Graft Versus Host Disease Workup

  • Author: Romeo A Mandanas, MD, FACP; Chief Editor: Mary C Mancini, MD, PhD   more...
 
Updated: Oct 28, 2010
 

Laboratory Studies

  • Complete blood count
    • Acute GVHD usually does not occur until after engraftment during transplantation.
    • Poor graft function may be a sign of autoimmune cytopenias (eg, thrombocytopenia, anemia, leukopenia) that may be observed with chronic GVHD.
  • Liver function tests (eg, bilirubin, AST, ALT, alkaline phosphatase, total protein, and albumin measurements)
    • Elevation of the alkaline phosphatase concentration is 1 of the early signs 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.
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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.
  • Barium swallow study can be used to detect esophageal changes of chronic GVHD, such as web formation, ringlike narrowing, and tapering structures of the middle and upper esophagus.
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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.[24] 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.[25]
  • 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.[26]
  • A biomarker panel (4 proteins: interleukin-2 receptor-α, tumor necrosis factor receptor 1, interleukin-8, and hepatocyte growth factor) measured in the serum by sequential ELISA at the onset of clinical symptoms was able to confirm GVHD with 95% specificity.[27] If validated in prospective studies, this high-risk biomarker profile may obviate the need for an invasive biopsy procedure to confirm the diagnosis of GVHD.
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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.
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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.

Acute graft versus host disease (GVHD). HematoxyliAcute 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.
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Contributor Information and Disclosures
Author

Romeo A Mandanas, MD, FACP  Research Site Leader, Integris Cancer Institute of Oklahoma

Romeo A Mandanas, MD, FACP, is a member of the following medical societies: American College of Physicians, American Medical Association, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Oklahoma State Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Antoni Ribas, MD  Assistant Professor of Medicine, Division of Hematology-Oncology, University of California at Los Angeles Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Marcel E Conrad, MD  Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group

Disclosure: No financial interests None None

Chief Editor

Mary C Mancini, MD, PhD  Professor and Chief, Cardiothoracic Surgery, Department of Surgery, Louisiana State University Health Sciences Center-Shreveport

Mary C Mancini, MD, PhD is a member of the following medical societies: American Association for Thoracic Surgery, American College of Surgeons, American Surgical Association, Phi Beta Kappa, Society of Thoracic Surgeons, and Southern Surgical Association

Disclosure: Nothing to disclose.

References

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  29. Mollee P, Morton AJ, Irving I, et al. Combination therapy with tacrolimus and anti-thymocyte globulin for the treatment of steroid-resistant acute graft-versus-host disease developing during cyclosporine prophylaxis. Br J Haematol. Apr 2001;113(1):217-23. [Medline].

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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.
Table 1. Procedures Associated with a High Risk of GVHD*
ProcedureGroups at High Risk
Allogeneic HCTPatients receiving no GVHD prophylaxis



Older patients



Recipients of HLA-nonidentical stem cells



Recipients of graft 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 productsNeonates and fetuses



Patients with congenital immunodeficiency syndromes



Patients receiving immunosuppressive chemoradiotherapy



Patients receiving directed blood donations from partially HLA-identical, HLA-homologous donors



Table 2. Clinical Staging of Acute GVHD
StageSkin FindingsLiver Findings (Bilirubin level, mg/dL)Gut Findings
+Maculopapular rash on < 25% of body surface2-3Diarrhea 500-1000 mL/d or persistent nausea
++Maculopapular rash on 25-50% of body surface3-6Diarrhea 1000-1500 mL/d
+++Generalized erythroderma6-15Diarrhea >1500 mL/d
++++Desquamation and bullae>15Pain with or without ileus
Table 3. Clinical Grading of Acute GVHD
Overall GradeStage
SkinLiverGutFunctional Impairment
0 (None)0000
I (Mild)+ to ++000
II (Moderate)+ to ++++++
III (Severe)++ to +++++ to +++++ to +++++
IV (Life-threatening)++ to ++++++ to ++++++ to +++++++
Table 4. Clinicopathologic Classification of Chronic GVHD
ClassificationClinicopathology
LimitedLocalized skin involvement and/or hepatic dysfunction due to chronic GVHD
ExtensiveGeneralized 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



Table 5. Screening Studies for GVHD by Organ or System
Organ or SystemClinical FindingsScreening Studies
SkinDyspigmentation, xerosis, erythema, scleroderma, onychodystrophy, alopeciaSkin biopsy with a 3-mm punch-biopsy sample from the back and forearm areas
MouthLichen planus, xerostomiaOral biopsy with sample from lower lip
EyesSicca, keratitisSchirmer test
LiverJaundiceAlkaline phosphatase, AST, bilirubin determinations
LungsObstructive and/or restrictive lung diseasePulmonary function studies, arterial blood gas analysis
VaginaSicca, atrophyGynecologic evaluation
GI (nutrition)Protein and calorie deficiencyWeight, measurement of muscle and/or fat stores
Multiple (clinical performance)Contractures, debilityDetermination of Karnofsky score and Lansky play index
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