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

The dominant past clinical model for child asthma is that of a largely allergic 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

Disease misclassification has been a large problem in asthma epidemiology Airway Obstruction viralinduced Allergeninduced Disease misclassification has been a large problem in asthma epidemiology Airway Obstruction viralinduced Allergeninduced HDM allergen induced other causes irritant-induced small airwayinduced obstrution

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

Within the spectrum of child asthma, the subgroup of children with severe disease are Within the spectrum of child asthma, the subgroup of children with severe disease are more likely to have asthma that is attributable to atopy With Respiratory Symptoms 1– 3 episodes of wheeze in past 12 mo compared to no wheeze episodes 4– 12 episodes of OR (95% Population With Respiratory With CI) for Attributable Atopy, Symptoms, Atopy, Respiratory Symptoms Fraction % % Symptoms No. Respira tory wheeze in past 12 mo compared to no wheeze episodes > 12 episodes of wheeze in past 12 mo compared to no wheeze episodes Without 119 66 526 38 3. 27 (2. 15– 4. 97) 49% 40 68 526 38 3. 44 (1. 75– 6. 75) 49% 25 84 526 38 8. 70 (3. 07– 24. 55) 75% Ponsonby et al Chest 2002

In large studies focusing on allergic airway disease, an improved signal-to-noise ratio will be 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

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

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

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

69 29 15 44 9 34 Unadjusted OR for HDM-specific sensitisation Adjusted OR for 69 29 15 44 9 34 Unadjusted OR for HDM-specific sensitisation Adjusted OR for HDM-specific sensitisation ( trend, p=0. 80) Unadjusted OR for ryegrass-specific sensitisation Adjusted OR for ryegrass-specific sensitisation (trend, p=0. 0001) Note, the difference in family size effect is significant, p=0. 02 Ponsonby et al PAI 2003 (in press)

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

Justification for main selected outcome measures ü Frequent wheeze (more than 12 wheeze episodes Justification for main selected outcome measures ü 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)). ü 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

The 1995 Tasmanian Asthma Survey Methods Full 1995 cross-sectional sample N = 6, 378 The 1995 Tasmanian Asthma Survey Methods Full 1995 cross-sectional sample N = 6, 378 (92% of eligible) with parental questionnaires The 1988 to 1995 Tasmanian Infant Health Survey (TIHS) 1988 N = 1, 111 (81% of eligible) infants participated in home interview and survived the first year. 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. Ponsonby et al Epidemiology 2003

Is the report of wheeze and wheeze frequency valid? • Previous validation work has 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

Statistical Methods A generalized linear model with a log link function and binomial error 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

Statistical Methods cont. Etiologic fraction of wheeze attributable to synthetic bedding [P (a. RR-1)/a. Statistical Methods cont. Etiologic fraction of wheeze attributable to synthetic bedding [P (a. RR-1)/a. RR] = 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

Infant synthetic pillow use and subsequent child asthma symptoms at age seven, 1995 follow-up Infant synthetic pillow use and subsequent child asthma symptoms at age seven, 1995 follow-up sample Infant synthetic pillow use and respiratory symptom* Respiratory symptom at age seven N No wheeze in past year + 599 81 14 Moderate wheeze (1 -12 episodes in past year) 190 31 16 1. 2 (0. 9 -1. 6) 1. 1 (0. 8 -1. 5) 9 32 2. 8 (1. 3 -6. 1) 2. 5 (1. 2 -5. 5) 671 85 13 157 34 22 Frequent wheeze (More than 12 episodes in past year) No night wheeze + Night wheeze 28 Infant synthetic pillow use % RR 95%CI ARR 1. 0 95%CI 1. 0 1. 6 1. 0 (1. 2 -2. 3) 1. 5 (1. 1 - 2. 1) Ponsonby et al Epidemiology 2003

Child wheeze frequency over the past 12 months by current use of synthetic bedding Child wheeze frequency over the past 12 months by current use of synthetic bedding , full 1995 cross-sectional sample Bedding Neither pillow nor quilt synthetic + Only pillow synthetic Only quilt synthetic Both pillow and quilt synthetic N Distribution of Frequent wheeze children by number * (more than 12 of wheeze episodes Episodes vs. none) (%) 0 1 -12 More ARR (95%CI) than 12 450 82 18 0. 6 1. 00 3091 80 19 2. 0 6. 03 (1. 5, 25) 148 76 21 2. 7 4. 4 (1. 1, 18) 2373 73 24 2. 7 6. 4 (1. 2, 35) Ponsonby et al Epidemiology 2003

An investigation of non-causal explanations for the synthetic-bedding wheeze association • Not due to 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 (a. RR=3. 2 (1. 0 -10. 1) • No evidence that synthetic bedding was linked to undermanagement of wheeze. (Among children with asthma, synthetic bedding ® asthma medication use). Ponsonby et al Epidemiology 2003

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

Causal Features • Biological plausibility • The adverse effect of synthetic bedding is more 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

A cross-sectional assessment of the combined effect of HDM sensitization and feather quilt use A cross-sectional assessment of the combined effect of HDM sensitization and feather quilt use on severe asthma symptoms and lung function a Adjusted rate HDM Feather Sensitiza quilt use tion C Ö C C Ö Ö Ö Lung function ratio (95% CI) P value FEV 1/FVC ratio P Value for severe change (%) symptoms over b (95% CI) the past year 1. 00 (reference) 1. 45 (0. 45 -4. 65) 1. 79 (0. 97 -3. 27) - 0. 00 (reference) 0. 54 -0. 37 1. 80 to 1. 06) 0. 06 -0. 31 -1. 33 to 0. 71) -0. 68 (2. 51 - 0. 0001 C 6. 38 1. 24 to 0. 13) 16. 23) - (- 0. 61 ( 0. 54 (0. 02 Ponsonby et al J Clin Epi 2002

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

Conclusions Careful consideration of disease misclassification within the spectrum of asthma is required for 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.

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