The mediators of GVHD are the donor T cells and the human leukocyte antigens (HLAs) in the host. HLA typing of a patient is a type of genetic fingerprint and is segregated in families in a Mendelian codominant manner. With the exception of identical twins, no two sets of HLA markers are completely the same. The genes on the HLA locus hold two different classes of cell surface molecules. Class I molecules are present on the surface of most nucleated cells, whereas class II molecules are more commonly expressed on the cells specific to the immune system. The class I antigens are HLA-A, HLA-B, and HLA-C; class II antigens include HLA-DQ, HLA-DR, and HLA-DP. Other antigens, called minor antigens, also exist, but these are less active mediators in the GVHD response.

Research has shown that the most important antigens involved in determining whether donor cells initiate a graft versus host response are HLA-A, HLA-B, and HLA-DR (Prasad et al., 1999). The major HLA molecules of the host are expressed on many of the host tissue cells. These molecules are seen by the immunocompetent donor T cells either as foreign or as “self.” If the molecules match the receptors on the donor T cells, they are seen as self and no response if mediated. If, however, the receptors do not match, the T cells understand the host cells to be foreign and mount an inflammatory reaction to them, eventually causing cell death and tissue destruction. Therefore the goal in stem cell transplantation is to match the donor cells and recipient cells as closely as possible. This is discussed in terms of “5/6 or 6/6” matching; this means that of the six HLA major molecules, the donor matches the host with 5 or 6 of the molecules. By closely matching these antigens on both the donor and recipient stem cells, the chance that the donor T cells will recognize the HLA molecules expressed on the recipient tissue as “self” increases, reducing the risk for GVHD. However, if the donor T cells recognize the host tissue cells as foreign, as may happen with a mismatched or a less than 6/6 matched donor transplant, the donor T cells mount a response against the host tissue; they produce a variety of cytokines that cause the inflammatory response. Some of these cytokines are tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-2 (IL-2).

The targeted organs in GVHD most often are the skin, liver, GI tract and, in chronic GVHD, the lungs and complete immune system. The overall result of this “attack on self” can range from mild manifestations (i.e., a slight skin rash) to overwhelming desquamation of cells, resulting in the patient’s death. The severity of the GVHD is categorized into different stages. Acute GVHD may be mild, moderate, severe, or life-threatening. For skin manifestations, stage 1 (mild) involves a skin rash over less than 25% of the body. Stage 2 (moderate) involves a rash over more than 25% of the body, along with mild liver involvement and/or mild diarrhea (not exceeding 1 L/day). Stage 3 (severe) involves severe rash over more than 50% of the body and moderate liver involvement and diarrhea. Stage 4 (life-threatening) involves blistering of the skin, bullous lesions, and severe liver disease and/or voluminous amounts of diarrhea (Stewart, 1992).

For liver manifestations, stage 1 is marked by a bilirubin level of 2 to 3 mg/dL; stage 2 by a level of 3.1 to 6 mg/dL; stage 3 by a level of 6.1 to 15 mg/dL; and stage 4 by a bilirubin level greater than 15 mg/dL.

For enteritis manifestations, stage 1 is considered to be diarrhea greater than 30 mL/kg or 500 mL/day; stage 2 is diarrhea greater than 60 mL/kg or 1000 mL/day; stage 3 is diarrhea greater than 90 mL/kg or 1500 mL/day; and stage 4 is diarrhea of 2 L or more per day and/or severe abdominal pain. The mortality rate for stage 4 acute GVHD is almost 100% (Alexander & Wong, 2000). Researchers are continuing to search for the ability to separate the graft versus leukemia from GVHD by depleting T cells that mediate GVHD, while sparing the T cells that are specific from tumor destruction (Chen et al, 2002).

Many providers use the IBMTR grading system. This system is broken up into grades A, B, C, and D. Grade A is grade 1 skin GVHD with no other systems involved. Grade B is grade 2 skin, and grade 1 or 2 liver. Grade C is a combination of grade 3 skin, gut, and liver. Grade D is a combination of grade 4 skin, gut, and liver.

As our understanding of the immune system has expanded and new treatments for GVHD have been found, a new concept has appeared, the graft versus tumor effect. This is the possibility that the donor cells may see malignant cells as foreign and thus react in the same manner as seen with GVHD: creating an actual immune response to the malignancy and preventing the cancer cells from proliferating; in fact, treating the cancer (Alexander & Wong, 2000).

