The onset of chronic obstructive pulmonary disease (COPD) can arise either from failure to attain the normal spirometric plateau or from an accelerated decline in lung function. Despite reports from numerous big cohorts, no single adult life factor, including smoking, accounts for this accelerated decline. By contrast, five childhood risk factors (maternal and paternal asthma, maternal smoking, childhood asthma and respiratory infections) are strongly associated with an accelerated rate of lung function decline and COPD. Among adverse effects on lung development are transgenerational (grandmaternal smoking), antenatal (exposure to tobacco and pollution), and early childhood (exposure to tobacco and pollution including pesticides) factors. Antenatal adverse events can operate by causing structural changes in the developing lung, causing low birth weight and prematurity and altered immunological responses. Also important are mode of delivery, early microbiological exposures, and multiple early atopic sensitizations. Early bronchial hyperresponsiveness, before any evidence of airway inflammation, is associated with adverse respiratory outcomes. Overlapping cohort studies established that spirometry tracks from the preschool years to late middle age, and those with COPD in the sixth decade already had the worst spirometry at age 10 years. Alveolar development is now believed to continue throughout somatic growth and is adversely impacted by early tobacco smoke exposure. Genetic factors are also important, with genes important in lung development and early wheezing also being implicated in COPD. The inescapable conclusion is that the roots of COPD are in early life, and COPD is a disease of childhood adverse factors interacting with genetic factors.
In 1977, in a classic report, Fletcher and Peto (1) proposed a model (their Figure 1) in which all comers attained a normal FEV1 at age 25 years, and progression to respiratory disability was solely determined by rate of decline of spirometry thereafter. Smoking history was seen as the chief determinant of rate of decline, and events before age 25 years were irrelevant. In their far less well known, but far more accurate Figure 2, they incorporated different starting levels of FEV1 at age 25 years, as well as different rates of decline, into their model. These findings have been taken forward and have had to be substantially modified by a recent study combining three cohorts. This confirmed two trajectories to chronic obstructive pulmonary disease (COPD) or, strictly speaking, to an FEV1/FVC ratio of less than 70%. There were approximately equal numbers in each trajectory. Of those who failed to attain an FEV1 of 80% before age 40 years, 26% had developed COPD during the 22 years of observation, whereas 7% with a normal FEV1 aged 40 years developed COPD within the same time period due to an accelerated rate of decline in FEV1 (2). Critically, the rate of decline was unrelated to smoking, nor could the authors identify any current feature associated with rapid decline in spirometry. The only logical conclusion is that all COPD risk is determined before the age of 40 years, either genetically or by environmental adverse influences or their interactions (Figure 1).
This conclusion is supported by a European study that identified five adverse childhood influences that were associated with a lower FEV1 and a more rapid rate of decline of spirometry (and, hence, a greater COPD risk in adult life) (3). These were maternal and paternal asthma, maternal smoking, and childhood asthma and severe respiratory infections. Childhood disadvantage was at least as important as heavy smoking. The focus is therefore on any adverse event increasing the likelihood of one or more of these disadvantages. The first lesson from normal lung growth for pediatricians is that by asking five simple questions (antenatally, asking the mother three simple questions) (Table 1) (4), a population of children at high risk for later premature airflow obstruction can be identified. Second, any factor increasing the likelihood of the development of childhood asthma or an increased propensity to respiratory infection will contribute to accelerated lung aging. Gene polymorphisms, for example in a disintegrin and metalloproteinase domain 33 (ADAM33), have also been associated with accelerated decline in lung function (5) (see below). Finally, no adult life influence, including smoking, has consistently been associated with accelerated decline in spirometry. The conclusion is inescapable: both the two recently described trajectories to COPD (2) are determined before adult life, and, if COPD is to be prevented, measures starting in adult life are too late.
|Antenatally and postnatally||Does the mother have asthma?|
|Does the father have asthma?|
|Does the mother smoke?|
|Postnatally only||Does the child have asthma?|
|Has the child had severe respiratory infections?|
The best description of the normal evolution of spirometry is from the Global Lung Initiative (6). The group used 97,759 measurements in healthy nonsmokers from 72 centers in 33 countries aged between 2.5 and 95 years to construct predictive equations for spirometry. From their smooth curves, three key stages emerge: for normal lung health, spirometry needs to be normal at first measurement (now best described by the raised volume, rapid thoracic compression technique at birth , or preschool standard spirometry , stage 1), needs to grow normally in childhood to attain a normal plateau at age 20 to 25 years (stage 2), and declines with aging at a normal rate (stage 3). Key influences on these stages are discussed in turn. Finally, new data challenging the concepts of normal alveolar growth are presented. Space allows only a summary of many factors leading to childhood asthma and respiratory infections.
