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Review

Risk factors and early origins of chronic obstructive


pulmonary disease
Dirkje S Postma, Andrew Bush, Maarten van den Berge

Chronic obstructive pulmonary disease is mainly a smoking-related disorder and affects millions of people worldwide, Lancet 2015; 385: 899–909
with a large effect on individual patients and society as a whole. Although the disease becomes clinically apparent See Editorial page 830
around the age of 40–50 years, its origins can begin very early in life. Different risk factors in very early life—ie, in utero Published Online
and during early childhood—drive the development of clinically apparent chronic obstructive pulmonary disease in August 12, 2014
later life. In discussions of which risk factors drive chronic obstructive pulmonary disease, it is important to realise http://dx.doi.org/10.1016/
S0140-6736(14)60446-3
that the disease is very heterogeneous and at present is largely diagnosed by lung function only. In this Review, we
Department of Pulmonary
will discuss the evidence for risk factors for the various phenotypes of chronic obstructive pulmonary disease during Diseases (Prof D S Postma MD,
different stages of life. M van den Berge MD) and
Groningen Research Institute
Background we will discuss important new insights into chronic for Asthma and COPD
(Prof D S Postma,
Chronic obstructive pulmonary disease, which is largely obstructive pulmonary disease, from risk factors to lung M van den Berge), University
a smoking-related disease, affects millions of people development, early origins, and different phenotypes of Medical Center Groningen,
worldwide. At present, it is the fourth leading cause of the disease. University of Groningen,
death worldwide, and between 1990 and 2010 the Groningen, Netherlands; and
National Heart and Lung
proportion of disability-adjusted life-years attributable to Disease phenotypes and the course of lung Institute, Imperial College,
the disorder increased by 34% in the USA, where it ranks function over a lifetime London, UK (Prof A Bush MD)
second in the top 30 contributing diseases.1,2 For decades, Any discussion of the risk factors that drive the Correspondence to:
chronic obstructive pulmonary disease has been development of chronic obstructive pulmonary disease Prof Dirkje S Postma,
characterised by incompletely reversible and usually and whether or not the disease has its origins in early life Department of Pulmonary
Diseases, University Medical
progressive obstruction of the airways that is associated first needs a definition of the disease itself. GOLD Center Groningen, University of
with inflammation.3 Textbooks generally state that guidelines have defined chronic obstructive pulmonary Groningen, Box 30.001,
chronic obstructive pulmonary disease becomes disease by incompletely reversible airways obstruction— Hanzeplein 1, NL-9700 RB,
clinically apparent around the age of 40–50 years, but that is, a ratio of the post-bronchodilator forced expiratory Groningen, Netherlands
d.s.postma@umcg.nl
this does not imply that the disease cannot have its volume in 1 s to the forced vital capacity (FEV1:FVC ratio)
origins in childhood, since it cannot be recognised at of less than 70%.5 However, the normal range of this ratio
that age. Rather, premature airflow obstruction can changes with age, such that the use of a fixed ratio to
persist from childhood onwards and then is erroneously diagnose any disorder is not useful in either an individual
considered under the umbrella term of smoking-related patient or in larger epidemiological populations in which
chronic obstructive pulmonary disease.4 In this Review, a lower limit of normal can be better applied.6,7 At the age
of 30 years, an FEV1:FVC ratio of 75% is very abnormal in
women, whereas 30% of healthy people older than
Search strategy and selection criteria 70 years of age will have a ratio below 70%. Furthermore,
Articles for this Review were identified from searches of PubMed,
Medline, our personal archives, and references from relevant
Key messages
articles, for articles published from Jan 1, 1985, to Sept 1, 2013.
We searched for papers published in English with the search • From this review of the published literature, it is clearly no
terms “COPD”, “small airways”, “emphysema” “chronic longer justifiable to state that chronic obstructive
bronchitis”, ”risk”, “risk factors”, hyperresponsiveness”, pulmonary disease is a disease of old age. It has its origins
“phenotypes”, “phenotyping”, “early origins”, ”lung before birth and in early childhood, where every effort
development”, “airway development”, “alveolar development”, must be made to ensure that lung health is preserved.
“in utero”, “antenatal”, “perinatal”, “respiratory infections”, “early • To try to obtain a history of early life events in adults with
childhood exposures”, “transgenerational”, “genetics”, “preterm respiratory disease is important, because to understand
birth”, “low birth weight“, “intrauterine growth retardation”, and its origins is crucial.
“fetal growth restriction”, either alone or in different • An important message is that among other approaches,
combinations. We mostly selected publications from the past preventive measures for the development of chronic
15 years but we did not exclude older publications. We also obstructive pulmonary disease lie in the prevention of
searched the reference lists of identified articles for further smoking in young people and stopping smoking in
relevant papers and cited review articles to provide readers with women before becoming pregnant, in view of the
more details and references that we could not include because of additive effects of smoking on the background of their
space limitations. prenatal effects.

