Graft versus host disease

Introduction

The American Leukemia Society reports that Graft Versus Host Disease (GVHD) affects approximately 50% of allogeneic bone marrow transplant patients and proves fatal in nearly 30% of patients who have clinically significant GVHD. GVHD refers to an acute and/or chronic condition that frequently complicates allogeneic bone marrow transplants. It develops when transplanted immunologically competent donor T-cells identify the patient's body as nonself, and, subsequently, launch an immune system attack on the patient's organs. Because the patient's immune system is suppressed prior to the transplant, it is unable to counter the attack. The risk of GVHD is minimized through careful matching of the recipient and donor HLA markers. The purpose of this article is to discuss GVHD, including the acute and chronic clinical presentation and the implications on physical therapy treatment.

HLA System

The HLA system, or the human leukocyte antigen system, refers to an inherited set of genetic fingerprints (HLA markers) found on the surface of human cells that define a person's tissue type. T-cells utilize the HLA markers to distinguish "self" from "nonself" cells and to summon the immune system to attack and destroy foreign antigens. The greater the disparity between the body's HLA markers and the foreign antigen, the swifter and more vigorous the attack. The success of a bone marrow transplant depends largely on how closely the donor and patient HLA-markers match.

It has been established that the HLA-A, HLA-B, and HLADR loci on white blood cells play an important role in determining the severity of GVHD. To minimize the risk of GVHD, a donor whose HLA type matches that of the patient is best. Because HLA markers are inherited, siblings are more likely to have similar HLA-antigens than unrelated persons. The ideal donor is an identical twin who genetically has the same antigens as the recipient at both the major loci (HLA-A, -B, and -DR) and the less well-known or harder to detect HLA sites. The next best donor is a sibling whose HLA-A, -B, and -DR antigens match those of the patient. A sibling mismatched for one antigen at either the HLA-A, -B or -DR site (a 5 out of 6 antigen match) is also a suitable bone marrow donor. However, when more than one antigen is mismatched, the incidence of severe GVHD significantly increases and long-term survival rates decrease.

Risk Factors

HLA mismatching is the primary risk factor associated with acute GVHD. The National Cancer Institute reports that 70% of patients receiving marrow with 2 mismatched antigens develop significant acute GVHD, as compared to 40% of patients receiving HLA-identical marrow. The prior occurrence of acute GVHD is the most prominent risk factor for developing chronic GVHD. Indeed, 70 to 80% of patients with acute GVHD develops the chronic condition. Other risk factors include an unrelated donor and recipient, a patient 30 years of age or older, a recipient and donor of the opposite sex, and a female donor with 2 or more viable pregnancies.

The results of a 1998 Carlen study indicate a positive correlation between the presence of multiple risk factors and the 5-year incidence of chronic GVHD. The 5-year incidence is 9% when no risk factors are present, 29% with 1 risk factor, 53% with 2 risk factors, 68% with 3 risk factors, and 75% with 4 risk factors.

Acute GVHD

Acute GVHD describes a syndrome, occurring within the first 100 days posta,llogeneic BMT, usually within 30 to 40 days, in which the proliferating transplanted immune competent cells destroy the epithelial cells in the gastrointestinal tract, liver, and skin. The classic clinical presentation of acute GVHD is dermatitis, hepatitis, and gastroenteritis (Table 1). Physicians quantify acute GVHD by, first, clinically staging each individual organ system based on its degree of involvement (Table 2). Then, an overall grade is assigned by combining the clinical stage of each involved organ (Table 3). Clinically significant acute GVHD is defined as an overall grade of II, III, or IV. Both pharmacological and nonpharmacological agents are used to reduce the severity and incidence of acute GVHD.

Pharmacological Agents Immunosuppressive drags, ie, Cyclosporine (alone or in combination with Prednisone and/or Methotrexate), are administered pre- and post-transplant to reduce the incidence and severity of GVHD. These drags may be administered in high doses for several months, particularly if acute GVHD progresses to Stage II or if the patient develops chronic GVHD. Side effects of Cyclosporine may include kidney toxicity, increased body hair growth, and, on rare occasions, neurological problems including seizures, confusion, anxiety, and changes in thought process. Inflammation of the mouth, nose, and/or throat is the most significant potential side effect of Methotrexate. Potential side effects of steroid administration consist of weight gain, fluid retention, elevated blood sugar level, mood swings, and/or confused thinking. Fortunately, the side effects of these drugs are temporary and disappear when drug administration is discontinued.

