Dose response relationships between asthma and allergen exposure

1. Dose response relationships between asthma and allergen exposure Elizabeth C. Matsui, MD MHS Associate Professor of Pediatrics, Epidemiology, and Environmental Health Sciences MADD5 November, 2011

2. How Did We Get Here? • Allergen exposure associated with more severe asthma • Patient report of pet exposure & asthma symptoms • Occupational asthma associated with laboratory animal exposure • Relocating asthma patients from climate conducive to house dust mites to a climate prohibitive of dust mites resulted in improvement • Identification of major allergens and development of immunoassays for quantifying allergen content of environmental samples

3. Dust Mites and Asthma • Birth cohort high risk children UK • Settled dust Der p 1 in early life • Weakly correlated with mite sensitization at age 11 • Strongly correlated with wheeze and asthma r = -0.66 p = 0.001 Sporik et al NEJM 1990

4. Cockroach Allergen Exposure and Asthma Morbidity in Inner City Children Hospitalizations Unscheduled Medical Visits p=0.001 p<0.001 0.4 3 0.3 2 Hospitalizations in Past Year No. of Visits in Past Year 0.2 1 0.1 0 0 Change in Care Giver’s Plans ’ neg neg skin test, low allergen exposure skin test, low allergen exposure p=0.006 neg neg skin test, high allergen exposure* skin test, high allergen exposure* 20 pos skin test, low allergen exposure pos skin test, low allergen exposure 15 pos skin test, high allergen exposure* pos skin test, high allergen exposure* Days With Changed Plans in Past Year 10 g 1 > 8 U/gram * * Bla Bla 5 0 Rosenstreich NEJM 1997 Rosenstreich et al., N Eng J Med, 1997

5. Mouse Allergen Exposure is Associated with Asthma Morbidity IRR (95%CI) OR (95%CI) Overalllsxs Cgh Noct SABA Slow Exer • Hospitalization Adjusted OR: 69.9 (5.8-838.9) • 9/10 hospitalizations occurred among sensitized/high exposure group • Adjusted for age, sex, atopy, cockroach sensitization and exposure, public health insurance, and study visit

6. Allergen Exposure • Allergen Exposure Allergen Reduction for Primary and Tertiary Prevention? Primary prevention Tertiary prevention -Treatment

7. Home-based Intervention Trial : The Exception? Morgan, NEJM 2004

8. Why Have Allergen Intervention Trials Failed? • Bystander effect: reduce “anti-allergic” microbes/microbial products • Most relevant to primary prevention trials • Heterogeneity across individuals • Insufficient reduction of allergen • Studies designed based on incomplete understanding of: • “exposure” • dose-response curve

9. Allergen “Exposure” is Complex • Incomplete understanding of “exposure” • Environmental sample may not represent exposure • Type of sample • Settled dust, airborne, nasal • Time of sample collection • Location of collection • Particle size collected • Many characteristics of “exposure” • Mean, variability, peak • Other routes of exposure • Incomplete understanding of dose-response curve

10. Allergen “Exposure” is Complex: So What?

11. Location of Sampling & Most Important Time of Exposure • 150 US inner-city children/adolescents with persistent asthma • Settled dust • Airborne dust • PM10 • Bedroom • Bed Mus m 1 most strongly predictive of acute health care visit for asthma among sensitized participants Acute Visit for Asthma, OR [95% CI] Mus m 1 μg/g or ng/m3

12. Exposure Has Many Characteristics • Typically, exposure assessment accomplished by collecting samples representative of average exposure • Settled dust may represent average exposure over a longer period of time (months?, years?) • Airborne dust represents the average airborne concentration over the period of time monitored • Other characteristics of exposure not well studied • Variability – magnitude and rate of change • Peak

13. Amplitude, Frequency, Peak Exposures • Frequency –rate that exposure changes over time • Amplitude –difference from mean • Peak –maximum concentration exposure mean time amplitude and frequency can both vary “real life” exposure vs. time curve peak

14. Combined Effects of Concentration and Variability of Allergen Exposure Peng et al JACI 2011 Hazard Ratio Hazard Ratio Variability Mean Exposure Mean Exposure Variability mouse-specific IgG4 +SPT to mouse Variability –deviation from the mean

15. Exposure-Response Relationships: Implications What is the shape of exposure-IgE response curve and the exposure-clinical response curve? Linear relationship Plateau Risk of IgE Sensitization/Symptoms Threshold Bell-shaped Allergen Exposure

16. Shape of Exposure-Response: Primary Prevention Platts-Mills Lancet 2001;357:752-6

17. +SPT Mouse Allergen Exposure and Skin Test Sensitivity: Primary Prevention Suburban Homes Inner-city Homes p < .01 for trend • ng/g in suburban homes vs. μg/g in inner-city • Dose-response in suburban asthmatics • Risk of +SPT attenuated at highest levels in inner-city Matsui et al JACI 2004 & 2007

18. Shape of Dose-Response Curve: Tertiary Prevention “Thanksgiving effect” • Observation that young people living with a cat who go away to college and then return home for Thanksgiving break develop worsening cat allergic symptoms • Platts-Mills reported decrease in cat-specific IgG levels when person is removed from home with cat • A marker of both exposure & of clinical tolerance

19. Cat-specific IgG Modifies Effect of Cat-specific IgE on Wheeze • UK population-based birth cohort • Wheeze & Fel d 1 antibodies assessed @ 5y Custovic et al JACI 2011

20. Mouse Allergen Exposure and Asthma Exacerbation *p<.01 §p=NS mouse SPT+* Predicted Probability of Asthma Exacerbation mouse SPT-§ Bed Dust Mus m 1 (μg/g)

21. What’s the Path Forward? • Primary Prevention • Allergen exposure reduction is ineffective • Better understanding of dose-response relationship may point to approaches aimed at optimizing exposure to reduce risk • ?pet ownership • ?allergen IT • Tertiary Prevention • Allergen exposure reduction can be effective • Exposure reduction strategies can be optimized with better understanding of: • Timing, location, characteristics of exposure that are most clinically relevant • Dose-response relationship