The nurse’s main roles in treating and preventing GVHD include early detection and prompt attention to provide treatment; educating the patient about signs and symptoms, as well as preventive measures; providing symptom management for the patient with active GVHD; and helping the patient with chronic GVHD gain a better quality of life or, in some cases, come to an acceptance and a peaceful end of life.


Chronic GVHD occurs in up to 50% of long-term survivors of fully matched (6/6) sibling transplants (Chao, 2006c). The incidence increases with certain risk factors, such as prior acute GVHD, and is reduced by other factors, such as the administration of GVHD prophylaxis with methotrexate and tacrolimus.

Transfusion-related GVHD is very rare; the incidence is estimated at 0.1% to 1% in immunocompromised patients. However, the mortality rate with this type of GVHD is 80% to 90% (Silvergleid, 2006).


Acute GVHD

• HLA disparity, particularly one or more of the major antigens in class I or class II

• Advanced age

• Donor and recipient gender disparity (female to male transplantation increases likelihood of GVHD)

Status of underlying disease: The more disease that is present on treatment, the more likely the patient is to have acute GVHD.

Amount of radiation delivered: Larger amounts of total body irradiation are more likely to cause acute GVHD. The greater the amount of radiation, the greater the tissue damage and, in turn, the greater the amount of T-cell proliferation.

• The risk is reduced with prophylactic use of methotrexate and cyclosporine or tacrolimus.

• The risk also is reduced by the presence of a sterile environment (i.e., gut decontamination with Flagyl and ciprofloxacin).

• There is no difference between patients receiving peripheral blood progenitor cells or cells harvested directly from bone marrow (Brown et al, 1999).

Chronic GVHD

• HLA disparity or mismatching

• Advanced age

• Subacute GVHD, usually detected by skin biopsy or buccal mucosal biopsy

• History of moderate to severe acute GVHD

• Previous splenectomy

• Cytomegalovirus seropositivity, either donor or recipient

• Second bone marrow infusions with boosts of donor leukocytes

• Previous herpes virus infection


The prognosis is directly related to the stage of GVHD. Patients with mild disease (stage 1 or stage 2) have a low mortality rate. In patients with stage 4 disease, the mortality rate approaches 100% (Ferrara & Deeg, 1991). The prognosis also depends on the response to treatment. Refractory GVHD has a higher mortality rate, because it often progresses to a more severe stage. Transfusion-related GVHD carries a mortality rate of 80% to 90%. With chronic GVHD, the prognosis is better if the patient has not had a previous episode of acute GVHD; a poorer prognosis is associated with advancing age. A combination of liver and skin GVHD with lichenoid findings carries a poor prognosis.


Acute GVHD

1. A maculopapular rash may develop around day +19 to +25, (Przepiorka et al, 1995) or around the time of white blood cell engraftment. This is the first and most common manifestation of acute GVHD. The rash usually involves the neck, back of the ears, shoulders, palms, and soles of the feet. It often is described as a “sunburn” and can be painful or pruritic (Chao, 2006b and Chao, 2006i). If left untreated, the rash may spread, eventually involving the entire integument, and in severe cases may form causing bullous lesions and peeling of the skin.

2. Skin biopsies are often performed, although treatment is initiated on the basis of the clinical picture. Findings consistent with GVHD include dyskeratotic epidermal keratinocytes and apaptosis at the base of crypts (Chao, 2006fChao, 2006g and Chao, 2006h). The initial treatment for these skin rashes is application of topical steroid creams.

3. An abnormal rise in liver function tests may be seen. The liver is the second most commonly involved organ. A rise in the serum levels of conjugated bilirubin and alkaline phosphatase are often the first signs reported. Other differentials to consider with this finding are hepatic veno-occlusive disease (see Chapter 21), viral hepatitis, and drug effects.

4. Liver biopsy is the only means of definitively diagnosing GVHD of the liver. Most often a transjugular hepatic biopsy is preferred because it poses a lower risk of bleeding. Findings consistent with GVHD are extensive bile duct damage, bile duct atypia and degeneration, and lymphocytic infiltration of small bile ducts with cholestasis. In some cases, Actigall may be beneficial in reducing the liver function values.

5. Jaundice, by assessing color of skin and sclera and liver function laboratory tests (AST, ALT). A yellowing tint to the skin and/or sclerae is another manifestation of liver damage from GVHD.

6. Ascites, by assessing weight and abdominal girth. Ascites may also accompany a rise in liver function values, suggests a differential of GVHD.

