Transfusion-Associated Graft-Versus-Host Disease

Transfusion-associated graft-versus-host disease (TA-GVHD), a rare (1 fatality reported to FDA 2011–15) and almost universally fatal complication of blood product transfusion, is due to the cotransfusion of viable lymphocytes in cellular blood products, such as whole blood, red blood cells (RBCs), platelets, granulocytes, and liquid (not previously frozen) plasma. If the immune system of the recipient does not recognize and produce an immune response against the cotransfused lymphocytes, they can engraft and mount an immune response against the host; thus the term graft-versus-host disease. The recipient’s immune system can be limited in responding to the cotransfused lymphocytes because of the following: (1) significant immunosuppression and (2) planned or inadvertent human leukocyte antigen (HLA) matching between donor and recipient. Irradiation or pathogen inactivation (PI) of the product can mitigate TA-GVHD. Both of these methods cause DNA damage in the cotransfused lymphocytes and render them incapable of cell division and engraftment. It is critical to identify recipients who are at risk of TA-GVHD and ensure that blood products are treated to prevent this lethal transfusion complication.

Normal Clearance of Transfused Lymphocytes

In a study investigating the clearance of cotransfused lymphocytes in immunocompetent recipients, three phases were found: (1) 99.9% of lymphocytes were cleared over the first 2 days, (2) there was a 1-log increase in the number of circulating donor lymphocytes on days 3–5, and (3) there was a second clearance event leading to the small number and percent of chimeric cells. It was postulated that the transient increase in donor lymphocytes represents one arm of an in vivo mixed lymphocyte reaction with activated donor T-lymphocytes proliferating in response to exposure to HLA-incompatible recipient cells. The second clearance step results from the recipient’s immune system mounting an augmented response against the donor cells. Irradiation of blood components eliminates the expansion of donor cells and thus abrogates transfusion-associated microchimerism (TA-MC) and TA-GVHD.

Pathophysiology

The mechanism of TA-GVHD is similar to that of acute GVHD after hematopoietic progenitor cell (HPC) transplantation, where donor lymphocytes attack host tissues. There are three separate phases of development: phase 1 is conditioning, phase 2 is the afferent phase, and phase 3 is the efferent phase. The conditioning regimen results in host tissue damage and activation, which leads to the production of inflammatory cytokines. The afferent phase results in donor T-cell activation through antigen presentation, followed by proliferation, and then differentiation of activated T-cells. Inflammatory cytokines are released during the efferent phase, leading to the damage of host tissues, and finally cell death and host tissue destruction.

Clinical Manifestations

Once coadministered viable lymphocytes have been infused with the blood products, they can engraft and produce an immune response against HLA-rich tissues and organs in the recipient. Symptoms include erythema, liver dysfunction, GI symptoms, and profound pancytopenia. Fever accompanies this process due to release of inflammatory cytokines. Pancytopenia of TA-GVHD differentiates it from HPC-associated GVHD and gives it a near 100% mortality.

TA-GVHD in adults results in death within 3 weeks from symptom onset in >95% of cases. In neonates, the clinical manifestations are similar, but the time between transfusion and symptom onset is longer than for adults: fever occurs around 28 days, rash around 30 days, and death around 51 days. In both groups, fever is usually the presenting symptom, followed by an erythematous maculopapular rash, which typically begins on the face and trunk and spreads to the extremities. Liver dysfunction usually manifests as obstructive jaundice or acute hepatitis. GI complications include nausea, anorexia, or diarrhea. Leukopenia and pancytopenia develop later and progressively become more severe, often times leading to sepsis and candidiasis, multiorgan failure, and death.

Diagnosis

Diagnosis is based on clinical findings in conjunction with laboratory and biopsy results. However, TA-GVHD is often not suspected, the symptoms, findings, and laboratory tests can easily be interpreted as being due to severe viral infection or adverse reaction to administered medication. Thus TA-GVHD is potentially underdiagnosed. Discovery of donor lymphocytes or DNA in the patient’s peripheral blood or tissue biopsy with the appropriate clinical picture confirms the diagnosis. Donor-derived DNA is usually detected by polymerase chain reaction (PCR)-based HLA typing, but other methods include use of restriction fragment length polymorphism analysis, variable number tandem repeat analysis, microsatellite marker analysis, fluorescence in situ hybridization, and cytogenetics.

The National Healthcare Safety Network Manual, Biovigilance Component, case definition criteria includes

A clinical syndrome occurring from 2 days to 6 weeks after transfusion characterized by the following:
- Rash (erythematous, maculopapular eruption centrally that spreads to extremities and may progress to generalized erythroderma and hemorrhagic bullous formation)
- Diarrhea
- Fever
- Hepatomegaly
- Liver dysfunction
- Marrow aplasia
- Pancytopenia
- Characteristic histological appearance of skin or liver biopsy
- WBC chimerism

Treatment

Treatment is largely palliative and aimed at attempting to improve the function of, or render the recovery of, the recipient’s immune system and bone marrow. This is largely unsuccessful. Approaches include corticosteroids, antithymocyte globulin, and cyclosporin used with hematopoietic growth factors. There are a few reports of spontaneous resolution, successful treatment with a combination of cyclosporin, steroids and OKT3 (anti-CD3 monoclonal antibody) or antithymocyte globulin, and treatment with autologous or allogeneic hematopoietic stem cell transplantation. Transient improvement has been seen with nafamostat mesilate, a serine protease inhibitor that inhibits cytotoxic T-lymphocytes.

Prevention

Patients at increased risk must be identified and transfused with lymphocyte-inactivated products, usually through irradiation or PI methods (see Chapter 42 ).

Risk Factors ( Table 42.1 )

Blood Product Factors

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here