Transfusion volume and duration of RBC storage significantly impacted the likelihood of developing healthcare-associated CDI. The relationship between RBC transfusion and CDI was not due to confounding by patient demographics, host genetic factors, or a past medical history of underlying chronic comorbidities because the comparator hospitalizations were obtained from the same individuals. Moreover, the findings regarding RBC storage duration and the development of healthcare-associated CDI were not due to confounding by indication, since only those who received transfusions (i.e., in whom transfusions were deemed indicated) were included in the analysis.
Patients who developed CDI were more likely to have undergone surgical procedures. However, the association between RBC transfusion and CDI remained after restriction to only those instances in which surgical procedures occurred in both the index hospitalization and the comparator hospitalizations. Our entry criteria were such that all patients who developed healthcare-associated CDI within the 3-year study period were included, reducing the likelihood of selection bias. In addition, the laboratory technicians assessing C. difficile
assays were blinded to the transfusion status of the patient, which reduces the likelihood of detection bias. Furthermore, the comparator hospitalizations occurred after the index hospitalization so, a priori
, one might expect a greater risk of CDI during subsequent hospitalizations 
– not a lower risk. It is interesting to note that the comparator hospitalizations (in which CDI did not occur) were more likely to be emergent admissions (63.6%) compared to the index hospitalization (54.5%) and this suggests that the patient’s condition at the time of admission was not necessarily graver when the healthcare-associated CDI occurred than during the comparator hospitalizations. While it is conceivable that there is some unknown simultaneous factor strongly correlated with RBC storage duration that confers increased risk for the development of CDI, to our knowledge such factor has not been identified in the literature. On the other hand, the evidence for immunomodulatory effects related with storage duration of RBCs has been widely documented 
The association between the volume of RBC transfusions and the development of CDI was dose-dependent. Each additional liter of RBCs transfused increased the odds of CDI by 76%. For hospitalizations in which cardiovascular surgeries were performed, the odds of developing CDI were 2.84 fold greater for each liter of RBCs administered. This is in agreement with our previous study in which we demonstrated a 3.16 fold increased odds of CDI with RBC transfusions in a Medicare population undergoing cardiac surgery 
. Crabtree et al.
also reported this association in cardiac surgery patients at two centers between 1997 and 2004 
. With a control population matched 3
1 based on date of surgery and institution, blood product transfusion was associated with a 3.28 fold increased odds of developing CDI in a multivariable model adjusted for baseline patient and operative characteristics 
. In 2013, results from a prospective study of 5158 adults who were observed for 65 days after cardiac surgery 
indicated a significantly higher rate of CDI in patients transfused with RBCs (RR
2.1; 95% CI 1.2–3.7 calculated from data in ).
Evidence for an elevated risk of infection from the use of a liberal blood transfusion strategy comes from a Cochrane meta-analysis of six randomized controlled trials 
. The summary effect indicated a 19% lower risk of infection when restrictive hemoglobin triggers are used 
. Underlying reasons for this relationship have been studied in some detail. Stored red cells have demonstrated a wide range of time-dependent changes including metabolic, enzymatic, oxidative and physiologic alterations, affecting both structure and function 
. Recently, transfusion-related acute gut injury has been described, linking RBC transfusion with necrotizing enterocolitis in the naïve gut 
. While the underlying mechanisms are still under investigation, it is interesting to note that, in both instances (naïve gut and post-antibiotic gut such as in CDI), there is dramatic flux in the intestinal microbiota, which may have implications for the gut’s normal role in modulating immune cell differentiation 
. With respect to immunomodulatory effects, RBCs have been shown to suppress monocyte function which is exacerbated by the length of storage and modified by the type of preservative solution 
. Packed red blood cells also depress peripheral T-cell proliferation in a dose-response manner 
. Stored RBCs elevate levels of plasma nontransferrin bound iron, encourage tissue deposition of iron, and initiate inflammation which increase inflammatory cytokines and oxidative damage 
. The clinical syndrome associated with the immune down-regulation following blood product administration has been referred to as transfusion-associated immunomodulation (TRIM). Clinical evidence for TRIM has been recognized in the medical literature for a considerable length of time 
, and our study potentially extends the role of TRIM to healthcare-associated CDI.
Each year, more than 300,000 C. difficile
infections occur in US hospitals alone, and CDI was reported as the 17th
leading cause of death in Americans ages 65 years and older in 2011 
. Moreover, infection with C. difficile
tends to recur, contributing to hospital readmissions; 32.7% of Medicare beneficiaries and 30.2% of Medicaid recipients experience a 30-day readmission after a hospitalization with CDI 
. The target of a 30% reduction in CDI in hospitals by the end of 2013 set by the National Action Plan for Prevention of Health-Care Associated Infections has not been met 
. This may be, in part, due to a greater need for initiatives that have been shown to impact clinical CDI outcomes. In a systematic review of prevention strategies to reduce the incidence of CDI, there was moderate evidence of the effectiveness of restrictive antibiotic practices but limited evidence regarding other approaches, such as environmental preventive interventions 
. Our finding that blood product transfusion may contribute to this problem is significant in that it highlights potential areas for improvement. The hope is that greater attention to blood management programs such as the Choosing Wisely® initiative will reap supplemental benefits for patients.