Early origins of chronic obstructive pulmonary disease

Summary

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and a significant challenge for adult physicians. However, there is a misconception that COPD is a disease of only adult smokers. There is a growing body of evidence to support the hypothesis that chronic respiratory diseases such as COPD have their origins in early life. In particular, adverse maternal factors will interact with the environment in a susceptible host promoting altered lung growth and development antenatally and in early childhood. Subsequent lung injury and further gene–environment interactions may result in permanent lung injury manifest by airway obstruction predisposing to COPD. This review will discuss the currently available data regarding risk factors in early life and their role in determining the COPD phenotype.

Introduction

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide.¹ COPD is usually defined by chronic airflow obstruction with a forced expired volume in one second/forced vital capacity (FEV₁/FVC) ratio of <0.7 following a bronchodilator challenge.² However, making a diagnosis of COPD purely on obstructive spirometry may be inaccurate as obstructive lung disease in adulthood can be caused by diseases such as cystic fibrosis (CF), non-CF bronchiectasis and asthma.³

More than 50 years ago, it was documented that cigarette smoking is a causal factor for developing COPD.⁴ However, in the past decade, results from a growing number of population-based studies suggest that the risk of COPD from cigarette smoking was ∼50%⁵ and that the burden of non-smoking COPD is much higher than previously believed.⁶ Alternate risk factors implicated in the non-smoking COPD phenotype include indoor and outdoor air pollution, specifically biomass fuel, occupational exposures to dust and fumes⁶ and the interaction of the environment with candidate genes. Less attention has been given to the ‘fetal origins hypothesis’ that is, the origins of many chronic adult diseases such as COPD may be found in early life. Early observations by Barker et al.⁷ concluded that low birth weight and respiratory infections in infancy reduced lung function in adulthood. Consistent with this, death from COPD was associated with lower birth weight.⁷

This review summarises the current and emerging evidence that many factors, both genetic and environmental, influence antenatal and postnatal lung growth, connecting early life events with COPD. Important concepts at the core of this review are: (i) knowledge of normal lung development; (ii) antenatal programming; and (iii) tracking of lung function.

Lung growth starts in utero and continues to early adolescence going through different phases. The embryonic phase, between the 4th and 7th weeks of gestation, begins with the formation of a groove in the ventral lower pharynx and a bud at the lower part of the groove. After further elongation and subdivision of the bud, the two main bronchi are formed. Between the 7th and 16th weeks, known as the pseudoglandular phase, the future bronchial trees continue to subdivide to form the terminal bronchioles. During the canalicular phase, from the 17th to the 26th week of gestation, airway branching is complete with the formation of the primitive saccules. The airway lumen enlarges and walls thin as connective tissue components are reduced. It is also during this phase that the cuboidal epithelium lining the saccules differentiates into type I and type II pneumocytes with concomitant increases in peripheral mesenchyme vascularization. From 27 weeks onwards in the saccular phase, the pre-acinar airways grow, additional respiratory bronchioles develop and acini are formed. Airway growth continues after birth with the airway diameter and length at least doubling until adulthood. Secondary septation subdividing the sacculi into smaller subunits or alveoli occurs although alveolar development is predominantly a postnatal process.8, 9 Alveoli continue to increase in number until and beyond birth. At 29 weeks’ gestation, there are ∼30 million alveoli and this increases to some 150 million alveoli by term, one-third to half the adult number.8, 9 Moreover, the molecular phases of lung development are not confined within these specific stages and rather represent a continuous dynamic process.¹⁰

With regards to the natural course of lung function from birth to adulthood, FEV₁ and FVC will increase from childhood and plateau in early adulthood (20–25 years of age). There is then a steady decline in both FEV₁ and FVC until ∼40 years of age, following which there is a more rapid decline in these values.¹¹ Changes in FEV₁/FVC ratio thus occur with age and a ratio of 0.7 is attained at ∼50 years of age in men and a few years later in women.¹¹ Adult lung function may be influenced by a number of abnormal patterns of airway growth which include: (i) abnormal lung function at birth; (ii) normal childhood lung growth and function but accelerated decline as an adult; or (iii) failure to achieve a plateau in lung function followed by a normal or abnormal rate of decline of lung function in mid-adulthood.

The ‘fetal origins hypothesis’ encompasses the concept of programming. This concept is well established in developmental biology and encapsulates the idea that stimuli or insults during critical or sensitive periods in early life will result in developmental adaptations that will produce permanent structural, physiological and epigenetic changes that may have lifetime consequences. For example, maternal smoking, inadequate maternal nutrition and maternal hypertension will contribute to placental insufficiency leading to low birth weight. There is now a wealth of data showing that low birth weight is associated with increased cardiovascular and respiratory morbidity in adulthood including systemic hypertension, ischaemic heart disease and COPD.7, 12

Tracking is defined as following a particular centile so that there is no deviation from that centile over time. For lung function, tracking would imply that there is no centile change from birth to childhood to adulthood. Longitudinal studies from childhood to adolescence demonstrate a high degree of tracking.¹³ In one of the first studies to track airway function from birth to early adult life, the Tucson Children’s Respiratory Study suggested that adult airway function is established very early in life, probably in utero in term babies.¹⁴ Infants with the lowest maximal expired flow rates at functional residual capacity (V_max FRC) had persistently low lung function at 6, 11, 16 and 22 years of age, although there was no further deterioration in lung function after 6 of age. Similarly in the Melbourne asthma cohort, lung function centiles at 50 years of age were established by 7 years of age.¹⁵ Even small lung function deficits result in premature airflow obstruction with lung aging, and this effect is magnified if there is an accelerated decline in lung function. For example, environmental stimuli such as pollution or a personal history of smoking may lead to accelerated loss of lung function even if a normal plateau is reached. An important general principle is that minor effects on lung function are magnified by lung aging.