Transfusion-associated graft-versus-host disease

INTRODUCTION — Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare and usually fatal complication of blood transfusion in which lymphocytes from the transfused blood component attack the recipient's tissues, especially the skin, bone marrow, and gastrointestinal tract. Recognition is often delayed because nonspecific symptoms are attributed to the patient's underlying diagnosis or another condition such as infection.

Unlike GVHD associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT), in TA-GVHD the lymphocytes from the transfusion attack the recipient's bone marrow, leading to bone marrow aplasia and profound pancytopenia, which is typically the cause of death. There are no highly effective treatments, so prevention is essential. This can be accomplished very effectively by treatment of the blood component to inactivate viable lymphocytes prior to transfusion.

This topic review will discuss the pathogenesis, presentation, diagnosis, management, and prevention of TA-GVHD. Separate topic reviews discuss other delayed transfusion reactions and the form of GVHD associated with allo-HSCT.

●Delayed hemolytic transfusion reaction (DHTR) – (See "Hemolytic transfusion reactions", section on 'Delayed hemolytic transfusion reactions and delayed serologic transfusion reactions'.)

●Post-transfusion purpura – (See "Immunologic transfusion reactions", section on 'Post-transfusion purpura'.)

●Transfusion-transmitted infections – (See "Blood donor screening: Medical history", section on 'Screening for infectious risks' and "Blood donor screening: Laboratory testing", section on 'Infectious disease screening and surveillance' and "Transfusion-transmitted bacterial infection".)

●Acute GVHD related to allo-HSCT – (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

●Chronic GVHD related to allo-HSCT – (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

PATHOGENESIS

Overview of pathogenesis — TA-GVHD is a rare complication of transfusion that may occur when transfused lymphocytes are viable and one of the following is present:

●The recipient is immunosuppressed

●There is partial HLA matching between the transfused product and the recipient

Specifically, viable T lymphocytes from the transfused blood component are able to engraft, proliferate, and attack human leukocyte antigen (HLA)-expressing tissues in the host (transfusion recipient) as foreign. Most commonly, HLA class II antigens are involved, although a case report has been published describing TA-GVHD in which a T cell clone against an HLA class I antigen was found [1]. Immune attack is mediated by the transfusion donor's T cells, either through direct destruction of host cells or via inflammatory cytokines that activate other immune cells including natural killer (NK) cells, macrophages, and other lymphocytes [2,3].

Viable lymphocytes are present in most blood components including whole blood, red blood cells (RBCs), platelets, and plasma that has never been frozen. Normally, lymphocytes present in the transfused component would be destroyed by the recipient's immune system before they can mount an immune response against the recipient. In TA-GVHD, the recipient's immune system either does not recognize the donor lymphocytes as foreign or is unable to mount an effective immune destruction.

●The recipient may not recognize the donor lymphocytes as foreign if there is partial HLA matching, which is most common in ethnically homogeneous populations, such as Japan, or with directed (family member) donations. (See 'Partial HLA matching' below.)

●The recipient's immune system may not mount an effective response against the donor lymphocytes if there is a deficiency in cell-mediated immunity, which can be due to an inherited or acquired immune deficiency state. (See 'Immunodeficiency' below.)

The attack of recipient tissues affects all tissues that express HLA class II. These cells include the hematopoietic stem cells (HSCs), intestinal epithelium, and skin. As a result, the recipient develops profound pancytopenia from bone marrow aplasia as well as gastrointestinal effects (diarrhea, abdominal pain) and skin changes (generalized erythroderma that can progress to desquamation). (See 'Host tissues targeted by donor lymphocytes' below.)

The lethality of TA-GVHD is due to the bone marrow aplasia, which generally cannot be rescued by autologous or allogeneic HSCs due to lack of immediate availability of these HSC sources. In GVHD associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT), the donor T cells and donor HSCs come from the same individual and are thus compatible. (See 'Treatment' below and 'Prognosis' below.)

Appropriate use of preventive strategies (blood product irradiation, pathogen inactivation, or other processes that inactivate lymphocytes) for at-risk transfusion recipients has reduced the incidence of TA-GVHD. (See 'Prevention' below.)

A case of mild TA-GVHD was reported in an individual who received a transfusion shortly after the birth of twins, and genotyping documented that the T lymphocytes were fetally derived [4]. (See '"Mild" TA-GVHD' below.)

Risk factors

Immunodeficiency — Immunodeficiency states can impair the ability of the transfusion recipient's immune system to destroy donor lymphocytes present in the transfused blood component. This includes hereditary and acquired immunodeficiency states associated with the following underlying conditions [2]:

●Primary immunodeficiency – A report from 1965 described two children with immunodeficiency who developed vaccinia infections following smallpox vaccination and whose treatment included transfusions (one of leukocyte-rich plasma and one of whole blood); both developed erythroderma, hepatomegaly, and pancytopenia, and both died [5]. Cases of TA-GVHD in individuals with various primary immunodeficiency syndromes have subsequently been described [6]. Severe combined immunodeficiency (SCID) and Wiskott-Aldrich syndrome are commonly represented in case series.

●Hematologic malignancy – Cases of TA-GVHD have been reported in individuals with Hodgkin disease, non-Hodgkin lymphoma, and acute myeloid and acute lymphoid leukemias (AML and ALL). Patients with chronic lymphocytic leukemia (CLL) treated with fludarabine have also developed TA-GVHD. (See "Classification of hematopoietic neoplasms".)

●Immunosuppressive drugs – Commonly used immunosuppressive drugs such as glucocorticoids and rituximab have not been associated with TA-GVHD. However, drugs that cause profound lymphocyte suppression such as fludarabine have been implicated, both in individuals with hematologic malignancy as well as non-malignant conditions (eg, systemic lupus erythematosus [SLE]) [7,8].

