Jason T Patregnani1,2,3, Michimasa Fujiogi4, Carlos A Camargo4, Bonnie A Brooks1, Claire E Hoptay2, Jonathan M Mansbach5, Stephen J Teach6, Robert J Freishtat2,6, Kohei Hasegawa4. 1. Division of Cardiac Critical Care Medicine, Children's National Hospital, Washington, DC, United States. 2. Department of Genomics and Precision Medicine, George Washington University, Washington, DC, United States. 3. Division of Pediatric Critical Care Medicine, Maine Medical Center, Portland, Maine; Tufts University, Medford, MA, United States. 4. Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. 5. Division of General Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States. 6. Division of Emergency Medicine, Children's National Hospital, Washington, DC, United States.
Abstract
BACKGROUND: Although bronchiolitis contributes to substantial acute (e.g., intensive care use) and chronic (e.g., recurrent wheeze and infections) morbidities in young children, the pathobiology remains uncertain. We examined relations of serum soluble receptor for advanced glycation end-products (sRAGE) with acute and chronic morbidities of bronchiolitis and whether the effect of serum sRAGE on development of recurrent wheeze is mediated through acute severity. METHODS: A multi-center, multi-year, prospective cohort study of infants hospitalized for bronchiolitis was analyzed. We measured serum sRAGE level at acute hospitalization and examined its association with intensive care use (use of mechanical ventilation and/or admission to intensive care unit) and development of recurrent wheeze by age 3 years. We performed causal mediation analysis to estimate indirect (mediation) and direct effects of sRAGE on recurrent wheeze. RESULTS: In 886 infants with bronchiolitis, median age was 2.9 months. Overall, 15% underwent intensive care and 32% developed recurrent wheeze by age 3 years. In the multivariable model adjusting for 11 confounders, higher presenting sRAGE level was associated with significantly lower risk of intensive care use (OR for each one-log increment, 0.39; 95%CI 0.16-0.91; P=0.03) and significantly lower rate of recurrent wheeze (HR 0.58; 95%CI 0.36-0.94; P=0.03). In mediation analysis, the direct effect was significant (HR 0.60; 95%CI 0.37-0.97; P=0.04) while the indirect effect was not (P=0.30). CONCLUSIONS: Serum sRAGE levels were inversely associated with acute and chronic morbidities of bronchiolitis. Effect of sRAGE on development of recurrent wheeze is potentially driven through pathways other than acute severity of bronchiolitis.
BACKGROUND: Although bronchiolitis contributes to substantial acute (e.g., intensive care use) and chronic (e.g., recurrent wheeze and infections) morbidities in young children, the pathobiology remains uncertain. We examined relations of serum soluble receptor for advanced glycation end-products (sRAGE) with acute and chronic morbidities of bronchiolitis and whether the effect of serum sRAGE on development of recurrent wheeze is mediated through acute severity. METHODS: A multi-center, multi-year, prospective cohort study of infants hospitalized for bronchiolitis was analyzed. We measured serum sRAGE level at acute hospitalization and examined its association with intensive care use (use of mechanical ventilation and/or admission to intensive care unit) and development of recurrent wheeze by age 3 years. We performed causal mediation analysis to estimate indirect (mediation) and direct effects of sRAGE on recurrent wheeze. RESULTS: In 886 infants with bronchiolitis, median age was 2.9 months. Overall, 15% underwent intensive care and 32% developed recurrent wheeze by age 3 years. In the multivariable model adjusting for 11 confounders, higher presenting sRAGE level was associated with significantly lower risk of intensive care use (OR for each one-log increment, 0.39; 95%CI 0.16-0.91; P=0.03) and significantly lower rate of recurrent wheeze (HR 0.58; 95%CI 0.36-0.94; P=0.03). In mediation analysis, the direct effect was significant (HR 0.60; 95%CI 0.37-0.97; P=0.04) while the indirect effect was not (P=0.30). CONCLUSIONS: Serum sRAGE levels were inversely associated with acute and chronic morbidities of bronchiolitis. Effect of sRAGE on development of recurrent wheeze is potentially driven through pathways other than acute severity of bronchiolitis.