Nonpharmacological T-cell depletion and CD-8 selective purging are 2 nonpharmacological preventative measures. In T-cell depletion, the T-cells are removed from the donor marrow prior to the transplant. This technique reduces the incidence of acute GVHD from approximately 50% to less than 15%. However, relapse rates are 65% and graft rejection rates are as high as 10 to 30%. Thus, long-term survival rates have not improved. CD-8 selective purging involves the removal of the CD-8 T cell from the donor marrow prior to an allogeneic transplant. This technique reduces the incidence of acute GVHD from 50% to 20%. Also, the high rate of relapse that occurs with T-cell depletion does not occur and the incidence of graft rejection is only 10%.

Chronic GVHD

Chronic GVHD presents 100 days to 3 years postallogeneic transplant. Twenty-seven percent of postallogeneic transplant patients develop chronic GVHD with 50% of these cases developing in patient's age 50 and older. In contrast, the condition develops in 10 to 20% of patients younger than 20 years of age. Diagnosis is based on clinical and lab parameters. Chronic GVHD affects multiple organs or organ systems, although the central nervous system is rarely affected (Table 4). The presentation of chronic GVHD is typical of an autoimmune condition, including autoantibody formation. In addition, because the disease and therapy are immunosuppressive, chronic GVHD is associated with marked immunodeficiency. The recovery of the immune system is significantly delayed and patients remain immunodeficient while the disease is active. Recurrent infections are problematic and account for the majority of morbidity and mortality associated with chronic GVHD. Chronic GVHD is graded as limited or extended based on the extent of organ involvement (Table 5). Prognosis A platelet count, greater than 1 00,000/ul, is regarded as the most significant prognostic factor for 5-year survival in patients with extensive GVHD. Patients with platelet counts exceeding 100,000/ul have an 80% 5-year survival rate while patients with counts below 100,000/ul have a 30 to 40% 5-year survival rate. Other known predictors of poor outcome include progressive presentation of GVHD, lichenoid changes in skin histology, and elevated bilirubin levels > 1.2 mg/dl. The longterm effects of GVHD include long-term skin sensitivity, persistent liver problems, lung problems, joint contractures, chronic diarrhea, photosensitivity, scarring of the skin, eye irritation, and failure of the stomach to absorb nutrients.

Implications for Physical Therapists and Occupational Therapists

The number of allogeneic transplants performed annually continues to rise. As allied health professionals, we should not overlook the opportunity to solidify our presence as an integral component of the post transplant rehabilitation team. The National Cancer Institute has issued a Support Statement that identifies exercise as a tool to combat fatigue. Additionally, early intervenlion is important to prevent or minimize the functional deficits that may occur once the severity of GVHD progresses.

Acute Care Setting In the acute care setting, patients with GVHD, benefit from physical therapy to minimize the effects of immobility. Virtually every organ system is affected by immobility, and as a result, severe complications may ensue. The benefits of getting patient's out of bed have been well documented. As pulmonary complications are associated with GVHD, chest percussion and postural drainage may be indicated. Also, aggressive mobilization programs, consisting of passive and active range motion, are necessary to thwart some of the deleterious sequelae of sclerodermatous skin changes, and to prevent or mitigate the severity of joint contractures.

Patients benefit from adaptive equipment, available through occupational therapy, which allows them to participate in selfcare activities and regain their locus of control. In addition, patient evaluations by physical and occupational therapy should evaluate transplant patients in order to issue the appropriate durable medical equipment.

Outpatient or Home Health Setting Opportunities for physical and occupational therapy intervention continue after patients are discharged from the hospital. Post-transplant patients, particularly those that had GVHD, benefit from continued therapy, or a home exercise program, to increase their independence with activities of daily living, to strengthen weak muscles, to improve dynamic balance, and to improve overall functional status. Transplant patients are discharged with numerous instructions. Therapists should monitor patient's adherence to these instructions. Therapists may also visit the patient's home to assess the patient's safety in the discharge environment.

References

1. Leukemia Society of America. Bone Marrow Transplantation and Peripheral Blood Stem Cell Transplantation. January 1997.

2. National Cancer Institute. Bone Marrow Transplantation and Peripheral Blood Stem Cell Transplantation. November 1994.

3. Klingebiel T, Schegel PG. "GVHD: overview on pathophysiology, incidence, clinical and biological features." Bone Marrow Transplantation. Suppl. 2 1998.

4. Burt R, Deeg J, Lothian S, Santos G. Bone Marrow Transplantation. NY: Chapman and Hall; 1996.

5. www. Cancernet.com

6. www.oncolink.com

Hilary Hyser, SPT

Medical College of Virginia/Virginia Commonwealth University Richmond, Virginia

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