Acute Graft-Versus-Host Disease (GVHD)
Diagnosis & Staging

Updated: November 2010

Acute graft versus host disease (GVHD) is the most frequent complication after allogeneic haematopoietic stem cell transplantation (SCT). The incidence of acute GVHD is related to the degree of mismatch between HLA proteins and ranges from 35-45% in recipients of fully matched sibling donors to 80% in recipients of unrelated donor grafts. Other major risk factors for the development of GVHD are older patient (and possibly older donor) age, greater intensity of the conditioning regimen, and donor/recipient sex mismatch, especially with allosensitised female donors. In non-myeloablative transplants, acute GVHD is more likely to occur if donor T-cell chimerism is established rapidly after transplantation. With conventional conditioning regimens, the time of onset of GVHD is typically 2-3 weeks after SCT. With reduced intensity conditioning regimens, acute GVHD may occur later (see below).

Classification

Historically, acute GVHD was distinguished from chronic GVHD by the time of onset (before or more than 100 days after HSCT). In the era of reduced-intensity conditioning regimens and donor lymphocyte infusions, this distinction is no longer clear-cut. Patients may present with a clinical picture of acute GVHD several months after SCT, while GVHD with characteristics of the ‘chronic’ form may occur within 60 days after transplantation. The NIH Consensus Conference recognises 2 categories of GVHD as follows:

1. Acute GVHD (absence of features of chronic), comprising

• classic acute GVHD (before day 100)
• persistent, recurrent, or late acute GVHD (after day 100, often upon withdrawal of immunosuppression).

2. Chronic GVHD, comprising

• classic chronic GVHD (no signs of acute GVHD), and
• an overlap syndrome, in which features of acute and chronic are present

Clinical Features

Skin is most commonly affected and is usually the first organ involved, often coinciding with engraftment of donor cells. The characteristic maculopapular rash is pruritic and can spread throughout the body, sparing the scalp. In severe cases the skin maybe painful, blister and ulcerate.

Gastrointestinal tract involvement of acute GVHD usually presents as diarrhoea but may also include vomiting, anorexia and/or abdominal pain. The diarrhoea is secretory and often voluminous. Bleeding occurs as a result of mucosal ulceration and carries a poor prognosis. Involvement may be patchy leading to a normal appearance on endoscopy.

Liver disease may be difficult to distinguish from other causes of liver dysfunction following SCT such as veno-occlusive disease, drug toxicity, viral infection or sepsis. The liver is rarely biopsied because of thrombocytopenia, therefore the diagnosis is made clinically.

Clinical Staging of Acute GVHD According to Organ Involvement

Stage	Skin	Liver*	Intestinal Tract*
+1	Maculopapular rash <25% of body surface	Bilirubin 35-50 μmol/l	Diarrhoea 500-1000 ml/day or nausea (± vomiting)**
+2	Maculopapular rash 25% -50% of body surface	Bilirubin 51-100 μmol/l	Diarrhoea 1000-1500 ml/day
+3	Generalised erythroderma	Bilirubin 101-255 μmol/l	Diarrhoea >1500 ml/day or cramps or blood or ileus
+4	Generalised erythroderma with bullous formation and desquamation	Bilirubin >255 μmol/l	Simultaneous presence of any two of the four criteria for stage 3 severity

* If patient has documented GVHD of the liver or gut, and documented alternative cause of hyperbilirubinaemia/diarrhoea (i.e. veno-occlusive disease or mucositis, CMV enteritis or C difficile infection) then downstage GVHD by 1 stage.

** with histological evidence

Functional Grading of Acute GVHD (Glucksberg)

Grade	Skin	Liver	Gut
0 (none)	0	0	0
I (mild)	+1 to +2	0	0
II (moderate)	0 to +3#, or	+1, and/or	+1
III (severe)*	---	+2 to +3 and/or	+2 to +4
IV (life-threatening)**	+4	+4	---

^# Stage 3 alone is considered overall grade II

* 25% long-term survival; ** 5% survival

** 5% long-term survival

The information contained in these guidelines is a statement of consensus of Leukemia/BMT Program of BC professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. Use of these guidelines and documents is at your own risk and is subject to the Leukemia/BMT Program of BC’s terms of use available at Terms of Use.