Design paper
The Childhood Asthma Prevention Study (CAPS): Design and Research Protocol of a Randomized Trial for the Primary Prevention of Asthma

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Abstract

The Childhood Asthma Prevention Study is a randomized controlled trial to measure whether the incidence of atopy and asthma can be reduced by house dust mite allergen reduction, a diet supplemented with omega-3 fatty acids, or a combination of both interventions. Six hundred and sixteen pregnant women whose unborn children were at high risk of developing asthma because of a family history were randomized prenatally. Study groups are as follows: Group A (placebo diet intervention, no house dust mite reduction), Group B (placebo diet intervention, active house dust mite reduction), Group C (active diet intervention, no house dust mite reduction), and Group D (active diet intervention, active house dust mite reduction). The house dust mite reduction intervention comprises use of physical and chemical methods to reduce allergen contact. The dietary intervention comprises use of a daily oil supplement from 6 months or at onset of bottle-feeding, and use of margarine and cooking oils based on sunflower or canola oils to increase omega-3 dietary intake. Data is collected quarterly until the infant is 1 year old and then half yearly until age 5 years. Questionnaires are used to collect respiratory illness history and information about diet and home environment. Dust is collected from the child's bed and bedroom and playroom floors. Blinded assessments are conducted at 18 months, 3 years, and 5 years. Skin prick tests to common allergens, blood tests, and detailed illness, medication use, and vaccination histories are collected. Primary outcomes will be the development of allergic sensitization and the presence and severity of asthma. This study is designed to measure the effectiveness of allergen reduction and dietary supplementation, both separately and in combination, for the primary prevention of atopy and asthma. The results of this study may have important implications for public health policies to reduce the incidence of childhood asthma. Control Clin Trials 2001;22:333–354

Introduction

Asthma is the most common chronic disease of childhood in developed countries and one of the few treatable conditions that has increased in prevalence and severity over the last 20 years. The recent International Study of Asthma and Allergies in Childhood showed that Oceania (comprising Australia and New Zealand) has the highest 12-month prevalence of wheeze in 6- to 7-year-old children [1]. In Sydney, the 12-month prevalence of wheeze was 22.4%. In regions such as this, where the prevalence of asthma symptoms are unacceptably high, it is important that primary preventative strategies are developed.

In the last decade, epidemiological studies have contributed important information about the environmental risk factors associated with childhood asthma, and modifications of these factors offer the best opportunities for prevention. The most important factors include exposure to allergens or environmental tobacco smoke, the presence of respiratory infections in early life, and dietary factors such as frequency of fish in the diet and sodium and antioxidant intake 2, 3, 4, 5.

In humid regions, the strongest risk factor for asthma in children is sensitization to house dust mite allergens [6]. House dust mite allergen exposure increases the risk of children developing sensitization and of sensitized children having more severe airway hyperresponsiveness (AHR). In a study of children in six regions of New South Wales, the proportion of children sensitized to house dust mites was higher in areas with higher house dust mite allergen levels, and the odds ratio for the children to have current asthma (both AHR and wheeze) doubled with every doubling of house dust mite allergen exposure level [7]. This suggests that, in population terms, the risk of current asthma could be reduced by half if levels of house dust mite allergen exposure are similarly reduced. A parallel relationship has also been demonstrated in clinical studies. In a study of house dust mite-sensitized asthmatics in the UK in which exposure to other allergens such as pollens and pets was controlled, the level of AHR also doubled for every doubling in the level of house dust mite allergen exposure [8].

