Special Blood Products II Irradiated Blood Products and Transfusion Associated Graft Versus Host Disease

The irradiation of blood products using high-energy radiation (gamma rays) is exclusively performed to prevent a rare but fatal complication of blood transfusion, known as transfusion associated graft versus host disease (TA-GVHD). Other forms of radiation involving the ultraviolet region (UV) have been used experimentally alone or in combination with photochemical agents to inactive leukocytes or microbes in blood products, but are not in routine use at this time. These blood products could also be called "irradiated blood". It is important to appreciate that only blood products, which contain viable cells, need irradiation, and it is a common error to request irradiation of acellular products such as plasma or cryoprecipitate.

TV-GVHD occurs because the transfused allogeneic leukocytes (an unintended part of the transfusion component) may be viable at the time of transfusion and may undergo multiplication. Under normal circumstances, when red cells or platelets are transfused, the "passenger" allogeneic leukocytes are capable of being detected in the circulation for several hours. These allogeneic leukocytes attempt to divide as they react immunologically to foreign antigens in the host, and multiplication of these cells can sometimes be observed 3-5 days after the transfusion using sensitive techniques, such as amplication of HLA-DR genotypes using the polymerase chain reaction (PCR). Under normal circumstances, however, the host (recipient) immunocytes are successful in eliminating the donor allogeneic leukocytes and thus no observed adverse clinical event is evident. In patients with a compromised immune system, however, the ability of the host immune system to destroy the donor allogeneic leukocytes is impaired, giving rise to a situation in which the donor immunocytes proliferate and recognize host tissue as foreign. A similar situation can arise uncommonly in a nonimmunocompromised recipient, if there is similarity between the HLA type of donor and the recipient. In this situation, the donor cells are not recognized as "foreign" by the host (recipient) immune system. For practical purposes, this type of situation (known as a one way HLA match) is almost always encountered when the donor is homozygous for a HLA haplotype, which is also present in the recipient.

Regardless of the mechanism by which this rare event occurs, TA-GVHD exhibits clinical manifestations 4-21 days after the transfusion and is, therefore, a delayed adverse reaction to blood transfusion (Chapter 33). TA-GVHD affects the liver, skin, and gastrointestinal tract, giving rise to hepatitis, skin rashes, erythema and diarrhea. These clinical manifestations are similar to a graft versus host reaction occurring in allogeneic bone marrow transplantation. The distinguishing feature of TA-GVHD, however, is the presence of pancytopenia due to bone marrow failure. Pancytopenia is the hallmark of TA-GVHD, accounting for the high mortality rate of at least 90%. The only potentially effective treatment is an emergency allogeneic bone marrow transplantation, which, under these circumstances, is rarely successful. It is on account of this high mortality that prevention is essential. Prevention is achieved by irradiating cellular blood products with gamma photons to a dose which renders allogeneic lymphocytes incapable of mitotic division. This can be achieved at doses as low as 500-600 rads but conventionally, the minimum dose recommended is 2,500 rads to the midplane of the blood product.

Irradiation of red cell products is known to damage the red cell membrane giving rise to an increase in extracellular potassium and a slight reduction in the recovery of red cells (a loss of about 7-8%). Irradiated red blood cells should not be stored for longer than 28 days after irradiation, or the end of the expiration period, whichever comes sooner. The potassium level at this time can sometimes be as high as 100 mEq/L, but is usually about 50-70 mEq/L. In practice, however, as discussed previously, this high potassium is only a problem in the context of neonatal exchange transfusion, massive transfusion in trauma or patients with impaired renal function (Chapter 14). It is best to irradiate red cells immediately before transfusion, if possible, as this minimizes the irradiation induced changes. Gamma irradiation at these doses has only a minimal effect on platelets and changes in potassium do not occur. Nevertheless, it is advisable to irradiate platelets immediately before transfusion, if practical, as with red blood cells.

