• Bone marrow transplantation (BMT)
• Transfusion of non-irradiated blood products (e.g., products containing viable T lymphocytes) to congenitally immunodeficient hosts
• Transfusion of non-irradiated blood products from a donor who is homozygous for one of the recipient’s human leukocyte antigen (HLA) haplotypes
• Intrauterine materno-fetal transfusions and exchange transfusions in neonates
• Solid organ grafts that contain viable T cells (e.g., small bowel transplants)

• Acute GVHD: epithelial cell necrosis involving the regenerative compartment of the three affected organ systems (e.g., the basal layer of the skin, the crypts of the large and small bowel, and the biliary epithelium of the portal triad).
• Chronic GVHD: the clinicopathologic findings are similar to those seen in autoimmune disorders such as scleroderma, systemic lupus erythematosus, and primary biliary cirrhosis (i.e., epithelial cell damage, a mononuclear inflammatory cell infiltrate, and fibrosis are prominent features).

• The major HLA gene complex is found on chromosome 6 and is inherited as a group or haplotype.
• Two full siblings have a 25% chance of being HLA identical.
• Minor histocompatibility antigen differences likely account for GVHD in the HLA identical sibling bone marrow transplant setting.

• The major risk factor is HLA disparity. GVHD is most common in unrelated donor marrow transplants and absent in identical twin transplants.
• Other risk factors include:
  • Prior pregnancies in the marrow donor (which give rise to allosensitization)
  • Older donor or recipient age
  • Gender mismatch

• Mortality from GVHD after BMT is usually related to infection.
• Rarely, patients die of hepatic failure or abdominal catastrophe.
• In transfusion-associated GVHD, the major cause of death is bone marrow aplasia due to destruction of the host’s marrow by donor lymphocytes.

• Acute GVHD is graded on a scale from I to IV with percent of total body surface involved (skin), volume of diarrhea (gut), and/or elevation of serum bilirubin (liver).
• Patients with grade I GVHD do not have a survival different from those without GVHD.
• Patients with grade IV GVHD have a survival of only 10% to 15% as do patients with progressive chronic GVHD (defined as acute GVHD, which does not resolve followed by chronic GVHD).

• Skin: dermal changes from chemoradiotherapy, drug reaction, viral exanthem
• Liver: hepatic venoocclusive disease (VOD), elevations of liver function tests due to total parenteral nutrition, drug toxicity or infection, especially bacterial sepsis and cytomegalovirus
• Gastrointestinal: diarrhea secondary to the BMT preparative regimen and infectious causes, especially Clostridium difficile and cytomegalovirus

Question: Rash? Itching?
Significance: Pruritus can precede the rash, which in BMT appears as the patient’s blood counts are beginning to rise. In transfusion-induced GVHD, symptoms usually start 1 week after the transfusion.

Question: Jaundice? Diarrhea?
Significance: Unusual for involvement to precede skin disease

Question: Dry eyes? Dry mouth?
Significance: Be sure to ask if the patient forms saliva or tears because sicca syndrome can develop.

Question: Dysphagia?
Significance: Complaints of difficulty swallowing or retrosternal pain may be due to esophageal strictures.

Finding: Skin
Significance: Often begins as erythema of the palms, soles, and ears. The rash can become confluent erythroderma, and in the most severe cases can lead to bulla formation and even denudation reminscent of burn injuries.

Finding: Liver
Significance: Jaundice can be seen but painful hepatomegaly, ascites, and rapid weight gain are atypical and are more often seen in VOD.

Finding: Gastrointestinal
Significance: Stool is often watery, green, and bloody (although it may only be guaiac positive).

Finding: Skin
Significance: Hyper- or hypopigmentation, patchy erythema, scaling, and sclerodermatous changes can be seen. The skin is involved in almost every patient.

Finding: Joints
Significance: Swelling can be seen: a detailed range of motion examination is crucial because contractures can be found in the absence of joint swelling.

Test: Laboratory
Significance: In hepatic GVHD isolated elevations of transaminases can be seen without hyperbilirubinemia. In more severe cases, a cholestatic picture is seen. Howell-Jolly bodies can be seen on peripheral blood smear in the functional asplenia of chronic GVHD.

Test: Radiological
Significance: Although total body irradiation and busulfan used in BMT can lead to pulmonary fibrosis, the picture of bronchiolitis obliterans on CT scan is considered a manifestation of chronic GVHD.

Test: Biopsy
Significance: Of note, during the first 3 weeks post-BMT, skin and gastrointestinal histological changes from chemoradiotherapy are indistinguishable from GVHD.

• Selection of a histocompatible donor
• Immunosuppressive therapy with the combination of cyclosporine and methotrexate is the gold standard.
• Steroids, usually in combination with cyclosporine, have been used for those patients who cannot tolerate methotrexate.
• When using an unrelated donor or partially matched family member, other options include ex vivo depletion of T lymphocytes from the donor marrow and in vivo administration of anti-T cell antibodies to the recipient.
• Monoclonal antibody therapy aimed at cytokine blockade is under investigation.

• Steroids at a dose of 2 mg/kg/d for 2 weeks followed by a taper over several months
• Cyclosporine or FK506 in those patients who did not receive it as prophylaxis
• Antithymocyte globulin (ATG) for steroid-resistant patients
• Mycophenolate mofetil is presently under investigation

• Steroids either alone or in combination with cyclosporine or FK506. Because many patients require treatment for months, the goal is alternate day therapy (e.g., steroids alternating with cyclosporine).
• Psoralen plus ultraviolet A (PUVA) is of some benefit in skin GVHD.
• Oral beclomethasone has been used for treatment of gastrointestinal GVHD.
• Ursodeoxycholic acid may be of benefit for hepatic GVHD.
• Thalidomide, clofazamine, etretinate, and, most recently, mycophenolate mofetil have shown some promise.
• Studies of azathioprine suggested a high infection rate when it was given with steroids.

• Acute GVHD: The institution of steroid therapy should lead to improvement within days in those patients who are destined to respond. However, gastrointestinal symptoms are notoriously slow to respond.
• Chronic GVHD: Acute GVHD, which merges directly into chronic GVHD, is termed progressive and has an extremely poor prognosis (approximately 10% survival at 5 years post-BMT). Thrombocytopenia is another poor prognostic factor. Such patients usually die of infection.
• Of note, patients with limited chronic GVHD have a decreased rate of relapse of leukemia and an increased survival rate.

• Do not immunize a patient with a live vaccine if they have chronic GVHD. This may result in symptomatic infection.
• Take sudden high fevers seriously in a patient with GVHD. Overwhelming bacterial sepsis is not infrequent. Patients with chronic GVHD are often functionally asplenic (even if Howell-Jolly bodies are not seen on peripheral blood smear). Many transplant centers place these children on prophylactic penicillin.

Q: If a child gets acute GVHD does that mean they will get chronic GVHD?
A: No. Approximately 30% of patients less than 10 years of age who receive an HLA identical sibling BMT will get acute GVHD, whereas only 13% will develop chronic GVHD. Of note, chronic GVHD can develop in a patient who did not have acute GVHD. This is termed de novo and is much more favorable than progressive chronic GVHD.

Q: Do patients with severe chronic GVHD all die?
A: No. Occasionally the GVHD will “burn out.” This is rare, and the process by which it happens is not understood.