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Review

the definition based on the FEV1:FVC ratio is so broad Emphysema


that many types of patients with distinct clinical The aforementioned findings corroborate earlier
characteristics, prognosis, and treatment response are studies that the association between emphysema and
included. For example, a subset of patients with asthma airflow obstruction is quite weak,14,15 and emphysema
develops fixed airflow obstruction in later adult life.8 The can already be present in patients with chronic
type of inflammation and remodelling in these patients obstructive pulmonary disease with mild airflow
will probably differ from that in smoking-related chronic obstruction only.14 This situation might have important
obstructive pulmonary disease.9 In addition to an overlap implications for the clinical expression of the disease,
with asthma in which a reduced FEV1:FVC ratio can also since more severe emphysema is an independent
occur, chronic obstructive pulmonary disease itself is a predictor of a worse health status, higher BODE index,16
heterogeneous disorder in terms of its clinical a marker of disease prognosis, a higher number of
presentation, rate of disease progression, and response chronic obstructive pulmonary disease exacerbations,
to treatment. Assessment of chronic obstructive and more rapid disease progression. The type of
pulmonary disease merely by lung function variables like emphysema might also be important in this respect,17,18
the FEV1:FVC ratio will not do justice to the which adds further complexity. Patients with
subphenotypes of the disease that underlie this ratio—ie, centrilobular emphysema have a higher degree of
the three major phenotypes discussed in the following inflammation in their small airways than do those with
sections: small airways obstruction, emphysema, and panlobular emphysema,17 a finding that is associated
chronic bronchitis. This topic has also been addressed in with thickening of the small airway walls and more
the new GOLD guidelines.3 severe bronchial hyper-responsiveness.18

