© 2007 American Thoracic Society doi: 10.1164/rccm.200608-1231ED
"Beam Me Up, Scotty!"Royal Brompton Hospital, London, United Kingdom
UMR-S 707, INSER and UPMC Paris 6, Medical School Saint-Antoine, Paris, France The title of this editorial recalls a phrase that is well known not just to Star Trek fans, but also is an all too familiar attitude of mind of many respiratory physicians, many of whom apparently believe that adults are created fully formed at age 18, and that any life event before that age is an irrelevance. How much space is devoted to normal lung development and the long-term effects of disease ante- and immediately postnatally in the average adult respiratory program, or even in major textbooks of respiratory medicine? Yet there is mounting evidence that before the child goes to school, lung function has been set on programmed tracks, and any damage done cannot be reversed. It is in very early life that the roots of much respiratory disease lie, and this is underscored by an article in this issue of the Journal (pp. 16–21) (1). Babies enter the second half of gestation with a normal complement of airway numbers (2). Thereafter, airway caliber can be reduced, most obviously by maternal smoking (3). Alveolar development is mainly a postnatal phenomenon, and is largely complete by two years of age (4). Furthermore, the fetal lung, which in utero faces only antigen challenges filtered by the placenta and delivered through a very limited blood supply, has to adapt postnatally to airborne challenges; the systemic immune system also encounters new threats for the very first time, while itself undergoing maturational changes that may determine lifelong how allergen challenges are dealt with. It is therefore not surprising that perturbations of these intricate processes may have long-lasting effects. Much of the current evidence of the importance of early life events comes from cohort studies. No study runs from pre-conception to death, so inferences have to be drawn from overlapping cohorts. Infants with transient wheeze have impaired lung function at birth, with some catch-up by six years of age. Conversely, those with persistent wheeze have normal lung function soon after birth, but airway obstruction at age six. Thereafter, in both groups, lung function tracks at least to 16 years of age (5). Others demonstrated tracking of lung function from the first to the fifth decades (6, 7). Is there any significance in a lifelong trivial reduction in forced expired volume in one second (FEV1)? A follow-up of the Aberdeen cohort in their fifth decade looked at three populations: (1) never wheezed, (2) a second group who have what would now be called "virus-associated wheeze" or "transient wheeze," and (3) individuals with asthma (8). As anticipated, the population with asthma had a reduced FEV1 compared with the other groups. However, the individuals with asthma and those with virus-associated wheeze were losing FEV1 at the same faster-than-normal rate. Therefore, events in very early life marked out a population with more rapidly declining lung function, who would therefore be at risk for chronic obstructive pulmonary disease (COPD). Crucially, without an understanding of early life events, the significance of this high-risk group would be missed. Death certificate data showed that the death rate from COPD was tightly correlated with infant mortality from pneumonia and bronchitis over many geographical areas (9). Thus, epidemiology has clearly taught us that early life events are pivotal in later onset respiratory disease. Pathologic data are much scantier, and little is as yet known about what drives the airway into a remodeled and inflammatory state. Endobronchial biopsy studies have shown that there is clearly a window of opportunity to intervene, in that wheezing infants, median age about one year, had no evidence of inflammation or remodeling (10), but by school age, structural airway changes similar to those of adults with asthma are present (11). Indeed, reticular basement membrane thickness apparently does not progress from early childhood. The nature of the triggers that switch the airway to this phenotype is not known, and likely lies in the interaction of the intra- and extrauterine environment, the nature and timing of viral infections, and the genotypes of both infant and mother. If this is to be sorted out, focused hypotheses will be needed; the importance of phenotypic plasticity, whereby a particular polymorphism may have directly opposite effects on phenotype depending on the extrauterine environment, is increasingly being appreciated (12). There is accumulating evidence of the importance of early life events in other respiratory diseases. The survivors of very preterm birth have chronic lung disease of prematurity, which generally shows improvement during childhood (13), but important effects persist into adult life. Such patients have airway obstruction early on, even if they needed no respiratory support at birth, and may be a population at risk of early and rapid decline in lung function, with a COPD-like illness. They are a novel cohort who likely will develop a respiratory disease, as yet uncharacterized, and probably with components of airflow obstruction and alveolar-capillary hypoplasia. The current large population study (1) is therefore particularly welcome in focusing attention on the developing fetus and infant. They have wisely divided the children into established broad phenotypes of wheeze, to facilitate comparisons with other studies. First, and reassuringly, they found no statistically significant effect (at least on wheeze) of amniocentesis or chorionic villus sampling, although they cannot exclude subtle derangements of lung function. This group has also extended a previous observation that maternal hypertension is associated with airflow obstruction shortly after birth (14) by showing that it also translates into an effect on wheeze. Surprisingly, this included late-onset wheeze, a phenotype reported by others to be associated with normal lung function (5). Maternal diabetes had an effect only on persistent wheeze, and antibiotic use for urinary tract infection only on transient wheeze. Another large population study has shown that early or threatened labor, and malposition or malpresentation of the fetus, is associated with childhood asthma (15); whether these pregnancy complications are causative, or merely a marker for a different underlying cause, remains to be determined. There are a number of possible mechanisms whereby antibiotic treatment may affect lung development, and as yet, these have not been sorted out. The first is that antibiotics themselves may have an effect, irrespective of the reason for which they have been prescribed, perhaps by changing maternal vaginal or infant gut flora leading to effects on the developing immune system. Second, the underlying reason for the prescription may in fact be the cause of the lung function effect. For example, chorioamnionitis is associated with accelerated fetal lung maturation (16), which may restrict the period of lung growth. Third, there may be maternal factors predisposing to infection, which also have an independent effect on lung growth. Thus, the findings reported here should not be taken as evidence to restrict antibiotic usage in pregnancy, but rather to generate testable hypotheses about the mechanisms of an apparent effect. This study is observational and hypothesis generating, and its major service is to point to early life events as the source of lifelong problems. It also directs us away from the foolish belief that an individual can be considered in isolation; we are all products of our parental genes, and the effects of these genes may be felt long after the environmental influences in which they operated have disappeared. Thus maternal glutathione S-transferase phenotype is important in the effects of intrauterine passive tobacco smoke exposure, and has effects on respiratory disease long after birth (17). It may be that the genetic contribution to an individual's COPD may actually lie in his or her mother's genes, and not in his or her own. In summary, early life events are not merely important in their own right, but have lifelong effects. Much adult disease will be unintelligible without understanding what happened before and immediately after birth. Perhaps more attention needs to be paid by clinicians to what happened to an adult at these crucial times, and researchers need to consider whether they are looking for answers or to test interventions long after the horse has left the stable, and disappeared over the horizon. FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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