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REVIEW ARTICLE
From the Department of Pathology, New York University
Medical Center, New York, NY; the Department of Pathology and Molecular
Medicine, McMaster University, London, ON, Canada; and Hamilton Blood
Center, Canadian Blood Services, Hamilton, ON, Canada.
Allogeneic blood transfusion results in the
infusion into the recipient of large amounts of foreign antigens in
both soluble and cell-associated forms. The persistence of these
antigens in the circulation of the recipient may create
conditions that allow the development of immune down-regulation.
Evidence from a variety of sources indicates that allogeneic blood
transfusion enhances the survival of renal allografts1 and
may increase the recurrence rate of resected malignancies2
and the incidence of postoperative bacterial
infections,3-7 as well as reduce the recurrence rate of
Crohn disease8 and/or activate infections with
cytomegalovirus9 or human immunodeficiency
virus.10 This clinical syndrome, the mechanisms of which
remain to be defined, has been referred to in the transfusion medicine
literature as allogeneic blood transfusion-associated immunomodulation
(TRIM).11 Clinical evidence for the existence of TRIM has been available since
1973. In their seminal study, Opelz et al1 provided evidence, counterintuitive at the time, that recipients of allogeneic blood transfusion had improved renal allograft survival. Subsequent clinical studies and studies in experimental animals corroborated the
results of Opelz et al,1 and allogeneic blood transfusions were used deliberately in the early 1980s to prevent rejection of renal
allografts.12 The beneficial effect of TRIM was obscured following the introduction of immunosuppression with cyclosporine, but
it was recently reported to persist even in renal allograft recipients
receiving modern immunosuppressive therapy.13 On the basis of the immunomodulatory effect of allogeneic blood
transfusion in renal allograft recipients, Gantt14 raised the question in 1981 whether the TRIM effect might also be associated with an increased risk of cancer recurrence in patients undergoing resection of a malignancy. Gantt's hypothesis was based on the premise
that, if allogeneic blood transfusion down-regulated the host's immune
surveillance mechanism that targets malignant cells, the receipt of
allogeneic blood transfusion could enhance tumor growth. A subsequent
hypothesis proposed that, if allogeneic blood transfusion causes
immunosuppression, then recipients of perioperative allogeneic blood
transfusion could be at increased risk for postoperative bacterial infection. Since 1981, more than 150 clinical studies have examined the
association of perioperative allogeneic blood transfusion with cancer
recurrence and/or postoperative bacterial infection. Most of these are
observational cohort studies comparing patients who had or did not have
transfusion.15-20 In addition, 7 randomized controlled trials (RCTs) have compared the risk of cancer
recurrence2,21,22 and/or postoperative
infection3-7,21-23 between a treatment arm receiving
standard7 or buffy-coat-reduced red blood cells
(RBCs)2,4-6,21,22 or whole blood3 and a control
arm receiving autologous or white blood cell (WBC)-reduced RBCs or
whole blood.24,25 These studies are based on the
assumption that the transfusion of autologous2,4,21,23 or
WBC-reduced3,5-7,22 RBCs, or whole blood, is
immunologically neutral. Both the earlier observational cohort studies
and the recent RCTs have produced contradictory findings, and The mechanism(s) of the TRIM effect(s) also remains elusive, and it is
possible that a large number of biologic mechanisms may underlie the
effect(s).28-31 The infusion of foreign antigen in either a
soluble31-36 or cell-associated37-43 form has
been shown to induce immune suppression, anergy, and clonal deletion in
studies in experimental animals. However, most studies evaluating
proposed mechanisms have been done in rodents, and these findings may
not be applicable to the human immune system.44 Caution
should be exercised, therefore, when findings from experimental animals are extrapolated to humans. Moreover, different biologic mechanisms may
be involved in each reported clinical manifestation of
TRIM,1-10 and the clinical evidence supporting each of the
aforementioned hypotheses1-10 should be examined on its own merits. The specific constituent(s) of allogeneic blood that mediates the TRIM
effect1-10 remains unclear. Allogeneic
plasma,31-36 allogeneic WBCs,30,37-43 and
substances that accumulate in blood components during
storage39 have been implicated in the pathogenesis of TRIM.
