Transfusion-Related Acute Gut Injury (TRAGI)

What is Transfusion-related acute gut injury (TRAGI)? This condition is occasionally seen in neonates within 48 hours after red blood cell transfusion and is often considered synonymous with transfusion-associated necrotizing enterocolitis (TANEC). Only about 25-40% of infants with NEC are noted to have received a transfusion prior to the onset of gut injury, however, so not all NEC is necessarily TRAGI.

TANEC was first described in 1987, although the term TRAGI seems to have been coined in 2006. The early clinical picture of NEC consists of feeding intolerance and failure to thrive, followed by abdominal distension, bloody stools, and retention of stomach contents. Late consequences include intestinal perforation, peritonitis, and severe illness. Treatment may include bowel rest, parenteral feeding, gastric tube, antibiotics, care in the ICU and surgical intervention.

TRAGI/TANEC occurs most commonly in infants born prematurely (≤ 28 weeks gestation). Other risk factors include smaller birth weight, a history of mechanical ventilation, and patent ductus arteriosus.  A strong association was found with infants who underwent feeding before and during transfusion, especially formula feeding (e.g. non-human milk). In fact, many hospitals adopted a policy of avoiding feedings before and during transfusion with a marked reduction in the occurrence of TRAGI/TANEC.  Infants with TRAGI/TANEC have been described as having onset of their symptoms later than non-transfused infants with NEC and as lacking the usual risk factors for non-transfusion-related NEC. Around 60% of TRAGI/TANEC patients require surgical interventions and the mortality is nearly 50%.

More recent literature discounts the association of TRAGI/TANEC with the transfusion itself but postulates it may be linked to the presence of the anemia that led to the transfusion. Many observational and randomized control trials have looked at the contribution of transfusion and/or anemia, as well as many other factors to the development of NEC, but in the end, meta-analyses of all these trials yield inconsistent conclusions.

Multiple authors (see La Gamma and Blau below) have theorized that the mechanism for TRAGI/TANEC is similar to transfusion-related acute lung injury (TRALI) in adult patients by having a “two hit” process to initiate the damage. They propose any number of situations could be the first hit, such as anemia, feeding, infection, or difficulty breathing, followed by transfusion and mediated by the RBC storage lesion and presence of cytokines or other serum molecules. The age of the transfused RBC unit did not seem to affect the likelihood of TRAGI/TANEC occurrence.

The best course of action seems to be to avoid severe anemia and resulting transfusion as much as possible in pre-term infants at risk for NEC. Clearly, more work needs to be done to explain the pathogenesis of this disease in these susceptible infants.

References:

Josephson CD, Wesolowski A, Bao G et al.  Do red cell transfusions increase the risk of necrotizing enterocolitis in premature infants? J Pediatr 2010; 157:972-978.

Christensen RD, Lambert DK, Henry E et al. Is “transfusion-associated necrotizing enterocolitis” an authentic pathogenic entity? Transfusion 2010; 50(5):1106-1112.

Blau J, Calo JM, Dozor D et al. Transfusion-related acute gut injury: necrotizing enterocolitis in vey low birth weight neonates after packed red blood cell transfusion. J Pediatr 2011; 158:403-409.

Christensen RD.  Association between red blood cell transfusions and necrotizing enterocolitis (editorial). J Pediatr 2011; 158:349-350.

La Gamma EF, Blau J.  Transfusion-related acute gut injury: feeding, flora, flow, and barrier defense.  Sem Perinatol 2012; 36:294-305.

Gephart SM.  Transfusion-associated necrotizing enterocolitis (TANEC): evidence and uncertainty.  Adv Neonatal Care 2012; 12(4):232-236.

La Gamma EF, Feldman A, Mintzer J et al.  Red blood cell storage in transfusion-related acute gut injury.  NeoReviews 2015; 16(7):e420-e430.

Patel RM, Knezevic A, Shenvi N et al.  Association of red blood cell transfusion, anemia, and necrotizing enterocolitis in very low-birth-weight infants. JAMA 2016, 315(9):889-897.

Rose AT, Saroha V, Patel RM.  Transfusion related gut injury and NEC.  Clin Perinatol 2020; 47(2):399-412.

Khashu M, Dame C, Lavoie PM et al.  Current understanding of transfusion-associated necrotizing enterocolitis: review of clinical and experimental studies and a call for more definitive evidence.  Newborn (Clarksville) 2022; 1(1):201-208.