Small airways obstruction Chronic bronchitis


FEV1, FVC, and their ratio explain only a small percentage Chronic bronchitis is usually defined as symptoms of
of the variation in symptoms and quality of life in chronic cough and phlegm (or sputum production) on most
obstructive pulmonary disease.10,11 Importantly, these days for more than 3 months in 2 consecutive years. It
parameters mainly indicate obstruction of the large airways, is present more frequently in smokers and patients
whereas the small airways and lung parenchyma are the with chronic obstructive pulmonary disease with more
main sites of disease activity in chronic obstructive severe airflow obstruction. Several studies have
pulmonary disease. Indeed, Hogg and colleagues12 showed suggested that chronic bronchitis contributes to
that a higher percentage of small airways containing dyspnoea and wheeze, worse health status, increased
inflammatory cells is associated with more severe airflow numbers of exacerbations, and more rapid disease
obstruction in chronic obstructive pulmonary disease. progression in chronic obstructive pulmonary
Furthermore, detailed radiological assessments showed disease.19–23 Increased mucus hypersecretion, cough, or
narrowing and loss of airways in patients with chronic both can be associated with respiratory infections or
obstructive pulmonary disease compared with healthy increased airway inflammation, both of which con-
people.10 Such changes are already present in mild chronic tribute to more frequent chronic obstructive pulmonary
obstructive pulmonary disease, even in lung regions disease exacerbations. In turn, these exacerbations can
without signs of emphysematous destruction. These induce symptoms of cough and sputum production
findings are in agreement with parametric response that can persist for weeks after their onset.24 The latter
mapping findings on CT made by Galban and colleagues,13 might introduce bias, leading to over-reporting of
which show that the severity of airflow obstruction is chronic bronchitis in patients with chronic obstructive
mainly determined by changes in the small airways, and pulmonary disease who have frequent exacerbations.
emphysema only contributes if severe emphysema is Controversy remains around this subject since the
present. However, emphysema and airways obstruction are ECLIPSE study did not find chronic bronchitis to be a
not independent. Therefore, emphysematous alveolar risk factor for chronic obstructive pulmonary disease
destruction leading to loss of alveolar tethering points will exacerbations, after adjustment for disease severity.14,25
contribute to airway obstruction through the loss of The differential results in studies investigating the role
interdependence. However, the contribution of this of chronic bronchitis in chronic obstructive pulmonary
mechanism to airway obstruction is difficult to measure in disease could be because of the use of varying
life in view of the challenges involved in reaching the small definitions or different populations under study.19,26
airways and lung tissue with noninvasive techniques. Furthermore, chronic bronchitis is not an objective
Taken together, these findings suggest that small airways measure and can be affected by factors such as sex and
disease in mild chronic obstructive pulmonary disease sociocultural behaviour.14,27
probably precedes the development of emphysema leading The three domains of chronic obstructive pulmonary
to more severe illness. More work is needed in this area, disease—small airways obstruction, emphysema, and
with the use of sensitive markers of distal airway disease chronic bronchitis—can be captured by similar lung
such as multiple breath washout. function abnormalities. Only in the last decade has

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much attention been given to the differential relevance Epidemiology of risk factors for chronic
of these subphenotypes. Thus, most studies that have obstructive pulmonary disease, and relation
attempted to address the issue of early origins of with its early origins
chronic obstructive pulmonary disease have not been The main risk factor for the development of chronic
designed to do so successfully. This is an unavoidable obstructive pulmonary disease is smoking.45 However, it is
weakness of our existing knowledge. not the only risk factor, since recent studies have shown
that many people develop the disease without ever having
The roots of chronic obstructive pulmonary smoked.46 Therefore, other factors besides personal
disease: importance of normal lung development smoking, such as indoor and outdoor air pollution and
Normal airway development other environmental triggers, such as second-hand smoke
The lung bud initially develops as an outpouching of the during pregnancy or early childhood, might also be
fetal foregut at 6 weeks’ gestation. By the end of the first important, as are dietary factors.45,47–49 Indeed, one study
trimester of pregnancy, airway generations down to the showed that early childhood disadvantage (defined as at
bronchiolar level and their accompanying vessels have least one of: maternal, paternal, or childhood asthma;
been formed. Type 2 cell differentiation and the first maternal smoking; and childhood respiratory infections)
appearance of surfactant occurs at around 23 weeks’ conveys as much risk for chronic obstructive pulmonary
gestation. Pre-acinar vessels follow airway development, disease as does smoking in adult life.49
whereas intra-acinar vessels follow the development of An important new insight is that chronic obstructive
alveoli. Recent transcriptomic approaches have identified pulmonary disease can also have its origins in childhood
different molecular phases of lung development,28 but so or even in utero. Lung function can be compromised
far this has not led to clinical applications. The most during lung development in utero—eg, low birthweight
recent work on postnatal airway functional changes babies or children whose mothers smoked in pregnancy
using spirometry has been undertaken by the Global have reduced lung function soon after birth.50 This For more on the Global Lung
Lung Initiative and has collated and refined much reduced function then continues throughout life, resulting Initiative see http://www.
lungfunction.org
previous work.29–31 Airway development has three key in a lower plateau at around 20–25 years of age (figure 1).
stages: the start point for lung growth, namely airway The question remains as to whether different factors
function at birth, with reduced lung function at birth contribute to different types of chronic obstructive
being a risk factor for asthma at 10 years of age;32 pulmonary disease. It might well be the case that several
childhood and young adult airway growth to the plateau genetic factors, environmental factors (smoking, air
at 20–25 years of age;33 and lung function decline, the pollution, occupational hazards, and infections) and
rate of which can vary substantially even in patients with lifestyle issues (diet and exercise), encountered at different
established chronic obstructive pulmonary disease.34,35
All risk factors for reduced lung function can be present
in an individual. A failure to reach the normal plateau
and accelerated loss of function in adulthood mean that
the threshold for respiratory symptoms and disability is
Lung function (FEV₁)

