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Chitinases in Asthmatic Children Undergoing Tonsillectomy

Chitinases in Asthmatic Children Undergoing Tonsillectomy. Maria B. Koenigs , BA 1 , Jonathan C Levin, BS 1 , Lisa Gagnon, APRN 2 , Eric D Baum, MD 2 , David E Karas , MD 2 and Geoffrey L Chupp , MD 1

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Chitinases in Asthmatic Children Undergoing Tonsillectomy

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  1. Chitinases in Asthmatic Children Undergoing Tonsillectomy Maria B. Koenigs, BA1, Jonathan C Levin, BS1, Lisa Gagnon, APRN2, Eric D Baum, MD2, David E Karas, MD2 and Geoffrey L Chupp, MD1 1Section of Pulmonary and Critical Care, Yale University School of Medicine, New Haven, CT,2Section of Otolaryngology, Yale University School of Medicine, New Haven, CT Maria KoenigsYale School of Medicine Class of 2014

  2. Chitin and Chitinases • Chitinis the 2nd most abundant polysaccharide in nature • Contributes to Th2 inflammation associated with asthma (Ober and Chupp, CurrOpin Allergy ClinImmunol2009) • Chitinasesbreak down chitin and modulate host immune response • Chitotriosidase(true chitinase), YKL-40 (chitinase-like) Seibold, J Allergy ClinImmunol2008 Lung Chitin Chitinases Chitin Chitotriosidase YKL-40 Th2 Inflammation

  3. Human chitinase and chitinase-like proteins are associated with asthma in children Chitotriosidase YKL-40 Elevated in serum of asthmatics (Chupp et al NEJM 2007) Elevated levels associated with increased hospitalization in asthmatic children (Cunningham, Annals of Aller, Asthma, and Immuno, 2010) • Primary chitinase of the lung • Higher activity in the serum in asthmatics (Bargagli, Respiration 2010) • Truncated form of protein found in asthmatic children (Vicencio, Pediatrics 2010) YKL-40 Chitotriosidase

  4. Chitotriosidase is overexpressed in hypertrophied adenoid tissue in children • Chitotriosidase found to be over-expressed in adenoids 41 children with • Chronic rhinosinusitis • Otitis Media • Allergic rhinitis Heo, Otolaryngol Head Neck Surg, 2011

  5. Adenotonsillectomy and Asthma • 1986- 40-45% improved asthma control (Garabedian, Ann OtolaryngolChirCervicofac) • Since then- small mostly single-armed studies • 2010-2012 renewed interest • Decreased ER visits and pediatrician visits • Decreased medication usage • Increased ACT score (Uliset al Unpublished data, (Piessens, Int Journal of Pediatric Otolaryngology, Busino, Laryngoscope) Biological effect of adenotonsillectomy on asthmatic inflammation has not yet been studied

  6. Hypothesis and Aim Hypothesis Adenotonsillectomy will improve asthma control and modulate inflammatory pathways associated with asthma Aim A prospective study to investigate the clinical and biological effect of adenotonsillectomy on asthma, chitotriosidase activity, and YKL-40 levels before and after surgery

  7. Study Design

  8. Study Methods

  9. Study Population at 130 patients • Mean Age: 6.2 (2-18 range) • Follow up rate: 80.7% • Primary Indication for tonsillectomy • 75% for tonsillar hypertrophy and OSA • 23% recurrent infection • Differences in asthmatics versus controls • Hispanic ethnicity • Comorbities: Sinusitis, hx of GERD, Atopy • Decreased FEV1

  10. Clinical Response to T&A in Asthmatics Levin et al Unpublished Data

  11. Chitinase Activity is modified by T&A Levin et al Unpublished Data

  12. Subpopulation AnalysisPoorly controlled asthmatics • Poor asthma control is defined as • ACT ≤ 19 • More than 2 ED/Urgent care visits per year • More than 2 oral steroid courses per year • More than 2x/week rescue SABA use

