HARVARD MEDICAL SCHOOL · 2019-12-16 · 3 School Inner-City Asthma Study Hypothesis/Research...
Transcript of HARVARD MEDICAL SCHOOL · 2019-12-16 · 3 School Inner-City Asthma Study Hypothesis/Research...
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Understanding the Relevance of School Exposure to Asthma in Children
Wanda Phipatanakul, M.D., [email protected]
Swineford Conference 1:30 to 2:15Professor of Pediatrics
Harvard Medical SchoolDirector, Asthma Clinical Research Center
Boston Children’s Hospital
HARVARDMEDICAL SCHOOL
Disclosures/Objectives
Funding NIH/NIAID/NHLBI, Genentech
Advisory Boards: Genentech, Novartis, Teva, GSK
1. To further our understanding of community risk factors for asthma and allergies
2. To discuss community engagement and environmental disparities
3. To identify interventions to reduce risk and even prevent disease outcomes
What do we know about the home allergen exposure and asthma
morbidity in children?
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Rosenstreich et al., N Eng J Med, 336: 1356-1363, 1997
Home Allergen Exposure and Asthma Morbidity in Inner City Children
Hospitalizations
p=0.001
Unscheduled Medical Visits
p<0.001
Change in Care Giver’s Plans
p=0.006
Hos
pita
lizat
ions
in
Pas
t Yea
r
No.
of V
isits
in
Pas
t Yea
r
Day
s W
ith C
hang
ed
Pla
ns in
Pas
t Yea
r
neg skin test, low allergen exposure
neg skin test, high allergen exposure*
pos skin test, low allergen exposure
pos skin test, high allergen exposure*
* Bla
0
0.1
0.2
0.3
0.4
0
1
2
3
0
5
10
15
20
neg skin test, low allergen exposure
neg skin test, high allergen exposure*
pos skin test, low allergen exposure
pos skin test, high allergen exposure*
* Bla g 1 > 8 U/gram
Similar Relationships in Home Mouse AllergenPhipatanakul et al, J Allergy Clin Immunol 2000; 106:1070-4Phipatanakul et al, J Allergy Clin Immunol 2000; 106:1075-80
Multi-Faceted Home Intervention Works in Reducing Asthma Morbidity In Urban Kids
Morgan et al., N Eng J Med, 351: 1068-1080, 2004
Reductions in cockroach and dust mite allergens highly correlated with reduced asthma morbidity
We have highlighted the importance of the Home Environment in Asthma Morbidity….
Where else does nearly every child in America spend the majority of his/her day?
“Required Occupation”
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School Inner-City Asthma Study Hypothesis/Research Question
R01 AI073964 - Phipatanakul PI
• Exposure to common indoor allergens in the classroom will increase the risk of asthma morbidity in inner-city children with asthma, even after controlling for home allergen exposures.
School Inner-City Asthma Study Repeating Annual Schema
Screening & Recruitment8-10 schools
75 Students/yr
Spring Summer
Baseline PhenotypeSurveySpirometrySkin testingBlood/Nasal
Fall
Quarterly Parental Surveys
Winter Spring
Asthma Symptoms
Class/HomeSampling
SpirometryFENO
Class/HomeSampling
SpirometryFENO
350 children38 schools
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Allergen Skin Testing– Molds (aspergillus, cladosporium,
alternaria, penicillium)
– Indoor allergens (cat, dog, dust mite, roach, mouse, rat)
– Outdoor allergens (grass, pollen, ragweed)
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Dust/Air Home/School Environmental Sample Testing
Multiplex array for indoor allergens (MARIA™)
Dust/Air Samples analyzed for common indoor allergens▪ Cockroach – Bla g 2▪ Dust Mite – Der f 1, Der p 1▪ Cat – Fel d 1▪ Dog – Can f 1 ▪ Mouse – Mus m 1 ▪ Rat- Rat n 1▪ Alt-a 1 (mold)
Classroom Mold Sampling Methods
• Airborne fungal spores were collected by Burkard samplers twice during the academic school year
• Slides read as spores per cubic meter of air (spores/m3) for collections during the school day
Particle, Pollutant, Weather, and Noise
PM2.5 & Coarse PM: Cascade Impactors at 5 LPM on Teflon filter and Polyurethane Foam placed
downstream of two size-selective inlet
Cascade
Sampler
NO2
Badge
Allergen
Sampler
Sidepak Inlet
Microbiome
Sampler
Weather
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School Sampling Visits- Want to Sign Up for This Study?
• 8 Air Samplers
• 2-3 Vacuums/ Dust Samplers
• 4 Burkard Mold Samplers
• 8 Pollution Particle Box Samplers
• 8 NO2 Samplers
• 3-4 Staff
• 1-2 CarsNot During Standardized
State Testing please
What We Do in 10 Minutes at School
FeNO‐ measurements
Spirometry/Piko
Nasal swabs
What did we find?
