Neil Blumberg

Health Care–Associated Infection After Red Blood Cell Transfusion: A Systematic Review and Meta-analysis

IMPORTANCE The association between red blood cell (RBC) transfusion strategies and health care-associated infection is not fully understood. OBJECTIVE To evaluate whether RBC transfusion thresholds are associated with the risk of infection and whether risk is independent of leukocyte reduction. DATA SOURCES MEDLINE, EMBASE, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, Cochrane Database of Sytematic Reviews, ClinicalTrials.gov, International Clinical Trials Registry, and the International Standard Randomized Controlled Trial Number register were searched through January 22, 2014. STUDY SELECTION Randomized clinical trials with restrictive vs liberal RBC transfusion strategies. DATA EXTRACTION AND SYNTHESIS Twenty-one randomized trials with 8735 patients met eligibility criteria, of which 18 trials (n = 7593 patients) contained sufficient information for meta-analyses. DerSimonian and Laird random-effects models were used to report pooled risk ratios. Absolute risks of infection were calculated using the profile likelihood random-effects method. MAIN OUTCOMES AND MEASURES Incidence of health care-associated infection such as pneumonia, mediastinitis, wound infection, and sepsis. RESULTS The pooled risk of all serious infections was 11.8% (95% CI, 7.0%-16.7%) in the restrictive group and 16.9% (95% CI, 8.9%-25.4%) in the liberal group. The risk ratio (RR) for the association between transfusion strategies and serious infection was 0.82 (95% CI, 0.72-0.95) with little heterogeneity (I2 = 0%; τ2 <.0001). The number needed to treat (NNT) with restrictive strategies to prevent serious infection was 38 (95% CI, 24-122). The risk of infection remained reduced with a restrictive strategy, even with leukocyte reduction (RR, 0.80 [95% CI, 0.67-0.95]). For trials with a restrictive hemoglobin threshold of <7.0 g/dL, the RR was 0.82 (95% CI, 0.70-0.97) with NNT of 20 (95% CI, 12-133). With stratification by patient type, the RR was 0.70 (95% CI, 0.54-0.91) in patients undergoing orthopedic surgery and 0.51 (95% CI, 0.28-0.95) in patients presenting with sepsis. There were no significant differences in the incidence of infection by RBC threshold for patients with cardiac disease, the critically ill, those with acute upper gastrointestinal bleeding, or for infants with low birth weight. CONCLUSIONS AND RELEVANCE Among hospitalized patients, a restrictive RBC transfusion strategy was associated with a reduced risk of health care-associated infection compared with a liberal transfusion strategy. Implementing restrictive strategies may have the potential to lower the incidence of health care-associated infection.

A clinical and immunologic study of blood transfusion and postoperative bacterial infection in spinal surgery

Allogeneic blood transfusion has been implicated as an independent risk factor for postoperative bacterial infection in clinical and animal studies. The association among transfusion, quantitative immunologic factors, and infection was examined in 102 patients undergoing 109 spinal fusion procedures. In 60 procedures, patients received autologous blood only; in 24 procedures, they received at least 1 unit of allogeneic blood, and in 25 procedures, they received no transfusions. Twenty-two patients developed bacterial infections, in 8 cases while in hospital and in 14 cases after discharge. Univariate analysis revealed that patients who received any allogeneic blood and those who received no allogeneic blood differed significantly in the rate of hospital-acquired infection (20.8 vs. 3.5%), length of stay (12.3 vs. 9.7 days), days of fever greater than or equal to 38 degrees C (4.0 vs. 2.9), days on antibiotics (3.9 vs. 2.5), duration of surgery (309 vs. 231 min), blood loss (1343 vs. 887 mL), surgeon, and postoperative drop in natural killer (NK) cells (-174 vs. -42/microL). Multivariate logistic and linear regressions revealed that the number of allogeneic units transfused was the only significant predictor of in-hospital infection (p = 0.016) or days on antibiotics and length of stay. None of the clinical, surgical, or transfusion variables was significantly associated with posthospital infection, although a significantly greater drop in NK cells had occurred in patients who developed infection (p = 0.0035). These data strongly implicate allogeneic transfusion as a risk factor for in-hospital postoperative bacterial infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Infection or suspected infection after hip replacement surgery with autologous or homologous blood transfusions

