Immunologic Aspects of Organ Transplantation

Susan Smith MN, PhD

Disclosures

June 17, 2002

GVHD

GVHD is the principal limitation to allogeneic and syngeneic bone marrow transplantation.[21] Although rare, GVHD can also occur after solid organ transplantation. GVHD occurs when donor immunocompetent T cells recognize immuno-incompetent recipient tissues as foreign and attempt to destroy them, and is usually associated with reduced levels of immunosuppression. The skin (dermatitis), liver (hepatitis), and GI tract (enteritis) are the main target organs of GVHD. Lung involvement can also occur. GVHD can manifest as an acute or chronic disease process ( Table 7 ). Acute GVHD can occur as early as the 7th to 10th posttransplant day or as late as 80 days after transplantation. Subclinical GVHD also occurs but is difficult to diagnose.

Acute GVHD occurs from 1 week to 3 months after transplantation of hemopoietic cells mismatched at MHC loci into an immunocompromised recipient. Risk factors for the development of GVHD are listed in Table 7 . The chronic form of GVHD is thought to be primarily related to mismatched mH antigens and usually manifests any time after the 3rd month following transplantation. There are 3 forms of chronic GVHD: (1) de novo, (2) quiescent, and (3) progressive. De novo chronic GVHD occurs after a lag period following the apparent resolution of acute GVHD. Quiescent chronic GVHD occurs after a lag period following the apparent resolution of acute GVHD. Progressive chronic GVHD, the most serious form, cannot be separated in time from acute GVHD but bears the histology and clinical complications of chronic disease.

Diagnosis of GVHD is made via target tissue biopsies and demonstration of chimeric levels in peripheral blood by in situ polymerase chain reaction.[22] Acute GVHD is characterized by leukopenia, fever, and cytolytic destruction of the recipient's skin, GI tract, and liver. Chronic GVHD is characterized by scleroderma-like changes in the skin, GI tract, and liver. Clinical GVHD in solid organ transplantation usually resolves with immunotherapy and therefore does not represent a major source of mortality after liver transplantation.

Skin Involvement

The skin is the most common organ involved and often shows the first changes specific to GVHD. The skin reaction usually begins as a fine, maculopapular, erythematous rash on the palms of the hands, soles of the feet, and earlobes and may spread to the chest and back. As the reaction progresses, generalized erythroderma, wet desquamation, blistering, and loss of superficial skin layers may occur. The severity of skin involvement is staged, based on the extent of injury to the skin ( Table 8 ). A skin biopsy is necessary to confirm the diagnosis of GVHD. Skin biopsy reveals epidermal basal cell degeneration and the presence of eosinophilic bodies, which represent dead epidermal basal cells. Severe involvement causes necrosis of basal cells, leading to separation of dermal epidermal junction and frank denudation resembling toxic epidermal necrolysis.

Liver Involvement

The liver is not involved when GVHD occurs after liver transplantation because the liver graft is the carrier of the donor immunocompetent T cells. Liver involvement results in physical and laboratory changes. Although patients with mild liver involvement may be asymptomatic, alkaline phosphatase and serum bilirubin levels generally are elevated. In addition, symptoms of right upper quadrant pain, hepatomegaly, and jaundice may occur. The severity of liver involvement is staged, based on the serum bilirubin level ( Table 8 ). A liver biopsy is required to confirm liver involvement of GVHD. Liver biopsy reveals atypical degeneration of small bile ducts in early GVHD, progressing to hepatic necrosis as the disease worsens.

GI Tract Involvement

Initial signs and symptoms of GI tract involvement include green, watery, and sometimes bloody diarrhea, abdominal cramping, nausea, vomiting, and anorexia. Severe hypoalbuminemia can occur in extreme cases. As the severity of involvement increases, villi are destroyed and the intestinal mucosa sloughs. Absorption in the GI tract is diminished and transit time decreases, resulting in copious volumes of diarrhea, fluid and electrolyte imbalances, malabsorption syndrome, guaiac-positive stool, and occasionally massive GI bleeding. Examination of the stool reveals leukocytes in the absence of pathogenic organisms. The severity of GI involvement is staged, based on volume of diarrhea and/or ileus and pain level ( Table 8 ). A biopsy of intestinal tissue through endoscopy or sigmoidoscopy is required to confirm GI involvement of GVHD. Small bowel biopsy reveals crypt cell necrosis. Later, crypt abscesses and cellular dropout occur. The bowel wall becomes thickened with flattening of villi and infiltration by mononuclear cells. Diffuse denudation of the mucosa can occur.

Lung Involvement

The main symptom of acute GVHD with lung involvement is acute respiratory distress. Signs and symptoms of chronic lung involvement include bronchitis, obstructive airway disease, sinopulmonary infection, and chronic pulmonary aspiration.

Care of the Patient With GVHD

Prophylaxis of GVHD is preferable to treatment. Two main strategies are used for GVHD prophylaxis: (1) recipient immunosuppression, and (2) elimination of T cells responsible for GVHD prior to the transfer of donor cells. Treatment of GVHD includes supportive and immunosuppressive therapy. GVHD predisposes patients to infection at a number of sites where skin and gut protective barriers are broken. Care of the patient with GVHD requires acute observation skills, documentation of serial changes in the patient's condition, and evaluation of patient responses to the disease and treatment. Nursing care of the patient is focused on detection of early signs and symptoms, support of patient comfort, and implementation of the medical plan of care, including fluid and electrolyte replacement, antidiarrheal therapy, antibiotic (particularly antifungal) therapy, immunosuppressive therapy, and nutritional support. Topical corticosteroid creams may be applied to the skin in patients with minimal skin involvement. In addition, patients with gut involvement may require narcotic analgesia to control pain. Adjustments to increase the level of immunosuppression with standard regimens are made. In addition, methotrexate has been used effectively in GVHD after bone marrow transplantation.

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