Adenotonsillectomy and Asthma

Chitinases in Asthmatic Children Undergoing Tonsillectomy Maria Koenigs Yale School of Medicine Class of 2014 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, 2Section of Otolaryngology, Yale University School of Medicine, New Haven, CT

CT,

Chitin and Chitinases • Chitin is the 2nd most abundant polysaccharide in nature – Contributes to Th2 inflammation associated with asthma (Ober and Chupp, Curr Opin Allergy Clin Immunol 2009)

• Chitinases break down chitin and modulate host immune response – Chitotriosidase (true chitinase), YKL-40 (chitinase-like) Seibold, J Allergy Clin Immunol 2008

Lung

Chitin

Chitinases Chitin

Chitotriosidase Th2 Inflammation

YKL-40

Human chitinase and chitinase-like proteins are associated with asthma in children Chitotriosidase

YKL-40

• Primary chitinase of the lung • Higher activity in the serum in asthmatics

• Elevated in serum of asthmatics (Chupp et al NEJM 2007)

(Bargagli, Respiration 2010)

• Truncated form of protein found in asthmatic children (Vicencio, Pediatrics 2010)

Chitotriosidase

• Elevated levels associated with increased hospitalization in asthmatic children (Cunningham, Annals of Aller, Asthma, and Immuno, 2010)

YKL-40

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

Adenotonsillectomy and Asthma • 1986- 40-45% improved asthma control (Garabedian, Ann Otolaryngol Chir Cervicofac)

• Since then- small mostly single-armed studies • 2010-2012 renewed interest – Decreased ER visits and pediatrician visits – Decreased medication usage – Increased ACT score (Ulis et al Unpublished data, (Piessens, Int Journal of Pediatric Otolaryngology, Busino, Laryngoscope)

Biological effect of adenotonsillectomy on asthmatic inflammation has not yet been studied

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

Study Design 184 pediatric patients (ages 2-18) undergoing adenotonsillectomy enrolled

107 Asthmatics (Physician Diagnosis)

77 Controls

Baseline - Asthma Questionnaires - Genotypes - Chitinase Levels - PFTs (age ≥6)

6 month follow-up - Asthma Questionnaires - Chitinase Levels - PFTs (age ≥6)

Study Methods YCAAD Asthma Questionnaire (Pediatric Version)

• Asthma Symptoms: Symptoms history, Triggers, Medication usage, ED visits • Comorbidities: sinusitis, atopy (allergies and eczema), GERD • Environmental, home, and product exposures • Personal and family med history • Socioeconomic data, school and work days missed • Asthma Control Test (ACT)

Objective Data

• Chitinase Genotype • Chitinase Activity • YKL-40 Level • IgE Levels • Pulmonary Function Testing • (age ≥ 6, and otherwise able)

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

Clinical Response to T&A in Asthmatics

Levin et al Unpublished Data

Chitinase Activity is modified by T&A

Levin et al Unpublished Data

Subpopulation Analysis Poorly 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

Composite Variable Asthma improvement in uncontrolled asthmatics at baseline

ED/Urgent Care Visits Decreased

SABA use decreased

18/28 (64%)

Asthma Improved in 36/48 (75%)

16/20 (80%)

24/35 (68%) Number Oral Steroid Courses Decreased

Levin et al Unpublished Data

ACT Score Increase > 3

19/22 (86%)

Baseline chitinase activity is elevated in poorly controlled asthmatics who improve with T&A

Levin et al Unpublished Data

Concept: Tonsillectomy induces changes in systemic inflammation associated with asthma Before Tonsillectomy   Serum Chitinases

Tonsil Hypertrophy/ Inflammation

 Systemic Th2 Response

Chitin

Asthma Severity After Tonsillectomy

Chitin

 Serum Chitinases

 Systemic Th2 Response Asthma Severity

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

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

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

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

Questions?

Adenotonsillectomy and Asthma • Mostly small, single-arm studies – 1986: 40-45% showed improvement (Garabedian, Ann Otolaryngol Chir Cervicofac)

– 2010: Prospective study of asthmatics and controls • Fewer ER/pediatrician visits, steroid courses, decreased asthma severity medication use post-op (Ulis et 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

Chitotriosidase (CHIT1) in Asthmatics • Primary active chitinase in the human lung (Seibold, J Allergy Clin Immunol 2008)

• CHIT1 24-bp exon 10 duplication (rs3831317): nonfunctional protein Wild Type

24 bp duplication Mutant EXON 9

EXON 10

EXON 11

–  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 Clin Immuno 2008) • 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

YKL-40 (CHI3L1) in Asthmatics • Elevated in the serum of asthmatics (Chupp et al., NEJM 2007)

• CHI3L1 Promoter SNP (rs4950928, -131CG) – Associated with elevated YKL-40 levels, severity of 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)