Laboratory Studies
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The diagnosis of graft versus host disease (GVHD) is established by clinical judgment, imaging studies, laboratory workup, and biopsy results.
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Anemia and thrombocytopenia are observed early in acute GVHD or in chronic GVHD.
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Eosinophilia (see Eosinophils) and Howell-Jolly bodies are observed on peripheral smear in chronic GVHD.
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In hepatic involvement, elevation of transaminase levels is observed early and followed by an increase in bilirubin and, finally, cholestatic picture with increased alkaline phosphatase and glucose tolerance.
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A panel of 4 biomarkers in the serum, including interleukin (IL)-2 receptor-α, tumor necrosis factor (TNF)-receptor-1, IL-8, and hepatocyte growth factor, have been reported to be useful to confirm the diagnosis of GVHD in patients at onset of clinical symptoms. [16, 17]
Acute graft versus host disease (GVHD). Hematoxylin-stained and eosin-stained tissue shows dyskeratosis of individual keratinocytes and patchy vacuolization of the basement membrane. A moderate superficial dermal and perivascular lymphocytic infiltrate is also seen in this case. Image courtesy of Melanie K. Kuechler, MD.
Imaging Studies
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Pulmonary fibrosis resulting from irradiation or chemotherapeutic agents
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Bronchiolitis obliterans on radiograph or CT scan observed in chronic GVHD
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Ultrasonography, CT scanning, and Doppler studies: These may be used to distinguish GVHD from other causes of jaundice or cholestatic liver function abnormalities. [18]
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Endoscopic studies of small bowel: These may reveal atrophy of the villi, ulceration, and bleeding. Barium swallow study may reveal the changes of chronic GVHD, such as ringlike narrowing and web formation.
Procedures
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Although a biopsy is not routinely performed, it can be very helpful to distinguish changes of GVHD from drug toxicity in skin and liver. Biopsy findings are necessary for confirming the diagnosis of chronic GVHD.
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Upper GI endoscopy is currently routinely performed in older patients with nausea, anorexia, and dyspeptic symptoms. This study is useful in grading.
Histologic Findings
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Acute GVHD
The skin demonstrates epidermal basal vacuolization, followed by epidermal basal cell apoptotic death with lymphoid infiltration. Eosinophilic bodies may be observed with increased severity. Bullous formation with epidermal separation and necrosis is observed in later stages.
Liver tissue undergoing acute GVHD can demonstrate damage to more than 50% of bile ducts with vacuolated cytoplasm, with duct cell nuclear pleomorphism and necrosis of individual cells (apoptosis). A lymphocytic infiltrate of portal tracts with endothelialitis (veins with lifting of endothelium from its basement membrane) is observed along with ballooning degeneration of hepatocytes and/or acidophil bodies.
GI biopsy specimens reveal diffuse edema and mucosal swelling followed by variable crypt cell apoptosis (eg, "exploding" crypts), a mixed chronic and predominantly lymphoplasmacytic infiltrate, and possibly crypt dropout.
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Chronic GVHD: Skin biopsy specimens can reveal epithelial acanthosis, dyskeratosis, and hyperkeratosis with a mononuclear infiltrate at the dermal-epidermal junction and in adnexal structures. This inflammatory process can evolve to dermal fibrosis and epidermal atrophy. Similarly, a mononuclear infiltrate is seen in the salivary glands on lip biopsy findings. The liver shows a portal mononuclear infiltrate with damage to the bile ducts and eventually ductopenia, changes that can be seen in the absence of clinical manifestations. GI findings of crypt destruction, increase in lymphoplasmacytic infiltrate with single cell drop out, and fibrosis of lamina propria are observed.
Staging
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Acute GVHD is traditionally graded in 5 stages (0-IV), based on involvement of the skin, liver, and GI tract. Grades I-IV are graded functionally.
Grade 0 indicates no clinical evidence of disease.
Grade I indicates rash on less than 50% of skin and has no gut or liver involvement.
Grade II indicates rash covering more than 50% of skin, bilirubin level of 2-3 mg/dL, diarrhea of 10-15 mL/kg/d, or persistent nausea.
Grade III or IV indicates generalized erythroderma with bullous formation, bilirubin level of more than 3 mg/dL, or diarrhea of more than 16 mL/kg/d.
Use the "Rule of Nines" or burn chart to determine the range of skin involvement. Downgrade one stage if an additional cause of elevated bilirubin level has been documented.
Volume of diarrhea applies to adults. For pediatric patients, the volume of diarrhea should be based on body surface area. Gut staging criteria for pediatric patients were not discussed at the consensus conference. Downgrade one stage if an additional cause of diarrhea has been documented.
Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.
Criteria for grading are given as the minimum degree of organ involvement required to confer that grade.
Grade IV may also include lesser organ involvement but with extreme decrease in performance status.
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Pathophysiological pathways and mechanisms of acute GVHD.
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This boy developed stage III skin involvement with acute graft versus host disease (GVHD) in spite of receiving prophylaxis with cyclosporin A. The donor was an human leukocyte antigen (HLA)-matched sister; however, the sex disparity increased the risk for acute GVHD. Image courtesy of Mustafa S. Suterwala, MD.
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This photo depicts the same boy who has progressed to grade IV graft versus host disease (GVHD). Both cyclosporin A and methylprednisolone had been administered in high dose intravenously. He later died with chronic pulmonary disease caused by chronic GVHD. Image courtesy of Mustafa S. Suterwala, MD.
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Autologous graft versus host disease (GVHD) involving the skin of a patient's arm shortly after showing signs of engraftment after an autologous peripheral blood stem cell transplant for ovarian cancer. Image courtesy of Romeo A. Mandanas, MD, FACP.
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Acute graft versus host disease (GVHD) involving desquamating skin lesions in a patient following allogeneic bone marrow transplantation for myelodysplasia. Image courtesy of Romeo A. Mandanas, MD, FACP.
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Oral mucosal changes in a patient with chronic graft versus host disease (GVHD). Note the skin discoloration (vitiligo), which can result from GVHD. Image courtesy of Romeo A. Mandanas, MD, FACP.
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Acute graft versus host disease (GVHD). Hematoxylin-stained and eosin-stained tissue shows dyskeratosis of individual keratinocytes and patchy vacuolization of the basement membrane. A moderate superficial dermal and perivascular lymphocytic infiltrate is also seen in this case. Image courtesy of Melanie K. Kuechler, MD.