However, both the animal and human data suggest that the TRIM effects
are most likely mediated by transfused allogeneic WBCs.45,46 Lee et al47 reported persistence of
donor WBCs in humans for up to 1.5 years after an allogeneic blood
transfusion. In murine and rabbit experimental models, Blajchman et
al37,38 and Bordin et al39 demonstrated a tumor
growth-promoting effect of allogeneic blood transfusion that appeared
to be associated with transfusion of allogeneic WBCs. The findings of
these experiments support the hypothesis that allogeneic WBCs actively
induce immune suppression in transfusion recipients. In another
relevant study, Kao40 induced immune suppression in mice
receiving donor WBCs free of plasma and platelets. These and several
other investigators41,42 also attributed an induction of
TH2 cells in transfusion recipients to the allogeneic donor
WBCs, showing that TH2 cells can produce immunosuppression
in transfusion recipients by down-regulating the activity of
TH1 cells. Mincheff et al43 implicated the
antigen-presenting cells of the allogeneic donor in the induction of a
state of anergy in the recipient and proposed that, during
refrigeration, antigen-presenting cells lose their ability to deliver
costimulation. These investigators hypothesized that after an
allogeneic transfusion, the recipient's T cells are stimulated by
allogeneic donor WBCs in the absence of costimulation and that this
interaction induces a state of anergy in the recipient's T cells. More than 100 observational cohort studies comparing patients with and
without transfusion, as well as 2 RCTs comparing recipients of
allogeneic and autologous RBCs,2,4,21,23 did not associate the TRIM effect with any particular blood constituent. Five recent RCTs3,5-7,22 were designed on the basis of the assumption that the allogeneic transfusion effect responsible for cancer recurrence and/or postoperative infection is mediated specifically by
allogeneic WBCs. These studies produced contradictory findings, and the
issue as to whether any deleterious TRIM effects are lessened or
abrogated by WBC reduction of the transfused allogeneic
cellular blood components remains unresolved.11,26,27,48
Jensen et al attributed an 86%3 and a 71%5
reduction in the incidence of postoperative infection to the use of
WBC-reduced allogeneic whole blood3 or RBCs,5
with the use of poststorage WBC reduction by filtration. In contrast,
Houbiers et al22 found no difference in the incidence of
postoperative infection between the recipients of WBC-reduced and
buffy-coat-reduced RBCs with the use of prestorage WBC reduction by
filtration. In the RCT by van de Watering et al,6 the use
of WBC-reduced RBCs decreased the incidence of postoperative infection
by 30% compared with that seen in patients having transfusion with
buffy-coat-reduced RBCs. Moreover, there was no difference in the
incidence of postoperative infection between the recipients of RBCs
that were WBC reduced by filtration before or after
storage.6 Recently, the United Kingdom, Ireland, and Portugal implemented
universal WBC reduction of all transfused cellular blood components, based on the hypothesis that this practice would prevent the
theoretical risk of transmission by transfusion of the agent of variant
Creutzfeldt-Jakob disease (vCJD).49,50 France and Canada
also implemented universal WBC reduction, primarily to enhance overall
transfusion safety.50 Following these developments, public
debate began regarding the appropriateness of introducing universal WBC
reduction in the United States and elsewhere. The risk of transmission
of vCJD by transfusion is considered only a theoretical possibility
because an epidemic of bovine spongiform encephalopathy and cases of
vCJD have occurred almost exclusively in the United Kingdom. Therefore, if a decision were made to implement universal WBC reduction in the
United States and elsewhere, such a policy would probably not be
introduced with an intent to prevent the transmission of vCJD, but to
reap other potential benefits of WBC reduction. Most of the published
evidence regarding such potential benefits pertains to the prevention
of the deleterious TRIM effects, and the public debate regarding the
implementation of universal WBC reduction is likely to focus mainly
(although not exclusively) on an examination of the efficacy of WBC
reduction in preventing these potential adverse effects of allogeneic
blood transfusion.27,51 Furthermore, the recently
described relation between WBC-containing allogeneic blood transfusion
and increased postoperative mortality from causes other than
postoperative infection,6 and the report by Hébert et al52 that a restrictive strategy of RBC transfusion may
be superior to a liberal transfusion strategy when mortality is
evaluated as an outcome in critically ill patients, may affect the
debate over whether to implement universal WBC reduction. Thirty-one physicians from academic blood banks in the United States
recently voiced their strong opposition to the intent of the Food and
Drug Administration (FDA) to mandate the implementation of universal
WBC reduction in the United States.53 In a letter to the
editor of Transfusion,53 they stated that "It
is our view that published reports fail to document a substantial
health benefit that would serve to justify WBC reduction of cellular blood components transfused to all patients.
