Laboratory Studies
The workup for graft versus host disease (GVHD) is guided by understanding of the disorder’s characteristics. Acute GVHD usually does not occur until after engraftment. Poor graft function may be a sign of autoimmune cytopenias (eg, thrombocytopenia, anemia, leukopenia) that may be observed with chronic GVHD.
On liver function tests (eg, bilirubin, aspartate aminotransferasealanine [AST], alanine aminotransferase [ALT], alkaline phosphatase, total protein, albumin), elevation of the alkaline phosphatase concentration is an early sign of liver involvement by GVHD. A cholestatic picture is usually observed. Hypoalbuminemia is typically due to GVHD-associated intestinal protein leak and a negative nitrogen balance.
Serum electrolytes and chemistries (eg, potassium, magnesium, bicarbonate levels) may be altered. Massive diarrhea and diminished oral intake can lead to serious electrolyte abnormalities.
Imaging Studies
Hepatic and Doppler sonography can be used to distinguish GVHD from other causes of jaundice or cholestatic liver function abnormalities, such as cholecystitis and veno-occlusive disease of the liver. A barium swallow study can be used to detect esophageal changes of chronic GVHD, such as the following [38] :
-
Webs, typically in the upper esophagus
-
Ringlike narrowing
-
Tapering structures of the middle and upper esophagus
Other Tests
The Schirmer test is used to measure the degree of tear formation by the lacrimal glands, which can be affected in chronic GVHD.
Pulmonary function tests and arterial blood gas analysis can be used to identify obstructive pulmonary disease (eg, obliterative bronchiolitis) in chronic GVHD.
Manometric studies of the esophagus can demonstrate poor acid clearance and motor abnormalities that range from aperistalsis to high-amplitude contractions.
Genetic polymorphisms, such as those seen in the adhesion molecule CD31 when it is mismatched between donor and recipient, are predictive of an increased risk for GVHD. [39] The IL-10-592A allelic polymorphism is a marker for a favorable outcome after transplantation in recipients of hematopoietic stem cells from HLA-identical siblings. [40]
Low numbers of circulating dendritic cells at the time of myeloid engraftment significantly increase the risk of relapse and acute GVHD and are predictive of death after allogeneic HCT. [41]
Researchers have identified and validated a number of blood biomarkers for GVHD that can provide diagnostic and prognostic information; however, most are not yet available for routine clinical care. [42, 43, 44, 45, 46, 47] The Mount Sinai Acute GVHD International Consortium (MAGIC), has validated an algorithm that combines two GI biomarkers (ST2 and REG3α) into a single value, the MAGIC algorithm probability (MAP), that estimates the probability of 6-month nonrelapse mortality for individual patients. The MAP, which reflects GI crypt damage, also predicts response to treatment and maximum GVHD severity and is commercially available. [48]
A preliminary study identified elevated serum prolactin levels as a potential biomarker for chronic GVHD. Patients with hyperprolactinemia were 6.4 times more likely to have active chronic GVHD, in comparison with patients with normal levels of prolactin (P < 0.001). The study included 316 long-term survivors of allogeneic HCT. [49]
Procedures
Findings on skin punch biopsy help establish the diagnosis of GVHD when the patient's clinical features are consistent with the syndrome.
Upper-GI endoscopy and biopsy, when performed in patients with persistent anorexia and vomiting, may reveal a variety of diagnoses, including GVHD, peptic ulceration, or mycotic or viral infection.
On gastroduodenal biopsy, alterations in endothelial cells in the absence of signs of infections may be predictive of the severity of GVHD. These alterations include rupture of capillary basement membranes and extravasated red blood cells.
Flexible sigmoidoscopy or colonoscopy with biopsy of sigmoid or colonic lesions may be helpful. In patients with diarrhea, GVHD may involve the colonic mucosa.
Liver biopsy is rarely performed, usually only in patients with isolated hepatic findings.
Histologic Findings
Characteristic findings on histologic examination of skin (eg, eosinophilic bodies), liver (eg, necrosis of the bile duct), and gut (eg, crypt-cell degeneration) soon after transplantation may be difficult to distinguish from the effects of the conditioning chemoradiotherapy. Serial biopsy and observation help establish the diagnosis and severity of acute GVHD.
On histology, mononuclear-cell infiltration and inflammation of affected epithelium is more subtle in chronic GVHD than in acute GVHD. Dermal fibrosis and inflammation of sweat glands can be used to distinguish chronic GVHD of skin from acute GVHD. Fibrosis of the submucosa and serosa is observed when chronic GVHD involves the GI tract. See the image below.
Acute graft versus host disease (GVHD). Hematoxylin and eosin–stained tissue shows dyskeratosis of individual keratinocytes and patchy vacuolization of the basement membrane. Moderate superficial dermal and perivascular lymphocytic infiltrate are also observed. Courtesy of Melanie K. Kuechler, MD.
