fact that there is not one gold standard test to confirm the diagnosis: analysis of chimerism is a promising technique, but needs to be interpreted in the context of the clinical picture, as some degree of chimerism is expected and even beneficial, as discussed previously.

With such a complicated picture, early diagnosis can only be the result of a high index of suspicion. Routinely measuring the percentage of chimeric lymphocytes at regular intervals after the transplant can be a promising approach, but further studies will be necessary to clarify whether its diagnostic yield is high enough to justify its widespread introduction into clinical practice.

Once the diagnosis is made (or suspected), the clinicians are presented with a consequence-laden decision: should they decrease immunosuppression, or increase it? In the first case, they rely on ability of the host immune system to get rid of the graft’s lymphocytes and stop the GvHD. This approach has the merit of reducing the risk of opportunistic infections, but increases the risk of graft rejection and there is generally less experience with it. If they choose instead to increase immunosuppression, both the graft’s and the host’s immune responses will be blunted. While this is the safest approach for graft survival, it carries an increased risk of serious infection, and can have potentially lethal consequences if the diagnosis of GvHD turns out to be incorrect.

A final answer as to which course of action is better does not exist at present, as randomised controlled trials are lacking due to the rarity of the condition. For this reason, clinical experience and sound clinical judgement are irreplaceable in order to cater therapeutic decisions to the specific patient.

Lesson learned

GvHD can, although rarely, present after solid organ transplantation and can be difficult to diagnose. The diagnosis requires a high index of suspicion and can be supported by specialised tests. Formulating a timely correct diagnosis is of paramount importance because if left untreated, the disease is often fatal; also, the treatment itself can increase the risk of serious infections. For these reasons, in-depth knowledge of the condition and early involvement of a multidisciplinary team are necessary to address it appropriately.


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Rogulj et al. Acute Graft versus Host disease in orthotopic liver transplasntation. Journal of Hematology & Oncology 2012, 5:50


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