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School Vs. Home Allergen Levels
0.2
0.05 0.04
0.47
0.08
0.41
0.02
0.56
1.66 ***
1.38
0.02
0.66 **
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Geo
met
ric
Mea
ns
(µg/
g)
SchoolHome
Bla g 2(Cockroach)
Fel d 1 (Cat)
Can f 1 (Dog)
Der f 1 (Dust Mite)** p < 0.001
Der p 1 (Dust Mite)
MUP (Mouse)
*** p < 0.001
0.2
0.05 0.04
0.47
0.08
0.41
0.02
0.56
1.66 ***
1.38
0.02
0.66 **
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Geo
met
ric
Mea
ns
(µg/
g)
SchoolHome
Bla g 2(Cockroach)
Fel d 1 (Cat)
Can f 1 (Dog)
Der f 1 (Dust Mite)** p < 0.001
Der p 1 (Dust Mite)
MUP (Mouse)
*** p < 0.001
Bla g 2(Cockroach)
Fel d 1 (Cat)
Can f 1 (Dog)
Der f 1 (Dust Mite)** p < 0.001
Der p 1 (Dust Mite)
MUP (Mouse)
*** p < 0.001Sheehan WJ, Phipatanakul W Ann Allergy Asthma Immunol. 2009;102:125-30 Permaul P, Phipatanakul W Peds Allergy Immunol. 2012 ;23(6):543-9
Environmental Peanut Levels are Higher in Schools in Homes
Sheehan, WJ and Phipatanakul W. JACI Dec 2017
P=0.015
P=0.94 P=0.003
Wh
ole
Pea
nu
t P
rote
in
mcg
/g
School Cafeteria
N=26
School Classroom
N=69
Home Bedroom
N=59
What are Policy Implications?
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Is the School Environment Important in Health Even After Adjusting for
Exposures at Home?
Dose Response Relation between School Mouse Allergen Levels Asthma Morbidity
Sheehan WJ/Phipatanakul W, JAMA Pediatrics 2017 ;171(1):31-38
P=0.02
School Mouse Allergen Levels
Ast
hm
a S
ymp
tom
s
FE
V1%
Pre
dic
ted
P=0.002
School Mouse Allergen Levels
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School NO2 Pollutant Exposure is Associated with Airflow Obstruction
Gaffin JM, et al, JACI 2018
P = 0.01
2.1
3.3
5.3
3.4
0
1
2
3
4
5
6
Sensitized to Alternaria Not sensiized to Alternaria
Pre
dic
ted
As
thm
a S
ymp
tom
Day
s Not exposed to Alternaria
Exposed to Alternaria
Classroom Mold Exposure and Mold Allergy Markedly Increases Asthma Symptoms
Baxi SN, et al Annals of Allergy In Press
Designed Phipatanakul lab/AAAAI
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We showed the school is important– but it’s not that straightforoward…
Complexities in the Environment
Sheehan WJ, et al JACI Dec 2017
Classroom Microbial Diversity is Different than Home and Associated with Asthma Symptoms
CovariateOdds Ratio
[95% CI] p-value
Male vs. female0.89 [0.26 -
3.00] 0.85
Age in years1.35 [0.74 -
2.47] 0.33
Hispanic vs. black race
1.55 [0.38 -6.42] 0.54
Other vs. black race
0.97 [0.17 -5.49] 0.97
Classroom microbial diversity
1.91 [0.99 -3.70] 0.05
Home microbial diversity
0.65 [0 -7183.18] 0.93
Season b0.94 [0.07 -
12.56] 0.97
Lai PS, Phipatanakul W. JACI 2018
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Our Findings Highlight the Importance of the School
Environment in Asthma Morbidity, Adjusting for Exposure in the Home
Next Logical Step:Is it possible to intervene?
