Normal lung development

It is impossible to understand the developmental consequences of prematurity and its treatment and how this results in long-term disease without understanding normal lung development. Antenatal lung development has been reviewed in detail elsewhere.9–12 Briefly, in the embryonic phase (0–6 weeks) the lung bud starts to differentiate from the primitive foregut and the main pulmonary arteries appear. In the pseudoglandular phase (7–16 weeks), the complete airway branching pattern is laid down, together with the pre-acinar vessels. The canalicular stage (16–26 weeks) is characterised by marked capillary multiplication, which establishes a loose three-dimensional network in the mesenchyme. There is flattening of the cuboidal cell layer and the first development of a thin air–blood barrier, with differentiation of type 1 and type 2 pneumocytes and the first appearance of surfactant. The saccular phase (27 weeks term) is followed by phase of alveolar development. These traditional anatomical stages have been shown to have accompanying gene expression patterns.13

Postnatally, the pattern of airway physiological development is best characterised by the global lung initiative (http://www.lungfunction.org/). The FVC and FEV₁ increase throughout childhood to a plateau at 20–25 years. Meanwhile, the ratio (FEV₁/FVC) decreases.14 Thereafter, there is a decline in both FEV₁ and FVC into old age (figure 1). As a general rule, lung function is thought to track throughout life, although under some circumstances there is potential for catch-up.15–20 The threshold for pathological airway obstruction may be crossed prematurely by any combination of (1) airway obstruction at birth, (2) failure to achieve normal airway growth in childhood and (3) accelerated decline in lung function.

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

The life course of lung function. Black line indicates term individuals, grey solid line indicates preterm-born individuals and grey dashed line indicates possible rates of decline in lung function in preterm-born individuals.

Traditionally, alveolar numbers have been thought to be largely complete at age 2 years, thereafter with alveoli increasing in size. Recent in vivo studies using hyperpolarised 3-helium MRI suggest that alveolar numbers increase throughout the period of somatic growth,21 confirmed by direct histological measurements in rhesus monkeys.22 Hyperpolarised 3-helium MRI studies suggest that alveolar volume increases with ageing,23 particularly in the apices and mid-zones.

Preterm birth and likely neonatal scenarios

Until recently most focus has been on preterm infants born at 32 weeks' gestation or less, especially if these infants required respiratory support with mechanical ventilation and increased ambient oxygen in the neonatal period due to neonatal respiratory distress syndrome (RDS). RDS results from failure to adequately expand the lungs after birth due to surfactant deficiency, which is especially relevant to preterm infants. Many of these infants progressed to prolonged supplemental oxygen dependency especially due to ventilator-induced and hyperoxic-induced acute lung injury of the fragile newborn lung. In 1967, Northway and colleagues first described the evolving clinical condition and associated pathological correlates of this lung injury and in the process coined the term bronchopulmonary dysplasia (BPD, often also called chronic lung disease of prematurity).24 Infants were more mature than the current preterm infant typically gestational ages of between 33 and 34 weeks and those who died from BPD had markedly fibrotic and atelectatic lungs.

With routine use of natural exogenous surfactant and antenatal maternal corticosteroids, together with gentler forms of mechanical ventilation (increasingly non-invasive use of CPAP ventilation), BPD is now largely confined to infants born at <28 weeks’ gestation with the pulmonary process being more of dysregulated lung growth with decreased numbers of enlarged alveoli rather than the fibrotic processes previously observed. The term ‘new’ BPD is often used to describe these changes. Thus, the effects of prematurity and its treatment have changed over time, and may change again in the future; it should not be assumed that follow-up studies of young ex-preterm adults are necessarily relevant to the preterm deliveries of today. There have been various attempts to define BPD but of most prognostic value is supplemental oxygen dependency at and beyond 36 weeks’ postconceptional age.25 More recently there have been attempts to define the severity of BPD on the basis of duration of oxygen dependency and any additional need for respiratory support.26 Admittedly, all these terms are crude, and more precise definitions of respiratory disease arising from prematurity are needed, preferably which predict outcome, but this is outwith the scope of this review.

There are several factors that may cause a premature birth and additionally likely to affect fetal lung development and adult outcomes; however, it is impossible to separate the causes from the neonatal consequences of prematurity. These include maternal smoking and chorioamnionitis.27 ,28 It is also becoming increasingly clear that even late preterm and early term delivery is associated with significant long-term morbidity. Another factor that can enhance airway obstruction is fetal growth restriction, which may be associated with preterm birth.