Accordingly, we feel that the currently available evidence regarding
the deleterious effects of allogeneic blood transfusion is not
sufficiently compelling to warrant universal WBC reduction for the
prevention of these effects." This present review examines the
available evidence from: (1) the observational cohort studies that
investigated the hypothesis that allogeneic blood transfusion provokes
cancer recurrence and/or postoperative infection; (2) the findings of
the RCTs that examined the possible deleterious TRIM effects associated
with allogeneic blood transfusion in general or with transfusion of allogeneic WBCs in particular; and (3) the results of the recent RCTs
that reported an association between allogeneic blood transfusion and
increased mortality.6,52 To help readers process and
understand the contradictory information, we include a section on the
rationale, design, and analysis of the clinical studies that
investigated these possible deleterious TRIM effects. Also, after
reviewing the available evidence regarding the association of
allogeneic transfusion with cancer recurrence or postoperative
infection, we discuss the various arguments for and against a potential
decision to implement universal WBC reduction of all transfused
cellular blood components to prevent the deleterious effects of
allogeneic transfusion-associated immunomodulation. Evidence in support of deleterious TRIM effects has been obtained
from observational cohort studies, RCTs, meta-analyses of the
observational cohort studies, and meta-analyses of the
RCTs.54 The observational studies were either
retrospective or prospective, and compared the risk of an adverse
clinical outcome between cohorts of patients who did or did not receive
transfusion and who differed with respect to baseline determinants of
the need for transfusion and the risk of cancer recurrence or
postoperative infection. These studies relied on multivariate
statistical analyses to adjust for the effects of possible confounding
factors. The RCTs were prospective clinical experiments comparing the
risk of an adverse outcome between patients randomly allocated to
receive different blood products, thus relying on randomization (ie,
chance) to distribute all possible confounding factors equally between
the treatment and control arms. The RCTs presented univariate (ie, unadjusted) analyses calculating the odds ratio (OR) of an adverse outcome in a treatment arm compared with that in a control arm, as
shown in Table 1. Such analyses are valid
if the counts in each of the 4 cells of the 2 × 2 contingency table
(Table 1) are free of the effects of confounding factors When the results of studies retrieved for a meta-analysis are discrepant, or if the variation among the reported findings is greater than can be attributed to chance (a situation called "heterogeneity of effects"), a meta-analysis can offer insight into the reasons for the disagreements among the available studies. Provided that the results from the available studies are concordant, meta-analysis can be used to derive, through the application of a number of quantitative techniques, a measure of the effect of allogeneic blood transfusion based on a combination of the available data. This "average" TRIM effect is more precise (and more likely to attain statistical significance) than the TRIM effects reported from individual studies because it is based on a much larger sample (ie, the study population accrued when the study populations from all available reports are combined). Before the results of studies are integrated, however, the degree of agreement among reports must be assessed both conceptually and statistically. The Q test statistic quantifies the probability that the variation in reported results might have arisen by chance. Most analysts hold that there is sufficient agreement (or "homogeneity") among studies to permit the undertaking of a meta-analytic synthesis of the results if P > .05 for the Q test statistic (ie, if there is a greater than 5% probability that the variation in reported results might have arisen by chance).55 In this review, we use meta-analysis both to investigate reasons for disagreements among studies (if P < .05 for the Q test statistic) and to integrate the results of the available studies for the calculation of an "average" TRIM effect across combined investigations (if P > .05 for the Q test statistic). Where meta-analysis is used in this review, results of homogeneous studies are integrated using the random-effects method of DerSimonian and Laird.56 Patients allocated to the treatment arm of the reviewed
RCTs3-7,22,23 were exposed to all the
constituents of allogeneic blood and were at risk for developing
adverse TRIM effects. Control-arm patients were presumed to be at
reduced risk because they were not exposed to allogeneic
WBCs3,5-7,22 or allogeneic WBCs and allogeneic
plasma.4,23 Five4-6,22,23 of 6 RCTs3-6,22,23 conducted in Europe transfused
buffy-coat-reduced RBCs to the treatment arm. In one
RCT,3 whole blood was given, and in one RCT7
conducted in the United States, standard RBCs (ie, not buffy coat
reduced) were transfused. The buffy-coat reduction method is used
widely in western Europe, but not elsewhere, for the preparation of
blood components from whole blood. Components produced by the
buffy-coat reduction method contain 60% to 80% fewer WBCs compared
with cellular blood components produced by North American
methods.57 Thus, the buffy-coat-reduced RBCs transfused
by Houbiers et al22 and van de Watering et al6 contained a mean of 0.8 × 109 WBCs per RBC unit; those
administered by Jensen et al5 contained a mean of
1.2 × 109 WBCs per unit. The number of allogeneic WBCs
contained in the average RBC transfusion dose given in 4 of the
European RCTs4,5,22,23 (eg, in a median dose of 3 U of
buffy-coat-reduced RBCs administered in the study of Houbiers et
al22) was equivalent to the number of allogeneic WBCs
contained in only 1 U of allogeneic RBCs produced in North America.
