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(Ulis et al Unpublished data, (Piessens, Int Journal of Pediatric Otolaryngology, Busino, Laryngoscope)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)