The morphological phases of lung development in utero have been well described; airway caliber is determined largely in the second half of pregnancy. Recently, the gene expression studies of normal lung development have been determined (9) and have broadly confirmed the utility of the morphological stages. The complexities of the pathways of branching morphogenesis have been reviewed (10, 11) and will not be discussed further, except insofar as they lead to important genetic clues into lung aging.
Preconception adverse events may impact the fetus. Grandmaternal smoking has a double-hit effect; it increases the risk of maternal asthma and, even if the mother herself does not smoke, increases the risk of her offspring having asthma (12, 13).
Antenatal adverse effects can be mediated through reducing airway caliber, altering fetal immune responses, inducing either or both prematurity and low birth weight, and influencing the mode of delivery. Many different antenatal adverse effects on lung growth have been described (14), including the effects of maternal stress on fetal immune responses (15), but most information is available for nicotine and tobacco smoke. These are worsened if mother or fetus have non-null GSTT1, highlighting the importance of gene–environment interactions (16). Recently, the adverse effects on early childhood spirometry of maternal exposure to environmental pollution have come to the fore (17, 18), and, although the mechanisms are speculative, it is clear that early airflow obstruction is the result (19).
Maternal hypertension of pregnancy has been described as causing airflow obstruction in the baby (20), but this has been disputed recently, with attention focusing on prepregnancy hypertension as being important (21). More studies are needed to confirm or otherwise the developmental role of maternal blood pressure on the baby.
Most of the data have come from animal models of nicotine exposure of the pregnant dam. Antenatal changes described include increased collagen deposition (22), increased MUC5AC expression (23), and airway lengthening and reduction in caliber (24). The readout in the fetus is airway obstruction and airway hyperresponsiveness (AHR) at birth. Note that AHR occurs in the absence of allergen exposure (mice) and any evidence of airway inflammation (mice, infants [24, 25]). The anatomical changes are likely also exacerbated by loss of alveolar tethering points (26) and increased airway smooth muscle thickness (27)
There are a large number of studies looking at the effects of pregnancy exposures on cord blood mononuclear cell function. Maternal smoking and previous pregnancies affect cord blood mononuclear cell proliferation to allergens (28). Abnormal cytokine responses at birth predict wheeze with viral infections in early life (29), including rhinovirus-induced wheeze, which is strongly associated with subsequent asthma (30). Maternal smoking is also associated with abnormal toll-like receptor function (31).
A recent metaanalysis has shown that any cause of low birth weight is associated with subsequent childhood and adult asthma (32). The Aberdeen Birth cohort demonstrated a linear relationship between birth weight (adjusted for relevant maternal factors) and spirometry at age 45 to 50 years (33). Tobacco smoking is a well-known cause of preterm delivery, the risk of which is reduced by tobacco legislation (34). Very preterm infants are well known to be left with fixed and variable airflow obstruction, and, although outcomes are improving (35), even those preterm babies requiring no treatment in the newborn period have airflow limitation (36), so improvements in neonatal intensive care are unlikely to abolish the problem. The decrements in spirometry in bronchopulmonary dysplasia survivors are greater than those of healthy preterm infants (37). Furthermore, even modest degrees of prematurity (up to 37 weeks’ gestation) are associated with impaired spirometry in the late teenage years (38) and increased use of asthma medications in childhood (39–41). Low birth weight of itself is a risk factor for subsequent asthma (32). There may be a differential effect of low birth weight in babies who are small (SGA), as opposed to appropriate (AGA), weight for gestation age; at age 20 to 22 years, spirometry was strongly predicted by birth weight in the SGA but not the AGA group (42). It should be noted that, as protocols for resuscitation of the newborn (43) and subsequent ventilation (44) have changed, so have the different contributions of airway and parenchymal disease in “new” and “old” bronchopulmonary dysplasia (45)
Delivery by caesarean section is associated with an increased risk of atopic disorders (46, 47), probably mediated via an effect on the fetal microbiome (48). Especially if at least one parent is allergic, children delivered by caesarean section have a higher prevalence of asthma at age 8 years, and children of nonallergic parents were more likely to be sensitized (49). Because there are no randomized controlled trials of caesarean section delivery, it is not possible to disentangle the effects of caesarean delivery from the causes leading to the need for caesarean delivery.
