It is clear from the results of large epidemiologic studies that while atopy is a major risk factor for asthma, it is usually not sufficient by itself to drive the disease process to chronicity, as less than 25% of atopics develop persistent asthma. The situation in childhood is further complicated by an additional series of development factors, related to postnatal maturation of respiratory function. Notably, a large proportion of children wheeze in infancy in response to airway infections, due principally to the small size of their airways. Most of these children grow through this phase and lose their tendency towards wheeze, simply as a result of airway growth (the so-called ‘transient wheezers’). However, in a subset of these children, wheezing persists and may become more intense, in particular in children who develop sensitization to inhalants during infancy.
A series of large prospective birth cohort studies are progressively providing plausible mechanism(s) for the underlying processes and in doing so are supplying testable hypotheses for the etiology of persistent asthma in childhood. The key observations from these studies are:
• risk for asthma persisting beyond the preschool years is at least doubled if children become sensitized to inhalants;
• the degree of risk is inversely related to the age at which sensitization first occurs;
• risk for persistent asthma is also doubled if children contract a respiratory infection in infancy sufficiently serious to trigger wheeze;
• the risk is doubled again if more than one severe wheezing lower respiratory tract infection (wLRI) occurs during this period; and
• maximum risk, involving a further two-to-threefold increase in the odds ratios for persistent asthma, is encountered when both early sensitization to inhalant(s) and wLRI occurs in the same infant.
This suggests that inflammation due to airway allergy and airway infection can interact synergistically to drive asthma pathogenesis, presumably as a result of damage to local tissues during the critical stage of lung growth during early life. The implications are that when tissue damage attains supracritical threshold levels, irreversible changes occur to growth and differentiation programs, resulting in potentially permanent structure/function changes in lung and airway tissues, which are in turn responsible for the hyperresponsiveness to exogenous irritant stimuli characteristic of the asthmatic phenotype.
This concept is supported by the results of prospective studies which indicate that analogous to long-term immunologic basic memory which is actively ‘programmed’ by experience of environmental (antigenic) stimuli, long- term respiratory function can similarly be shaped early in life by exogenous stimuli. Notably, infants who develop abnormal lung function tend to continue to track at the low end of the functional range as they grow into childhood, and are likely to track within this part of the range into adulthood, i.e. just as children’s height tracks along centile lines as they grow, growth of lung function follows a similar process. This implies that insults that result in a relative loss of lung function in early life will have potentially permanent effects, and this possibility is supported by the results of recent studies.
Thus, the key to protection against asthma may lie in the early identification of children who are at HR of early lung and airway damage due to atopy and respiratory infection, with parallel development of more effective drugs for the amelioration of airway neural inflammation in this very young age group.