●Hematopoietic stem cell transplantation (HSCT) – Allo-HSCT carries a risk of acute or chronic GVHD from the donor hematopoietic cells, but patients undergoing HSCT also receive cytotoxic therapy and numerous transfusions, which may include HLA-matched products. Thus, these individuals could potentially be at risk for TA-GVHD as well. One case report described TA-GVHD in four individuals who underwent autologous HSCT for solid tumors [9].

●Fetuses and neonates – Several case reports have described TA-GVHD in fetuses receiving intrauterine transfusions or exchange transfusions [2]. Only rare case reports have described TA-GVHD in preterm infants or neonates, and these may be explained by partial HLA matching, as they either occurred in Japan or in the setting of a transfusion from a related donor [2]. There does not appear to be an increased risk in healthy, full-term infants.

In the largest case series, which included 348 cases of TA-GVHD, 19 percent had a hematologic malignancy and 7 percent had a congenital immunodeficiency [10].

TA-GVHD has not been described in individuals with HIV infection or AIDS. Several explanations have been proposed, including the possibility that the lymphocytes in the transfused product become infected by HIV, the use of irradiated blood products in this population is already high, the diagnosis is missed, or these individuals have an intact CD8⁺ T cell response, which is critical for preventing TA-GVHD [2].

Partial HLA matching — Partial human leukocyte antigen (HLA) matching refers to a situation in which the transfusion recipient and the blood product donor share some but not all HLA antigens (haplotypes).

In TA-GVHD, the mismatch occurs in such a way that the recipient's immune system fails to identify donor T cells as foreign, and thus does not mount an immune response against them, but the donor T cells do recognize the recipient's tissues as foreign. This type of mismatch occurs when the transfusion recipient is heterozygous for an HLA haplotype for which the donor is homozygous, as illustrated in the figure (figure 1).

In contrast, if the donor and recipient are perfectly HLA-matched (eg, identical twins), there is no recognition of HLA disparity or immune attack by recipient or donor lymphocytes.

A 2015 systematic review that included 348 cases of TA-GVHD identified between 1966 and 2013 found that in 84 individuals for whom HLA data were available, partial HLA matching was present in 60 (71 percent) [10]. The frequency of partial HLA matching was higher than expected in those with an immunocompromised state, and partial HLA matching was seen in virtually all of those who were immunocompetent. The authors concluded that partial HLA matching appears to play an important role in the development of TA-GVHD in recipients with all levels of immune function, though possibly to a greater degree in those without impaired immunity.

The two most common settings in which partial HLA matching occurs is in ethnically homogenous populations, especially in Japan, and from related donors.

●Genetically homogeneous populations – Genetically homogenous populations include island countries such as Japan as well as those in which there is a high rate of consanguineous marriage.

•Japan – Cases of "postoperative erythroderma" have been described in Japanese literature since 1955; these were originally attributed to infection but were subsequently proposed to be TA-GVHD due to partial HLA matching [11,12]. In a survey that included 122 cases of TA-GVHD in Japan, the most common underlying condition for which transfusion was administered was cardiovascular surgery (56 cases [46 percent]), followed by solid tumors in 32 percent [13]. It has been estimated that the frequency with which blood from an individual homozygous for an HLA haplotype is transfused into a recipient heterozygous for that haplotype is approximately 1 in 659 in Japan compared with 1 in 500 to 1 in 7174 in the United States and 1 in 16,835 in France [14,15].

Because of this increased risk, blood products in Japan are routinely irradiated prior to transfusion, even for immunocompetent recipients. (See 'Gamma irradiation' below.)

•Consanguineous marriage – Consanguineous marriage increases the chance that certain HLA antigens will be highly prevalent in a population [16,17].

●Directed donations – Directed donations are those in which one individual donates a blood product specifically for transfusion to another individual. This may be useful in selected cases in which the recipient has a rare blood type or a rare HLA type. However, when the donor and recipient are related as first- or second-degree relatives, they have a much higher chance of sharing some HLA antigens than would occur with a random donor, which puts them at increased risk for TA-GVHD [2]. In the largest case series, which included 348 cases of TA-GVHD, 14 percent were recipients of a blood component from a related donor [10].

Implicated blood products — In principle, any blood product containing viable T-lymphocytes can cause TA-GVHD in an at-risk individual. This includes:

●Whole blood

●Red blood cells (RBCs)

●Platelets

●Plasma that has not been frozen

●Granulocytes

In the largest case series involving 348 cases, the implicated component was RBCs in 38 percent, whole blood in 26 percent, platelets in 6 percent, and plasma in one case [10]. In the remaining cases, the component was not identified or multiple components were transfused. Granulocyte transfusions are rare and were not evaluated in this study.

While leukocyte reduction is not sufficient to prevent TA-GVHD, risk is highest with products that have not been leukocyte depleted [18]. Also, lymphocyte viability may decline over time during storage. In an analysis of the storage time in 158 cases of implicated components, the component was ≤10 days old in 148 (94 percent) and 11 to 14 days in the remaining 10 [10]. No implicated components were stored for >14 days. However, leukocyte reduction is not sufficient to prevent TA-GVHD.

Studies in animals suggest that the dose of lymphocytes correlates with the risk of TA-GVHD, with approximately 10⁷ lymphocytes per kg of recipient weight required to produce disease in a susceptible host [19]. Data for humans are lacking, but there are likely sufficient lymphocytes in most blood products, including those that are leukoreduced, to lead to TA-GVHD.

