Volume 4, Issue 1, Pages 28-39 (March 2003)

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ABSTRACT

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Effects of childhood respiratory diseases on the anatomical and functional development of the respiratory system

Abstract

The anatomical and functional development of the lung appears especially vulnerable to a whole range of insults during gestation and the first few years of life. A significant proportion of adult lung disease originates in utero or early infancy. Most publications on this topic are descriptive retrospective studies. An important limitation of these is that structural changes may precede abnormalities in lung function and development of symptoms. Little is known with certainty with respect to the long-term effects of early insults to the respiratory system. Furthermore, the reversibility of the functional and/or structural defects is hardly ever adequately investigated and it is probably not correct to extrapolate findings from adult studies to paediatric pulmonary diseases. Promoting or facilitating optimal lung growth in fetuses and infants and reducing the incidence of lower respiratory tract infection in infancy may reduce the incidence of adult chronic lung disease in generations to come.

Keywords: lung growth, remodelling, sequelae, lung function, childhood respiratory disease, outcome

Article Outline

• Abstract

• INTRODUCTION

• PHYSIOLOGICAL DEVELOPMENT OF THE RESPIRATORY SYSTEM

• Study tools

• History of respiratory symptoms and physical examination

• Lung function measurements

• Radiological imaging

• Histology

• INSULTS TO THE DEVELOPING LUNG

• Prenatal and postnatal passive smoking, and outdoor air pollution

• Passive smoking

• Outdoor air pollution

• Chorioamnionitis

• Chronic lung disease of prematurity

• Asthma

• Infections of the lower respiratory tract

• Bacterial infections

• Pertussis

• Viral infections

• Adenovirus

• Respiratory syncytial virus bronchiolitis

• Infections in ciliary dyskinesia

• Infections in the immunocompromised child

• Aspiration

• Congenital abnormalities of the lungs, respiratory tract and diaphragm

• Adult respiratory distress syndrome and sepsis

• Sickle cell anaemia

• CONCLUSIONS

• PRACTICE POINTS

• RESEARCH DIRECTIONS

• References

• Copyright

INTRODUCTION

The anatomical and functional development of the respiratory system may be affected by insults to the lung that are of an infectious, metabolic/toxic, solely inflammatory, traumatic or genetic nature, and this may commence prenatally. Whether or not structural and functional damage to the lungs and airways occurs depends on factors such as the timing, severity and duration of the insult, the host response, the subsequent repair process and the effects of initial and chronic treatment, if applied. During gestation, and during the periods of rapid growth of the airways and air spaces in the first few years of life, the impact of such disturbing factors can be profound. In fact, a significant proportion of adult respiratory disease represents the sequelae of what has gone wrong during pregnancy or childhood.1 The natural history of disease is usually not documented since treatment is directed towards fighting the adverse effects of disease on the function and structure of the lungs and airways. Consequently, older studies that describe the net result of disease and treatment on lung function growth in childhood respiratory disease may be outdated because of altered treatment strategies. The aim of this review is to collate what is known on the disturbance of structure and function of the respiratory system as a result of several common “insults to the lung” during childhood. Pathophysiological characteristics and some typical histological findings caused by childhood respiratory trouble are summarised. Rare systemic disorders and biochemical and in vitro studies are beyond the scope of this paper.

PHYSIOLOGICAL DEVELOPMENT OF THE RESPIRATORY SYSTEM

The prenatal and postnatal differentiation, development and dimensional growth of the lungs and airways have been the topic of several reviews.2., 3., 4., 5., 6. The human bronchial tree is formed in the first trimester of pregnancy. By the end of gestation, airways are complete in number; structural maturation and dimensional growth occur thereafter. Alveoli begin to appear around the 28th week of gestation and exhibit an enormous increase in number in the first 2 years of age, only to slow down between ages 2 and 8 years and be followed by dimensional growth.7 Hence, the growth of airways and air spaces in healthy subjects does not occur in parallel or in an isometric pattern, either before or after birth. This pattern of unequal growth4 has been coined “dysanapsis”8 and is not necessarily a feature of disease: it is a normal biological phenomenon with considerable differences between subjects and gender.4 These differences may, however, constitute a risk factor for developing disease or more severe respiratory symptoms. The natural variability in alveolar number is significant and it seems likely that a large biological variability in airway dimensions also exists. The growth and development of the respiratory system are largely programmed in utero9 and there are reasons to assume that once the basic structure of the respiratory system has been realised during this critical phase, the development of lung function and anatomy has a more or less fixed course and exhibits tracking well into adolescence (Fig. 1).10., 11.

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Figure 1. Development of airway function relative to lung growth in adolescent boys and girls from a general population, with and without mild respiratory symptoms. MEF80%TLC, MEF60%TLC and MEF40%TLC are the forced expiratory flows at 80%, 60% and 40% of the total lung capacity (TLC) remaining in the lungs, respectively, which are used as measures of the patency of the large, intermediate and small airways. Airway function in children with and without respiratory symptoms grow in parallel without any signs of catch-up growth. (Reproduced with permission from ref. 11.)

