1. Childhood Asthma with an emphasis on disease misclassification and synthetic bedding. Anne-Louise PonsonbyAnne-Louise Ponsonby 1,2 Terence Dwyer 2 Jennifer Cochrane 2 Andrew Kemp 3 David Couper 4 Allan Carmichael 5 February 2003

2. The dominant past clinical model for child asthma is that of a largely allergic (atopic) aetiology However, a systematic review of population based studies found mean population attributable risk for asthma due to atopy was only 38%. Pearce et al Thorax 2000

3. Disease misclassification has been a large problem in asthma epidemiology HDM - allergen induced other causes small airway- induced obstrution viral- induced irritant-induced Allergen- induced Airway Obstruction

4. Misclassification can occur between: - Asthma and other respiratory diseases - Different types of asthma within the asthma spectrum - Different types of allergy within atopy (allergy)

5. Within the spectrum of child asthma, the subgroup of children with severe disease are more likely to have asthma that is attributable to atopy Ponsonby et al Chest 2002 75% 8.70 (3.07– 24.55) 38 5268425 > 12 episodes of wheeze in past 12 mo compared to no wheeze episodes 49% 3.44 (1.75– 6.75) 38 526 6840 4–12 episodes of wheeze in past 12 mo compared to no wheeze episodes 49%3.27 (2.15– 4.97) 38 52666 119 1–3 episodes of wheeze in past 12 mo compared to no wheeze episodes Population Attributable Fraction OR (95% CI) for Respiratory Symptoms With Atopy, % Without Respiratory Symptoms, No. With Atopy, % With Respira tory Symptoms No. Respiratory Symptoms

6. In large studies focusing on allergic airway disease, an improved signal-to-noise ratio will be obtained by focusing on symptoms that indicate severe or persistent disease

7. Atopic Disease Subgroups also occur within the broad group of ‘atopic’ or allergic children because different children are allergic to difference substances

8. Again, this issue is important to consider in aetiological studies because the causal factors involved in different allergen- specific atopy may differ.

9. 44 9 6 29 34 House dust mite (Non-atopic n= 292) Other Ryegrass HD M -specific (n=84) Ryegrass - specific (n=43) 69 34 29 44 15 9 6 34 Ryegrass House dust mite Other Ponsonby et al PAI 2003 (in press)

10. 69 34 29 44 15 9 Ponsonby et al PAI 2003 (in press) Unadjusted OR for ryegrass-specific sensitisation Unadjusted OR for HDM-specific sensitisation Adjusted OR for HDM-specific sensitisation ( trend,p=0.80) Adjusted OR for ryegrass-specific sensitisation (trend,p=0.0001) Note, the difference in family size effect is significant, p=0.02

11. Bedding analysis Aim To examine the role of infant upper bedding composition in the development of house dust mite allergen induced airway disease

12. Justification for main selected outcome measures Frequent wheeze (more than 12 wheeze episodes in the past 12 months – this outcome is strongly linked to HDM atopy (RR=19.6 (6.94, 55.56)). Night wheeze – temporally related to exposure of interest (bedding). X Asthma – not used - only weakly associated with HDM atopy (RR = 1.65 (1.30-2.09)). Ponsonby et al J Clin Epi 2002

13. Methods The 1995 Tasmanian Asthma Survey Full 1995 cross-sectional sample N = 6,378 (92% of eligible) with parental questionnaires 1995 Follow-up sample N = 863*(78%), TIHS children born in 1988 with 1988 home interview Data, plus 1995 asthma data avail ble and parental consent for record linkage. The 1988 to 1995 Tasmanian Infant Health Survey (TIHS) 1988N = 1,111 (81% of eligible) infants participated in home interview and survived the first year. Ponsonby et al Epidemiology 2003

14. Is the report of wheeze and wheeze frequency valid? Previous validation work has shown the report of wheeze over the past 12 months has a sensitivity of 0.81 and a specificity of 0.78 for the physician diagnosis of asthma in childhood. Increasing wheeze frequency is associated with increasing deficits in child lung function. Jenkins et al, Int J Epidemiol 1996; Ponsonby et al, Chest 2002

15. Statistical Methods A generalized linear model with a log link function and binomial error structure was used. Age at onset – discrete proportional hazard modelling. Armitage P, Berry G. Statistical Methods in Medical Research, 1994