Fetal programming

The hypothesis that in utero events can reprogramme an individual for immediate adaptation to gestational disturbances but with deleterious consequences for later responses to adverse events, known as the Developmental Origins of Health and Disease hypothesis, has been studied in animal models in respiratory diseases.29 For example, in utero smoke exposure leads to enhanced responses to postnatal allergen and fungal exposure.30 In murine models, neonatal hyperoxia may affect adult cardiovascular function and lifespan31 and alter pulmonary oxidative stress and immune responses.32 ,33 The mechanism may be epigenetic, through DNA methylation.34 ,35 The most intriguing human data have come from a study of the responses to high-altitude hypoxia of adult survivors of persistent pulmonary hypertension of the newborn.36 Compared with 10 matched controls, the mean increase in pulmonary artery pressure at altitude measured by echocardiography at high altitude was significantly greater. There was no difference in the fall in arterial oxygen saturation. The relevance of this or any other effect of fetal programming and perinatal treatment in human survivors of prematurity is an important subject for future research. Whether similar abnormalities of the pulmonary arterial circulation persist in adult survivors of preterm birth is unknown, and it is speculative whether, if present, they may increase the risk of pulmonary hypertension if there is a second insult, for example, alveolar hypoxia at altitude.

Preterm birth and childhood lung health

In summary, the evidence below suggests that childhood survivors of preterm birth, irrespective of whether they require neonatal intensive care, have (a) increased respiratory symptoms; (b) at least partially reversible airflow obstruction, but with little evidence of eosinophilic inflammation; and (c) abnormal thoracic imaging.

Preterm birth and young adult lung health

The most persuasive evidence suggests respiratory symptoms are increased and that clinically relevant lung function impairment exists into early adulthood.47 ,48 However, most of these studies were undertaken in subjects at an age where lung growth was still ongoing and some of the findings contrast those reported elsewhere, which have provided some evidence for a more optimistic perspective.20 Ultimately the existing literature in adult survivors of preterm birth has been difficult to interpret49 for reasons that include small sample size50 and the lack of suitable control groups.51 These factors may contribute to a clinician ‘blind spot’.

Clinical presentations

There are likely two different groups to consider: those presenting to clinic with respiratory symptoms and those with no symptoms who may have significant lung impairment; this latter group would likely be detected at routine medical screening or at consultation for an intercurrent unrelated illness. Such patients should have their airway function evaluated in detail as above; correct management may reveal to the patient that in fact they were more symptomatic than previously realised. Key is questioning about early life.

Appropriate questioning in clinics in those presenting with respiratory symptoms

In addition to a full ‘adult’ clinical respiratory history, specific questions that are relevant in adults who may be presenting with lung disease in part attributable to early-life events include

• birth weight

• gestational age

• time course on a neonatal unit

• the presence of respiratory distress at birth and/or the need for mechanical ventilation or oxygen

• maternal antenatal or postnatal smoking.

However, this in itself poses challenges in that unless the adult is accompanied by their parents they are unlikely to know some of these details. However, they usually know at least if they were very premature, if from no other source than family discussions. While paediatricians are more attuned to ask, have the ‘red book’ and parents to inform, a more systematic method for recording neonatal data in adult patient records is required. Linked electronic datasets and patient records should address this issue in the future.

Worryingly, our recent British Thoracic Society survey highlighted that few adult respiratory physicians routinely consider early-life factors during patient assessment.8 Raising awareness across primary and secondary care will be imperative through structured education opportunities and is one of the purposes of this review.72

Diagnostic labels acquired in childhood should always be reconsidered in the adult Chest Clinic, together with reports of impaired physical fitness judged against peers and susceptibility to respiratory infection throughout childhood.

Investigations

Core pulmonary function tests would include pre-bronchodilator and post-bronchodilator spirometry including flow volume loop. Reversible airflow obstruction may exist without an eosinophilic inflammatory process, which expired nitric oxide (FeNO) measurement may help differentiate. Although pragmatically determining the presence or absence of eosinophilia is a challenge as part of a routine clinical assessment, it would seem justified in these young adults to measure FeNO or induced sputum eosinophils (if available) before committing them to an expensive inhaled corticosteroid therapy with risk of adverse effects.

Through expert consensus, we advocate a low threshold for more detailed physiological testing (total lung volume, gas transfer) when the clinical picture in an adult born premature presents with symptoms and clinical findings atypical for major prevalent respiratory diseases, particularly asthma and COPD. This may also require cross-sectional imaging with CT scanning. However, both approaches require validation before being able to make firm recommendations.