Methods of reducing house dust mite allergen exposure for the treatment of asthma were first suggested in studies of asthmatic children who were moved to high altitudes where allergen levels were naturally low [9]. In these uncontrolled studies, both objective and subjective measures of asthma improved, with a reversal of this trend after reexposure at sea level. Other avoidance measures including chemical methods (use of acaricides), physical methods (barrier methods, vacuum cleaning, ventilation, air filtration, and ionizers) or a combination of both methods have been evaluated. A recent meta-analysis evaluated the efficacy of chemical and physical methods of allergen avoidance for the secondary and tertiary prevention of asthma in a total of 23 randomized trials [10]. There was little improvement in people in the intervention groups compared with the control groups for asthma symptom scores, medication use, and peak flow. The authors suggest that the lack of effect may be because the total number of subjects (230 from 23 trials) was insufficient to reveal a clinically relevant effect. The failure of most of the studies to improve asthma can be attributed to the fact that 12 out of the 23 studies did not decrease house dust mite allergen concentrations and therefore did not achieve reductions in actual exposure levels. Also, all but two of the trials enrolled older asthmatics in whom the disease is likely to be established and not reversible by any means. Studies have shown that avoidance measures for relief of asthma symptoms are more effective in children or adults with mild asthma and therefore need to be applied at an early stage of the disease to be clinically effective [11].

The most effective method of preventing asthma from developing in the first instance may be to prevent allergen exposure in infancy. Clinical studies show that priming of the immune system begins in early infancy and that sensitization can be associated with very low allergen exposure concentrations 12, 13. In addition, there is evidence that sensitization is related to the level of allergen exposure at the time of birth and that sensitization acquired in early life has a greater impact on the subsequent development of asthma 14, 15. This suggests that primary preventive strategies for allergen avoidance will be more effective if they are initiated at birth, especially for infants at high risk of developing asthma.

There have been relatively few studies of allergen avoidance for the primary prevention of asthma. A randomized controlled trial conducted in the UK enrolled high-risk infants and used a combined environmental and dietary approach over a 4-year period 16, 17. Although there was no significant difference in the prevalence of asthma between the intervention and control groups at the age of 4 years, the estimated reduction was 11.4%, which may be important in population terms. Also, the intervention group had significantly less total allergy (p < 0.02), definite allergy (p < 0.005), and atopic dermatitis (p < 0.05) than the control group. This result could be important because children who develop atopy in later childhood or who have less severe atopy are at a significantly reduced risk of developing severe asthma [18]. This study had a small sample size (n = 120) and may have been underpowered to detect a clinically and epidemiologically relevant benefit of the intervention. However, it provides a valuable model of how primary preventive measures have the potential to be effective.

A second randomized controlled trial of 57 infants with atopic eczema and IgE antibodies to food allergens showed that the use of bedding encasements and other avoidance measures soon after birth effectively reduced sensitization to house dust mites and symptoms of atopic dermatitis 1 year later [19]. If this reduction in atopy could be achieved at a community level, it would have the potential to be important in reducing the incidence and severity of asthma.

At least one other trial of allergen avoidance in early life for the primary prevention of asthma is now underway. The Manchester asthma and allergy study is a prospective, prenatally randomized study that follows the development of asthma and atopy in a cohort of infants at high risk (both parents atopic) who are randomized to full house dust mite allergen avoidance measures or a normal regimen [20]. Avoidance measures include new cribs and crib mattresses encased with house dust mite-proof material, house dust mite-proof covers for the parental bed, use of high filtration vacuum cleaners, vinyl coverings for the infants' bedroom floors, benzyl benzoate on soft furnishings and carpets, bed linens washed in hot water weekly, and a supply of washable soft toys. These aggressive environmental control measures were used to maintain a low allergen environment during pregnancy and the first year of life. The long-term follow-up of the infants will provide critical evidence of whether living in a low allergen environment prevents sensitization and the risk of developing atopy and asthma.

Population studies show that children who eat fish more than once a week are 30–70% less likely to have asthma than children who eat fish less often 21, 22. This association was confirmed by conducting a large case-control study of children in which asthma was measured by exercise challenge and diet was measured by food frequency questionnaire. In this study, children who did not eat fish were three times more likely to have asthma than children who ate fish regularly [23]. An association between asthmatic symptoms and fish intake has also been demonstrated in the National Health and Nutrition Examination Survey in the USA [24].