Therefore, if the TRIM effect is mediated by allogeneic WBCs, the WBC
dose given to patients in the treatment arm of most European
RCTs4,5,22,23 may have been insufficient to provoke
clinically significant TRIM effects. In a study of New Zealand White
rabbits with established tumors, Blajchman30 reported a
significant (P < .0001) decrease in the tumor
growth-promoting effect of allogeneic blood transfusion in association
with buffy-coat reduction of whole blood (Table
2). The ameliorative effect of buffy-coat
reduction was not complete, however, and the median number of pulmonary
nodules seen in rabbits receiving buffy-coat-reduced whole blood was
significantly (P = .0004) greater than that seen in
control animals receiving no transfusion or in animals receiving WBC-reduced blood.30
All 5 RCTs administering WBC-reduced RBCs5-7,22 or whole
blood3 to the control arm transfused RBCs prepared by
leukocyte filtration. Prestorage-filtered RBCs were prepared by
passing, within 246 or 4822 hours of
collection, a buffy-coat-reduced RBC unit through a
leukocyte-reduction filter. Poststorage-filtered RBCs were prepared by
passing a unit of buffy-coat-reduced RBCs5,6 or whole
blood,3 stored for 6 or more days, through a
leukocyte-reduction filter. The average WBC content of transfused
WBC-reduced RBCs was less than 5 × 106 per unit, and was
often as low as 1 × 106 per unit. The timing of the
filtration procedure is important because biologic response modifiers
released from WBC granules in a time-dependent manner during storage
may mediate the adverse TRIM effects,39,48,56-60 and
Observational studies have compared the incidence of cancer recurrence, death due to cancer recurrence, and/or overall mortality15-18 between patients undergoing cancer resection who did or did not receive transfusion; or the incidence of postoperative bacterial infection with or without transfusion in patients undergoing gastrointestinal surgery, orthopedic operations, cardiac surgery, or various other procedures. These studies tended to indicate that patients having transfusion (compared with those not having transfusion) had a higher incidence of cancer recurrence or death due to cancer recurrence as well as a shorter overall survival after a cancer resection operation; and almost always had a higher incidence of postoperative bacterial infection.16 These studies also indicated that patients having transfusion generally differed from those without transfusion in several prognostic factors, including clinical stage of the malignancy; size, histologic grade, and type of tumor; age; preoperative hemoglobin; duration and extent of surgery; amount of perioperative blood loss; the frequency of chronic systemic illness, such as congestive heart disease, lung disease, liver disease, kidney failure, or diabetes mellitus; and the presence of risk factors for postoperative urinary tract infection (UTI), pneumonia, or wound infection.18,19,61 These 2 sets of observations have led to different interpretations of the results of the studies that compared patients who did or did not receive transfusion. Some authors concluded that perioperative allogeneic blood transfusion had a direct deleterious effect on the recipient, causing an increase in the incidence of cancer recurrence and/or postoperative bacterial infection.16 Other investigators concluded that allogeneic blood transfusions were a surrogate marker for a variety of adverse prognostic factors and that the other variables that generated the need for perioperative transfusions determined the subsequent clinical outcome.19 The latter school of thought reasoned that the adverse prognostic factors that were associated with both the need for perioperative transfusion and the cancer recurrence and/or postoperative bacterial infection were confounders of the relation between transfusion and these outcomes, and engendered a spurious association between allogeneic transfusion and cancer recurrence and/or postoperative infection.19 In many of the reported observational studies, the authors used
multivariate regression analysis to adjust the effect of transfusion for the effects of confounding factors. Regression analysis can calculate an allogeneic blood transfusion effect that is independent of
the effects of known and measurable confounders, provided that: (1) the
investigators measure all known potentially confounding factors; (2)
the variables that are associated with both transfusion and cancer
recurrence and/or postoperative infection in a particular set of data
are identified as true confounders; and (3) all true confounders are
included in the final regression model on which the conclusions are
based.19 In most published observational studies, however,
important potential confounding factors were not considered by the
investigators61; and the multivariate regression model on
which the conclusions were based was built by a stepwise (as opposed to
forced-entry) method, which did not ensure the inclusion of several
measured confounders in the final model.19 For example,
although postoperative UTI was the most frequent type of postoperative
infection in most observational studies that reported an association
between transfusion and postoperative infection, the number of patient
