1. Prostacyclin Promoter Polymorphism is Associated with Severity of Infant Respiratory Viral Infection S Van Driest 1, T Gebretsadik 3, P Moore 2, S Reiss 2, T Hartert 4,5 Vanderbilt University School of Medicine, Departments of Pediatrics 1, Division of Allergy, Immunology and Pulmonary Medicine 2 ; Biostatistics 3 ; and Medicine 4, Division of Allergy, Pulmonary, and Critical Care Medicine 5 Results Background Bronchiolitis is the leading cause of infant hospitalization in the US and a major cause of infant mortality worldwide Treatment is limited to supportive care In mice with RSV bronchiolitis, prostacyclin synthetase expression protected against severe infection A variable number of tandem repeats (VNTR) modulates human prostacyclin production VNTR length inversely correlated with severity of RSV bronchiolitis in Japanese infants Objectives Determine the relationship of VNTR length to bronchiolitis severity in a larger cohort representing multiple ethnicities and viral etiologies Assess whether VNTR length is associated with risk for bronchiolitis vs. upper respiratory infection (URI) Methods Population: 674 term, non-low birth weight, previously healthy infants with either URI or bronchiolitis recruited for the parent study (Tennessee Children’s Respiratory Initiative) Outcome Measure: Questionnaires and medical record data were used to determine the Bronchiolitis Severity Score DNA source: DNA extracted from infant whole blood or buccal swabs from a subset of 233 infants Genotyping: The prostacyclin VNTR region was amplified by PCR and analyzed for length via gel electrophoresis Analysis: Wicoxon rank-sum or Kruskal- Wallis (for continuous variables) and Pearson (for categorical variables) tests were used to assess for differences between categories Characteristics of Cohort (n=674)Bronchiolitis Severity Score and Prostacyclin VNTR Length Among Genotyped Patients with Bronchiolitis (n=134) Conclusions Among infants with bronchiolitis there was no statistically significant difference in Bronchiolitis Severity Score by prostacyclin VNTR genotype, though a trend is evident Increasing prostacyclin VNTR length is associated with less severe respiratory disease as measured by final diagnosis (URI vs. bronchiolitis) Limitations Subgroup of whole cohort genotyped to date Small group size for some genotypes VNTR length may be marker for linked polymorphism in prostacyclin or nearby gene References Hashimoto K, et al. 2004. J Virol. 78:10303; Iwai N, et al. 1999. Circulation 100:2231; Hashimoto K, et al. 2008. J Med Virol. 80:2015 This study was supported by Thrasher Research Fund Grants (TVH and SVD), NIH K24 AI 77930, and Vanderbilt CTSA NIH RR24975. Future Directions Examine role of ethnicity, environment and viral etiology Functional correlation via urine prostacyclin metabolite Identification of other genetic polymorphisms that may influence susceptibility to severe bronchiolitis, enabling more accurate prediction of infants at risk for severe respiratory illness Pharmacologic intervention with prostacyclin may treat or prevent severe bronchiolitis 20 (9)26 (6)Other 148 (64)306 (69)Bronchiolitis Final Diagnosis 93 (40)201 (46) Supplemental Oxygen 144 (62)309 (70) Hospital Admission^ 4 [1,7]5 [2,8] Bronchiolitis Severity Score*^ 13 [6,31]12 [6,26] Age (weeks)* 3345 [3033,3657] 3289 [2977,3629] Birth Weight (grams)* 51 (22)124 (28)Other 50 (21)97 (22)Black 132 (57)219 (50)White Race 98 (42)194 (44)Female 135 (58)247 (56)Male Gender Genotyped n=233 n (%) Not Genotyped n=441 n (%) 65 (28)109 (25)URI *Median [interquartile range]; ^P<0.05 Prostacyclin VNTR Genotypes* (n=233) Frequency of Bronchiolitis vs. URI Inversely Correlates with Prostacyclin VNTR length (n=191, P = 0.034) The Tennessee Children’s Respiratory Initiative Bronchiolitis Severity Score Prostacyclin VNTR Genotype 4R/6R n=33 5R/6R n=18 6R/6R n=77 7R/6R n=6 Prostacyclin VNTR Genotype 4R/6R n=40 5R/6R n=32 6R/6R n=106 7R/6R n=13 83%59%73%46% 17%41%27%54% Respiratory Rate Flaring or Retractions Oxygen Saturation WheezingScore ≤ 30None≥ 95%None0 31-45Mild90-94%End Expiratory1 46-60Moderate85-89%Full Expiratory2 > 60Severe< 85% Audible without stethoscope 3 Bronchiolitis Severity Score (BSS) 49% 16% 7% 9% 18% 4R/4R n=1 5R/4R n=8 5R/5R n=6 7R/5R n=4 8R/6R n=3 6R/6R n=114 5R/6R n=38 4R/6R n=43 7R/6R n=16 Other n=22 *Genotypes identified as #repeats shorter allele / #repeats longer allele