Homologous blood transfusions have been associated in both animals and humans with an increased risk of acute postoperative infectious complications. Eighty‐four patients who underwent hip replacement surgery and were transfused with 2 or 3 units of blood were analyzed to determine whether those receiving homologous transfusions had different outcomes than those receiving autologous blood only. Only patients free of other risks for postoperative infection were studied. Those receiving homologous blood had a 32 percent (16/50) rate of proven or suspected infections, which was significantly higher than the 3 percent (1/34) rate in patients receiving autologous blood (p = 0.0029). Wound infections accounted for only a minority (6/17) of the proven or suspected infections, which suggests that nonsurgical factors contributed to these complications. The patients identified as being infected required significantly more antibiotic therapy (mean, 7.6 days) and lengthier hospital stays (mean, 15.5 days) than the patients who remained free of evidence of infection (means: 2.3 days of antibiotics and 12.3 days in the hospital) (p = 0.0001 for each variable). Other potential risk factors for infection, such as duration of surgical procedure, advanced patient age, amount of blood loss, type of anesthesia, surgeon performing the operation, use of a cemented versus porous‐coat prosthesis, leukocytopenia, anemia, and underlying medical diagnosis, did not account for the differences in infection rates seen in those receiving homologous and autologous transfusions. These results confirm previous reports of an increased risk of postoperative infection in patients receiving homologous transfusions. Homologous transfusion may contribute to an increased risk of infection by immunologic modulation of the recipient. If confirmed by other studies, these results provide another powerful argument in favor of autologous blood transfusion.

Relation between recurrence of cancer of the colon and blood transfusion

Data suggest that blood transfusion can cause immunosuppression. The incidence of recurrence of tumours was examined retrospectively in patients who had undergone potentially curative operations for cancer of the colon during 1970-81. Tumours recurred in six of 68 patients (9%) who had not been given transfusions and in 56 of 129 patients (43%) who had (p much less than 0.0001). Transfusion was also found to be significantly associated with the time to recurrence after adjustment for other baseline prognostic factors (p less than 0.05). Perioperative transfusion may be a significant risk factor in the prognosis of cancer of the colon. Whether this association is causal is unknown.

Blood Transfusions, Thrombosis, and Mortality in Hospitalized Patients With Cancer

BACKGROUND Anemia is frequent in patients with cancer, but there are concerns regarding treatment with erythropoiesis-stimulating agents. Blood transfusions are commonly used as an alternative, but with little data regarding outcomes. METHODS In a retrospective cohort study, we investigated the associations between transfusions and venous thromboembolism, arterial thromboembolism, and mortality in hospitalized patients with cancer using the discharge database of the University HealthSystem Consortium, which included 504 208 hospitalizations of patients with cancer between 1995 and 2003 at 60 US medical centers. RESULTS Of the patients included, 70 542 (14.0%) received at least 1 red blood cell (RBC) transfusion and 15 237 (3.0%) received at least 1 platelet transfusion. Of patients receiving RBC transfusions, 7.2% developed venous thromboembolism and 5.2% developed arterial thromboembolism, and this was significantly greater than the rates of 3.8% and 3.1%, respectively, for the remaining study population (P < .001). In multivariate analysis, RBC transfusion (odds ratio [OR], 1.60; 95% confidence interval [CI], 1.53-1.67) and platelet transfusion (1.20; 1.11-1.29) were independently associated with an increased risk of venous thromboembolism. Both RBC transfusion (OR, 1.53; 95% CI, 1.46-1.61) and platelet transfusion (1.55; 1.40-1.71) were also associated with arterial thromboembolism (P < .001 for each). Transfusions were also associated with an increased risk of in-hospital mortality (RBCs: OR, 1.34; 95% CI, 1.29-1.38; platelets: 2.40; 2.27-2.52; P < .001). CONCLUSIONS Both RBC and platelet transfusions are associated with increased risks of venous and arterial thrombotic events and mortality in hospitalized patients with cancer. Further investigation is necessary to determine whether this relationship is causal.

Platelet derived CD154 (CD40 ligand) and febrile responses to transfusion

Summary Febrile responses are a common and sometimes life-threatening occurrence in patients receiving platelet transfusions. The cause is largely unknown. We showed that CD154 is present at 3000-7000 ng/L in the supernatant of nine preparations of human platelets used for transfusions and induces prostaglandin E 2 synthesis in human fibroblasts. Since CD154 is a potent inducer of the cyclo-oxygenase-2 enzyme and prostaglandin E 2 , the main fever inducers, infusion of platelet preparations containing CD154 may incite febrile responses.