reached earlier than normal (figure 1). Importantly, the


first 4 years of life are a crucial time window; for the
most part, there is no catch-up in airway function after
the age of 4–6 years.36–39 The sole exception might be
some survivors of chronic lung disease of prematurity,
since one study showed that spirometry was clearly
abnormal at age 7–9 years,40 but had normalised by
20–22 years of age.41

Normal alveolar development 0 20 35 70


Age (years)
The timing of alveolar development is more uncertain No risk, normal genetic profile
than that of airway development. Conventional wisdom Smoking from 15 years of age
Mother smoked in pregnancy
suggests that there are around 5×10⁵ alveoli at birth, Mother smoked in pregnancy plus environmental exposure and/or environmental tobacco smoke
that there is a rapid phase of secondary septation and in childhood and adulthood
alveolar development in the first 2 years of life, and that Mother smoked in pregnancy plus environmental exposure and/or environmental tobacco smoke
in childhood and adulthood plus personal heavy smoking
thereafter few, if any, new alveoli develop. Recent
histological studies in monkeys42 and hyperpolarised Figure 1: Risk factors for chronic obstructive pulmonary disease during the different stages of life and how
helium studies in human beings43,44 suggest that in fact they can affect the risk for the development of clinically apparent disease
FEV1=forced expiratory volume in 1 s. Any or all of a reduced starting point at birth, a failure to reach the normal
alveoli continue to develop throughout the period of plateau, and accelerated loss of function in adulthood mean that the threshold for respiratory symptoms and disability
somatic growth. Little is known about normal alveolar is reached earlier than normal. The extent of the effects of smoking varies between individuals and has been reported
ageing. differently; therefore, the figure is a scheme to show the effects of smoking during the different stages in life.

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Figure 2: Graphic representation of the risk factors for chronic obstructive pulmonary disease during the different stages of life
Risk factors are shown for in utero and perinatal life (upper left corner), early childhood (lower left corner), and adulthood (lower right corner). General risk factors are
also shown (upper right corner). COPD=chronic obstructive pulmonary disease.

stages of life, can lead to different types of the airflow Furthermore, patients with chronic obstructive pulmonary
obstruction that are referred to as the single disease entity disease had the lowest lung function compared with
chronic obstructive pulmonary disease (figure 2), healthy people and asthmatics at 10 years of age, which
depending on when they are encountered and in what continued through to 50 years of age.54 Taken together,
combinations. The panel summarises the different these cohorts show that spirometry at 4–6 years of age
environmental risk factors for chronic obstructive affects the height of the spirometry plateau achieved at
pulmonary disease, which will be discussed in more detail 20–25 years, and hence the start point for spirometry
in the following sections. decline. Although clearly cigarette smoking is a highly
important determinant of the rate of decline of spirometry
Low lung function at an early age in adult life, early life events are also important.
The most informative birth cohort studies have come
from Tucson (AZ, USA) and show that in healthy people Bronchial hyper-responsiveness
without wheezing illness, lung function centile shortly Bronchial hyper-responsiveness is often thought to be a
after birth affects lung function centile in the third decade hallmark of asthma, but it has also been shown to be
of life.38,51,52 Prospective data in this population to the age present in chronic obstructive pulmonary disease.55–57
that chronic obstructive pulmonary disease becomes Bronchial hyper-responsiveness precedes the develop-
clinically apparent are eagerly awaited. Cohort studies ment of chronic obstructive pulmonary disease-like
following participants into middle age, most notably the symptoms in the general population58 and more severe
Melbourne asthma cohort, have shown the effectiveness bronchial hyper-responsiveness is associated with
of tracking of lung function—ie, the spirometry centile in subsequent accelerated lung function decline.8,59,60 What
mid-childhood determines the spirometry centile in drives the relation between bronchial hyper-responsive-
middle age.53 Notably, the Melbourne cohort showed that ness and chronic obstructive pulmonary disease has not
severe asthma was an important risk factor for the yet been elucidated. It has been suggested that bronchial
development of chronic obstructive pulmonary disease, hyper-responsiveness consists of variable and fixed
and was a more prominent indicator than was smoking. components.61 The variable components largely derive