16. Statistical Methods cont. Etiologic fraction of wheeze attributable to synthetic bedding [P (aRR-1)/aRR] = 16% of moderate wheeze attributable* to synthetic bedding = 79% for frequent wheeze attributable* to synthetic bedding *Statistically attributable, causality not yet fully proven. Ponsonby et al Epidemiology 2003

17. Infant synthetic pillow use and subsequent child asthma symptoms at age seven, 1995 follow-up sample Ponsonby et al Epidemiology 2003 Respiratory symptom at age seven N Infant synthetic pillow use Infant synthetic pillow use and respiratory symptom Infant synthetic pillow use and respiratory symptom * NN % No wheeze in past year + 59981 14 1.0 Moderate wheeze (1-12 episodes in past year) 19031161.2 (0.9-1.6)1.1 (0.8-1.5) Frequent wheeze (More than 12 episodes in past year) 9322.5 (1.2-5.5) No night wheeze + 6718513 1.0 Night wheeze 15734221.6 (1.2-2.3)1.5 (1.1- 2.1) RR 95%CI ARR 95%CI 28 2.8 (1.3-6.1)

19. Child wheeze frequency over the past 12 months by current use of synthetic bedding, full 1995 cross-sectional sample Ponsonby et al Epidemiology 2003 (1.2, 35) 6.42.72473 2373 Both pillow and quilt synthetic (1.1, 18) 4.4 2.72176 148 Only quilt synthetic (1.5, 25) 6.032.019803091 Only pillow synthetic 1.00 0.61882450 Neither pillow nor quilt synthetic + (95%CI) 1-12 ARR More than 12 0 Frequent wheeze * (more than 12 Episodes vs. none) Distribution of children by number of wheeze episodes (%) N Bedding

20. An investigation of non-causal explanations for the synthetic-bedding wheeze association Not due to parent’s introduction of synthetic bedding as part of an allergen reduction strategy (synthetic bedding not associated with markers of active allergen avoidance, e.g. allergen-occlusive mattress covers) No evidence parents of children with an-at-birth family history of asthma were selecting synthetic bedding. (Even among children with no family history of asthma, the consistent use of a synthetic pillow in early life was associated with night wheeze (aRR=3.2 (1.0-10.1) No evidence that synthetic bedding was linked to under- management of wheeze. (Among children with asthma, synthetic bedding  asthma medication use). Ponsonby et al Epidemiology 2003

21. Features indicative of a causal relationship High strength of association Dose-response patterns Temporality  prospective association evident  earlier use of bedding  earlier disease onset Ecological coherence  Between 1978 and 1991, declining use of feather pillows could account for 20% of increase in current wheeze overtime Butland Thorax 1997 Consistency  Many cross-sectional studies. These results are consistent with one other birth co hort (feather bedding protective) Nafstad CEA 2002

22. Causal Features Biological plausibility The adverse effect of synthetic bedding is more evident among atopic than non-atopic children, thus atopic mechanisms may be involved. The adverse effect of non-feather bedding is particularly evident among HDM allergic children (see next slide). HDM and other allergens are much higher in synthetic than feather bedding ? Direct allergen loading near the face ? Volatile organic compounds ? Lack of protective endotoxin products

23. A cross-sectional assessment of the combined effect of HDM sensitization and feather quilt use on severe asthma symptoms and lung function 0.02 -0.68 (- 1.24 to 0.13) 0.0001 6.38 (2.51-16.23)  0.54 -0.31 (-1.33 to 0.71) 0.06 1.79 (0.97-3.27)  0.61 -0.37 (- 1.80 to 1.06) 0.54 1.45 (0.45-4.65)  - 0.00 (reference) - 1.00 (reference)   P Value Lung function FEV 1 /FVC ratio change (%) (95% CI) b P value Adjusted a rate ratio (95% CI) for severe symptoms over the past year Feather quilt use HDM Sensitiza tion Ponsonby et al J Clin Epi 2002

24. Causal Features cont. Experimental data from randomised controlled trials are not yet available. An RCT on this issue is underway in Australia.

25. Conclusions Careful consideration of disease misclassification within the spectrum of asthma is required for all studies investigating the aetiology of asthma. Synthetic bedding is prospectively associated with the subgroup of asthma that represents house dust mite related airway disease.

26. Conclusions cont… Observational studies have demonstrated several causal features with regard to the synthetic bedding- frequent child wheeze association. Randomised trials are required, however, to fully exclude selection bias with regard to family choice of child bedding.