MINI-SYMPOSIUM: COHORT STUDIES
What have we learned from the Tucson Children’s Respiratory Study?

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Abstract

The Tucson Children’s Respiratory Study was the first longitudinal assessment of the natural history of asthma in which children were enrolled at birth. Over 1200 children were originally included and over 800 were still participating at age 13. The study has provided general indications about the most important risk factors for and the prognosis of different phenotypes associated with recurrent airway obstruction during childhood. The most important conclusion from the study is that asthma is a heterogeneous disease, with different predominant expressions at different ages. The form of the disease that is associated with atopy is not very frequent in early life, but becomes preponderant during the school years. However, this form is more persistent and is associated with significant deficits in lung function growth up to age 11. Up to two-thirds of infants who wheeze have a transient form of recurrent airway obstruction associated with low premorbid lung function. Many children who wheeze during the preschool years do so only during viral infections. These children usually have a history of wheezing due to respiratory syncytial virus during early life and low levels of lung function during the school years. Understanding the different asthma phenotypes of childhood will provide new clues for strategies for the primary prevention of the disease.

Section snippets

INTRODUCTION

During the 1970s, an observation was made that changed the way chronic obstructive pulmonary disease (COPD) would be understood for the rest of the century: subjects who had COPD in adult life were more likely to recall respiratory troubles during childhood than those who did not have such illnesses.1., 2. Although in these initial studies information on events occurring during the first years of life was obtained by self completed questionnaires and was thus prone to be biased by preferential

ASSOCIATION BETWEEN LUNG FUNCTION AND LRI IN EARLY LIFE

The first objective of the CRS was to detect and evaluate most LRIs occurring during the first 3 years of life. This time frame was arbitrarily chosen: the main objective was to avoid missing LRIs occurring after the first 2 years which could also have an influence on respiratory outcome. Several hundred such episodes were assessed and, in most cases, information directly derived by the paediatricians regarding each LRI (including screening for wheezing, stridor and crackles by auscultation)

ASTHMA AND WHEEZING DURING THE FIRST 6 YEARS OF LIFE

The observation that lower levels of lung function present shortly after birth preceded and predicted the development of LRI suggested a potential explanation for the link between LRI and subsequent recurrent episodes of airway obstruction and lower levels of lung function. Thus, if lung function tracked with age, then children born with lower lung function would still have low lung function several years later. They would also be more prone to LRI, because their narrower airways would be more

IMMUNE RESPONSES DURING LRI AND SUBSEQUENT WHEEZING

To test that hypothesis we used blood samples obtained at the time of the first acute episode of LRI and during the convalescent period for that same LRI in children who went on to become either persistent wheezers or transient wheezers.19 We measured total serum IgE levels and performed eosinophil counts on both occasions in both groups and in a third group of children who never wheezed but who had LRIs diagnosed as either pneumonia or croup.

We found that children who would go on to become

ASTHMA AND ALTERNARIA IN A DESERT ENVIRONMENT

During the 1980s influential writers proposed the hypothesis that exposure to certain specific aeroallergens could be causative in the development of asthma.21., 22. The data seemed to be quite overwhelming: many studies performed in coastal areas had consistently showed that sensitisation to house dust mites was almost universally present among school-age children with asthma. The concept emerged that avoidance of exposure to house dust mites could become a successful strategy for the

DEVELOPMENT OF IFN-γ RESPONSES IN EARLY LIFE

The nature of this derangement is still intensely debated. In the early 1990s studies performed in different parts of the world suggested that children with a family history of allergies were more likely to have impaired IFN-γ responses at birth compared with those who had no such family history.28 During that same period it was reported that two types of murine T-helper cells could be identified based on the cytokines they were able to produce: Th-1 cells produced IFN-γ and interleukin-2

DAY CARE, SIBLING EXPOSURE AND WHEEZING DURING CHILDHOOD

After these studies were published, this particular area of research became particularly active. The hypothesis was proposed by us and others that microbial burden during early life could contribute to the maturation of Th-1 responses.31 A thorough review of these issues goes beyond the scope of this paper. The initial impetus for these ideas was provided by Strachan,32 who observed an inverse association between number of older siblings in the household and prevalence of allergic rhinitis in a

OUTCOME OF RSV-LRIs: NON-ATOPIC PERSISTENT WHEEZING

In the above discussion I have stressed the evidence derived from the CRS that suggests that the Th-2-like responses, characteristic of atopic asthma, are established very early in life. However, as mentioned earlier, only 60% of persistent wheezers showed positive skin test reactivity to aeroallergens at age 6. Both this observation and clinical experience suggested to us that, during the toddler and early school years, atopy-associated asthma could co-exist with a different form of the

CONCLUSIONS

In this brief summary I have tried to stress the most important analyses of data from the Tucson Children’s Respiratory Study (CRS) that were intended to elucidate the natural history of asthma during early life. These results have provided a framework within which to understand the complex nature of asthma-like symptoms during the first years of life. I am convinced that the Tucson CRS has provided the paediatrician, the paediatric allergist and the paediatric pulmonologist with new elements

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