Mini-Symposium: Early life origins of chronic diseaseImpact of early life exposures on respiratory disease
Introduction
Despite the dramatic advent of CoVID-19, non-communicable diseases remain an important cause of morbidity and mortality. Important definitions of the common non-communicable airway disease are given in Fig. 1. Chronic obstructive pulmonary disease (COPD) remains in the top five causes of death worldwide. The World Health Organisation (WHO) estimated there were 3.17 million deaths from COPD annually worldwide (5% of all deaths in 2015), and 251 million patients living with COPD (2016) [1]. COPD comprises airway obstruction, parenchymal destruction (emphysema) and systemic comorbidities, all of which have their roots in childhood. However, of the eleven bullet points in the WHO fact sheet, only one refers to early life and that only to the antenatal effects of pollution [1]. WHO also estimated there were 316 million people with asthma worldwide, with 417,918 deaths and 24.8 million disability adjusted life years attributable to asthma in 2016 [2], [3], [4]. Early life events leading to the disease do not get mentioned at all in the fact sheet [5], which focuses on trigger factors and ensuring adequate supplies of basic medications all over the world, which is highly laudable, but essentially palliative care [6].
It is the contention of this review that the views of WHO and so many others are fundamentally and dangerously flawed, implying as they do that interventions in adult life are what is needed to reduce the burden of adult asthma and COPD. The evidence points conclusively to the fact that the risk of airway disease is established by the time the child first walks through the school gate, by which time interventions are too late.
For normal lifelong lung health to be achieved, there are three key milestones which must be attained for lifelong lung health [14]:
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Lung function must be normal at birth.
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Growth of lung function in childhood must be normal, attaining a normal plateau at age 20–25.v
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Thereafter, rate of decline in lung function must not accelerate above normal.
We know that most asthma first manifests in childhood [15], and that at least 50% of COPD is due to failure of normal lung growth [16]; if lung growth is normal up to the plateau in young adult life, COPD risk is greatly reduced. There are no adult life factors, including smoking, which consistently associate with an accelerated decline in lung function in the large COPD series (below). Of course smoking in adult life is harmful for a multiplicity of reasons, but if the first two key milestones in lung growth are achieved, the risk of smoking associated COPD is at the very most 6%, and probably much lower; which is likely the explanation why some heavy smokers escape the disease. Airway disease begins early; the horse has bolted way over the horizon by the end of the preschool years.
Section snippets
Pre-conception: is there a transgenerational risk?
Two [17], [18] of the three studies [17], [18], [19] which have sought a transgenerational effect on airway disease have shown that if a grandmother has been a smoker, even if her daughter has not smoked, her grandchildren are at increased risk of asthma, or at least an airway disease. The mechanism is unclear [20], but could hypothetically relate to germline epigenetic changes. Undoubtedly smoking leads to numerous epigenetic modifications [21], [22], [23]. However germline reprogramming in
Antenatal: not safe in the womb
The foetus is fed transplacentally but is also endangered by the same route from hazards to which the mother has first been exposed. The effects of such maternal adverse exposures on the foetus will depend in part on the maternal and foetal genome and epigenome [25]. There are four outputs pertaining to the respiratory system from such exposures:
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Low birth weight and premature delivery.
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Altered lung structure with secondary effects on function
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Altered immunological function.
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The “ticking bomb”
The growing child: postnatal adverse events
Absolute values of spirometry increase with age to a plateau at age 20–25 years [8]. This is the second key stage, lung function at birth being the first, and is discussed in this section. Thereafter there is a decline with age, the third key stage, and if this is accelerated, there is an increased risk of COPD (below).
Decline and fall: what determines the rate of decline in spirometry?
Contrary to the views of Fletcher and Peto in their classic paper [94], the two main factors leading to accelerated decline in spirometry are genetics and early life disadvantage, and not smoking. This is not to advocate that smoking is a good idea, but to recommend a sober look at the data, which is summarised in Table 1. Genes which relate to rate of decline include ADAM33 [95] and CC-16 [96], but a detailed discussion is beyond the scope of this review. Two studies have shown that rate of
Tracking of lung function
The ideal study, with recruitment pre-conception and follow up to the grave, has yet to be done. In general, the earlier the inception of the study and the longer the follow-up, the stronger the conclusions. The focus has shifted from study of growth in disease groups (e.g. asthma, viral wheeze, which have convincingly demonstrated the tracking of lung function for groups) to data-driven determination of individual lung growth patterns. The data are conflicting. The Tucson group [99] reported
COPD starts in childhood
There are three long-term studies spanning six decades, unfortunately all only recruiting as late as in early childhood. The Tasmanian study [59] measured pre-bronchodilator FEV1 Z-score at age 7, 13, 18, 45, 50 and 53 years. A childhood history of asthma, bronchitis, eczema, allergic rhinitis, food allergy, pneumonia, breast feeding, weight status, parental asthma and parental smoking was determined by parental report. A total of 8583 children were originally recruited, of whom 2438 had at
What about late onset asthma?
The fact that occupational asthma has its roots in early childhood was discussed above. Adult difficult asthma series also describe late onset asthma, typically in adult women who are not atopic [105], [106]. This is a mythical disease, or rather, should be called late resurgent asthma. The Tucson group retained 849 of 1246 babies to age 22 years [107]. Of the 181 with active asthma at age 16–22 years, 49 (27%) were newly diagnosed, with a female preponderance (36, 71%). However, looking back,
The canary in the mine: what is the wider significance of a low FEV1?
It is becoming increasingly apparent that a low FEV1 is a marker for more than just adverse respiratory outcomes. The Tucson group showed that those in the lowest tercile of FEV1 had significantly increased all-cause mortality as early as the third decade of life [110]. Every 10% decrease in baseline FEV1 percent predicted was associated with an increase in all-cause mortality risk of 15%. There is no conceivable plausible biological model whereby the loss of a few dozen millilitres of FEV1
Summary and conclusions
This review has marshalled the compelling evidence that susceptibility to COPD and adult asthma is hugely determined by antenatal and preschool adverse events, and probably also transgenerational pre-conception factors. Not merely do these adverse events lead to irreversible and lifelong changes in spirometry, but they also set the child up to be at increased risk of damage from adulthood insults. While clearly it is important to prevent the second hit of (for example) smoking or occupational
Practice points
Optimizing long term lung health:
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Paediatricians need to advocate now to get across the message that early life events are crucial, and prevention must start in childhood.
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Paediatricians need to take seriously the protection of the unborn child nicotine (tobacco and vaping) and environmental pollution.
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Low spirometry is a marker of future risk, and the child needs to be protected as far as is possible from second hits.
Educational aims
The reader will come to:
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Appreciate that asthma and chronic obstructive pulmonary disease are paediatric not adult diseases in their origins.
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Understand the nature of preconception, antenatal and early year adverse effects and how these impact normal development.
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Realize the lifelong importance of early abnormalities in lung function, not merely for respiratory outcomes, but also cardiovascular and all cause morbidity and mortality.
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Appreciate that early life adverse events may set the child up for
Directions for future research
Adverse effects of early life influences:
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Understand the mechanisms of catch-up growth in the rare children who achieve this, to try to develop novel therapies to reverse early life adverse influences.
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Determine the pathways whereby adverse events cause airflow obstruction to try to intervene to protect the growing lung.
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Find out the best timing to determine risk practically, how to intervene, and show population health benefits.
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ORCID: 0000-0001-6756-9822.