Association between transfusion of whole blood and recurrence of cancer

Transfusion affects the immune response to renal transplantation and may be associated with recurrence of various human neoplasms. Data from patients with colonic, rectal, cervical, and prostate tumours showed an association between transfusion of any amount of whole blood or larger amounts of red blood cells at the time of surgery and later recurrence of cancer. Recipients of one unit of whole blood had a significantly higher incidence of recurrence (45%) than recipients of a single unit of red cells (12%) (p = 0.03). Recipients of two units of whole blood also had a higher rate of recurrence (52%) than those receiving two units of red cells (23%) (p = 0.03). Recipients of any amount of whole blood had similar recurrence rates (38-52%). Recipients of four or more units of red blood cells had a higher rate of recurrence (55%) than those receiving three or fewer units of red blood cells (20%) (p = 0.005). Mortality due to cancer in patients receiving three or fewer units of red blood cells (2%) was similar to that in patients who did not have transfusions (7%) and significantly lower than that observed in patients receiving three or fewer units of whole blood (20%) (p = 0.003). A proportional hazards risk analysis showed that transfusion of any whole blood or more than three units of red blood cells was significantly associated with earlier recurrence and death due to cancer. These data support an association between transfusion and recurrence of cancer. They also suggest that some factor present in greater amounts in whole blood, such as plasma, may contribute to the increased risk of recurrence in patients who have undergone transfusion. Until the questions raised by retrospective studies of cancer recurrence and transfusion can be answered by prospective interventional trials with washed red blood cells, red blood cells should be transfused to patients with cancer in preference to whole blood when clinically feasible.

Transfusion-Induced Immunomodulation and Its Clinical Consequences☆

The bulk of experimental and clinical data support the theory that homologous transfusion causes significant down-regulation of immunologic functions in a number of settings. These changes in immune function may account for the beneficial associations of transfusion with increased renal allograft survival, and decreased recurrence in Crohns disease. Conversely, these transfusion-induced effects may be responsible in part for the deleterious association of homologous transfusion with increased cancer recurrence, and increased posttransfusion bacterial and viral infection rates. Host defenses against malignancy and infection may in some instances be severely compromised by transfusions of homologous blood, but the circumstances under which this occurs need to be better defined. Likewise, the hypothesis that modification of blood components to contain fewer leukocytes or less plasma might ameliorate these effects is attractive, but little or no data exist to support or refute it. Future clinical studies will no doubt address these issues.

An association of soluble CD40 ligand (CD154) with adverse reactions to platelet transfusions

BACKGROUND: Removal of stored supernatant abrogates most transfusion reactions to leukoreduced platelets (PLTs), suggesting that PLT‐derived soluble mediators are involved. PLTs are the primary source of soluble CD40 ligand (sCD40L). Engagement of the receptor for CD40L induces synthesis of proinflammatory mediators including interleukin (IL)‐6, IL‐8, and monocyte chemotactic protein‐1 (MCP‐1).

Hospital variation in transfusion and infection after cardiac surgery: a cohort study

BackgroundTransfusion practices in hospitalised patients are being re-evaluated, in part due to studies indicating adverse effects in patients receiving large quantities of stored blood. Concomitant with this re-examination have been reports showing variability in the use of specific blood components. This investigation was designed to assess hospital variation in blood use and outcomes in cardiac surgery patients.MethodsWe evaluated outcomes in 24,789 Medicare beneficiaries in the state of Michigan, USA who received coronary artery bypass graft surgery from 2003 to 2006. Using a cohort design, patients were followed from hospital admission to assess transfusions, in-hospital infection and mortality, as well as hospital readmission and mortality 30 days after discharge. Multilevel mixed-effects logistic regression was used to calculate the intrahospital correlation coefficient (for 40 hospitals) and compare outcomes by transfusion status.ResultsOverall, 30% (95 CI, 20% to 42%) of the variance in transfusion practices was attributable to hospital site. Allogeneic blood use by hospital ranged from 72.5% to 100% in women and 49.7% to 100% in men. Allogeneic, but not autologous, blood transfusion increased the odds of in-hospital infection 2.0-fold (95% CI 1.6 to 2.5), in-hospital mortality 4.7-fold (95% CI 2.4 to 9.2), 30-day readmission 1.4-fold (95% CI 1.2 to 1.6), and 30-day mortality 2.9-fold (95% CI 1.4 to 6.0) in elective surgeries. Allogeneic transfusion was associated with infections of the genitourinary system, respiratory tract, bloodstream, digestive tract and skin, as well as infection with Clostridium difficile. For each 1% increase in hospital transfusion rates, there was a 0.13% increase in predicted infection rates.ConclusionAllogeneic blood transfusion was associated with an increased risk of infection at multiple sites, suggesting a system-wide immune response. Hospital variation in transfusion practices after coronary artery bypass grafting was considerable, indicating that quality efforts may be able to influence practice and improve outcomes.