History and exam

Key diagnostic factors

common

allogeneic hematopoietic cell transplantation (HCT) recipient

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

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

human leukocyte antigen (HLA) mismatch and unrelated donor

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

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

parous female donor

A significant risk factor for graft versus host disease.[23][32][40]​​​​​​

female donor with male recipient

A significant risk factor for graft versus host disease.[32][33][34][39]​

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 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@2df3b9cb

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 diarrhea, 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.

cyclophosphamide + total body irradiation (Cy/TBI) conditioning regimen

Cy/TBI conditioning chemotherapy has been shown to be a significant risk factor for development of grade II to IV acute GVHD.[24]

peripheral blood stem cell transplant

Peripheral blood stem cell transplants have been associated with increased risk for the development of chronic GVHD.[42]

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 hematopoietic 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 hematopoietic 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 hematopoietic 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 hematopoietic cells or hematopoietic 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 leukemia have a greater relative risk for developing grade II to IV acute GVHD compared with patients with acute myeloid leukemia or acute lymphoblastic leukemia.[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 randomized 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 cyclosporine 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 socioeconomic status

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

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