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from the acute release of pro-inflammatory mediators as a


result of ongoing airway inflammation.55,62–64 The persistent Panel: Risk factors for chronic obstructive pulmonary
components result from structural changes in the airways disease that have a role during different stages of life
such as epithelial desquamation, goblet cell metaplasia, Host factors
fibrosis, increased smooth muscle mass, angiogenesis, • Family history of chronic obstructive pulmonary disease
and extracellular matrix changes. These changes can • Family history of asthma/atopy
occur in both the large and small airways and are • Genetic constitution
associated with a reduced number of airways, especially • Bronchial hyper-responsiveness
the smaller airways, in chronic obstructive pulmonary • Atopy
disease.11 An interesting idea is that small airway • Low lung function
abnormalities might be associated with the severity of
bronchial hyper-responsiveness in chronic obstructive Perinatal factors
pulmonary disease, just as in asthma, but at a more acinar • Maternal smoking
level, which links bronchial hyper-responsiveness to • Maternal exposure to air pollution
chronic obstructive pulmonary disease development in • Antibiotic use
association with small airway disease.65 Moreover, • Mode of delivery
bronchial hyper-responsiveness at 1 month of age is a risk • Preterm birth
factor for reduced lung function in childhood.66–68 This Childhood exposures
association might be compatible with the hypothesis that • Respiratory tract infections
abnormal lung development underlies the presence of • Maternal smoking
bronchial hyper-responsiveness, which might be partly • Indoor and outdoor air pollution
due to maldevelopment of the airways in utero.69 Taken • Obesity/nutritional development
together, the presence and severity of bronchial • Childhood asthma
hyper-responsiveness is an independent risk factor for the • Airway failure to thrive
development of chronic obstructive pulmonary disease.
Adult exposures
In-utero and early childhood exposures • Occupational exposures
Adverse events in the mother can have direct effects on • Indoor biomass exposure
the fetus or child, or prime the body of a child to develop • Cigarette smoking
an abnormal response to an event later in life. According • Outdoor air pollution
to the developmental origins of health and disease • Indoor air pollution
(DOHAD) hypothesis,70 in-utero events can reprogramme
an individual for immediate adaptation to gestational effects also have a role in human beings, it will become
disturbances, which can have consequences for the risk important to obtain a more detailed antenatal and
of the development of metabolic diseases later in life. A perinatal history from adult patients, which is not often
changed gestational environment has been linked to done at present.75 The following issues have been
adult metabolic disease by both in-utero caloric deficiency described and will be discussed in more detail below:
(from famine or uteroplacental insufficiency) and in-utero transgenerational effects, antenatal effects, perinatal
caloric abundance (from a maternal high-fat, calorie-dense effects, and early childhood exposures.
diet). Other chronic diseases have followed a pattern of Worryingly, transgenerational epigenetic effects on
prenatal environmental effects on adult life, and chronic asthma risk have been shown to exist. Thus, a grand-
obstructive pulmonary disease might also have links with mother who smoked increases the risk of her daughter’s
the DOHAD hypothesis. Indeed, Barker’s hypothesis children having asthma, even if the daughter herself
emerged almost 25 years ago from epidemiological does not smoke.76 The mechanism of this effect is thought
studies of birth and death records that showed a high to function through gene methylation.77 The possibility
geographical correlation between rates of infant mortality that diet, pollution, and other known epigenetic effects
and particular classes of later adult deaths (eg, respiratory might also have epigenetic transgenerational effects on
disease) and an association between birthweight and the fetus cannot be excluded. Preventive strategies are
rates of adult death from ischaemic heart disease.71,72 mandatory, but will probably only deliver results in the
These theories stimulated interest in the fetal origins of very long term.
adult disorders. The DOHAD hypothesis has been The most important and most studied adverse
studied little in respiratory diseases, but examples include antenatal event is maternal smoking, which, together
the effect of in-utero smoke exposure leading to enhanced with maternal atopy and maternal hypertension, leads to
responses to postnatal allergen and fungal exposure,73 impaired lung function soon after birth.78,79 Studies in
and neonatal hyperoxia in mice leading to changed animals have shown that maternal nicotine exposure
inflammatory and fibrotic responses to influenza A leads to a reduction in airway alveolar tethering points,
infection when the mice reached adulthood.74 If such increased lung collagen deposition, longer airways with