days with an indwelling urinary catheter As a result, TRIM effects reported as "independent" by many teams of investigators were not truly free of the effects of known and measurable confounding factors, and the calculated TRIM effect decreased in magnitude (or became statistically insignificant) depending on which confounding factors were included in the final regression model.61 These caveats notwithstanding, allogeneic blood transfusion often emerged as the leading predictor of cancer recurrence and/or postoperative bacterial infection from multivariate analyses, and was reported to increase the risk of postoperative infection in patients having transfusion (compared with those not having transfusion) by up to 10-fold.16 Cancer recurrence Chung et al,62 Vamvakas,17 and Brand and Houbiers18 used meta-analysis to integrate the findings from the univariate (ie, unadjusted; Table 1) analyses of the observational studies of the association of perioperative allogeneic blood transfusion with cancer recurrence, death due to cancer recurrence, or overall mortality. The most recent meta-analysis18 also included studies not published in English and considered 7 cancer sites; 100 observational studies were identified as eligible for analysis. There was agreement among the 3 meta-analyses with regard to the magnitude and statistical significance of the calculated summary ORs of the risk of an adverse clinical outcome in patients having transfusion (compared with those not having transfusion). Figure 1 shows the unadjusted summary OR of an adverse outcome for 7 cancer sites. As shown in Figure 1, when the unadjusted results were integrated from 28 reports on colorectal cancer, 14 reports on head and neck cancer, 10 reports on breast cancer, 8 reports on gastric cancer, 8 reports on lung cancer, 6 reports on cervical cancer, and 6 reports on prostate cancer, the summary OR of an adverse clinical outcome with transfusion (versus without transfusion) was statistically significant (P .05) for all sites except the cervix
(P > .05). These unadjusted results contrast with the
conclusions of most of the studies that presented a multivariate
analysis. A statistically significant (P .05) TRIM
effect adjusted for the effects of confounding factors was reported
from only 11 studies of colorectal cancer,17 4 studies of
head and neck cancer, 1 study of breast cancer, 2 studies of gastric
cancer, 4 studies of lung cancer, and 2 studies of prostate
cancer.18
On the basis of such a statistical combination of the unadjusted findings of the retrieved observational studies, Chung et al62 concluded that allogeneic blood transfusion given for a cancer resection operation had an adverse effect on subsequent prognosis; Vamvakas17 and Brand and Houbiers18 reached the opposite conclusion. In the case of colorectal cancer studies, there was marked variation among the findings of the available reports, and the probability that such variation might have arisen by chance was smaller than 1 per 1000 (P < .001 for the Q test statistic). As already discussed, this situation precludes the calculation of a summary estimate of the allogeneic transfusion effect across the available studies by the techniques of meta-analysis.55 Brand and Houbiers18 separately analyzed the studies that reported on colorectal cancer recurrence (27 studies), death due to colorectal cancer recurrence (15 studies), or overall mortality following colorectal cancer resection (30 studies). When the unadjusted findings from these reports were integrated, there was still unexplained heterogeneity (P < .001 for the Q test statistic) in all 3 analyses. Meta-regression was used to adjust the summary OR of cancer recurrence for the effects of tumor location and clinical (Dukes) stage of tumor; the summary OR of death due to cancer recurrence for the effect of tumor location; and the summary OR of death from any cause for the effects of tumor location, clinical (Dukes) stage of tumor, and mean patient age. After adjustment for the effects of these confounding factors, no association was found between perioperative transfusion and cancer recurrence (P = .55) or death due to cancer recurrence (P = .19), but the relationship between perioperative transfusion and overall mortality persisted (P < .001). Brand and Houbiers18 therefore reasoned that, because meta-regression could attribute the association of transfusion with cancer recurrence (or death due to cancer recurrence) to the effects of confounding factors, and because only a minority of the published observational studies had reported a significant adverse TRIM effect based on multivariate analyses, a link between perioperative transfusion and colorectal cancer recurrence could not be established. These investigators concluded that the observed effect of allogeneic transfusion on overall mortality might be due to an association of perioperative transfusion with causes of death other than cancer recurrence.18 It is also possible to ascribe the observed effect of allogeneic transfusion on mortality to a greater physiologic severity of illness in patients having transfusion than in those not having transfusion. Most observational studies presented data on the severity of disease in the included subjects; that is, they reported the clinical (Dukes) stage of tumor. In contrast, severity of illness incorporates both the severity of disease and the prevalence and severity of comorbidities, such as diabetes mellitus, congestive heart disease, lung disease, liver disease, or kidney failure. Such chronic systemic illnesses may have as much of an impact on overall mortality as the clinical (Dukes) stage of tumor, but the available observational studies did not present data on chronic systemic illness, making it impossible to adjust for the effect of illness severity in the meta-analysis. It is thus possible that the patients having perioperative transfusion survived for a shorter period after the cancer resection operation simply because they were sicker at the time of surgery than the patients who did not require transfusion. The findings of the available observational studies on the association of perioperative transfusion with cancer recurrence may no longer be relevant to the management of contemporary