Excerpted from Chapter 6 of Understanding Asthma: A Management Companion, by Ronald S. Walls, D.Phil., & Christine R. Jenkins, M.D.

Copyright © 2000 by MacLennan & Petty Pty Limited. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.

Epidemiological factors

Several epidemiological factors are associated with the development of asthma.

Asthma in a parent or sibling

One of the best predictors for the development of asthma in an individual is the presence of asthma in a parent or sibling. The presence of asthma in one parent approximately doubles the chance of asthma developing in an offspring; if both parents have asthma, the risk of asthma in an offspring is 3 to 4 times greater. The presence of asthma in a sibling also increases the risk of developing asthma. These data come from older studies, and, as asthma has become more common, the proportions quoted may not be true now. In addition, familial data should not be taken as a demonstration of the magnitude only of the genetic effect of asthma, as families share their environment as well as their genes.

Atopy in a parent or sibling

Atopy is another important familial factor predisposing to asthma. If one parent has atopy, the risk of an offspring developing asthma is more than doubled; if both parents have atopy, the risk is more than tripled. Asthma is also more likely if an older sibling has atopy.

Presence of atopy

If a child has other manifestations of atopic disease, the chance of developing asthma is increased. Of these manifestations, pre-existing eczema is probably the most important — mainly because eczema is common in the first year of life, and thus predates the emergence of asthma in most individuals.

Early onset of symptoms

Recurrent wheeze is very common in the first two or three years of life and as has been noted, many children will cease wheezing by school age. However, in children who wheeze in later childhood, onset of wheeze before the age of 2 tends to be associated with a more severe course than in children who first wheeze after the age of 2. Furthermore, there is a correlation between the number and severity of attacks of wheeze under the age of 2 and the course of asthma in later childhood.

Gender

Approximately twice as many boys as girls wheeze in the first five years of life, yet by adolescence similar numbers of boys and girls wheeze. In the absence of reliable longitudinal data, there are two theories that could explain these findings. One theory, generally accepted, is that the prognosis for infants with asthma is better for boys than girls: in other words, many of the boys and few of the girls grow out of their asthma. The assumption here is that the infants and the older children have the same condition. An opposing theory is that many of those who wheeze in infancy have a different condition from asthma in adolescents: the former condition affects boys much more than girls, and the latter condition affects the sexes equally. This theory would argue that some of the early wheezers will have early manifestations of the asthma seen in older children but the majority have a different condition. Recent data support the latter theory.

Maternal smoking

The problem with determining the relative effects of smoking during pregnancy and passive smoke exposure after birth is that the vast majority of subjects receive both exposures. Few mothers either smoke during pregnancy and stop smoking as soon as they have given birth or do not smoking pregnancy and start smoking after delivery. There can be little doubt that exposure in utero is harmful, as respiratory function in 1-month-old infants is impaired in those whose mothers smoked during pregnancy. Whether the substantial increase in respiratory symptoms during the first year or two of life in children of smoking mothers is related to in-utero damage or a result of the irritation of ongoing inhalational exposure is less clear. Discounting the potential effect of the latter would seem most unwise for three reasons. First, the greatest level of passive smoke exposure in children is in early life. This has been shown by using urinary cotinine levels in infants. Cotinine is an accurate marker of the level of nicotine exposure, and an inverse relationship has been shown between urinary cotinine level and age in infants of smoking mothers. Second, there is a dose-response relationship between reported level of parental smoking and impaired lung and airway growth in later childhood. Third, maternal smoking has been shown in one study to increase the prevalence of asthma in children. In summary, the data on maternal smoking support a major effect of maternal smoking during pregnancy on long growth in utero, and this exposure plus inhalational exposure affects the development of wheeze and cough in early life. Epidemiological studies have suggested that long-term exposure is likely to impair lung growth and increase the prevalence of asthma.

Season of birth

Studies in the northern hemisphere have shown that asthma is more likely to develop in children born during the months of spring. The reason for this association is still not known, but is presumably related to the balance between the development of tolerance and sensitisation to seasonal inhalant allergens.

Physiological factors

Recent longitudinal studies beginning before or soon after birth have revealed interesting physiological abnormalities, which are present within weeks of birth and predate the development of asthma symptoms.

