Irradiation of Blood Products
Graft versus host disease (GVHD) occurs when donor lymphocytes engraft in a susceptible recipient. These donor lymphocytes proliferate and damage target organs, especially bone marrow, skin, liver, and gastrointestinal tract, which ultimately can be fatal. The disease initially was recognized as a complication of intrauterine transfusion and transfusion to recipients of allogeneic marrow transplant in patients who had received total body irradiation. GVHD also has been seen in other immunologically incompetent patients whose exposure to donor lymphocytes has been from transfusion of cellular blood products or, rarely, a transplanted organ. Finally, the most commonly-reported setting for transfusion associated GVHD (TA-GVHD) is immunocompetent recipients of blood from biologically related or HLA identical donors.
In contrast to GVHD seen in allogeneic bone marrow transplant patients, the marrow is the primary target of donor lymphocyte mediated immune attack in TA-GVHD. Consequently, TA-GVHD runs a more fulminant course than marrow transplant-associated GVHD and mortality is about 80% with a median survival of only 21 days after transfusion. Death usually is due to complications of infection or hemorrhage that follow pancytopenia. By comparison, only 10 to 20% of cases of marrow transplant-associated GVHD are fatal. The rarity of TA-GVHD and the paucity of published experience make the definition of groups at risk for the disease difficult. A review of experience outside the transplant setting1 revealed only 87 cases in the literature. However, with increasing awareness of the disease and with increasing numbers of patients experiencing immune suppression during radiation and chemotherapy, it is prudent to review the conditions where irradiation of products for transfusion should be considered to prevent TA-GVHD. Historically, the disease has been underreported, especially among immunocompetent hosts.2,3
TA-GVHD has been reported in 13 children with diseases involving impaired cellular immunity, including Wiskott-Aldrich syndrome, severe combined immunodeficiency and thymic hypoplasia.4 TA-GVHD is not, however, a risk for patients with defective humoral (antibody mediated) immunity like Bruton's or common variable agammaglobulinemia, nor is it a risk for patients with neutrophil dysfunction, such as chronic granulomatous diseases. TA-GVHD also has been documented in 6 infants with erythroblastosis fetalis being treated by exchange or intrauterine transfusion. TA-GVHD also has been described in 4 premature infants, 25 to 33 weeks gestation, after small volume transfusion for anemia who did not have any other risk factor for TA-GVHD.
In patients with hematologic malignancies, TA-GVHD has been reported in Hodgkin's disease (15 patients) and non-Hodgkin's lymphoma (8 patients) receiving chemotherapy alone or in conjunction with radiation therapy. TA-GVHD is a rarer complication of transfusion in patients with leukemia. There are 12 case reports of patients with acute myelocytic leukemia and 6 case reports of patients with acute lymphoblastic leukemia acquiring GVHD after transfusion. TA-GVHD may be less likely in leukemia because cellular immune responses are better preserved than after treatment for Hodgkin's disease.
There also are isolated case reports describing TA-GVHD in patients with neuroblastoma, glioblastoma, rhabdomyosarcoma and immunoblastic sarcoma. Although there are isolated case reports of TA-GVHD in orthotopic organ transplant recipients, in at least one of these cases, HLA typing of the responsible donor lymphocytes revealed them to be identical to those of the organ donor.
While some form of immune suppression on the part of the recipient usually sets the stage for GVHD in marrow transplant or transfusion recipients, a number of cases of fatal TA-GVHD have been described in apparently immunologically normal patients who received directed blood donations from first degree relatives. When the donor is homozygous for an HLA haplotype that the recipient with normal immune function shares, the affected blood recipient's immune system cannot recognize the shared tissue type of the donor, but donor lymphocytes mediate damage to the unique determinants of the recipient. This mechanism has been invoked as the cause of postoperative erythroderma, a disease of transfused cardiac surgery patients that is well described in the Japanese literature. The genetic homogeneity of the Japanese population increases the likelihood that donors will be homozygous for an extended HLA haplotype and contributes to the apparent increased risk of the disease in Japan. While less well reported outside Japan, many similar cases have been observed. Second degree relatives pose a significant risk as well.5 The risks from directed donor blood have been calculated6 and rates similar to their predictions now are emerging.
Although individuals with AIDS (and/or HIV infection) have impaired cellular immunity, GVHD has not been described in these patients.
Products implicated in cases of TA-GVHD include non-irradiated whole blood, packed red blood cells, platelets, granulocytes and fresh non-frozen plasma. Frozen deglycerolized red blood cells, fresh frozen plasma and cryoprecipitate have not been implicated. While the absolute dose of lymphocytes sufficient to induce TA-GVHD in a susceptible transfusion recipient is unknown, a recent case report described a patient with non-Hodgkin's lymphoma who developed GVHD after receiving components that had been transfused through white blood cell reduction filters.7 For this reason, filtration, even with the new, highly-efficient filters, must not be regarded as a substitute for irradiation.
At present, gamma irradiation of blood products is the only procedure known to prevent transfusion associated GVHD. The most common irradiation sources are cobalt-60 and cesium-137. Most blood centers rely on a nominal dose of 25Gy with no less than 15Gy delivered to any area of the bag for these isotopes to inactivate lymphocytes in cellular products for transfusion.8
these doses have not been shown to impair platelet function, there is
some evidence that irradiation causes a modest leakage of potassium,
reducing the storage time of red blood cells and decreasing their
survival after transfusion. Therefore, irradiated red blood cells are
given a reduced storage time. While some physicians believe that
irradiated red blood cells for exchange transfusion should be washed to
remove potassium, this step is not regarded as routinely necessary and
should be reserved only for selected problem patients - for example,
neonates receiving exchange transfusion with pre-existing hyperkalemia
or renal failure. Other concerns about the effect of irradiation remain
(PCT) inactivation of bacterial and viral pathogens in blood components
using psoralens and UV-A light irradiation may also serve as prophylaxis
against TA-GVHD. Several reports document the efficacy of PCT to
inactivate T cells and prevent TA-GVHD.9 Alternatively, a
mouse model documented prevention of GVHD using less intense UV-B
irradiated donor leukocytes.10 Since licensed devices to
irradiate components using UV light are not available, and the presence
of red cells precludes the efficacy of this treatment, further advances
in this technology are required before it can routinely be applied to