The ideal study would have recruited babies antenatally and followed them through with repeated measurements until death; such a study has not been done, and so we have to rely on a series of overlapping cohorts (50–53), reviewed in Reference 54. Although there are some discrepancies, the general message is that lung function at age 4 to 6 years is determined by lung function and bronchial hyperresponsiveness soon after birth, and thereafter tracks; hence, decrements at age 4 to 6 years are reflected in adult lung function, at least to age 50 years. There may be further deterioration at school age and beyond, but no improvements.
This view has recently been challenged, at least in the context of preterm survivors. A group of preterm babies at age 7 to 9 years had evidence of airflow obstruction, the degree of which related to the intensity of neonatal treatment, but this had normalized by age 20 to 22 years (42); interestingly, birth weight was a strong determinant of airflow obstruction in the SGA but not the AGA low birth weight babies. However, this difference was not found in another study (55). The differences might relate to the proportions of SGA and AGA babies in the different studies or the relative insensitivity of spirometry to distal airway disease. Overall, however, it is clear that the preschool years represent a critical window for long-term lung health.
The presence of AHR is important in long-term lung function and requires a developmental perspective. Three groups have measured neonatal AHR, and all showed significant relationships with long-term outcomes, albeit with slightly different results (56–60). The COPSAC (Copenhagen Prospective Studies on Asthma in Childhood) data (59) suggested that 40% of airway obstruction at age 7 years was determined antenatally and 60% postnatally; neonatal AHR was more strongly associated with asthma at age 7 years than neonatal lung function. It should be noted that neonatal AHR is not related to airway inflammation (25) and is presumably determined by anatomical factors (see above); thus, small airways increase resistance more for a given proportionate radius change because resistance is inversely related to the fourth power of the radius. Although AHR and lung function at birth were described as independent risk factors for childhood lung function (61), in reality abnormal anatomy is likely to underlie both. Finally, the longest-running study of AHR from birth to adult life showed that the adult relationship between AHR and asthma was established before age 6 years (62).
The effects of passive smoking were described in a series of metaanalyses (63–69), which have been recently updated (70); they are sufficiently well known that, in the interest of space, they will not be further discussed. Of interest, recent data showed that maternal smoking and the child taking up smoking have additive effects on the child’s lung function (71).
The association of exposure to outdoor pollution postnatally with poorer lung function, asthma, respiratory infections, and a lower rate of growth of spirometry has been well described (72–74), but it may be difficult to disentangle the confounding effects of socioeconomic status. Recently, the beneficial effects of legislation leading to improved air quality on the growth of children’s lungs have been described (2). Globally, indoor exposure to burning biomass fuels may be most important, and measures to improve indoor air quality improve children’s lung function (75). Organophosphorus pesticides have recently been implicated as affecting child lung development (76).
Early impairment of lung function is associated with objectively diagnosed asthma at age 10 years (77). It has long been known that early sensitization to aeroallergens is associated with persistent wheeze, loss of lung function, and the development of AHR (78). Understanding has advanced with the realization that atopy is not an all-or-none phenomenon but can be quantified (79) and has a developmental perspective. The Manchester group used machine learning approaches to analyze data on patterns of wheeze and atopic sensitization and showed that only multiple early sensitizations were important (80). In a subsequent study, they showed that persistent wheeze, early multiple atopic sensitizations, and asthma attacks are associated with reduced growth in lung function (81). Asthma itself is associated with poorer lung growth. As yet unexplained, in the CAMP (Childhood Asthma Management Program) study, approximately one-third of subjects lost percent predicted lung function over the study period, independent of prescribed treatment (82).
That acute viral infections are important causes of early respiratory morbidity due to bronchiolitis and wheeze is indisputable. However, whether they cause asthma to develop in an infant who would otherwise not go on to the disease, or are a marker for an asthma propensity, or both, is controversial. It is clear from cord blood studies (see above) that there is antenatal programming favoring viral wheeze; a study from Perth showed that respiratory function was impaired before the development of bronchiolitis, and this decrement tracked into mid-childhood (83). Respiratory syncytial virus bronchiolitis is a devastating illness, but studies as to whether it is causally associated with asthma are controversial (84, 85). Recently, attention has focused on rhinovirus as being more associated with later asthma (30). The balance of evidence is that allergic sensitization precedes viral wheezing (86), and it is likely that sensitization rather than viral infections drive the march to asthma. However, this conclusion must still be considered tentative.
