Graft versus host disease (GVHD) is a frequent complication of allogeneic stem cell transplantation and a much rarer complication of blood transfusions. The conditions for GVHD are met when immunocompetent donor cells are introduced into an immunocompromised recipient, or host, which expresses tissue antigens that are not present in the donor. The donor cells recognize the recipient antigens as being foreign and react by attempting to destroy the tissue. The recipient, by virtue of being immunocompromised, is unable to mount an effective response to this attack and therefore is unable to destroy the donor cells, leading to the manifestation of clinical symptoms. The GVHD reaction was first reported when irradiated mice were injected with spleen cells. Although they recovered from treatment and began engraftment, they eventually died of a secondary disease that manifested in symptoms of diarrhea, weight loss, and skin and liver abnormalities (Jaksch & Mattson, 2005).

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).

GVHD can be categorized into two subtypes, acute and chronic. Patients may develop either type or even both. Acute GVHD is distinguished from chronic GVHD by the different clinical manifestations and time of onset. Most practitioners consider acute GVHD to be GVHD symptoms that develop before day + 100 from transplantation, and chronic GVHD usually is classified as occurring after day + 100. However, more current studies use the clinical symptoms, rather than the time of onset, as defining characteristics (Chao, 2006b and Chao, 2006c).

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.

The incidence of acute GVHD varies but is inversely proportional to the number of HLA matches. The more major antigens that are matched, the less likely it is that acute GVHD will occur. In the case of two or three mismatched HLA antigens, the incidence increases to 80%; it is closer to 40% to 50% in fully matched siblings (Alexander & Wong, 2000). The severity of GVHD correlates directly with the amount of T cells infused. Therefore it is important to strike a balance between providing the patient with enough stem cells to stimulate adequate engraftment and not stepping over the boundaries and giving too many donor T cells, which would tip the scales in favor of development of GVHD. Acute GVHD accounts for 50% of nonrelapsed deaths. The onset of clinical symptoms occurs, on average, between day + 19 and day + 25 after transplantation, or during the time of significant WBC engraftment. If acute GVHD occurs, the estimated 100-day survival rate is as follows:

Grade 1: 78% to 90%

Grade 2: 66% to 92%

Grade 3: 29% to 62%

Grade 4: 23% to 25%

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).

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.