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smaller diameters, and mucus hypersecretion.69,80–82 disease, whereas “new” babies with the disorder, who are
These factors probably all contribute to airway obstruction smaller and more preterm, receive surfactant and are
and increased bronchial hyper-responsiveness in mice ventilated with faster rates at lower pressures, and have
postnatally, even if they were not exposed to allergen.69 pulmonary hypoplasia and alveolar maturation arrest,
Exposure to smoke also leads to changes in cord blood albeit possibly with some recovery of alveolar numbers.44
immunological responses.83,84 Other antenatal effects that The mode of delivery is believed to exert long-term
can affect fetal lung development, immune responses in consequences by affecting the nature of early bacterial
cord blood, or both include maternal diabetes, maternal colonisation of the baby—vaginal delivery leads to
medication use (eg, paracetamol and antibiotics),79 maternal vaginal and bowel flora predominating, whereas
maternal exposure to air pollution,85 and previous caesarean section favours environmental bacteria.97 The
pregnancy (including miscarriage).84 Maternal diet in importance of the microbiome is discussed in the next
mice has been shown to exert epigenetic effects on the section. What is clear is that caesarean delivery is
pups,86 but this has not yet been shown in human beings. associated with an increased subsequent risk of atopy and
Even if reductions in lung function are small, they can food allergy, and changed fecal flora at 7 years of age.88,89
still be of relevance. In a recent study, Guerra and Place of delivery has been the least studied factor.
colleagues87 showed that early childhood reductions in Babies of atopic parents who were delivered at home had
lung function caused by parental smoking are important a reduced prevalence of atopic disease (asthma, eczema,
and affect rates of development of chronic airflow and food allergy) at 6–7 years of age, and faecal Clostridium
obstruction when these children smoke themselves. difficile isolation at 1 month was positively associated with
Therefore, they showed that parental and active smoking atopic disease at the same age.90
act synergistically to affect early lung function deficits in
young adulthood. 87 Thus, even if early life exposures do Early childhood exposures
not directly produce major lung function deficits, they The adverse effects of parental cigarette smoking are well
can also play a part in increasing susceptibility to active documented. However, a key controversial question is
smoking and predisposing people to the progressive whether or not early viral infections cause asthma and thus
nature of chronic obstructive pulmonary disease, as has long-term susceptibility to chronic obstructive pulmonary
been recorded in at least some patients. disease. Infection with respiratory syncytial virus, and
Perinatal effects comprise the timing of delivery especially rhinovirus, is unquestionably associated with the
(prematurity), the mode of delivery (caesarean section later development of asthma;98 however, the most convincing
versus vaginal), and the place of delivery (home or evidence suggests that the association is not causative.
hospital).88–90 The effects of prematurity are well Immunological abnormalities are detectable in the cord
documented. Premature birth, even if the baby does not blood of babies who subsequently develop wheezing lower
require ventilatory support, is associated with decrements respiratory tract illness,99 and impaired lung function
in lung function in the perinatal period, and these effects precedes the first wheezing episode.100 Furthermore, the
are more pronounced with the need for more intensive 17q21 locus is associated with rhinovirus-induced
and prolonged treatment. Interestingly, so-called late wheezing.101 Therefore, viral infections are a marker of
preterms (week 33 up to week 40 gestation) also have pre-existing impaired structure and function that lead to
impaired childhood spirometry,91 and late preterm birth asthma, rather than being directly causal.
is much more frequent than is extremely preterm Other important factors also impinge on lung health.
delivery. The evolution of lung function after preterm The role of early bacterial colonisation is an active research
birth is controversial: some early life studies have shown topic. We now know that the lower airway, far from being
catch up in lung function,41 whereas others have reported sterile, contains a rich bacterial flora, as shown by
an even further decline in lung function in early life.92,93 molecular microbiology techniques.102 Furthermore,
Wheeze is common in childhood, but importantly is not normal immunological development and response to
associated with evidence of airway inflammation, as allergens is critically dependent on a healthy lower airway
indicated by the concentration of exhaled nitric oxide94 flora.102,103 The relevance of the flora to the development of
and exhaled breath temperature,95 although evidence of chronic obstructive pulmonary disease remains to be
increased oxidative stress might be present.96 This established. However, childhood respiratory infections are
finding is important because these children might known to affect later risk of chronic obstructive pulmonary
develop irreversible airflow obstruction, similar to disease.49 Therefore, changes in the airway microbiome
chronic obstructive pulmonary disease, later in life. and the consequent risk of chronic obstructive pulmonary
However, this disorder does not necessarily have a disease are probably worth investigating. The effects of
similar pathophysiology to the airflow obstruction in the microbiome on airway immune responses and thus
lifelong smokers. A further degree of complexity is the risk of atopic disease is another mechanism whereby the
changing nature of preterm survivors; “old” risk of chronic obstructive pulmonary disease might be
bronchopulmonary dysplasia babies were bigger, were modulated. The protective effects of the farming
ventilated at higher pressures, and had a mainly airway environment on atopic disease have long been known,

