History and exam

Key diagnostic factors

common

presence of risk factors

Factors that may increase the likelihood of acute graft-versus host disease (GVHD) include: human leukocyte antigen mismatch, older age of recipient or donor, donor and recipient gender disparity (particularly a female donor with a male recipient), parous female donor, type and stage of the underlying malignant condition, transplant conditioning regimen intensity, absent or suboptimal GVHD prophylaxis.

Factors that may increase the likelihood of chronic GVHD include: prior acute GVHD, older age of recipient or donor, female donor with male recipient, parous female donor, use of peripheral blood stem cells, donor lymphocyte infusion.

allogeneic haematopoietic cell transplantation (HCT) recipient

Graft-versus-host disease (GVHD) occurs in the setting of allogeneic haematopoietic cell transplant.

Distinguishing between acute and chronic GVHD depends on characteristic clinical manifestations and symptoms, and timing post-transplant.[1]

new-onset painful mouth sores

The specific presence of lichen planus-like lesions in the mouth is a diagnostic feature of chronic graft-versus-host disease.[1]

hyperpigmented skin lesions

The specific presence of poikiloderma and other skin features that are lichen planus-like, sclerotic, morphea-like, or lichen sclerosus-like are diagnostic features of chronic graft-versus-host disease.[1]

Generally, skin and mouth are the most commonly involved sites.

diffuse maculopapular rash

Maculopapular rash is one of the presenting clinical signs of acute skin graft-versus-host disease.

In severe cases (stage 4), the skin may blister and ulcerate.​[Figure caption and citation for the preceding image starts]: Acute graft-versus-host disease (GVHD) of the skin (grade I)Courtesy of Dr John Levine, Professor, Blood and Marrow Transplantation Program, University of Michigan; used with permission [Citation ends].com.bmj.content.model.Caption@4bb7edd4

genital signs and symptoms

Genital manifestations of chronic graft-versus-host disease include: lichenoid features, vaginal scarring or clitoral/labial agglutination, phimosis or urethral/meatus scarring or stenosis.[1]

nausea, vomiting, abdominal pain, profuse diarrhoea, and anorexia

Classic gastrointestinal (GI) symptoms suggestive of acute GI graft-versus-host disease.

Other diagnostic factors

common

joint stiffness or tightness

​Joint stiffness and contractures secondary to fasciitis or sclerosis are diagnostic features of chronic graft-versus-host disease.[1]

day +21 to day +25 after HCT

Median onset of acute graft-versus-host disease ranges between 21 and 25 days after transplantation.

dry, gritty, and painful eyes

Manifestation of chronic graft-versus-host disease (GVHD).

Schirmer test can measure the degree of tear formation by the lacrimal glands. The test may be useful to monitor chronic GVHD and can be performed routinely in the office.

uncommon

jaundice

Jaundice is a sign of liver graft-versus-host disease (GVHD).

Jaundice can also be commonly seen in other causes of liver dysfunction following haematopoietic cell transplantation (HCT), such as veno-occlusive disease/sinusoidal obstructive syndrome, drug toxicity, viral infection, sepsis, total parenteral nutrition cholestasis, or iron overload.

hepatomegaly

May be noted in some patients with liver graft-versus-host disease.

scleroderma

Sclerodermatous features are considered a high-risk feature in chronic graft-versus-host disease.

May involve the skin, muscles, fascia, and joints.[1]

Risk factors

strong

HLA mismatch and unrelated donor

Human leukocyte antigen (HLA) mismatch is the greatest risk factor for acute GVHD. The greater the degree of HLA mismatch, regardless of the type, the higher the likelihood of developing acute GVHD.[31][48][49][50]

Incompatibility for HLA-A and HLA-C alleles between the donor and recipient of haematopoietic stem cells have been shown to be strong risk factors for the development of severe acute GVHD.[50][51]

Analysis of US National Marrow Donor Program (NMDP) data from 3857 allogeneic haematopoietic cell transplants between 1988 and 2003 found that high-resolution DNA matching for HLA-A, -B, -C, and -DRB1 (8/8 match) was the minimum level of matching associated with the highest survival. A single mismatch at HLA-A, -B, -C or -DRB1 (7/8 match) was associated with higher mortality.[52]

The risk of developing acute GVHD following an unrelated donor transplant ranges from 60% to 80% depending on the human leukocyte antigen (HLA) mismatch.[53][54]

The risk of developing chronic GVHD is 60% to 70% in recipients of mismatched haematopoietic cells or haematopoietic cells from an unrelated donor.[21]

The US National Marrow Donor Program and the Center for International Blood and Marrow Transplant provide matching guidelines and typing strategies for unrelated adult donor and cord blood selection.[55]

prior acute GVHD

Prior acute GVHD has been consistently reported as a risk factor for chronic GVHD.[8][46]​ 

recipient or donor in older age group

Older age of the recipient or of the donor have been shown to be associated with increased risk for GVHD.[24][29][31]​​[36]

female donor with male recipient

Studies have shown a female donor paired with male recipient to be a significant risk factor for GVHD.[32][33][34][39]

parous female donor

A parous female donor has been shown to be a significant risk factor for GVHD.[23][32][40]

type and stage of underlying malignant condition

Patients with chronic myeloid leukaemia have a greater relative risk for developing grade II to IV acute GVHD compared with patients with acute myeloid leukaemia or acute lymphoblastic leukaemia patients.[24]

Advanced malignant disease has been associated with increased risk for developing acute GVHD.[23]

high-intensity conditioning radiation regimen

High doses of radiation are associated with increased GVHD severity.[35][24]

peripheral blood stem cell transplant

Significantly higher incidence of chronic GVHD has been reported with peripheral blood stem cell transplantation than with bone marrow transplantation (53% vs. 41%) in one randomised controlled trial of patients undergoing allogeneic transplant from unrelated donors.[42]

donor lymphocyte infusion (DLI)

Chronic GVHD attributable to donor lymphocyte infusion is common.[7][45]

Risk-adapted donor lymphocyte infusion may reduce risk for GVHD.[56][57]​​ 

absent or suboptimal GVHD prophylaxis

The risk of developing GVHD is significant in patients who do not receive any acute GVHD prophylaxis.[58] Reduction of methotrexate and ciclosporin administration, primarily due to renal or hepatic dysfunction, is also associated with increased risk for acute GVHD.[23]

weak

white or black race

White and black people have been found to have an increased risk for acute GVHD compared with those of Asian or Hispanic ethnicity, although overall survival rates may be similar between ethnic groups.[24][37]

The association of ethnicity with acute GVHD is controversial.

cytomegalovirus (CMV) seropositive

A significantly increased risk of grade II to IV acute GVHD in CMV-negative patients and a higher treatment-related mortality in CMV-positive recipients has been reported.[24][59]

splenectomy

Splenectomy has been reported to be a risk factor for GVHD.[60]

Evidence is equivocal.[41][60]

low performance status score

Poor performance status has been found to correlate with increased risk for acute GVHD.[24]

low socio-economic status

Low socio-economic status has been associated with increased rates of acute and chronic GVHD, increased transplant-related complications within the first 100 days post haematopoietic cell transplant, and decreased overall survival.[38]

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