Host tissues targeted by donor lymphocytes — Donor lymphocytes can attack any tissue in the recipient that expresses HLA class II. Typically affected tissues and the resulting findings include the following:

●Hematopoietic cells – Pancytopenia

●Intestinal epithelium – Diarrhea

●Liver – Hepatomegaly and abnormal liver function tests

●Skin – Erythroderma or macular rash

Mechanism of preventive procedures — Irradiation effectively renders dividing cells non-viable because it introduces significant damage to DNA and RNA, preventing cell proliferation and transcription, respectively. Thus, any product that has been properly irradiated prior to transfusion will not cause TA-GVHD. (See 'Gamma irradiation' below.)

As discussed below, certain pathogen inactivation (PI) procedures that are used prior to transfusion, or the freeze-thaw process, can also inactivate lymphocytes and serve as effective prevention for TA-GVHD [18]. Products that have been subjected to these procedures have not been implicated in TA-GVHD. (See 'Pathogen inactivation techniques' below and 'Freeze-thaw' below.)

INCIDENCE — TA-GVHD is an extremely rare transfusion complication. The true incidence is not known and is expected to vary by population and preventive strategies used. (See 'Prevention' below.)

In the 1980s, the overall incidence was estimated at 0.1 to 1 percent among at-risk individuals (see 'Risk factors' above), although this number has decreased considerably with greater recognition of risk factors and institution of preventive strategies [18,20]. As an example, the incidence was approximately 0.15 percent in Japan between 1981 and 1986, whereas there were no cases reported in Japan during 2000 or 2001 [2].

In the largest series of cases, the countries with the most cases of TA-GVHD were Japan (146 cases), the United States (50 cases), and the United Kingdom (36 cases) [10]. Smaller numbers (<20 cases) were reported from Turkey, Lebanon, Germany, and India. Other countries reported fewer than 7 cases. More cases were reported in males.

PREVENTION

Overview of prevention — Since TA-GVHD is highly preventable and very hard to treat, prevention is of primary importance. Prevention is best achieved by irradiating (or otherwise inactivating) lymphocytes in any blood components transfused to at-risk recipients. Leukodepletion may provide some protection but it is not sufficient to eliminate all viable lymphocytes. (See 'Methods to inactivate viable T cells' below.)

There are two approaches to the use of lymphocyte inactivation procedures:

●Selective irradiation – Identifying at-risk individuals (table 1) and ensuring that products they receive are properly treated is reasonable in populations in which the baseline risk of TA-GVHD is low. (See 'Identifying at-risk individuals' below.)

●Universal irradiation – Treatment of all blood products is reasonable in populations in which the baseline risk of TA-GVHD is high. Examples include countries with genetically homogenous populations or groups of patients at high risk such as "all individuals admitted to the hematology transplant service."

Japan is often cited as the country with a very high population risk of TA-GVHD due to genetic homogeneity. Other regions of the world where the baseline risk is high include areas with a high frequency of consanguineous marriage and directed blood donation, such as rural Turkey [17].

Institutions may use a hybrid approach such as universal irradiation for all neonates and selective irradiation for other individuals. Regardless of what approach is used, hospital policies should facilitate appropriate use of irradiation that minimizes the chance for error [21].

The United States policy of selective treatment of blood products for certain recipients was questioned when an immunocompetent individual developed TA-GVHD after receiving a random donor transfusion [22,23]. However, the potential benefits of universal treatment (irradiation or pathogen inactivation) must be weighed against the possible reduction in the availability of blood products (due to reduced shelf life, increased potassium levels, small time delay, and/or increased cost).

Identifying at-risk individuals — A key to prevention is identifying at-risk individuals and making sure the transfusion service is aware of their at-risk status.

The table (table 1) lists classes of individuals at increased risk for TA-GVHD for whom irradiation or other treatment of blood products prior to transfusion is appropriate; this list is based on Guidelines developed by the British Society of Hematology (BSH), last updated in 2020 [18].

In addition to identifying diagnoses and therapies that require a preventive intervention, the Guidelines document also makes recommendations concerning the duration for which irradiated products are needed (lifetime versus defined intervals). In some cases, the recommendation to use a lymphocyte inactivation procedure lasts indefinitely (eg, Hodgkin lymphoma, congenital primary immunodeficiency syndrome). In others, there may be a time-limited recommendation (eg, for three months after autologous hematopoietic stem cell transplantation [HSCT] or for six months if total body irradiation was used; for as long as GVHD from the allogeneic hematopoietic stem cells [HSCs] is present after allogeneic HSCT). The 2020 Guideline also provides information about newer immunosuppressive therapies including selected monoclonal antibodies (eg, alemtuzumab) and newer patient populations (eg, CAR-T recipients, individuals with congenital hemophagocytic lymphohistiocytosis [HLH]) [20].

Neonates receiving exchange transfusions are included as at-risk in the 2020 Guidelines, whereas a general neonatal population is no longer included [18]. However, some institutions continue to include all neonates as an at-risk population; institutions in the United States (US) generally consider very low birth weight infants and other neonates to be at risk [21]. Some health systems irradiate all blood components for children <6 years old due to the rare possibility of potentially undiagnosed immunodeficiency states at these ages.

In the United States, every hospital transfusion service establishes its own policy as to which groups of patients should receive irradiated blood components [24]. A 2014 survey of practices at approximately 2100 United States institutions performed by the College of American Pathologists (CAP) revealed substantial differences in which diagnoses were associated with the use of irradiated units [25]. Some institutions perform universal irradiation of all transfused cellular components, "block" irradiation for all patients on a given service or section of the hospital, or for all very young patients due to possible undiagnosed immunodeficiency.

Avoiding directed donations in populations at risk for partial human leukocyte antigen (HLA) matching is also reasonable, especially if universal irradiation is not being used. (See 'Partial HLA matching' above.)

In the largest series, approximately one-half of the 348 individuals who developed TA-GVHD had a recognized risk factor for the disease but did not receive irradiated components [10]. This suggests that increased vigilance can reduce the risk of the disease but by itself will not eliminate all cases.