Differential diagnoses

Given that the major spirometric manifestation of a preterm birth and BPD in adults appears to be airflow obstruction, the differential diagnosis is primarily that of asthma and COPD, or an ‘Asthma COPD Overlap Syndrome’. Ascertaining where airflow obstruction is likely due to preterm birth is important given the potential for misdiagnosis and therefore undertreatment and overtreatment. A diagnosis of COPD generally considered as fixed or partially reversible airflow obstruction following sufficient exposure to noxious particles or gases (in particular, cigarette smoke) may need to be reconsidered in the young adult with little smoking history but fixed airflow obstruction. Likewise, although asthma, at least in its mildest forms, should typically be associated with a significant degree of bronchodilator reversibility, it may not be the correct diagnosis in a preterm-born young adult with exertional wheeze and dyspnoea. Characterising airways disease in adult survivors of preterm birth in terms of extent and nature of airflow obstruction, pattern of any inflammation and presence of airway reactivity is key.

Consideration of other neonatal interventions (eg, subglottic stenosis from repeated intubation or tracheomalacia or bronchomalacia secondary to prolonged mechanical ventilation) that may lead to later symptoms and impaired lung function is fundamental. One study reported that 7/13 adults who had undergone surgery for a patent arterial duct had a left recurrent laryngeal nerve palsy; misdiagnosis as asthma was common, but laryngoscopy correctly diagnosed the abnormality.73 This thankfully remains rare.

Management

There are no evidence-based or consensus-based guidelines. What is clearly essential is to eschew labels such as ‘asthma’ and ‘COPD’ in the preterm survivor; rather the individual components of any lung disease (fixed or variable airflow obstruction, airway inflammation (if any) and hypoxaemia) should be identified and treated on their merits, without extrapolating uncritically from evidence-based management of commoner airway diseases. The standard chronic respiratory disease principles of smoking cessation, annual influenza immunisation, maintaining physical fitness and a general healthy lifestyle should be adhered to. Although individuals born preterm are often risk-averse,74–76 smoking is common20 and may impact synergistically with other respiratory insults.77 Targeted approaches for smoking avoidance or cessation are key and focus on the young age and where smoking may be indoctrinated across generations of one family.

There is no current evidence to advocate widespread use of bronchodilators or inhaled corticosteroids, although a component of variable airflow obstruction may be present. Additional evidence for optimal treatment is required.78 They should be introduced on the basis of an individual therapeutic trial and should be discontinued unless there is documented objective improvement. A lack of improvement should not lead to stepwise increments in doses of bronchodilators or particularly inhaled corticosteroids. The failure to correctly diagnose respiratory disease in adults born preterm raises concerns regarding under-appropriate, over-appropriate or inappropriate prescribing. Typically, airflow obstruction, when present, is not associated with asthma-type airway inflammation,43 which may or may not respond to asthma therapy.79 Therefore, an asthma misdiagnosis in a symptomatic individual is likely to lead to inappropriate stepwise increases in high-dose inhaled and/or oral corticosteroids with the associated deleterious effects of cumulative therapy: bone mineral loss,80 increased respiratory infection81 and cost. Whether long-term monitoring for (accelerated) decline of lung function is required is uncertain.

Transition of care from paediatrics to adult

The survivors of preterm birth will reach adult life with airflow obstruction but possibly other comorbidities, including neurodevelopmental with secondary musculoskeletal issues such as joint contractures, visual impairment and possibly pulmonary hypertension, poor growth, bone disease and systemic hypertension.

In childhood, an integrated schools and community therapeutic team will have monitored and treated many of these children; when the child leaves school, none of this is available. Given the lungs continue to develop during childhood, the respiratory issues are unlikely to be majorly symptomatic, often merge with the array of normal childhood respiratory infections and may therefore be overlooked—a ‘forgotten generation’.

Likely impact on adult services

It remains unknown whether all young adults born preterm should have lung function and symptoms assessed. Since introduction into Quality and Outcomes Framework, spirometry has become integrated into primary care for the confirmation of COPD and therefore readily available. However, we currently do not know whether this is the optimal method to determine lung disease of prematurity from other physiological tests. Children and adults born preterm have increased risk of respiratory infections, and the impact on future hospital admissions is likely underestimated.82 ,83

Research priorities

There are large gaps in our understanding of lung disease associated with prematurity that now must be addressed through extensive research (box 1). A real likelihood of longstanding structural and functional limitation into adulthood for those born prematurely highlights the dearth of evidence for identifying and treating this condition. Further, the majority of research in young adults born prematurely that is currently available, by nature, is based on subjects born 20+ years ago where neonatal care and the size of babies was very different from today; and likely, in 20 years’ time, practice will have changed again.

However, the most important priorities remain the prevention of preterm delivery (and in this regard, the effects of tobacco legislation have been salutary84), the optimisation of lung health throughout childhood, and above all, ensuring that adult physicians realise the ongoing burden of respiratory disease and comorbidities in this population. The goalposts are not so much moving as disappearing over the horizon as neonatal intensive care salvages ever smaller babies, and uses ever more innovative treatments, which may, however, cause the baby to pay a heavy price in the long term; and this is the chief future challenge for the next generation of adult chest physicians.