  13. Composite VariableAsthma improvement in uncontrolled asthmatics at baseline 18/28 (64%) 16/20 (80%) 24/35 (68%) Levin et al Unpublished Data 19/22 (86%)

  14. Baseline chitinase activity is elevated in poorly controlled asthmatics who improve with T&A Levin et al Unpublished Data

  15. Concept: Tonsillectomy induces changes in systemic inflammation associated with asthma Tonsil Hypertrophy/Inflammation Before Tonsillectomy   Serum Chitinases Chitin  Systemic Th2 Response Asthma Severity After Tonsillectomy Serum Chitinases  Systemic Th2 Response Chitin Asthma Severity

  16. Summary and Conclusions • Tonsillectomy improves asthmatic control in a majority of pediatric patients • Chitinase activity is decreased in asthmatics following adenotonsillectomy • Higher baseline chitinase activity may predict which poorly controlled asthmatics will have improved asthma control after adenotonsillectomy

  17. Limitations • Seasonal variability • Batch effect – sample collection and processing • Limited PFT data in young population • Small loss to follow-up

  18. Future Directions • Currently: Genome-Wide Expression Analyses • on Tonsillar Tissue, Nasal Epithelial Tissue, and Blood • Prospective study to explore the use baseline chitinaseactivity to predict response to adenotonsillectomy • Comparison with matched non-surgical control group

  19. Acknowledgements • Jon Levin, Yale School of Medicine ‘13 • Lisa Gagnon, APRN • Dr. Geoffrey Chupp and Dr. David Karas • Dr. Susan He • Connecticut Pediatric Otolaryngology • Yale Center for Asthma and Airway Diseases • Yale-New Haven Hospital Pediatric Surgery Center • North Haven Surgical Center

  20. Questions?

  21. Adenotonsillectomy and Asthma • Mostly small, single-arm studies • 1986: 40-45% showed improvement (Garabedian, Ann OtolaryngolChirCervicofac) • 2010: Prospective study of asthmatics and controls • Fewer ER/pediatrician visits, steroid courses, decreased asthma severity medication use post-op (Uliset al Unpublished data) • 2011: Retrospective study of asthmatics and controls • Fewer hospital visits, steroid courses, medication use • Improved ACT scores (Busino, Laryngoscope) • 2012: Decreased respiratory meds after surgery (Piessens, Int Journal of Pediatric Otolaryngology) Biological effect of adenotonsillectomy on asthmatic inflammation has not yet been studied

  22. Chitotriosidase(CHIT1) in Asthmatics • Primary active chitinase in the human lung (Seibold, J Allergy ClinImmunol2008) • CHIT1 24-bp exon 10 duplication(rs3831317): nonfunctional protein •  rate of mutant allele in 6 asthmatic children with fungal sensitization (Vicencio, Pediatrics 2010) • Higher activity in serum of asthmatics (Bargagli, Respiration 2010) • Lower activity in BAL of asthmatics (Siebold, J All ClinImmuno2008) • Hypertrophied Adenoids: chitotriosidase overexpression in 41 children with chronic rhinosinusitis, otitis media, and allergic rhinitis (Heo, Otolaryngol Head Neck Surg, 2011)genotype for CHIT1 and asthma, hospitalizations, or ED visits Wild Type 24 bp duplication Mutant EXON 9 EXON 10 EXON 11

  23. YKL-40 (CHI3L1) in Asthmatics • Elevatedin the serum of asthmatics (Chupp et al., NEJM 2007) • CHI3L1Promoter SNP (rs4950928, -131CG) • Associated with elevated YKL-40 levels, severityof asthma, bronchial hyperresponsiveness, and reduced pulmonary function; minor allele is protective (Ober et al., NEJM 2008) • Associated with asthma hospitalizations in children (Cunningham, Annals of Aller, Asthma, and Immuno, 2010)

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