Which products should be treated? — Once an individual has been identified as being at risk for TA-GVHD, the following products should be treated due to potential presence of viable T cells (see 'Implicated blood products' above):

●Whole blood

●Red blood cells (RBCs)

●Platelets

●Plasma that has not been frozen

●Granulocytes

Fresh frozen plasma (FFP) or other plasma products that have been frozen do not require irradiation because the free-thaw process is sufficient to inactivate T cells. (See 'Freeze-thaw' below.)

Hematopoietic stem cells should not be irradiated because they will become inviable.

Methods to inactivate viable T cells — Inactivation of lymphocytes in the transfused blood component is done by exposing the product to gamma irradiation; this is done in the blood bank before the component is delivered to the patient's bedside. (See 'Gamma irradiation' below.)

For platelets, another procedure that may be highly effective, less time consuming, and that does not reduce the shelf life of the platelet product, is pathogen inactivation. (See 'Pathogen inactivation techniques' below.)

Leukocyte reduction may partially reduce risk but is not considered a fully effective strategy by itself. (See 'Leukoreduction (not sufficient as an alternative)' below.)

Gamma irradiation — Irradiation is a relatively straightforward procedure that inactivates any nucleated cells (including T cells) in the blood component by damaging their DNA and RNA to the point that the cells cannot replicate.

This procedure does not expose the recipient to any radiation, and it does not substantially reduce the efficacy of transfusions, although it does alter the plasma membranes of RBCs, in turn causing potassium leak and reducing cell viability.

●In the United States, the allowable storage time for RBCs is decreased to 28 days post-irradiation. In other countries, the product must be irradiated within 14 days of collection and then the post-irradiation storage time is limited to 14 days.

●There is no impact on the shelf-life of plasma (which is used to provide non-cellular factors) or platelets (which is already very short due to room temperature storage).

Plasma that has been frozen (Fresh Frozen Plasma [FFP] or Plasma Frozen Within 24 hours After Phlebotomy [PF24]) does not need to be irradiated because the freeze-thaw process inactivates lymphocytes. (See 'Freeze-thaw' below.)

According to a memorandum from the US Food and Drug Administration (FDA; dated July 22, 1993), the dose of delivered gamma irradiation should be 25 Gy, targeted to the central portion of the container, and a minimum of 15 Gy to any other point [15]. A 2020 BSH Guideline states that the minimum dose should be 25 Gy, and no portion of the product should be exposed to more than 50 Gy [18]. This dose should result in effective lymphocyte inactivation, including a five to six log reduction in T cell response to mitogen, and complete inhibition of the mixed lymphocyte culture response.

Either a cesium-137 or cobalt-60 source can be used as a gamma source. The latter is usually present in radiation therapy departments and is less suited for irradiation of blood components. Thus, cesium-137 is the preferred source and is most often found in specifically designed, self-contained blood product irradiators. Due to bioterrorism concerns, the United States government is encouraging institutions to move to an X-ray source, which has similar impact on RBC membranes and potassium leakage as gamma irradiation [26]. According to the 2020 BSH guideline, either gamma irradiation or x-irradiation is acceptable [18]. A study from 2021 demonstrated that x-irradiation and gamma-irradiation have similar impact on in vitro quality of RBCs, as measured by hemolysis, metabolism, microparticles, ATP, and 2,3-DPG [27]. X-irradiation slightly increased potassium levels compared with gamma-irradiation for RBC units stored <5 days.

Irradiation has the following disadvantages, which explain why the procedure is not done universally:

●Given the special handling required, as well as access to the source of radioactivity, it can take as much as one-half hour to select and prepare a unit of blood for transfusion.

●It alters the plasma membrane of RBCs, resulting in a reduced storage time

●It increases the potassium load of a RBC transfusion, which may cause complications for patients with a small plasma volume (eg, fetuses, neonates).

●It adds cost and occupies personnel who would otherwise be working to provide other blood components to other patients.

Some recommend that fetuses or neonates receiving irradiated RBCs that have been stored for more than two to three weeks after irradiation should have the plasma removed from the product before it is transfused to reduce the potassium load. (See "Red blood cell (RBC) transfusions in the neonate", section on 'Indications for irradiated RBCs'.)

Pathogen inactivation techniques — Pathogen inactivation (PI) procedures are used to reduce the risk of transmitting an infectious organism in a blood product. Data from preclinical testing suggest that PI techniques are at least as effective, and possibly more effective, than gamma irradiation in preventing TA-GVHD [3,28,29]. Data using this approach in humans are more limited than for gamma irradiation [18].

PI techniques are primarily used for plasma and platelets, but methods for inactivating pathogens in RBCs are also under development, and pathogen-reduced RBCs are available in some countries. (See "Pathogen inactivation of blood products".)

Certain PI procedures can inactivate nucleated cells in much the same way that they inactivate pathogens. There are two methods by which PI procedures work, damaging nucleic acids or damaging cell membranes. Only the PI procedures that damage nucleic acids would be expected to prevent TA-GVHD; examples include amotosalen with UVA light (used for platelets and plasma), riboflavin with UV light (used for platelets and RBCs), or amustaline with glutathione (used for RBCs).

Nucleic acids (DNA and RNA) can be damaged (adducts created and interstrand crosslinks formed) using a number of intercalating agents and ultraviolet (UV) light exposure. In principle, these types of methods can be used to inactivate lymphocytes as well, and they can be used with any blood product that does not require viable nucleated cells (ie, these types of methods can be used for RBCs, plasma, or platelets).

