Transfusion‐associated graft‐versus‐host disease: less fresh blood and more gray (Gy) for an aging population

Blood transfusion is a transplant. Most transfused cells survive for no more than a few days or weeks. Clinicians have recognized for more than 40 years, however, that in some patients transfused cells engraft, expand, and circulate. A number of early observations may have biased our understanding of the consequences. When immunocompetent T-lymphocytes engraft in an immunosuppressed patient, a highly lethal disorder known as transfusion-associated graft-versus-host disease (TA-GVHD) frequently results.1 But the pathogenesis of this disease is not so simple. TA-GVHD probably represents one extreme of a broad immunologic spectrum. At the other extreme, transfused maternal cells circulate for years in relative harmony with the host tissues of neonates who undergo fetal and exchange transfusion.2 A great deal may happen in between. Transfused WBCs engraft briefly in some patients with acute leukemia, but cause GVHD in others. In a seminal article, Schechter and coworkers3 reported “subclinical GVHD,” the transient appearance of activated, proliferating lymphocytes in the circulation of adult recipients of fresh whole blood. Some transfused cells achieve a state of tolerance in adults analogous to the stable mixed chimerism that develops when cells traffic between mother and fetus during pregnancy. Conventional wisdom has held that stable microchimerism, regardless of cell derivation, causes little or no harm.4 This hypothesis begs rigorous testing. In this issue of TRANSFUSION, Triulzi and colleagues5 describe fatal TA-GVHD in an elderly, apparently immunocompetent recipient of a unit of randomly selected 8-day-old RBCs.6 Whereas the report lacks cytogenetic confirmation of donor lymphoid engraftment, the definitive diagnostic criterion of TA-GVHD, nevertheless the characteristic rash, hepatitis, and severe pancytopenia occurring in the setting of a recent transfusion from a donor homozygous for a shared HLA haplotype make the diagnosis all but certain. The report should surprise no one. Many similar cases have been reported.6-10 Yet the death of this elderly cardiac surgery patient raises several timely and provocative issues: How unusual are these cases? What predisposes transfused patients to develop either stable microchimerism or GVHD? How should we define “immunocompromised?” And finally, to what lengths should we go to prevent this disease? The early reports of TA-GVHD in “immunocompetent” adults often involved patients undergoing open heart surgery, a condition not usually associated with severe immune suppression, and treatment for malignancy.10 Only rarely was the condition described in patients transfused for other reasons, for example, for pregnancy or cholecystectomy.11, 12 We know now that the balance or imbalance of a number of donor and host factors influences the development and severity of TA-GVHD. Chief among these determinants is the degree of donor-recipient disparity at the HLA locus. The frequency of shared haplotypes explains the increased risk observed with transfusions from first-degree relatives and from unrelated subjects in countries like Japan, where HLA haplotype homogeneity is much greater than in the United States. Certain diseases such as lymphoid malignancies clearly place patients at increased risk, as does immunosuppressive therapy with nucleoside analogs, even in the absence of malignancy.13 As with this case, freshly collected, leukoreplete blood predisposes to TA-GVHD, probably because it contains a full complement of viable immune cells. Frozen deglycerolized RBCs and FFP, both of which contain viable lymphocytes, do not. The minimum number of viable T cells or the repertoire of accessory cells required for GVHD is unknown, although as few lymphocytes as 104 per kg may be lethal for a severely immunosuppressed host.14 Current methods of filtration leukoreduction appear insufficient to prevent the disease in every patient.15 That is not to say that leukoreduction plays no role at all. Extrapolation from the marrow transplant literature suggests that dose is important. At some degree of graft leukoreduction, mild, transient, or treatable illness should occur. The number of TA-GVHD cases reported in the United States falls far short of the 1 in 17,700 to 1 in 39,000 predicted if calculated HLA haplotype frequencies in random blood donor-recipient pairs were the sole determinant.15 Underreporting and misdiagnosis undoubtedly contribute to this discrepancy. It is equally likely that the complex and incompletely understood interaction between host and recipient immune cells results in fewer than expected cases as well as atypical presentations that are less fulminant than the oft-quoted 90 percent lethal form. The observation that fetal cells can be found in maternal tissue during the self-limited rash known as polymorphic skin eruption of pregnancy raises