Chitinases in asthmatic children undergoing tonsillectomy
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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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Chitinases in asthmatic children undergoing tonsillectomy

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


Chitin and chitinases

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


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

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


Chitotriosidase is overexpressed in hypertrophied adenoid tissue in children

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

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


Hypothesis and aim

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

Study Design


Study methods

Study Methods


Study population at 130 patients

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

Clinical Response to T&A in Asthmatics

Levin et al Unpublished Data


Chitinase activity is modified by t a

Chitinase Activity is modified by T&A

Levin et al Unpublished Data


Subpopulation analysis poorly controlled asthmatics

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


Composite variable asthma improvement in uncontrolled asthmatics at baseline

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%)


Baseline chitinase activity is elevated in poorly controlled asthmatics who improve with t a

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

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


Summary and conclusions

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

Limitations

  • Seasonal variability

  • Batch effect – sample collection and processing

  • Limited PFT data in young population

  • Small loss to follow-up


Future directions

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


Acknowledgements

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

Questions?


Adenotonsillectomy and asthma1

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


Chitotriosidase chit1 in asthmatics

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


Ykl 40 chi3l1 in asthmatics

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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