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School Inner-City Asthma Intervention Study- IPM vs. Cont / Classroom HEPA vs Sham
U01 AI 110397 PI Phipatanakul
Screening & Recruitment8-10 schools
75 Students/yr
Spring Summer
Baseline PhenotypeSurveySpirometrySkin testingBlood/Nasal
Fall
Follow-up Health Surveys Linked to Environmental Sampling
Nasal/Buccal x 1- Epigenetics
Winter Spring
2, 4, 6 months
Class/HomeSampling
ClassSampling
Spirometry, FENO x 2
300 children40 schools
RmzInt
ends
An asthma associated IL4R polymorphism Increases Airway Inflammation by Conversion
of regulatory T cells to Th17-like Cells
• IL-4R -Q576R polymorphism
– R allele frequency 68% (blacks); 20% (whites)
– R allele associated with severe asthma
– Unique among IL4Rpolymorphisms, directly drives TH2 to TH17 response
Massoud et al, Nat Med 2016; 22(9):1013-22
Mixed Endotoxin Signals and Th17 skewingmay be explained by GxE Interactions
• High endotoxin exposure
– Found in urban homes with lowest SES4
– Associated with ↑ TH17 skewing1,2
– Associated with asthma symptoms in schools3
– Endotoxin’s differing effects on asthma morbidity could potentially be explained by these mixed mechanisms
1 Thorne et al AJRCCM 2012; 2 Glader et al ERJ 2010; 3 Lai et al Chest 2015
•Figure from Noval-Rivas & Chatila, JACI 2016
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Distribution of the IL-4R -Q576R genotypes amongst the School Inner City Asthma Study
Asthma Symptoms Differ by Genotype and School Specific Exposure
Lai PS, et al JACI 2017 In PRESS
Q/Q wild type: Protective
Asthma Symptoms Differ by Genotype and School Specific Exposure
Lai PS, et al JACI 2017 In PRESS
Q/Q wild type: Protective
Q/R heterozygous mutant: Equivocal
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Asthma Symptoms Differ by Genotype and School Specific Exposure
Lai PS, et al JACI 2017 In PRESS
Q/Q wild type: Protective
Q/R heterozygous mutant: Equivocal
R/R homozygous mutant: Harmful
Implications and Future
• G×E (IL4R -Q576R × School endotoxin) interaction
• May contribute to asthma disparities
• May explain previous disparate effects of endotoxin on asthma
• Suggests that reducing harmful school specific exposures such as endotoxin exposure should be targeted• Inner-city schools with high proportion of
black/mixed race children also have a higher prevalence RR genotype and could be targets for intervention, including precision intervention trials
Dupilumab® Blocks Signaling Through the IL-4/IL-13 Receptor/Ligand System
Type I ReceptorIgE responses, Th2 –mediated
inflammation, reduced antimicrobial peptides
Type II ReceptorReduced skin barrier function,
increased Th2 responses
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IL-4R-R576 variant drives mixed TH2/TH17 cell inflammation in the airways by subverting allergen-specific induced T regulatory (iTreg) cell responses into the TH17 cell lineage, and that pediatric age asthmatics harboring this variant will manifest a particular favorable response to Dupilumab associated with the acquisition of favorable long-term tolerance.
New U01 AI143514 (Phipatanakul/Chatila)
Hypothesis
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Effect of IL-4RαR576 polymorphism on response to Dupilumab in children with Asthma, a Genotype stratified,
randomized-placebo controlled trial (I-DAG Study)
Screening/Eligibility Run-in
Health Outcomes
Years 11 month
Randomize
•Treatment –Dupilumab or
Placebo Observation
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6 Month
Primary Outcomes
Gentoype Characteirization
NIH U01 AI143514 – Phipatanakul/Chatila
In Summary…• School environment is important in asthma morbidity,
where nearly every child spends their day
• We can intervene on relevant school specific exposures
• Future impact may enable us to benefit communities through a school a school-based intervention, as opposed to individuals in the home, where prior to this most of the efforts have been home focused
• Decade of community relationships allow us to expand our work into understanding of microbial exposure and genex environment interactions in a home/school setting and its effects on disease outcomes- Infrastructure feeds to other investigations
• Future trial building on targeted interventions based on genotype is planned
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Acknowledgements/FundingCOLLABORATORS• Diane Gold, MD, MPH-Environment• Elliot Israel, MD-Clinical Trials• Petros Koustrakis, PhD-Monitoring• Carter Petty, MS-Stats• Brent Coull, PhD-Stats• Andrea Baccarelli, MD, Molecular Bio• Susan Redline, MD, Sleep• Tala Chatila, MD-Immunology/GeneticsTRAINEES• Margee Louisias, MD K12 HS 0229860• Marissa Hauptman, MD MPH
T32HD0757270, • Brittany Esty, MD, MPH- Patient Quality• William Sheehan, MD K23 AI104780• Perdita Permaul, MD, K 23 AI123517• David Kantor, MD, PhD K-23 HL138162• Lisa Bartnikas, MD, K23 AI125732• Fellows: T32• Michelle Maciag, MD• Nicole Akar-Ghbiril, MD• Mehtap Haktanir-Abul, MD
NIH GRANTS- NIAID/NHLBI/NIAMS
• R01 AI073964 /U01 AI 110397 (SICAS1 & 2) (Phipatanakul)
• U10HL098102 (AsthmaNet MPI)• U10HL109172 (SARP)• K24 AI 106822 (Phipatanakul)• U01AI126614(Phipatanakul) PARK
Mech-Oettgen• R01HL137192 (Phipatanakul) EASY• U19AR069526- PEPR (Ghershon)• U10HL119952 (Celedon)-Vit D • U01 HL 1300045 (Martinez)- ORBEX• UG1 HL139124 (Israel- PreCISE)• R01AI065617 (Chatila)• R01 AI144119 (Lai)- microbiome-
SICAS• R01 ES030100 (Gaffin)- Env/BPD• U01 AI143514 (Phipatanakul/Chatila)COMMUNITY/Schools/ Staff
[email protected] 857-218-5336