-
Autologous graft versus host disease (GVHD) involving the skin of a patient's arm appeared shortly after signs of engraftment appeared. The patient had undergone autologous peripheral blood stem-cell transplantation to treat ovarian cancer. Courtesy of Romeo A. Mandanas, MD, FACP.
-
Acute graft versus host disease (GVHD) involving desquamating skin lesions in a patient after allogeneic bone marrow transplantation for myelodysplasia. Courtesy of Romeo A. Mandanas, MD, FACP.
-
Oral mucosal changes in a patient with chronic graft versus host disease (GVHD). Note the skin discoloration (vitiligo), which can be a result of GVHD. Courtesy of Romeo A. Mandanas, MD, FACP.
-
Interactive factors involved in the pathogenesis of graft versus host disease (GVHD.) Courtesy of Romeo A. Mandanas, MD, FACP.
-
This boy developed stage III skin involvement with acute graft versus host disease (GVHD) despite of receiving prophylaxis with cyclosporin A. The donor was his HLA-matched sister; the sex disparity increased the risk for acute GVHD. Courtesy of Mustafa S. Suterwala, MD.
-
Same boy as in previous image progressed to grade IV graft versus host disease (GVHD). High-dose cyclosporin A and methylprednisolone had been administered intravenously. He later died from chronic pulmonary disease due to chronic GVHD. Courtesy of Mustafa S. Suterwala, MD.
-
Acute graft versus host disease (GVHD). Hematoxylin and eosin–stained tissue shows dyskeratosis of individual keratinocytes and patchy vacuolization of the basement membrane. Moderate superficial dermal and perivascular lymphocytic infiltrate are also observed. Courtesy of Melanie K. Kuechler, MD.
Tables
Procedure |
Groups at High Risk |
Allogeneic HCT |
Patients receiving no GVHD prophylaxis Older patients Recipients of HLA-nonidentical stem cells Recipients of grafts from allosensitized donors Recipients of grafts from unrelated donors |
Solid-organ transplantation (organs containing lymphoid tissue) |
Recipients of small-bowel transplants |
Transfusion of unirradiated blood products |
Neonates and fetuses Patients with congenital immunodeficiency syndromes Patients receiving immunosuppressive chemoradiotherapy Patients receiving directed blood donations from partially HLA-identical, HLA-homologous donors |
*Modified from Ferrara and Deeg, 1991. [15] HLA = Human leukocyte antigen. |
|
Stage |
Skin Findings |
Liver Findings (Bilirubin Level, mg/dL) |
Good Findings |
+ |
Maculopapular rash on < 25% of body surface |
2-3 |
Diarrhea 500-1000 mL/d or persistent nausea |
++ |
Maculopapular rash on 25-50% of body surface |
3-6 |
Diarrhea 1000-1500 mL/d |
+++ |
Generalized erythroderma |
6-15 |
Diarrhea >1500 mL/d |
++++ |
Desquamation and bullae |
>15 |
Pain with or without ileus |
Overall Grade |
Stage |
|||
Skin |
Liver |
Gut |
Functional Impairment |
|
0 (None) |
0 |
0 |
0 |
0 |
I (Mild) |
+ to ++ |
0 |
0 |
0 |
II (Moderate) |
+ to +++ |
+ |
+ |
+ |
III (Severe) |
++ to +++ |
++ to +++ |
++ to +++ |
++ |
IV (Life-threatening) |
++ to ++++ |
++ to ++++ |
++ to ++++ |
+++ |
Classification |
Clinicopathology |
Limited |
Localized skin involvement and/or hepatic dysfunction due to chronic GVHD |
Extensive |
Generalized skin involvement or localized skin involvement and/or hepatic dysfunction due to chronic GVHD, plus 1 of the following: - Liver histology showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis - Involvement of the eye (Schirmer test with < 5-mm wetting) - Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy - Involvement of any other target organ |
Organ or System |
Clinical Findings |
Screening Studies |
Skin |
Dyspigmentation, xerosis, erythema, scleroderma, onychodystrophy, alopecia |
Skin biopsy with a 3-mm punch-biopsy sample from the back and forearm areas |
Mouth |
Lichen planus, xerostomia |
Oral biopsy with sample from lower lip |
Eyes |
Sicca, keratitis |
Schirmer test |
Liver |
Jaundice |
Alkaline phosphatase, aspartate aminotransferase, bilirubin determinations |
Lungs |
Obstructive and/or restrictive lung disease |
Pulmonary function studies, arterial blood gas analysis |
Vagina |
Sicca, atrophy |
Gynecologic evaluation |
GI (nutrition) |
Protein and calorie deficiency |
Weight, measurement of muscle and/or fat stores |
Multiple (clinical performance) |
Contractures, debility |
Determination of Karnofsky score and Lansky play index |