Due to the rarity of TA-GVHD, the efficacy of PI techniques for prevention have not been compared with gamma irradiation in a clinical trial. However, cell culture and mouse model studies show excellent efficacy in inactivating lymphocytes, perhaps greater than irradiation. As an example, treatment with the PI agents amotosalen and UVA or riboflavin and UV light resulted in full inhibition of T cell proliferation and cytokine production and the ability to fully prevent the classic findings of TA-GVHD in animals [30,31]. This effect was preserved even when the dose of the PI agents was reduced by several thousand-fold. In contrast, a reduced dose of radiation by only one-fifth resulted in failure to inactivate lymphocytes.

Institutions that routinely use pathogen-reduced platelets for all recipients are no longer treating these platelets with gamma irradiation, and no cases of TA-GVHD have been reported with this approach.

Freeze-thaw — As noted above, the freeze-thaw process appears to be effective in inactivating lymphocytes, and TA-GVHD has not been reported with Cryoprecipitate, plasma that has been frozen (eg, Fresh Frozen Plasma [FFP], thawed plasma, Plasma Frozen Within 24 hours After Phlebotomy [PF24]) or RBCs that have been frozen (eg, frozen, deglycerolized RBCs). Thus, these products are not considered to confer an increased risk for TA-GVHD. However, freezing and thawing of RBCs is expensive, time consuming, and requires addition of an agent such as glycerol to prevent lysis of the cells. Thus, it is not an appropriate approach for prevention on a large scale.

Leukoreduction (not sufficient as an alternative) — Leukoreduction involves passing the blood product through a filter with a pore size small enough to prevent passage of white blood cells (WBCs); it is almost always done at the time of blood collection but can also be done at the bedside. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Pre-storage leukoreduction'.)

Leukoreduction is not considered protective against TA-GVHD and should not be used as an alternative to the methods discussed above. In the large series of 348 cases of TA-GVHD, 23 occurred with leukoreduced blood components [10].

However, leukoreduction using third- and fourth-generation filters can produce a three- to five-log reduction in the number of WBCs, including lymphocytes, potentially reducing the intensity of exposure to donor T cells. Even though many lymphocytes are of similar diameter as RBCs, they are less deformable and less adhesive, and therefore, less likely to pass through the filter.

In a 2007 report from the United Kingdom Serious Hazards of Transfusion (SHOT) hemovigilance database that compared transfusion complications before and after institution of universal leukoreduction of the blood supply in 1999, there were 13 instances of TA-GVHD but none reported since 2001 [32]. This suggests that leukoreduction may reduce the risk of TA-GVHD. However, case reports have described TA-GVHD in recipients of blood that was leukoreduced, further emphasizing the lack of complete T cell inactivation [33,34].

CLINICAL PRESENTATION

Time-course — Clinically recognized TA-GVHD typically develops between 4 to 30 days after a transfusion, although the immunologic process is likely initiated earlier. (See 'Overview of pathogenesis' above.)

In the largest series of cases, the median time to development of the first symptom (often skin rash) was 11 days (range, 1 to 198 days; interquartile range [IQR], 8 to 14 days) [10].

Typical findings — Patients typically present with findings related to immune attack of the skin, gastrointestinal tract, and bone marrow. In the largest case series, the frequency of findings was as follows [10]:

●Rash – 80 percent

●Fever – 68 percent

●Transaminase elevation – 66 percent

●Pancytopenia – 65 percent

●Diarrhea – 43 percent

●Bone marrow hypoplasia or acellularity – 40 percent

●Hepatomegaly – 14 percent

An average of four of these findings was present per patient [10].

A skin rash is often the first finding to be clinically apparent. The typical skin rash begins as an erythematous, maculopapular rash (picture 1), which often progresses to generalized erythroderma (picture 2) and, in extreme cases, to toxic epidermal necrolysis. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Gastrointestinal symptoms include anorexia, vomiting, increased transaminases, hepatomegaly, abdominal pain, and profuse diarrhea (up to 7 to 8 L/day). Diarrhea can be severe enough to cause significant electrolyte abnormalities. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Gastrointestinal tract'.)

Findings associated with bone marrow failure include pancytopenia and bone marrow aplasia. Consequences include fever due to infection or bleeding associated with thrombocytopenia.

"Mild" TA-GVHD — A report from 2018 identified 12 published cases of TA-GVHD that appeared to have had milder symptoms or a more attenuated course than seen in typical cases [3]. In nine of the cases, microchimerism was identified, confirming that TA-GVHD was present. (See 'Confirmed diagnosis' below.)

Clinical findings were mild in four, delayed in two, and non-fatal in 11 [3]. A feature common to these cases that distinguished them from typical, more severe cases was receipt of a leukoreduced or irradiated blood component, the latter at an irradiation dose that would no longer meet the recommended standard. Some received therapy and some did not. Only two received a hematopoietic cell transplant; one was an infant with severe combined immunodeficiency (SCID) and the other an adult who developed TA-GVHD following hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) and was treated with a second transplant [35].

This mild TA-GVHD was speculated to be part of a disease spectrum that may not have been previously recognized and that may occur in the setting of a smaller dose of immunologically competent lymphocytes in the transfused component.

TA-GVHD related to fetomaternal hemorrhage — A 2023 report described severe pancytopenia, diarrhea, and desquamating full-body rash three weeks after delivery of twins [4]. The T lymphocytes were determined to be fetally derived, and she recovered two weeks later after treatment with glucocorticoids alone (before hematopoietic stem cell transplantation [HSCT] was initiated).

DIAGNOSTIC EVALUATION

When to suspect TA-GVHD — Recognition of TA-GVHD is frequently delayed, as patients who develop this complication are often ill from other conditions that led to transfusion in the first place. Other reasons for delayed diagnosis include the mildness and lack of specificity of the initial symptoms and rarity of TA-GVHD relative to other diagnoses such as infection, liver disease, or drug reaction that are considered initially. Thus, it is important to maintain a high level of suspicion in any individual who develops fever, rash, gastrointestinal symptoms, or cytopenias following transfusion.