7. Diarrhea is seen, distinguished by large volumes (up to 10 L/day) and a consistency that is mostly water and occasionally bloody. Diagnosis is clinical, but a definitive diagnosis can be made through colon biopsy. Another differential to consider is cytomegalovirus (CMV) infection, because its presentation is almost identical.

8. Colon biopsy findings consistent with GVHD show crypt cell necrosis; with severe disease, large areas of the colon may be denuded and show total loss of the epithelium, leading to malabsorption (Chao, 2006e).

9. Malabsorption is often seen in labs with low levels of oral medications, hypomagnesemia, hypokalemia, and other electrolyte abnormalities.

10. An increased risk of infections exists as a result of pancytopenia and a drop in serum concentrations of immunoglobulins.

11. A reduction in precursor cells is seen, leading to thrombocytopenia.

Chronic GVHD

2. Skin changes in the form of thickening or lichen planus are seen. Histologic findings include epidermal atrophy and dermal fibrosis. The onset may be marked by general erythema or plaques, often with a history of photoactivation. Areas of hyperpigmentation may alternate with hypopigmentation.

3. The skin may become fixed to underlying fascia, causing joint contractures (Chao, 2006c).

4. Serum alkaline phosphatase and bilirubin are elevated. Biopsy may show chronic persistent hepatitis.

5. Changes occur in the oral mucosa. Dry mouth and pain secondary to ulcerations may be presenting complaints. Physical findings include an erythematous mucosa with lichenoid lesions.

6. BOOP (bronchiolitis obliterans see Chapter 7) may be present. Patients present with dyspnea and a nonproductive cough. BOOP is a nonspecific inflammatory reaction that mostly affects the small airways. It is characterized by an organizing intraluminal exudate.

• The hallmark sign of BOOP is the presence of intraluminal fibrotic buds, called Masson bodies, which are found in bronchioles and alveoli. Inflammatory changes occur around alveolar walls with macrophages present and are considered the organizing pneumonias.

• Chest x-ray film (CXR) changes noted with BOOP include diffuse infiltrates, and restrictive ventilation is seen on pulmonary function tests (PFTs).

• A bronchoscopy commonly is performed to try to obtain a biopsy sample from the affected lung. Bronchoscopy may show destruction of the small airways, with fibrous obliteration of the bronchioles.

• Bronchodilators and cough suppressants are used to control cough. Macrolide antibiotics, such as erythromycin, are used because their mechanism of action reduces the circulating T lymphocytes. Steroids are also used to treat BOOP, as they are for skin, intestine, and liver GVHD (King, 2006).

• BOOP is often associated with decreased serum IgG levels.

• Risk factors include advanced age; therefore this is seen more often in the adult transplant population (Kaner, 2006).

7. Recurrent infections are seen in chronic GVHD as a result of prolonged and profound immunosuppression.

8. Pancytopenia, abnormal liver function tests, and electrolyte abnormalities are the most common laboratory results.

Transfusion-Associated GVHD

1. The patient may have a history of blood transfusion in the past 4 to 30 days.

2. Presenting symptoms of transfusion-related GVHD are fever; an erythematous, maculopapular rash; vomiting; diarrhea; and cough (Silvergleid, 2006).

3. Laboratory findings show profound pancytopenia, abnormal liver function tests, and electrolyte abnormalities.

4. Transfusion-related GVHD is most often associated with administration of nonirradiated blood products (Slivergleid, 2006).

5. Prevention is the best treatment. All blood products given to immunocompromised patients should be irradiated with 25 Gy and leukocyte reduced.

6. Currently no adequate treatment exists for this type of GVHD. Steroids, ultraviolet radiation, TNF inhibitors, and thalidomide all have been tried, to no avail.


1. Recognize the patients at risk for GVHD (i.e., allogeneic patients with any risk factors).

2. Administer preventive measures. The most frequently used prophylactic regimen is methotrexate and cyclosporine (Chao, 2006f). Cyclosporine is administered beginning at day 2 and continues through day +90, when weaning the dose can begin if no GVHD exists. Cyclosporine is also given intravenously for the first several weeks to ensure adequate absorption. Remember to assess liver function tests and creatinine before administering methotrexate, because this drug can cause kidney and liver toxicities. Methotrexate is most often administered IV on days +1, +3, +6, and +11.

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Oct 19, 2016 | Posted by in NURSING | Comments Off on 18. GRAFT VERSUS HOST DISEASE

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