Study tools

Suitable methods for prospective studies on respiratory morbidity in childhood should ideally be non-invasive, child friendly, sensitive, reproducible and quick. They all, however, have their limitations.

History of respiratory symptoms and physical examination

These data are regarded as functional parameters in large epidemiological investigations and are suitable for prospective studies. Questionnaires may be validated and reproducible, whereas physical examination is not standardised and is poorly reproducible. Both methods lack sensitivity and specificity.

Lung function measurements

Measurements of lung function seem the most suitable technique to assess the net effect of structural and functional integrity of the bronchial tree, lung parenchyma, thoracic and muscular function (and sometimes pulmonary perfusion) and are useful for the cross-sectional and longitudinal assessment of moderate-to-severe airways obstruction, disturbed diffusion capacity and restrictive function disorders (Fig. 2). Important drawbacks are that these tests can be carried out reliably in only older children, and they are quite insensitive to abnormalities in the peripheral airways12 or lung parenchyma.

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Figure 2. Schematic individual development and decline of lung function in different circumstances. (a) Normal pattern (healthy subject); (b) progressive disease, presenting in adulthood; (c) impaired airway function in childhood and adulthood as a result of stable (“controlled”) lung disease or congenitally small airways; and (d) progressive disease, commencing in childhood, with an accelerated decline in adulthood. FEV1, forced expiratory volume in 1second.

Radiological imaging

Because plain chest X-rays lack sensitivity and standardised scoring systems, they are not suitable for prospective studies. Promising new applications13., 14., 15. and scoring systems16 have, however, been developed for high resolution computed tomography (CT) scans. Although providing only structural information (at relatively high lung volumes), valuable imaging is obtained on the peripheral structure of the lung (such as bronchiectasis) and thickness of airway walls that can easily be missed when using lung function testing alone (Fig. 3).17

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Figure 3. Discrepancy between the lung function test (normal flow–volume curve) and the high-resolution computed tomography scan of the thorax of an adolescent boy with cystic fibrosis showing bronchiectasis in both lower lobes (arrows). (Courtesy of H.A.W.M. Tiddens.)

Histology

The incomplete restoration of histological integrity has been coined “remodelling” referring to the irreversible alteration of airway or lung tissue, and has been most widely studied in adult asthma.18 Very few studies have actually described the inflammatory changes in childhood asthma since this can be ethically justified only in severe or difficult asthma.19 Histological data on other paediatric chronic lung diseases are also rare and largely limited to post mortem studies that demonstrate only one end of the disease spectrum. One would, therefore, have to look for reliable indirect techniques that might reflect inflammation or structural changes of the airways and lung parenchyma, such as surrogate markers for altered structure and/or function. For asthma, examples are exhaled nitric oxide and other gases, induced sputum/breath condensate and studies of bronchial hyperresponsiveness. The latter technique has often been incorporated into long-term epidemiological asthma studies.

INSULTS TO THE DEVELOPING LUNG

Prenatal and postnatal passive smoking, and outdoor air pollution

Passive smoking

Of all possible chronic prenatal intoxications, prenatal passive smoking is probably the most prevalent (and preventable) and the most investigated cause of chronic lung disease in childhood and adults. The prenatal growth of lungs and airways is diminished as a result of passive smoking,20., 21., 22., 23. and there is no reason to assume that catch-up growth occurs in later life.24

Recent animal studies indicate that alveolar attachments in the developing lung are reduced by passive smoking,25 and if this occurs in humans as well, it could co-determine the development of chronic obstructive pulmonary disease (COPD), even in the absence of active smoking. There are thus several mechanisms explaining a higher prevalence of COPD following prenatal passive smoking. In addition, passive smoking often continues after birth, is a risk factor for more severe infections in general, and is associated with severe lower airways infection such as that caused by respiratory syncytial virus (RSV), and chronic respiratory symptoms in children with and without asthma. Extensive reviews exist on this topic.26., 27.

Outdoor air pollution

Traffic exhaust fumes, especially from diesel engines, are associated with reduced lung function28 and diminished lung function growth in schoolchildren.29 This is probably caused by chronic bronchitis/airway inflammation that can be reversed by reduced exposure to traffic exhaust, but reversibility studies are lacking.

Chorioamnionitis

Normal lung development is determined by a finely regulated balance between transcriptional factors, peptide growth factor signalling, matrix components and physical forces.30 The release of lipopolysaccharide endotoxin by micro-organisms in the amniotic and/or tracheal fluid could disturb this balance.

