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Understanding the Relevance of School Exposure to Asthma in Children

Wanda Phipatanakul, M.D., M.S.wanda.phipatanakul@childrens.harvard.edu

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

Questions?wanda.phipatanakul@childrens.harvard.edu

asthma@childrens.harvard.edu 857-218-5336