Transfusion of stored blood impairs host defenses against Gram‐negative pathogens in mice

Abstract

BACKGROUND Although human red blood cell (RBC) units may be refrigerator stored for up to 42 days, transfusion of older RBCs acutely delivers a large bolus of iron to mononuclear phagocytes. Similarly, iron dextran circulates in plasma for hours to days and is progressively cleared by mononuclear phagocytes, which return iron to plasma. Finally, malaria infection continuously delivers iron to macrophages by intra- and extravascular hemolysis. Studies suggest that iron administration increases infectious risk. STUDY DESIGN AND METHODS To assess the effects of increased iron availability on susceptibility to infection, we infected mice with model Gram-negative intracellular or extracellular pathogens (Salmonella typhimurium or Escherichia coli, respectively), accompanied by RBC transfusion, iron dextran administration, or malarial coinfection. RESULTS In our mouse models, transfusion of older RBCs exacerbates infection with both Gram-negative pathogens. Although iron dextran exacerbates E. coli infection to a similar extent as transfusion of corresponding amounts of iron, higher iron doses are required to produce comparable effects with S. typhimurium. Coinfection of mice with Plasmodium yoelii and S. typhimurium produces overwhelming Salmonella sepsis. Finally, treating mice with antibiotics abrogates the enhancing effect on E. coli infection of both older RBC transfusion and iron dextran administration. CONCLUSIONS Transfusion of older RBCs exacerbates Gram-negative infection to a similar extent as malaria coinfection or iron dextran administration. Appropriate antibiotic therapy abrogates the effect of older RBC transfusions on infection with E. coli. Iron delivery to macrophages may be an underappreciated mechanism mediating, at least some, adverse effects of RBC transfusions.

Red Blood Cell Storage Duration and Trauma

“…Laboratory findings have shown that longer stored RBCs are more actively phagocytosed [105][106][107] and thereby could possibly induce immunosuppressive effects, including increased susceptibility to infection [88,105]. Prolonged storage renders RBCs more susceptible to mechanical fragility and altered membrane permeability that can increase intravascular hemolysis [108,109].…”

“…Interest in the possible intersection of storage-related RBC changes and trauma has sparked new laboratory-based research to investigate the potential immune and vascular effects resulting from transfusion of longer stored RBCs in critically ill patients [83,84]. A "two-insult" model of posttransfusion injury has been suggested by several investigators as a working hypothesis [85][86][87][88]. This model proposes that the first insult is the patient's underlying immunomodulatory condition (eg, trauma injury) that primes the patient's immune-vascular system and a second inflammatory insult triggers full-scale activation that broadens the injurious state.…”

Red blood cell transfusion is associated with increased hemolysis and an acute phase response in a subset of critically ill children

“…Thus, transfusions of fresh RBCs produce no laboratory evidence of hemolysis, whereas transfusions after longer storage durations result in substantial clearance of storage-damaged RBCs, inducing increased levels of circulating bilirubin, iron, and non-transferrin-bound iron [10]. This circulating non-transferrin-bound iron (e.g., iron not bound to transferrin, the physiologic iron transporter) enhances bacterial growth in plasma in vitro [10] and may enhance bacterial infection in vivo [16]. Furthermore, hemolysis is associated with poorer survival in septic patients [17,18].…”

Transfusion of fresher vs older red blood cells in hospitalized patients: a systematic review and meta-analysis

“…51 Hemolysis and free iron have been associated with multiple complications of transfusions and diseases such as sickle cell anemia. 52,53 Authors did not, however, report these aspects of blood processing consistently or completely enough to allow for further analyses.…”