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and have recently been related to greater environmental compromised lung function at birth78,113 and in
bacterial and fungal diversity.104 However, the COPSAC adulthood,114,115 and with respiratory symptoms116,117 and
study showed that early upper airway colonisation with increased risk of chronic obstructive pulmonary disease.118,119
Haemophilus influenzae, Moraxella catarrhalis, or Environmental tobacco smoke exposure can therefore
Streptococcus pneumoniae, alone or in combination, is affect lung development in utero, lung growth during
associated with worse wheeze outcomes,105 and, more childhood, and lung function loss during adulthood. A
recently, with raised amounts of Th1, Th2, and Th17 gene–environment interaction exists since it has been
cytokines in nasal samples.106 The precise interactions shown that infants from mothers carrying GST-null
between bacteria and viruses, the host immune system, polymorphisms are most susceptible to the adverse effects
and long-term outcomes have yet to be established, but of smoking.120,121 A recent study showed that polymorphisms
clearly anything that can modulate the host airway flora, in GSTO genes interact with environmental tobacco smoke
such as antibiotic therapy, could potentially have profound exposure both in utero and in adulthood and significantly
effects. Excessive weight gain in the first year of life is affect FEV1 in adulthood, thus supporting the notion that
associated with failure of normal lung development.107 genes and environmental stimuli interact at different
Postnatal exposure to air pollution is another major cause stages of life (figure 2).122 However, the authors
of failure of normal lung growth.108,109 In the CAMP study, acknowledged that they did not record consistent significant
25% of participants with mild asthma showed impairment interaction effects of the GSTO single nucleotide
of lung growth over a 4-year period, irrespective of polymorphisms and environmental tobacco smoke
treatment (budesonide, nedocromil, or placebo).110 The exposure on the FEV1:FVC ratio. Further analyses showed
basis of this intriguing finding is not known. that the effects were restrictive in origin, rather than
An important aspect of the development of the lung in obstructive, which draws attention to the problems that
childhood is that a disconnect exists between lung exist with the use of just a reduction in FEV1 as a sign of
structure (growth) and lung function. Longtitudinal chronic obstructive pulmonary disease.
cohort studies into the course of lung function and A factor that limits research into the early origins of
growth have invariably used spirometry as a surrogate chronic obstructive pulmonary disease is the logistical
for both structure and function. This approach is not difficulty of combining studies of early life events and the
ideal—spirometry is only indirectly related to lung size presence of the disease about 50–60 years later in the
and respiratory mechanics, and gives no indication of the same people. Therefore, research has to rely on indirect
size of the pulmonary capillary bed. Furthermore, evidence. Population-based studies have connected genes
spirometry is insensitive to distal airway function. important for lung growth, such as ADAM33, with
Therefore, caution is needed when drawing inferences susceptibility to chronic obstructive pulmonary disease,123
about lung growth and aspects even of airway function in and patient studies have confirmed this finding by
the studies published so far. recording different prevalences of single nucleotide
polymorphisms between healthy controls and patients
