Necrotizing enterocolitis (NEC), a disease characterized by rapid development of intestinal inflammation, often resulting in gut necrosis, is a leading cause of neonatal morbidity and mortality. NEC pathogenesis is poorly understood, and there are no diagnostic tests to predict which infants will develop NEC; furthermore, there are no effective prevention strategies. Recent studies have identified red blood cell (RBC) transfusion, a common therapy in extremely low birth weight (ELBW) infants, as an important risk factor and potential causative factor in the development of transfusion-related NEC (TR-NEC), defined as NEC developing within 48 hours of a RBC transfusion. However, biologic and clinical determinants of RBC TR-NEC remain poorly understood. Our proposed study will enroll 220 ELBW infants and be the first prospective, large, multicenter cohort study to investigate the pathophysiologic mechanisms that underlie the development of NEC following RBC transfusion. Our overarching hypothesis is that irradiation of RBC units followed by prolonged storage perturbs RBC metabolism/function, leading to paradoxical microvascular vasoconstriction, tissue hypoxia and TR-NEC in transfused infants with already impaired gut oxygenation due to significant anemia. Our three specific aims will test key aspects of this hypothesis. This study will utilize innovative methods to study TR-NEC, including metabolomics (Aims 1 and 2), near-infrared spectroscopy (NIRS) which is an in vivo non-invasive measure of mesenteric regional saturation of oxygen (MES-rSO2;
Aims 1 and 3), and in vitro RBC functional studies (Aim 2). This proposed study will fill key knowledge gaps regarding the effects of RBC storage time and irradiation on neonatal gut injury. Further, these data will guide development of new interventions, such as using NIRS to identify susceptible infants, limiting IST of stored RBC products, and using metabolite biomarkers to predict RBC safety. This project addresses the P01 central theme since ELBW preterm infants are a population vulnerable to the development of TR-NEC with antecedent RBC transfusion(s). This project interacts with Projects 1, 3, and 4 by identifying metabolic biomarkers that are associated with adverse transfusion events. Additionally Core A (regulatory approvals, sample repository), Core B (metabolomics), and Core C (biostatistics) are utilized heavily in the proposed studies.

Public Health Relevance

Necrotizing enterocolitis is a devastating disease of neonates born with a very low birthweight. There are no good ways to determine which neonates will develop this disease, and the mechanisms are not understood. Data generated from this prospective study may be paramount in designing prevention strategies, identifying putative biologic mediators, and informing optimal transfusion practices in these infants.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL086773-06A1
Application #
8794966
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2015-07-01
Budget End
2016-04-30
Support Year
6
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Sullivan, Samaah; Kelli, Heval M; Hammadah, Muhammad et al. (2018) Neighborhood poverty and hemodynamic, neuroendocrine, and immune response to acute stress among patients with coronary artery disease. Psychoneuroendocrinology 100:145-155
Marin, Terri; Patel, Ravi M; Roback, John D et al. (2018) Does red blood cell irradiation and/or anemia trigger intestinal injury in premature infants with birth weight???1250 g? An observational birth cohort study. BMC Pediatr 18:270
Guo, Ying; Wang, Yikai; Marin, Terri et al. (2018) Statistical methods for characterizing transfusion-related changes in regional oxygenation using near-infrared spectroscopy (NIRS) in preterm infants. Stat Methods Med Res :962280218786302
Hammadah, Muhammad; Sullivan, Samaah; Pearce, Brad et al. (2018) Inflammatory response to mental stress and mental stress induced myocardial ischemia. Brain Behav Immun 68:90-97
Schultz, William M; Kelli, Heval M; Lisko, John C et al. (2018) Socioeconomic Status and Cardiovascular Outcomes: Challenges and Interventions. Circulation 137:2166-2178
Sullivan, Samaah; Hammadah, Muhammad; Al Mheid, Ibhar et al. (2018) Sex Differences in Hemodynamic and Microvascular Mechanisms of Myocardial Ischemia Induced by Mental Stress. Arterioscler Thromb Vasc Biol 38:473-480
Swimm, Alyson; Giver, Cynthia R; DeFilipp, Zachariah et al. (2018) Indoles derived from intestinal microbiota act via type I interferon signaling to limit graft-versus-host disease. Blood 132:2506-2519
Samman Tahhan, Ayman; Hammadah, Muhammad; Raad, Mohamad et al. (2018) Progenitor Cells and Clinical Outcomes in Patients With Acute Coronary Syndromes. Circ Res 122:1565-1575
Runco, Daniel V; Josephson, Cassandra D; Raikar, Sunil S et al. (2018) Hyperleukocytosis in infant acute leukemia: a role for manual exchange transfusion for leukoreduction. Transfusion 58:1149-1156
Hajjar, Ihab; Hayek, Salim S; Goldstein, Felicia C et al. (2018) Oxidative stress predicts cognitive decline with aging in healthy adults: an observational study. J Neuroinflammation 15:17

Showing the most recent 10 out of 72 publications