cancer patients. Many of these studies (eg, all of the studies that reported on patients with gastric cancer) examined only overall survival; others did not report a multivariate analysis; still others included patients operated on before 1980 and over an extended period. For example, only 3 of the 14 studies of head and neck cancer retrieved for the meta-analysis of Brand and Houbiers18 fulfilled the selection criteria of reporting on cancer-specific complications rather than overall mortality, adjusting for the effects of confounding factors by multivariate analysis, and including patients operated on after 1980 and over a period of less than 5 years. Only 1 of these 3 studies reported a statistically significant adverse effect of allogeneic blood transfusion.18 Furthermore, the findings of the available observational studies of the association of perioperative transfusion with cancer recurrence may reflect the effect of publication bias,63-65 a consideration that may also apply to the discussion of the reported observational studies of the relationship between perioperative transfusion and postoperative infection. Studies reporting null results are less likely to be published than studies reporting statistically significant findings. Easterbrook et al63 documented a statistically significant 3.8-fold increase in the odds of publication for observational studies reporting significant findings, compared with studies with null results. Multivariate analysis showed that the better odds of publication could not be explained by the quality of the study design. On the contrary, there was a trend toward a greater number of significant results with poorer quality studies.63 Rather than comparing patients with or without transfusion, Ness et al66 prospectively compared the recurrence rate of prostate cancer in 309 recipients of autologous or allogeneic blood transfusion, and observed no clinical benefit from the use of autologous blood. The hazard ratio of allogeneic transfusion in a univariate Cox proportional hazard model of time to tumor recurrence was 0.87 (P > .05), and Ness et al66 commented that a beneficial TRIM effect could not be excluded. It is noteworthy that allogeneic blood transfusion is not associated with an adverse prognosis in patients with cervical cancer, even when all available univariate (unadjusted) results are combined (Figure 1). Because human papillomavirus (HPV) is implicated in the pathogenesis of cervical cancer, cytotoxic T cells directed against HPV antigens expressed on the surface of tumor cells could contribute to immunologic control of the growth of residual tumor cells following cancer resection. Accordingly, if allogeneic blood transfusion induced immune suppression, it could down-regulate these cytotoxic T-cell responses, promoting tumor cell growth. Transfusion would thus be expected to have a larger adverse effect in patients with cervical cancer than in patients with cancer from other sites (Figure 1) where the tumors are not virus induced and are probably subject to weaker immunologic control mechanisms. However, it has been observed that early in the development of cervical intraepithelial neoplasia, the expression of class I HLA molecules on malignant cells is specifically down-regulated. HPV-specific, HLA-restricted cytotoxic T cells (whose function may be suppressed by allogeneic blood transfusion) may not be effective against cervical cancer cells because of the reduction in class I HLA molecule expression on the tumor cells.67 Postoperative infection Except for a handful of studies,61,68-70 observational investigations of the association of allogeneic blood transfusion with postoperative bacterial infection almost uniformly have reported a relationship between perioperative transfusion and infection, which persisted after statistical adjustment for the effects of the confounding factors considered by the authors.16,19 Postoperative infection often develops, however, because of a higher physiologic severity of illness and a higher prevalence of risk factors for postoperative infection at specific sites in patients having transfusion compared with those not having transfusion. As already discussed in the context of cancer recurrence, in most published observational studies of transfusion and postoperative infection, the reported allogeneic transfusion effect was adjusted for the effect of severity of disease (ie, the severity of the principal diagnosis), but the severity of the principal diagnosis differs from the severity of a patient's overall illness. In a study that compares the frequency of postoperative infection with or without transfusion in patients undergoing colorectal cancer resection, the presence and severity of comorbidities (eg, diabetes mellitus, congestive heart disease, lung disease, liver disease, or kidney failure) may be a more important determinant of postoperative infection than the severity of the principal diagnosis according to the clinical (Dukes) stage of tumor. Furthermore, the number of patient days with an indwelling urinary catheter may be the most important determinant of postoperative UTI; the number of days of endotracheal intubation and/or impaired consciousness may be a cardinal determinant of postoperative pneumonia; and so on.61Until recently, observational studies reporting an association between allogeneic blood transfusion and postoperative infection did not adjust for the effects of severity of illness and/or risk factors for postoperative infection at specific sites. Some teams of investigators secured partial control for the effects of these variables by excluding UTIs from the definition of postoperative infection69,71; by limiting the outcome variable to postoperative wound infection72-74; or