Genetics with chronic obstructive pulmonary disease in most
Chronic obstructive pulmonary disease is a multifactorial studies and by linking gene polymorphisms with chronic
disease in which genes and the environment interact to obstructive pulmonary disease pathophysiology.124–126
drive the development of the disease.111 Several genome-wide Additionally, reduced lung function in childhood has been
association studies have discovered genes that are shown to be associated with ADAM33 single nucleotide
associated with both the presence of the disorder and the polymorphisms, specifically in children of mothers who
severity of airflow obstruction—namely, CHRNA3, smoked during pregnancy—another example suggesting
CHRNB3/4, HHIP, and FAM13A. Furthermore, several that in-utero effects might have imprinting effects on lung
genes have been associated with low lung function in the function after birth.127 Another study showed that SOX5, a
general population, including AGER, GPR126, GSTCD, gene necessary for lung development, is associated with
HTR4, THSD4, and TSN1. However, low lung function in chronic obstructive pulmonary disease,128 which again
the general population could be due to asthma, chronic suggests that the development of the disease might have
obstructive pulmonary disease, or both, especially in older its origins in utero. This finding is corroborated by a
people. This situation greatly hampers the study of the recent study addressing the genetics of chronic obstructive
genetics of chronic obstructive pulmonary disease and pulmonary disease through an investigation of genes that
indeed these published genes might not be specific for were previously associated in genome-wide association
either asthma or chronic obstructive pulmonary disease. studies with chronic obstructive pulmonary disease, low
They might also indicate abnormal lung development in lung function, or both.129 These genes were then associated
utero, different environmental drivers of disease, or both. with transient early wheeze, a phenotype in early
In addition to active cigarette smoking, passive environ- childhood that is associated with low lung function early
mental tobacco smoke exposure also induces lung in childhood and with low lung function in later
inflammation and oxidative stress.112 Environmental childhood.129 Of note, children with wheezy bronchitis (or
tobacco smoke exposure has been associated with episodic viral wheeze as it is now known) had an

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accelerated rate of decline in spirometry at age 45–50 years, Declaration of interests


a known risk factor for chronic obstructive pulmonary DSP has been a consultant for AstraZeneca, Boehringer Ingelheim,
Chiesi, GSK, Takeda, and TEVA, and has received grants to the
disease.130 AGER, a gene previously associated with University from Chiesi and AstraZeneca. MvdB has received grants to
chronic obstructive pulmonary disease, showed replicated the University from TEVA, AstraZeneca, and Chiesi. AB declares no
association with the FEV1:FVC ratio in childhood. competing interests.
Furthermore, some genes known to be associated with Acknowledgments
chronic obstructive pulmonary disease in general DSP and MvdB were supported by the Royal Dutch Academy of Arts and
population studies interacted with environmental tobacco Sciences. AB was supported by the NIHR Respiratory Disease Biomedical
Research Unit at the Royal Brompton and Harefield NHS Foundation
smoke, showing lower FEV1 in exposed children. Some Trust (London, UK) and Imperial College London (London, UK).
genes showed an interaction only with in-utero tobacco
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