Epidemiological studies have suggested that a diet high in marine fatty acids (fish oil) may have beneficial effects on inflammatory conditions such as rheumatoid arthritis, psoriasis, and possibly asthma 25, 26, 27, 28. The potential anti-inflammatory effects of fish oil for asthma are thought to derive from a high content of the omega-3 series fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which competitively inhibit the metabolism of arachidonic acid (AA). EPA and DHA are substrates for the generation of less active prostenoids and leukotrienes than AA, thereby potentially acting to reduce airway inflammation and consequent airway abnormalities that are a central feature of asthma [28].

Despite this evidence, the few clinical trials of omega-3 fatty acid supplementation in subjects with established asthma have not demonstrated any significant improvements in symptoms 29, 30, 31, 32. A recent Cochrane review of dietary marine fatty acids for asthma found no convincing evidence that dietary supplementation with omega-3 fatty acids leads to an improvement in asthma symptoms, medication use, AHR, or FEV1 [33]. This may be because asthma in adulthood is an established and irreversible condition or because the studies were too brief and a longer time period may be required for significant clinical benefits to develop. The effectiveness of modifying the dietary ratio of omega-3 to omega-6 fatty acids as a primary preventive strategy has not been investigated.

The only dietary studies for the primary prevention of asthma in children have involved avoidance of food allergens such as cow's milk, peanuts, and eggs by infants and by their mothers in pregnancy and lactation 34, 35. These studies provided encouraging results that dietary manipulation could reduce the proportion of infants with recurrent wheeze. In another prospective randomized controlled study of food allergen avoidance in infancy, the intervention and control groups did not differ in the incidence of food allergy, atopic dermatitis, lung function, or food or aeroallergen sensitization at age 7 years 36, 37. The authors conclude that food allergen avoidance during infancy without concurrent effective aeroallergen avoidance may not affect the development of respiratory disease in later childhood.

We hypothesize that dietary manipulation needs to begin early in life, be combined with effective house dust mite allergen avoidance, and be sustained over a long period of time in order to down-regulate the allergic and inflammatory processes that lead to the development of asthma. Because the symptoms of wheeze before the age of 3 years may not be associated with ongoing asthma, trials of primary prevention will need to be continued until the children are at least 5–6 years old, and perhaps much longer, before the true effectiveness of intervention is known.

The Childhood Asthma Prevention Study (CAPS) is a prenatally randomized controlled trial in which the effectiveness of house dust mite allergen reduction and supplementing the diet with omega-3 fatty acids both separately and in combination will be investigated in the primary prevention of asthma.

Section snippets

Ethics Approval

Ethical approval for this study was obtained from the ethics committees of the Children's Hospital at Westmead, The South Western, Western and Central Sydney Area Health Services and the University of Sydney.

Recruitment of Subjects

Pregnant women whose unborn children were at high risk of developing asthma because of a parent or a sibling with a current diagnosis of asthma or with frequent wheeze were recruited from the antenatal clinics of six hospitals in Sydney, Australia. The selection criteria are detailed in

Interventions

In CAPS, house dust mite reduction and supplementation of the diet are being tested both separately and in combination. The interventions are summarized in Figure 2.

Summary

We have presented a detailed research protocol for the Childhood Asthma Prevention Study. This is the first randomized trial to address the most important known risk factor for asthma (house dust mite allergens) in conjunction with the most important known protective factor (dietary omega-3 fatty acids) on the primary prevention of asthma. The results of this study may have important implications for public health policies to reduce the incidence of childhood asthma.

Acknowledgements

Funding for the core study was obtained from the National Health and Medical Research Council of Australia from 1997–2001, The Children's Hospital at Westmead from 1997–1998, and from New South Wales Health Department for 1997–1999. This latter contribution has subsequently been incorporated with additional funds into the Cooperative Research Centre for Asthma. For contributions of goods and services, we thank Allergopharma Joachim Ganzer KG Germany, John Sands Australia, Hasbro, Refrigerated

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