The role of bacteria in normal and abnormal immune development, as well as exacerbations of airway disease (87), has recently come to the fore. The lower airway is now known not to be sterile as was once believed (88). Early nasopharyngeal bacterial colonization is associated with altered immune responses (89), a greater likelihood of wheezing (90), and worse respiratory infective outcomes (91)—therefore, a double hit at least hypothetically in accelerating lung aging subsequently. It is likely that the fundamental abnormality is an underlying mucosal immune defect, but this is still contentious. By contrast, environmental bacterial and fungal diversity is associated with a reduced risk of asthma (92). Animal studies have shown that the microbiome is essential for normal immune development (93), and interactions between allergens and the microbiome influence the body’s immune responses (94, 95). The long-term effects of an abnormal microbiome on lung aging are currently unknown, but their influences on asthma risk mean that they are likely significant (see above).
There has been much recent information that has increased our understanding of lung aging since Fletcher and Peto’s manuscript (2, 98–101). In summary, it is clear that many patients with COPD have a normal rate of lung aging, and, indeed, those who fail to attain the normal plateau in early adult life are at the highest risk of COPD. Asthma and bronchial hyperresponsiveness are risk factors for accelerated decline, but no other environmental factor, including smoking, has consistently been implicated as a cause. The Framingham study reported traffic pollution as being important (102), but the caveats about socioeconomic status (see above) remain.
The role of asthma and AHR in accelerated decline in airway function is multifactorial. The combination of a preexisting low FEV1 and airway inflammation (as shown by elevation in fractional exhaled nitric oxide) is associated with accelerated decline (103), as are asthma attacks (104). The Groningen group showed that patients with asthma who stopped smoking and used inhaled corticosteroids had a slower rate of decline; AHR predicted decline independent of baseline FEV1 (105). However, the two are interrelated; they also showed that low childhood FEV1 and less increase over time was associated with adult AHR (106)
Genetic factors, including gene-by-environment interactions via a variety of epigenetic mechanisms, are clearly important in lung development and aging. It is likely that a rich harvest of COPD genes will be found in normal lung development (107). There are substantial commonalities between genes causing reduced lung function in both smokers and nonsmokers (108). The conventional approaches have recently been taken forward by using systems genetic approaches (109).
ADAM33 is an exemplar gene with different roles at different developmental stages. It is important antenatally during airway branching morphogenesis (110). Levels in the fetus depend on maternal atopy, via an IL-13 pathway (111). There is an adverse interaction between antenatal tobacco exposure and ADAM33 polymorphisms and lung function at age 8 years (112). ADAM33 polymorphisms are associated with increased airway resistance in the preschool years (113), are associated with asthma and bronchial hyperresponsiveness in adults (114), and those known to convey susceptibility to COPD were associated with an accelerated rate of decline in spirometry in a Dutch general population (5).
The β-receptor gene links early lung function, asthma, and COPD. Much is known about β-receptor function in asthma, but very little is known about any possible role in infancy. Maximal flow at functional residual capacity and bronchial hyperresponsiveness (BHR) were measured soon after birth in infants; having any Glyn 27 or Arg 16 allele was associated with reduced maximal flow at functional residual capacity (1), independent of maternal smoking or atopic status, but BHR was independent of genotype. The patients were restudied at age 11 years, and β-receptor genotype had no association with either spirometry or BHR, possibly because of low statistical power. More than 80% of the children had at least one parent with asthma, so caution should be exercised before extrapolating to low-risk populations. In another study (115) there was an association between arg16 gln27 and a positive BHR at age 6 years. The gly16 gln27 haplotype was associated with better spirometry at 6 and 11 years of age and less likelihood of an asthma diagnosis at the later time point, but at age 11 years, arg16 gln27 was associated with worse spirometry. A further study found associations with β-receptor haplotypes in adults with COPD, asthma, and other respiratory problems (116). β-receptor polymorphisms also predicted symptoms of asthma continuing into adult life (117), but like other genetic studies, the association was weak. One study examined the genetics of preschool wheeze phenotypes and related them to COPD genes (118). They found that at least three COPD genes were involved in lung growth and development and were involved in antenatal and early life responses to tobacco smoke exposure. More recently, low circulating concentrations of the antiinflammatory protein CC16, which are known to be associated with an accelerated decline in FEV1 in patients with COPD (98, 119), have also been found to be associated with accelerated decline in a general adult population and impaired childhood lung function (120).