Infant lung function

Two separate studies have now shown that infants who cough and wheeze in the first three years of life have impaired respiratory function compared with those who remain asymptomatic during this period. The most consistent abnormality is a decrease in maximal flow at functional residual capacity (V'maxFRC) in the first months of life, before any record of abnormal respiratory symptoms. V'maxFRC is obtained by squeezing the infant using a jacket which inflates rapidly at end inspiration and produces a maximal forced expiratory flow-volume curve. V'maxFRC is thought to reflect a decrease in small-airway calibre, but it may also reflect increased airway wall compliance. After 3 years of age, V'maxFRC ceases to predict outcome. This suggests that airway growth or improved airway wall compliance during the first three years of life has restored normal physiological function. The airway wall abnormality is a likely reason for the entity of early viral-induced wheeze in infancy.

Infant airway responsiveness

Only one study has measured airway responsiveness in infancy and followed subjects longitudinally into childhood. In this study, the level of airway responsiveness was taken as the concentration of inhaled histamine needed to decrease V'maxFRC by 40% (PC40). Of all the parameters measured, PC40 was the strongest predictor of the development of asthma by 6 years of age. It also predicted the level of FEV₁, and airway responsiveness at this age. PC40 appeared to be independent of atopy, as it did not correlate with the level of total or specific IgE at 6 years of age. These findings are intriguing, as increased airway responsiveness at any age is likely to predispose to the development of asthma, but the reasons for increased airway responsiveness at such a young age are still completely obscure. Future studies should concentrate on understanding these reasons, as they are likely to be the key to a better knowledge of the aetiology of asthma.

Immunology factors

The association between clinical evidence of atopy and the development of asthma has been noted above.

Immunoglobulin E (IgE)

IgE is the antibody most closely associated with allergic disease. In studies of groups of older children and adults, an association between raised total serum IgE and asthma is invariably seen. The same is true of the presence of raised specific IgE levels. Several studies have assessed cord blood IgE to determine whether or not it is predictive of the development of asthma. Although some studies have reported such a relationship, the strength of prediction is usually poor and most studies have not found cord IgE predictive of asthma. The problem with cord IgE is likely to be that the young immune system, which has not been exposed to the environment, has not had the chance to produce more than trace levels of specific IgE.

T-cell function

Recent studies have suggested that repeated viral or bacterial infections may cause a shift toward Th1 responses and away from the Th2 responses that predispose to asthma. Further recent work from several laboratories has shown that T-lymphocyte function is different in infants 'at risk' of developing asthma. 'At-risk' status is usually determined by the presence of atopy or asthma in one or both of the parents. This is a crude way of dividing subjects of research studies into those who are and those who are not genetically predisposed to asthma. Nevertheless, the presence of antigen-specific T-cells in cord blood is likely to be an early marker predicting the development of asthma. Just how useful such markers might be will require the passage of sufficient time to establish the natural history of asthma in study subjects. Crucial information is still missing on the role of antigen exposure at critical periods of development in the induction of either sensitisation or tolerance. Allergen avoidance measures in early life, designed to avoid sensitisation to antigens, run the risk of promoting sensitisation by adversely affecting the development of tolerance.

Molecular genetic factors

These factors are discussed in Chapter 5. Several genotype markers have been found that are associated with differences in asthma phenotype. Studies examining the relationship between these markers and phenotypic data related to asthma in early life are now underway, and the early results are intriguing. Although these will require confirmation in other populations, they illustrate the potential for molecular genetics to improve knowledge of asthma aetiology. Examples of recent findings are as follows.

The A38G 16kDa Clara cell protein (CC16) polymorphism. CC16 is an anti-inflammatory protein secreted by epithelial cells in the respiratory tract, and is the commonest protein found in bronchoalveolar lavage fluid. As such, an important role for CC16 is asthma is plausible. A common polymorphism (A38G) has been found in the first exon of CC16, and homozygotes for A38have been found to have an increased risk of asthma. In a subsequent preliminary analysis, A38 has been found to be associated with increased airway responsiveness at 1 month of age and with the presence of asthma at 6 years of age.

The beta-2 andrenoreceptor polymorphisms. This is the principal receptor controlling airway smooth muscle responses. A polymorphism affecting this receptor would be a reasonable candidate for involvement in susceptibility to asthma. In two preliminary studies, the arg16 polymorphism in this gene was shown to be associated with childhood asthma in Scottish and Western Australian children.