Table 37.1 shows the major indications for the irradiation of cellular blood products. It is important to distinguish two clinical situations. First, blood is irradiated for some patients who are immunocompromised. These are patients with hereditary T-cell deficiencies; fetuses and premature infants; neonates, particularly low birth weight newborns, and some patients with pediatric malignancies such as young children with neuroblastomas. Patients with Hodgkin's disease requiring blood transfusion should routinely receive irradiated blood on account of the known T-cell immune defect—regardless of whether these patients exhibit any clinical evidence of a cell mediated immune defect. Bone marrow transplant recipients should receive irradiated blood products under certain circumstances. Candidates for allogeneic transplants should receive irradiated blood just prior to the start of the conditioning regimen until at least two years postsuccessful en-graftment, and it is not uncommon to routinely transfuse irradiated blood products to these patients indefinitely after transplantation. Candidates for autologous transplants should receive irradiated blood products: (1) two weeks prior to any stem cell collection either by apheresis or bone marrow harvest. The rationale for this recommendation is that allogeneic leukocytes present from a recent transfusion could be harvested during the stem cell collection, subsequently cryopreserved, and re-infused with the transplant. (2) Autologous stem cell transplant patients should receive irradiated blood from the start of the conditioning regimen until after engraftment. After successful engraftment of an autologous transplant, it is questionable whether irradiated blood is required. However, it is not an uncom-

Table 37.1. Irradiated blood products

(I) Irradiation for recipient reasons, i.e., immunocompromised patients.

(a) Hereditary Immune T-Cell Deficiencies

(b) Fetuses: and Neonates

(c) Pediatric Malignancies (e.g., neuroblastomas)

(d) Hodgkin's Disease

(e) Bone Marrow Transplants:

1. Allogeneic: from the start of conditioning regimen until at least two years post successful engraftment.

2. Autologous: Two weeks prior to any stem cell collection by apheresis/bone marrow harvest and from the start of conditioning regimen until three to six months after engraftment.

(II) Irradiation for product reasons:

(a) Directed donations, where the donor is genetically related to the recipient

(b) HLA matched platelets mon practice to routinely administer irradiated blood for a period of 3-6 months after engraftment. Thereafter, the immune system should be reconstituted and capable of preventing TA-GVHD.

The second clinical situation is irradiation of blood products because of product type. Directed donations from donors who are genetically related to the recipient should all be irradiated prior to transfusion. All HLA matched platelets should be irradiated. In many cases, however, HLA matched platelets are irradiated in any event since the recipient may be immunocompromised.

Table 37.2 shows clinical situations where blood is sometimes routinely irradiated, but where the data demonstrating the appropriateness of this practice is lacking. First, patients with AIDS, although clearly having an immunocompromised state, do not need to routinely receive irradiated blood; (this is discussed in more detail in Chapter 12). In some clinical centers, all adult patients with hematological malignancies are routinely given irradiated blood products and in some pedi-atric oncology units it is common practice to irradiate blood products for all recipients with hematologic and nonhematologic cancers. Although there are some accepted indications in pediatric oncology for the use of irradiated products, the routine use of irradiated products in the treatment of the common liquid tumors, such as leukemias and lymphomas, and for many of the solid tumors (such as Wilms disease), would appear to be unjustified. In the past, granulocyte transfusions have been implicated in causing TA-GVHD in patients with acute leukemia,

Table 37.2. Clinical situations where blood is sometimes requested as irradiated, but where inadequate data exists to justify the practice as routine

(a) AIDS Patients (Chapter 20)

(b) Solid Organ Allografts Recipients (Chapter 12)

(c) All Adult Hematologic Malignancies (Chapter 15)

(d) All Pediatric Malignancies (hematologic and solid)

(e) All Granulocyte Products and for this reason is has become common practice to routinely irradiate granu-locytes. However, granulocytes should not be irradiated simply because of the large dose of viable immunogeneic leukocytes. Granulocytes should be irradiated if there is a recipient indication for the irradiation. In practice, however, granulo-cytes are used for severely septic and neutropenic patients, and it is often difficult to exclude a possible immunocompromised state.

Cellular blood products have been implicated in the causation of TA-GVHD only when the product had been stored for less than 14 days. Although all platelets transfused are stored for five days or less, many red cell products are transfused beyond this storage period. Theoretically requesting older red cells could be adequate prophylaxis for TA-GVHD, but in practice, this is cumbersome, has potential for error and should be avoided.

Special Blood Products III: Cytomegalovirus Low Risk Blood Products and the Prevention of Primary CMV Disease

Serological evidence of previous cytomegalovirus (CMV) infection is present in a very significant number of blood donors. Depending on geographic location and donor age, this varies between 25-70%. Thus, the potential for blood products to transmit CMV infection is high. Only subpopulations of blood donors who are serologically positive for CMV are capable of transmitting CMV, however, perhaps as few as 5%. Regardless, this subpopulation of CMV seropositive donors cannot be accurately identified prospectively at this time. As discussed in Chapter 34, CMV belongs to the Herpes group of viruses and the reservoir for this virus in asymptomatic donors is circulatory T lymphocytess. The ability to transmit CMV by blood transfusion, however, may be correlated with the presence of the virus in either donor monocytes or granulocytes at the time of donation. It follows, therefore, that leukoreduction has the potential to eliminate this complication.