It is especially important to have a high level of suspicion for TA-GVHD in an individual with pancytopenia, rash, or gastrointestinal symptoms within a month of receiving a transfusion.

Clinical evaluation — The initial evaluation generally focuses on eliminating other possible causes of the patient's symptoms and determining whether the transfused product was properly irradiated or otherwise treated.

Communication with the transfusion service — If TA-GVHD is under consideration, it is always appropriate to communicate with the transfusion service, both to determine which components were transfused and whether they were treated with irradiation or pathogen inactivation technologies, as well as to ensure that any other transfused components are properly treated.

Laboratory testing and bone marrow — Laboratory testing is primarily directed at evaluating possible causes of the findings and determining the extent of the illness. This may include:

●Complete blood count (CBC) with platelet count and differential, as well as peripheral blood smear review to identify findings suggestive of infection, hemolytic anemia, or hematologic malignancy. (See "Evaluation of the peripheral blood smear".)

●Metabolic panel with creatinine and liver function tests, including coagulation tests. (See "Approach to the patient with abnormal liver biochemical and function tests".)

●For those with pancytopenia and/or elevated transaminases, testing for viral hepatitis (eg, with viral serologies) and hemophagocytic lymphohistiocytosis (HLH; eg, with serum ferritin, triglycerides, and coagulation studies). (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis", section on 'Laboratory evaluation' and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "Approach to the adult with pancytopenia".)

●For those with diarrhea, stool testing for infectious organisms including Clostridioides difficile. (See "Approach to the adult with acute diarrhea in resource-abundant settings", section on 'Evaluation'.)

Bone marrow evaluation (aspirate and biopsy) is performed in most individuals with pancytopenia and should be evaluated for cellularity and the presence of abnormal cells. In TA-GVHD, cellularity can be profoundly reduced with hypoplastic or aplastic marrow. A lymphohistiocytic infiltrate may also be seen.

Biopsy (skin or liver) — The diagnosis of TA-GVHD is supported by typical findings on tissue biopsy, although this is not always performed. Biopsy is appropriate in any individual for whom the diagnosis is suspected and cannot be made in another way such as demonstration of microchimerism. Typically, skin biopsy is less invasive than liver biopsy, easier to perform, less likely to cause bleeding, and sufficient for diagnosis if a rash is present.

●Skin – Many individuals will have a skin biopsy to evaluate an unexplained rash. Classic findings on biopsy of affected skin include vacuolization of the basal layer and a histiocytic infiltrate (picture 3). Skin biopsy occasionally shows an almost pathognomonic finding, satellite dyskeratosis, which is characterized by single, dyskeratotic cells accompanied by lymphocytes [36].

●Liver – Liver biopsy may be performed in patients with abnormal transaminases or hepatomegaly, especially if an alternative cause of these findings is suspected (eg, alcoholic or non-alcoholic fatty liver disease, viral hepatitis). Findings of TA-GVHD on liver biopsy are most pronounced around the area of the bile ducts and include changes to the biliary epithelium such as nuclear pleomorphism and other nuclear changes, cytoplasmic vacuolization, and lymphocytic infiltrate, along with biliary stasis and mild inflammation [37].

Confirmed diagnosis — The case definition criteria for TA-GVHD from the National Health and Safety Network (NHSN) Biovigilance Component of the Centers for Disease Control and Prevention (CDC) in the United States includes a combination of clinical findings (see 'Typical findings' above) and histologic findings occurring between two days and six weeks after a transfusion [38]. Cases in which biopsy confirmation was not obtained may be referred to as "probable TA-GVHD" [38].

Demonstration of white blood cell (WBC) chimerism in the absence of an alternative diagnosis is considered definitive proof [38]. This involves identifying a different HLA phenotype in circulating lymphocytes compared with the HLA phenotype of host tissue cells. This is often the least invasive means of diagnosing TA-GVHD if HLA typing of lymphocytes is feasible (ie, if the lymphocyte count is high enough to allow HLA typing) and should be performed. If this cannot be done, biopsy of skin or other affected tissue may be performed instead. (See 'Biopsy (skin or liver)' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of TA-GVHD includes a variety of serious systemic illnesses that cause pancytopenia and its complications (fever and infection, anemia, thrombocytopenia, and bleeding), rash, or gastrointestinal symptoms.

●Aplastic anemia – Aplastic anemia refers to bone marrow failure due to any one of a number of inherited syndromes or an acquired insult or autoimmune attack of the hematopoietic system. Like TA-GVHD, there is typically progressive pancytopenia and its complications. Also, like TA-GVHD, most individuals with aplastic anemia receive transfusions. Unlike TA-GVHD, in aplastic anemia the pancytopenia develops first and transfusions are given as treatment, whereas in TA-GVHD a transfusion precedes development of pancytopenia. Unlike TA-GVHD, aplastic anemia is not usually associated with erythroderma or rash.

●Infection – A number of infections can cause pancytopenia along with rash and/or gastrointestinal symptoms.

•Viral - Viral infections that may present similarly to TA-GVHD include HIV, hepatitis B and C viruses (HBV and HCV), parvovirus B19, Epstein-Barr virus (EBV, including chronic active EBV [CAEBV]), and dengue virus. Like TA-GVHD, these viral infections may cause fever, rash, hepatic dysfunction, and bone marrow failure. Unlike, TA-GVHD, serologic testing or nucleic acid testing for the virus will be positive, and skin biopsy will not show typical TA-GVHD findings. (See "Acute and early HIV infection: Clinical manifestations and diagnosis" and "Hepatitis B virus: Clinical manifestations and natural history" and "Clinical manifestations and natural history of chronic hepatitis C virus infection" and "Dengue virus infection: Clinical manifestations and diagnosis".)