by adjusting for the effects of serum albumin,75,76 insertion of a urinary catheter,77,78 or presence of chronic systemic illness,70 or diabetes mellitus.79 However, adjustment for the effects of all these factors in combination has rarely been presented in the literature. In a study of 492 patients undergoing colorectal cancer resection, Vamvakas et al61 calculated the probability of infection in association with perioperative blood transfusion with and without adjustment for the effects of chronic systemic illness, number of days with an indwelling urinary catheter, endotracheal intubation, and impaired consciousness. In an analysis that adjusted only for the effects of 18 confounding variables considered by previous authors and that adjusted for insertion of a urinary catheter (as opposed to number of patient days with an indwelling urinary catheter), these investigators61 detected a highly significant (P < .001) transfusion effect on the risk of postoperative infection at any site. However, when adjustment was also made for the effects of the aforementioned variables, the association between transfusion and postoperative infection at any site disappeared (P = .407); the only significant predictors of postoperative infection were the number of patient days with an indwelling urinary catheter, the presence of chronic systemic illness, the number of days of impaired consciousness, and the duration of anesthesia. Except for the duration of anesthesia, the 17 other confounding variables considered by previous authors proved to be insignificant predictors of postoperative infection in this analysis. Observational studies of the association of allogeneic blood
transfusion with postoperative infection in patients having orthopedic surgery secured partial adjustment for the effect of greater illness severity in the transfusion group by comparing subjects who received autologous or allogeneic blood transfusion. At least to some extent, patients who made preoperative autologous blood donations did so
because they were in better health than subjects who did not make
autologous donations. Also, autologous blood may have been transfused
more liberally than allogeneic blood, after less surgical blood loss,
and it is difficult to attribute any increase in the infection rate
seen in the allogeneic (compared with the autologous) transfusion group
to the allogeneic transfusion per se if adjustment is not made for the
effects of chronic systemic illness and risk factors for postoperative
infection at specific sites. Duffy and Neal20 conducted a
meta-analysis of the univariate (ie, unadjusted) results of 5 observational studies68,70,80-82 and 2 RCTs4,83 comparing the postoperative infection rates of patients having transfusion with similar volumes of autologous or allogeneic blood. Patients receiving no transfusion or a mixture of autologous and allogeneic RBCs in these studies4,68,70,80-83 were excluded from the meta-analysis. Because it is uncommon for more than 3 predonated units of autologous blood to be available, subjects receiving 4 or more units of allogeneic RBCs were also excluded. The
studies of Busch et al21,23 and Triulzi et al84
were excluded because of insufficient published information. The
summary OR across the 7 studies was 2.4 (95% confidence interval
[CI], 1.6-3.6; P < .0001). Figure
2 updates the meta-analysis of Duffy and
Neal20 by including the study of Innerhofer et
al.78 The 8 available studies were homogeneous
(P = .50 for the Q test statistic), and the summary OR of
postoperative infection in the allogeneic (compared with the
autologous) transfusion group was 2.1 (95% CI, 1.3-3.4;
P < .001).
Recently, Carson et al71 conducted a retrospective cohort study of 9598 consecutive patients with hip fracture who underwent surgical repair between 1983 and 1993 at 20 hospitals across the United States. The primary outcome variable was serious bacterial infection, defined as bacteremia, pneumonia, deep wound infection, or septic arthritis/osteomyelitis. Information was collected on numerous variables, including comorbid conditions such as the determinants of the Charlson Comorbidity Index, but the method used for building the statistical models was not described. The adjusted relative risk of serious postoperative infection with transfusion (versus without transfusion) was 1.43 (95% CI, 1.16-1.78; P = .001). Chang et al74 analyzed a database of 1349 patients undergoing elective colorectal surgery for any disease of the colon or rectum at 11 university hospitals across Canada. To better adjust for the effects of factors confounding the association of transfusion with postoperative infection, these investigators limited the outcome variable to postoperative wound infection. Ten prognostic variables were found to be associated with both transfusion and postoperative wound infection, and the final regression model adjusted for 4 of these identified confounders. Allogeneic blood transfusion was reported to be a significant independent predictor of postoperative wound infection (OR = 1.18; 95% CI, 1.05-1.33; P = .007). Vamvakas and Carven60 reported a retrospective cohort study of 416 consecutive patients admitted to one hospital for coronary artery bypass graft (CABG) operations. The outcome variable was limited to postoperative wound infection or pneumonia, and adjustment was made for the effects of chronic systemic illness and specific risk factors for wound infection or pneumonia. Statistical models were built by the forced-entry method, and the adjusted risk of postoperative wound infection or pneumonia increased by 6% per unit of allogeneic RBCs and/or platelets transfused (P = .0284), or by 43% for a patient receiving the mean transfusion dose of 7.2 U of RBCs and/or platelets.
