The Effect of Washed vs Unwashed Packed Red Blood Cell Transfusion on Immune Responses in the Extremely Preterm Newborn: A Randomised Trial

Abstract

Packed red blood cell (PRBC) transfusions continue to result in adverse inflammatory responses and increased rates of morbidity despite modifications in processing such as leukodepletion. It remains unknown if this is due to adverse physiological responses, inflammatory processes related to transfusion related immunomodulation (TRIM) or both. Washing of PRBCs may reduce the immunomodulatory potential and transfusion related adverse outcomes. This study aimed to investigate whether transfusion with washed leukodepleted PRBCs in the preterm newborn reduces post-transfusion inflammatory cytokine responses compared to transfusion with unwashed leukodepleted PRBCs, improving physiological stability. Extremely preterm newborns (n=154) were randomised to transfusion with unwashed or washed leukodepleted PRBCs, determined by the restrictive threshold of the PINT transfusion study, until primary hospital discharge (77 per arm). Plasma cytokines, markers of endothelial activation and measures of cardiorespiratory stability where measured pre- and post-transfusion. Transfusion with washed PRBCs resulted in decreases in pro-inflammatory cytokines while unwashed PRBCs resulted in increases in IL-17A and TNF. By the 3rd transfusion this response to unwashed PRBCs was associated with increases in MIF and PAI-1, markers of endothelial activation, an effect not seen with washed PRBCs. This response was influenced by donor sex with exposure to PRBCs from a female donor resulting in increases in pro-inflammatory cytokines, an effect ameliorated by PRBC washing. Changes over time and in response to the type of packed red blood cells transfused were seen with a greater reduction in cardiac output and increase in systemic vascular resistance and mean airway pressure seen in those infants transfused with washed PRBCs. However, none of these alterations met the current accepted definitions for either transfusion-associated circulatory overload or transfusion-associated lung injury. The current study suggests that the association between transfusion and poor outcome have a predominantly immunomodulatory basis, a relationship that may be altered by the use of washed packed red blood cells for the extremely preterm infant. The apparent lack of significant changes in cardio-respiratory responses to a transfusion may reflect the need for specific diagnostic criteria for transfusion related complication in the preterm newborn. The current results provide strong mechanistic data supporting a potentially beneficial effect of transfusion of washed packed red blood cells in this high-risk population. The next critical step is investigating whether the use of washed packed red blood cells is associated with a significant reduction in clinical outcomes, a finding which would have wide ranging implications for both transfusion medicine and the field of neonatology.