•Bacterial or fungal – Bacterial or fungal infections can present similarly to TA-GVHD, especially if there is overwhelming infection. Leptospirosis is a bacterial infection acquired from environmental exposure to contaminated water or soil, especially in tropical climates. Like TA-GVHD, patients may have fever, rash, pancytopenia, and abnormal liver function tests. Unlike TA-GVHD, serologic or microbiologic testing will reveal a specific organism, and skin biopsy will not show the typical findings of TA-GVHD. (See "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

●Drug reaction – Patients with underlying hematologic conditions who require transfusion are also often receiving a variety of medications that may cause systemic reactions. These may cause allergic reactions, non-allergic skin eruptions, or a severe syndrome of drug reaction with eosinophilia and systemic symptoms (DRESS). Like TA-GVHD, drug reactions can cause fever, rash, pancytopenia, and abnormal liver function tests that are temporally separated from the transfusion. Unlike TA-GVHD, these drug reactions often have a temporal relationship to drug administration, and skin biopsy will show typical findings of the drug reaction rather than TA-GVHD. (See "Drug hypersensitivity: Classification and clinical features" and "Drug eruptions" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

●Liver failure – Liver failure can be caused by certain medications, either by dose-dependent hepatotoxicity (eg, acetaminophen) or an idiosyncratic reaction (eg, antibiotics, anticonvulsants). Other non-infectious causes of liver failure include autoimmune and metabolic conditions. Like TA-GVHD, liver function may be severely impaired. Unlike TA-GVHD, patients with liver failure often do not have rash or pancytopenia; skin biopsy or liver biopsy will show typical findings of the specific disease. (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis" and "Acute liver failure in children: Etiology and evaluation".)

●Underlying illness – The illness leading to the original indication for transfusion may include aplastic anemia, a hematologic malignancy, or an immunodeficiency syndrome. Some patients may also receive cytotoxic chemotherapy or hematopoietic stem cell transplantation (HSCT). Like TA-GVHD, these conditions may be associated with pancytopenia and systemic illness. Unlike TA-GVHD, these conditions typically precede transfusions, whereas in TA-GVHD the transfusions precede the development of fever, rash, and pancytopenia. In addition, the underlying illness or malignancy will not cause typical findings of TA-GVHD on skin biopsy.

●GVHD associated with allogeneic HSCT – GVHD associated with allogeneic HSCT may also cause fever, rash, diarrhea, and liver failure. Unlike TA-GVHD, GVHD from allogeneic HSCT does not typically cause bone marrow failure. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

●Hemophagocytic lymphohistiocytosis – Hemophagocytic syndromes including hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are characterized by profound immune dysregulation leading to uncontrolled macrophage activation; there are a variety of hereditary predisposing factors and environmental triggers. Like TA-GVHD, patients with HLH or MAS can be acutely ill with fever, rash, liver failure, and pancytopenia. Unlike TA-GVHD, HLH/MAS often are associated with other laboratory findings (eg, very high ferritin, coagulation abnormalities, hypertriglyceridemia), neurologic findings, and hemophagocytosis on bone marrow examination. Patients with HLH would not be expected to have either typical TA-GVHD skin (or organ) biopsy results or demonstrable microchimerism. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

TREATMENT — There is no effective treatment for TA-GVHD other than hematopoietic stem cell transplantation (HSCT), and HSCT is rarely a viable option because there is usually insufficient time to identify an appropriate donor, test them for suitability to donate, and obtain sufficient hematopoietic stem cells (HSCs) for transplant. In some cases, immunosuppressive therapy has been effective in attenuating the course of the disease.

As soon as a diagnosis of TA-GVHD is confirmed (or strongly suspected), management should be guided, either directly or in close consultation, by an individual with experience in managing patients undergoing HSCT with GVHD. Early recognition may allow more time to institute supportive or immunosuppressive therapies, as well as to identify a potential hematopoietic stem cell donor.

There are no prospective trials or studies comparing different interventions for treatment. A systematic review from 2015 identified 348 cases of TA-GVHD and evaluated therapies used in the small number of individuals who survived as well as the large number of individuals (92 percent) who died [10]. HSCT and immunosuppression were associated with slight increases in survival, as follows:

●Hematopoietic stem cell transplantation – HSCT could potentially provide a new source of HSCs that could repopulate the bone marrow and provide immune cells capable of destroying the T-lymphocytes responsible for TA-GVHD. Of the 29 (8 percent) from the systematic review who survived, 3 (10 percent of the survivors) were treated with HSCT [10]. One of these was a person with chronic lymphocytic leukemia (CLL) who developed TA-GVHD 10 days following transfusion of non-irradiated blood components [39]. By coincidence, she had cryopreserved autologous peripheral blood stem cells available from a prior autologous HSCT. She was treated with immunosuppression (methylprednisolone, cyclosporine, high-dose cyclophosphamide, antithymocyte globulin) and underwent autologous HSCT, with complete recovery from both TA-GVHD and CLL. Among the 312 individuals who died, only five (2 percent) underwent HSCT.

●Immunosuppression – Immunosuppression could mitigate the activity of the T-lymphocytes responsible for TA-GVHD. Of the 29 individuals from the systematic review who survived, more than one-half received some form of immunosuppression [10]. The most commonly used agents included glucocorticoids, cyclosporine, intravenous immune globulin (IVIG), and antithymocyte globulin (ATG) or antilymphocyte globulin (ALG). Numbers were too small to detect a significant association of any treatment with improved outcomes.