Cancer recurrence The 3 RCTs that compared the incidence of cancer recurrence between recipients of buffy-coat-reduced allogeneic RBCs and recipients of autologous whole blood21 or RBCs2 or WBC-reduced, buffy-coat-reduced allogeneic RBCs22 were medically and statistically homogeneous. All 3 studies enrolled patients undergoing colorectal cancer resection. The proportion of patients having transfusion varied from 58%21 to 64%22 among the studies, and the proportion of patients developing recurrent cancer varied from 23%2 to 25.5%.22 There was also agreement among the findings of these RCTs (Figure 3), as the noted variation in reported results was sufficiently modest to be attributed to chance (P > .10 for the Q test statistic).55 Accordingly, the findings of the studies were combined in 2 meta-analyses,24,25 and the summary OR of cancer recurrence in the allogeneic transfusion (compared with the control) group across the 3 studies was 1.04 (95% CI, 0.81-1.35; P > .05) (Figure 3). The summary OR of death due to cancer recurrence was 0.98 (95% CI, 0.76-1.26; P > .05).24
Busch et al21 reported on 423 of 510 randomized patients; Houbiers et al22 reported on 697 of 1021 randomized subjects; and Heiss et al2 reported on 100 of 120 randomized patients. In addition to the patients who did not have transfusion (42%, 36%, and 40% of the study samples, respectively), 28%, 10%, and 33%, respectively, of the subjects randomized to receive autologous or WBC-reduced allogeneic RBCs also received buffy-coat-reduced allogeneic RBCs. Many violations of the experimental protocol occurred in the studies of Busch et al21 and Heiss et al2 because of a design problem that needs to be discussed. Patients randomly allocated to the autologous transfusion arm in these studies donated 2 U of whole blood before surgery, and, if they needed transfusion of more than 2 U of RBCs perioperatively, they were given buffy-coat-reduced RBCs. In addition, because of the preoperative autologous blood donations, these patients presented to the operating room with a lower hematocrit than patients from the allogeneic transfusion arm. Therefore, autologous transfusion recipients probably received transfusions sooner, after less surgical blood loss, than did patients allocated to the allogeneic transfusion arm. It is thus possible that patients from the autologous arm having transfusion with a particular number of RBC units may have had less invasive surgery than patients from the allogeneic transfusion arm given the same number of RBCs; this design problem may have led to overestimation of any adverse effect of allogeneic blood transfusion, as discussed by Heiss et al.2,4 It is impossible, for ethical reasons, to perform RCTs in which
patients are randomly allocated not to receive blood transfusion or to
always receive transfusion; only patients prospectively randomized to
receive different blood products Because of the high frequency of patients who did not have transfusion
and the protocol violations in the 3 RCTs investigating the association
of allogeneic transfusion with cancer recurrence,2,21,22 a
deleterious TRIM effect on colorectal cancer recurrence could be
evaluated in an effective sample of only 696 patients across the 3 studies.18 Therefore, the meta-analysis of the 3 RCTs24 did not have adequate statistical power to rule out
the possibility of an adverse TRIM effect smaller than a 33% increase
in the risk of cancer recurrence among the recipients of
buffy-coat-reduced allogeneic RBCs, compared with the recipients of
autologous or WBC-reduced allogeneic RBCs. Moreover, as already
discussed, if allogeneic WBCs are assumed to mediate the deleterious
TRIM effect(s), then the problem of limited statistical power is
compounded by the problem of limited exposure to allogeneic WBCs in
these RCTs in which buffy-coat-reduced RBCs were transfused to the
treatment arm.2,21,22 The question that is pertinent to
clinical transfusion practice in North America Furthermore, the setting of colorectal cancer resection may be inappropriate for the detection of a deleterious TRIM effect on cancer recurrence. Allogeneic transfusion-associated immunomodulation can be expected to increase the recurrence rate of a resected malignancy if the growth of residual cancer cells is indeed controlled by immunologic mechanisms. The existence of a specific immune response to colorectal cancer cells has not been proven.18 Although it is possible to generate cytotoxic T cells in vitro that recognize antigens expressed by colorectal cancer cells, the relevance of these cytotoxic cells in tumor growth may be limited because of loss of the expression of HLA molecules and adhesion molecules on colorectal cancer cells.85,86 If further RCTs are to be conducted, it may be preferable to concentrate on tumors known or presumed to be virus-induced and/or tumors that occur with increased frequency in patients receiving high doses of immunosuppressive drugs for the prevention of organ allograft rejection (ie, skin cancers, lymphoma, cervical carcinoma, and Kaposi sarcoma, as well as vulvar, perineal, and renal tumors).87 The reports of the 3 RCTs2,21,22 also presented observational comparisons of the incidence of cancer recurrence between patients having or not having transfusion in each study. The results of these analyses were conflicting.18 In the study of Houbiers et al,22 blood transfusion was not associated with cancer recurrence, and there was a statistically significant association between blood transfusion and mortality from causes other tha |
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Introduction
Design of clinical studies
because of the discrepancies among the published studies