There have been a large number of recent important genome-wide association studies both of normal lung function (121–123) and of COPD, many but not all of the latter focusing on lung function (122–126). A recent genome-wide association study implicated the CHRNA5/3 region and in particular HTR4 in airflow obstruction (127). At least some of the genes identified are also active in important in utero developmental pathways (e.g., wnt/β-catenin ). However, other genes important in premature onset of adult COPD (129), such as alpha-1 antitrypsin, appear not to have a developmental role, although interestingly those heterozygous for mutations in this gene appear to have increased respiratory reserve (130)
Conventional wisdom was that alveolar growth was largely a postnatal phenomenon, with an initial rapid phase in the first 2 years of life and a much slower phase until age 8 years, whereupon alveoli increased in size but not in number. A series of recent papers have challenged this concept. In nonhuman primates, where alveolar counts can be made at different ages, alveolar numbers increase until adult maturity. In humans, inhalation of hyperpolarized helium (He3) can be used to calculate alveolar size using a number of mathematical modeling techniques and has demonstrated that alveolar size does not change between the ages of 7 and 21 years (131).
Adverse effects on alveolar growth have really only been studied in the context of prematurity and its treatment. In animal models, hyperoxia, systemic steroids, and nicotine all impair secondary septation and neoalveolarization (132–134). He3 data in humans (135) suggest that maternal smoking in pregnancy may increase alveolar size and reduce numbers. The fact that nicotine itself is implicated in both impaired airway and alveolar development calls into question the safety of e-cigarettes (136). There is also some evidence of catch-up growth, although this is based on cross-sectional studies, not longitudinal data; there are no neonatal data with corresponding studies in childhood and adult life. One group used carbon monoxide transfer as a surrogate for the size of the alveolar–capillary membrane and showed this was normal at rest and on exercise in adult life (137). He3 data in preterm survivors in adolescence showed that alveolar size was normal (138). Nitrogen washout can be used to partition gas mixing abnormalities into airway (Scond) and alveolar (Sacin) (139, 140). Compared with normal infants, preterm survivors in childhood had, as expected, an abnormal Scond, but Sacin was normal, implying normal alveolarization (141). However, it should be said that if many alveoli were completely destroyed, Sacin would still be normal, because they would give no signal. Also, all these studies assumed that alveolarization had been abnormal in the newborn period, but they could not measure it, so that there had been true catch-up growth remains conjectural. However, taken together, the evidence is that alveolarization continues for longer, and there is greater potential for catch-up growth, than was previously believed. Certainly, lungs apparently destroyed by necrotizing pneumonias usually recover completely (142), so at least the potential for catch-up is certainly present. Intriguingly, being brought up at altitude in hypoxic conditions appears to stimulate alveolarization while having no effect on airway function (143); this raises the intriguing question as to whether keeping the preterm survivors very well oxygenated is as wise as we believed.
There is one final lesson to be learned from developmental aspects of lung growth. The Global Initiative for Chronic Obstructive Lung Disease defines COPD as an FEV1/FVC ratio less than 70%. However, this ratio changes with age (144); the lungs of young children empty so efficiently that the forced expiratory volume in 0.5 second (FEV0.5)/FVC ratio has to be used (7), because FEV1/FVC is 100%. Conversely, after age 50 years, increasing numbers of normal people will have FEV1/FVC ratio less than 70%, and after age 70 years, more than 15% of normal people will have FEV1/FVC ratio less than 70%. This use of a fixed ratio without considering the developmental background has two important consequences. The first is that many more normal elderly people will be diagnosed as having COPD (145). The second is that the severity of the premature airflow obstruction in young adults and even children will not be appreciated; an FEV1/FVC ratio of 75% will be very abnormal at this age. This underscores the fact that premature airflow obstruction is primarily a pediatric disease; this is being overlooked, and intervention delayed, by relying on a ratio that is falsely reassuring at a young age.
It is clear that if we are to prevent COPD from becoming an ever more important cause of death in adults, we must optimize lung health from before birth and in early childhood. We have much to learn about detailed mechanisms, but there is much we can do now while these studies are going on. We must focus on three preventive measures that have been shown to work. As a matter of urgency, we need to tighten our grip on all forms of tobacco and nicotine exposure, including e-cigarettes. We must legislate to reduce exposure to outdoor pollution, in particular ensuring that very tight controls on vehicle emissions in residential areas are enforced. We need to acknowledge that healthy aging starts in childhood, and unhealthy aging does as well. If fundamental research in the prevention of COPD is to be done, it will be done in early life. Finally, in particular in low- and middle-income country settings, we must ensure that indoor biomass fuel exposure is minimized. The message needs to be gotten across that COPD is not all about a disease that smokers bring on themselves but is in fact just disease of childhood disadvantage and genetics, which must be addressed in childhood if death rates are to drop.
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