Case reports have described other immunosuppressive agents or experimental treatments that have been tried, none with substantial success; these include methotrexate; the serine protease inhibitor nafamostat mesylate; ultraviolet irradiation; succinylacetone; inhibitors of the production of tumor necrosis factor such as pentoxifylline, interleukin-1 receptor antagonists, and thalidomide [40-44]. Other approaches such as rituximab, ibrutinib, or photopheresis have not been evaluated [45].

CASE REPORTING — All cases of TA-GVHD should be reported to the hemovigilance system used in the country in which they occur. The information required in the case report will be specified by each hemovigilance system.

In the United States, there is an additional requirement to report any fatal case of TA-GVHD to the Center for Biologics Evaluation and Research (CBER) within the US Food and Drug Administration (FDA).

PROGNOSIS — The mortality of TA-GVHD is high.

In a systematic review of 348 cases of TA-GVHD, the survival rate was 8 percent. Death occurred at a median of 24 days after transfusion (interquartile range [IQR], 19 to 32 days) [10]. The likelihood of surviving was higher in younger patients, those who received a leukoreduced product, and those whose product had a longer storage duration. These latter two features may be surrogates for a lower dose of donor T-lymphocytes. Survivors were more likely to have an underlying indication for irradiation and to have been treated with hematopoietic stem cell transplantation (HSCT). Survival more than doubled from the pre-2000 era to the post-2000 era (from 8.2 to 19.7 percent), suggesting improvements in supportive care and perhaps greater access to HSCT.

Milder cases of TA-GVHD in which the condition resolves and the patient survives may go unrecognized and/or unreported. In a series of 12 individuals with mild disease or an atypical course, one-half survived [3]. Thus, the survival rate for some individuals may be higher than noted in the systematic review. (See '"Mild" TA-GVHD' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Transfusion and patient blood management".)

SUMMARY AND RECOMMENDATIONS

●Definition – Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare transfusion reaction in which a blood component containing viable T-lymphocytes is transfused to a recipient whose immune system either does not recognize these lymphocytes as foreign or is unable to mount an appropriate immune response against them (table 1). Failure to recognize donor lymphocytes as foreign can occur when there is partial human leukocyte antigen (HLA) matching (figure 1). Viable donor lymphocytes from the transfusion attack the recipient's skin, gastrointestinal tract, and hematopoietic system. (See 'Pathogenesis' above.)

●Epidemiology – TA-GVHD is extremely rare. The true incidence is not known and is expected to vary by population and preventive strategies. In the 1980s, the overall incidence was estimated at 0.1 to 1 percent among at-risk individuals (see 'Risk factors' above). Since then, this number has decreased considerably. At-risk individuals include those in a genetically homogenous population and those who receive directed donations from family members, as well as immunosuppressed individuals, including those with primary immunodeficiency syndromes and hematologic malignancies. (See 'Incidence' above.)

●Prevention – Since TA-GVHD is highly preventable and very hard to treat, prevention is of primary importance. Prevention is best achieved by irradiating (or otherwise inactivating) lymphocytes in blood products for all at-risk individuals (table 1). Irradiation is done using a gamma or X-ray source in the blood bank. Pathogen inactivation techniques that damage nucleic acids are also effective in preventing TA-GVHD, perhaps more so than irradiation; pathogen inactivation is more common than irradiation for platelet products. Freezing and thawing typically prevents TA-GVHD but is not done expressly for this purpose. Leukodepletion may provide some protection, but leukodepletion is not sufficient to eliminate all viable lymphocytes or to prevent GVHD. (See 'Prevention' above and 'Pathogen inactivation techniques' above.)

●Time course and presentation – TA-GVHD typically occurs within 2 to 30 days after transfusion. Typical findings include rash (picture 1 and picture 2), transaminase elevation, and pancytopenia. Affected individuals may also develop severe diarrhea, fever, and/or hepatomegaly. A milder form of the disease has also been reported. (See 'Clinical presentation' above.)

●Evaluation – Recognition of TA-GVHD is often delayed, as patients are often ill from other conditions that led to transfusion in the first place. TA-GVHD is rare, and other diagnoses are considered first. It is important to maintain a high level of suspicion in any individual who develops fever, rash, gastrointestinal symptoms, or cytopenias following transfusion. The initial evaluation focuses on identifying other explanations for these findings such as infection, drug reaction, liver disease, malignancy, or other immune conditions (eg, hemophagocytic lymphohistiocytosis [HLH]) and in determining the bone marrow cellularity. Biopsy of affected skin is generally performed; clinical and histologic findings are used to make the diagnosis. Demonstration of white blood cell (WBC) chimerism is considered definitive proof, but this is not always performed. (See 'Diagnostic evaluation' above.)

●Differential diagnosis – The differential diagnosis of TA-GVHD includes aplastic anemia, certain infections, drug reactions, malignancies, and HLH. (See 'Differential diagnosis' above.)

Separate topic reviews discuss other delayed complications of transfusion and the form of GVHD associated with hematopoietic stem cell transplantation (HSCT). (See "Hemolytic transfusion reactions" and "Immunologic transfusion reactions" and "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

●Treatment – Treatment of TA-GVHD is rarely effective, unless HSCT can be performed. Most affected individuals do not have autologous hematopoietic stem cells (HSCs) available and do not have sufficient time to identify an allogeneic hematopoietic stem cell donor. Immunosuppression is often tried but is rarely effective. (See 'Treatment' above.)

●Prognosis – Prognosis is poor, with a survival rate in the largest series of 8 percent and a higher rate (nearly 20 percent) in the post-2000 era. Cases of milder disease with higher survival rates have been reported. Survival also appears to be better in younger patients, those who received a leukoreduced product, and those whose product had a longer storage duration. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff gratefully acknowledges the extensive contributions of Arthur J Silvergleid, MD, to earlier versions of this and many other topic reviews.