the intriguing possibility that some “drug rashes” observed in immunosuppressed patients may be formes frustes of TA-GVHD.16 Perhaps some clinical manifestations of circulating allogeneic immune cells appear and regress as tolerance (or immunocompetence) waxes and wanes in a “not-so-stable microchimerism.” Modern molecular techniques that can detect one alien lymphocyte in a million host cells reveal that transfusion-related microchimerism is far more common than previously appreciated.9, 17 Small-scale studies suggest that 10 to 50 percent of transfused patients develop some degree of microchimerism. Allogeneic lymphocytes may expand a thousandfold within 3 to 5 days of transfusion—an alarming prospect—but these cells turn out to be benign 2-week transients in most surgical, sickle cell, thalassemic, and HIV-infected patients.18, 19 The notable exception is the trauma patient, even the young and previously healthy one, in whom transfused cells may comprise 3 to 4 percent of peripheral blood WBCs and persist at such levels for as long as 2 years after transfusion—even if the transfused component was leukoreduced blood.20-22 Somewhat reassuring is the report that six of seven recipients of intrauterine transfusion had detectable donor cells circulating up to 20 years later, but none of the six had evidence of disease.23 Nevertheless, molecular detection of unexpected numbers of male cells in the circulation and skin lesions of adult females with systemic sclerosis, a disease strikingly evocative of chronic GVHD, has raised the suspicion that under certain circumstances, dormant allogeneic cells may involve themselves in “autoimmune” disorders.16, 24 Perhaps an active host mechanism that inhibits the GVHD response in immunocompetent, long-term stable chimeras weakens over time or can be interrupted.25 It is sobering indeed to consider how many of us may carry “sleeper” allogeneic immune cells awaiting some signal to become activated and form an immune insurgency. Over the past half-century, we have come to appreciate that immune competence is less an absolute than a matter of degree. Whereas genetic factors may be the principal determinants, a bewildering number of external factors including trauma, infection, and pharmaceuticals disrupt the normal immune response. Old age—and the patient described here was 82—and cardiac surgery are among them.26, 27 As yet no association between TA-GVHD and advancing age has been established. “Immune senescence,” however, has become a widely accepted explanation for the age-related decline in immune function that contributes to susceptibility to infection and malignancy. Age is becoming an increasingly relevant health factor as the populations of developed countries gray. Americans aged 65 and older represented 13 percent of the US population in 2000, but will form an estimated 21 percent of the population by the year 2030 (approx. 65 million people). The group expected to grow most rapidly in the next 30 years is the “oldest” old, 85 years and older (21 million people).28 Many of them would be expected to undergo cardiac surgery and other invasive therapies and many more will receive blood transfusions. We need to know whether chimerism remains stable as the host ages and whether we should expect more cases of TA-GVHD as elderly patients are exposed to fresh blood. TA-GVHD cannot be treated effectively, but it can be prevented by subjecting blood components to 15- to 30-Gy doses of gamma or X-irradiation—which not coincidentally prevents the development of stable microchimerism.9 Most US institutions still perform selective irradiation of blood components for recognized susceptible patients, a policy guaranteed to place at-risk “immunocompetent” patients such as the unfortunate man reported by Triulzi and coworkers not to mention patients at known risk who receive nonirradiated cells in error. In January 1999, the Japanese Blood Transfusion Society issued a thoughtful set of detailed guidelines that outlined the indications for selective blood irradiation—cardiac surgery, cancer surgery, the elderly recipient (>65 years), severe trauma, congenital immunodeficiency, newborn infants, and other immunocompromised patients.20 To their credit, the Japanese quickly realized the absurdity of trying to apply such a complicated strategy to medical practice, and Japan moved expeditiously to a policy of universal blood component irradiation. Despite the lower theoretic risk, the astute clinicians, and the sophisticated patient identification systems found in the United States, our transfusion community needs to reflect seriously on this decision. The disadvantages of universal irradiation include additional cost and some shortening of the 42-day storage period.29 Until some other universally applied technology such as pathogen reduction obviates the need for component irradiation, however, those tradeoffs seem increasingly reasonable. Perhaps with age will come wisdom.