CMV infection must be distinguished from CMV disease. The transmission of CMV by blood transfusion (CMV infection) is common, largely asymptomatic, and can only be recognized by subsequent serological testing. CMV disease, however, is a potentially catastrophic clinical complication. Severe pneumonia, gastroenteritis or retinitis characterizes CMV disease and can result in a fatal outcome in certain transfusion recipients, for example, patients undergoing alloge-neic transplantation. Prevention, therefore, is critical. Primary CMV disease refers to the occurrence of CMV disease in a seronegative recipient; secondary CMV disease represents reactivation of CMV in a CMV seropositive recipient. CMV low risk products are used to prevent primary CMV disease and have no known role in preventing secondary CMV disease.

There are several different approaches to the prevention of primary CMV transmission by blood transfusion, as shown in Table 38.1. Historically, the most widely accepted practice is the transfusion of blood products from donors known to be serologically negative for CMV at the time of donation. Leukoreduction however, using third or fourth generation filters (Chapter 36), has also been shown to be effective in preventing CMV infection. The use of frozen deglycerolized red cells in renal transplant patients is known to be effective, but, in practice, frozen red cells are rarely used to prevent CMV transmission and, thus, the choice of product

Table 38.1. Types of CMV low risk blood products a) Donations which are serologically negative for CMV

b) Leukoreduction by a third or fourth generation filter (Chapter 36)

c) Frozen - deglycerolized red blood cells (Chapter 39)

d) Blood products which do not contain viable white cells e.g. frozen plasma or cryoprecipitate

Table 38.2. Indications for CMV risk reduced blood products

(a) Intrauterine transfusions and low birth weight (<1.2 kg) infants

(b) Pregnant females of unknown or CMV seronegative status

(c) Bone marrow transplantation:

(I) Allogeneic transplantation of CMV negative stem cell product to a CMV negative recipient (both potential candidates and identified recipients).

(II) Autologous transplantation in a CMV negative patient

(d) Solid Organ Transplantation: CMV Seronegative candidates

(e) T cell-immunodeficiency state in a CMV seronegative patient e.g. Acquired Immune Deficiency Syndrome; Severe Combined Immunodeficiency Disease.

generally is between CMV seronegative components and leukoreduced blood. Studies in the last ten years have shown leukoreduced blood to be essentially equivalent to CMV seronegative blood components. CMV transmission has similarities with irradiated blood (Chapter 37) in that only cellular blood products transmit CMV and red cells stored for more than 14 days are not known to transmit CMV. Frozen plasma or cryoprecipitate are CMV low risk products and, therefore, do not need to be either filtered or manufactured from donations, which are CMV seronegative.

The appropriate patient populations who should receive CMV low risk blood products are shown in Table 38.2. All intrauterine transfusions and transfusions to low birth weight infants (< 1.2 Kg) should be CMV low risk; either a seronegative donor or a leukoreduced product is acceptable for this purpose. Pregnant females of unknown CMV status or who are known to be CMV seronegative should receive CMV low risk products. The occurrence of primary CMV infection in pregnancy can have catastrophic complications for the fetus, especially in the first trimester. One of the major indications for CMV low risk products is in the management of patients undergoing bone marrow transplantation. Potential allogeneic transplant patients who are CMV seronegative and who will receive a CMV seronegative stem cell (bone marrow) product should receive CMV low risk products. In this patient population, there is a strong preference for the use of blood products from serologically negative donors, although current data would indicate that a leukoreduced product is equivalent. Autologous transplants need only receive a CMV low risk product if the patient-donor is known to be CMV seronegative. A leukoreduced product is generally acceptable. CMV disease is less commonly observed in autologous transplantation. Solid organ transplants constitute another important population of patients for whom CMV low risk products (Chapter 12) are appropriate if the recipient is CMV seronegative. CMV low risk products are not known to be useful in CMV seropositive allograft recipients. Although CMV disease may occur due to a different strain of CMV ("second strain CMV"), this second strain of CMV virus has only been shown to be of allograft origin and not transfused derived. A last miscellaneous group constitutes patients with T-cell immunodeficiency status, such as patients with HIV or severe combined immunodeficiency disease. Although most patients with HIV infection (approximately 85-90%) are CMV seropositive at the time of diagnosis, there is still a subpopulation who are CMV seronegative, and the occurrence of primary CMV transmission in this population needs to be avoided. Leukoreduction is a reasonable approach in these patients.

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