Chorioamnionitis is probably harmful to the developing respiratory system but may have some protective or beneficial effects as well. In animals, chorioamnionitis in early gestation is associated with improved preterm lung function despite changes in surfactant level and lung growth that are similar to those in the lungs of ventilated animals developing bronchopulmonary dysplasia.31 When such experiments are repeated in early gestation in animals born at term, however, such functional improvements and corresponding structural alterations in the lungs are not observed 2 months after term birth.32 This suggests that the effects of such “controlled” inflammatory processes are temporary. If chorioamnionitis results in an adaptive response improving the chances of surviving prematurity, it is likely to benefit only the relatively big premature babies with relatively mature lung development.33

Chronic lung disease of prematurity

The original description of bronchopulmonary dysplasia34 is of a syndrome that is now hardly encountered. The infants who nowadays eventually develop chronic lung disease (CLD) are the ones who are extremely preterm, have a birth weight of less than 1kg and often have little lung disease soon after birth.35 The syndrome develops as a result of the net effects of pulmonary inflammation, oxidant stress, mechanical trauma caused by artificial ventilation, patent ductus arteriosus and respiratory tract infections. In addition, an arrest in alveolar and vascular development takes place,35 which is illustrated by the abnormal development of infant lung function.36 Pathological studies of fatal cases have shown that CLD lungs have overdistended and atelectatic zones with increased airway wall thickening and airway smooth muscle mass, obliterative bronchiolitis, peribronchial fibrosis, alveolar hypoplasia and pulmonary vascular remodelling with hypertensive vascular lesions.37 During the perinatal period, alveolar development and micro-vascular maturation are especially susceptible to disruptive factors such as temperature, oxygen tension, cigarette smoke, malnutrition, drugs and hormones. The treatment of preterm infants with corticosteroids to try to wean them off the ventilator and to diminish the severity of CLD may occur at the expense of alveolar number and diffusion capacity. Proof of this is, however, is lacking.38

The respiratory symptoms seen in CLD vary from mild to severe and tend to improve with age. Common respiratory symptoms are wheezing, increased work of breathing, exercise intolerance and chronic and irreversible airway obstruction. Typically, young children with CLD are highly susceptible to a more dramatic course of (viral) respiratory infections, especially caused by RSV. The radiological sequelae of CLD are best visualised using CT scanning and characteristically include air trapping, bronchial wall thickening, reduced lung attenuation and bullae. In the majority of children and adolescents with CLD, persisting CT abnormalities can be found that correlate well with abnormalities of lung function.39 The functional abnormalities include a wide spectrum of airways obstruction, air trapping, exercise intolerance, reduced gas transfer and pulmonary hypertension that is consistent with the concept of loss of alveoli, reduced airway patency and parenchymal destruction.39 The prognosis for the present population of infants with CLD is probably not comparable to that reported in the literature and new follow-up studies are needed. There is serious concern that many children who developed CLD will develop progressive COPD in (early) adulthood.

Asthma

Several studies describing the course of childhood asthma report that between 30% and 70% of children improve or ‘grow out’ of their asthma in late adolescence or early adulthood, depending on the definitions used for the asthma and its symptoms,40., 41., 42., 43., 44., 45. whereas functional abnormalities include persisting airways obstruction,44., 46., 47. elevated lung volumes,44., 48., 49., 50. and different effects of asthma on the development of forced vital capacity for the sexes.47., 50. Hence, young adults with a history of childhood asthma seem to have a functional disadvantage compared with healthy subjects.

Furthermore, the decline of lung function with age in adult asthmatics occurs at a greater rate than is seen in normal individuals,51., 52., 53. and long-standing asthma may be difficult to distinguish from chronic bronchitis and COPD.54., 55. These studies suggest that asthma is associated with functional changes that start in childhood, continue into adulthood and may end in chronic obstructive lung disease with a substantial irreversible component. Reduced pulmonary function throughout childhood asthma may reflect diminished lung growth or be the result of enhanced bronchomotor tone and/or altered airway mechanics caused by remodelling of the airways.18., 56., 57., 58., 59., 60. It is difficult to infer from these studies that the growth of lung and airways is diminished in asthma and whether this is irreversible or not. Most studies have been based on pre-bronchodilator data and have not ruled out the effects of enhanced bronchomotor tone and/or inflammation on expiratory flows and volumes. In addition, the relationship between height and lung function is complex during puberty and the delay of the pubertal growth spurt in asthmatics may introduce additional problems. This complicates comparisons with a normal population.

The structural changes of the conducting airways include injury and loss of the surface epithelium, thickening of the reticular basement membrane, increases in the amount of underlying collagen, blood vessels and airway smooth muscle, and plugging of the airways by exudate.18., 61. Airway inflammation is also present in paediatric asthma,19., 62., 63., 64. and even young asthmatic patients who have become asymptomatic may have persisting mucosal inflammation of the bronchi and subepithelial collagen deposition.65 It is assumed, but not proven, that inflammation and remodelling eventually result in irreversible functional abnormalities in asthmatic children. The relationships between inflammation, remodelling, bronchial hyperresponsiveness and reduced pulmonary function are, however, still not clear.

There is an ongoing debate over what the relationship may be between the structural and functional changes caused by remodelling in adult asthmatics66 and whether or not this is reversible.67., 68. Several studies suggest that anti-inflammatory treatment can at least partly reverse the histological alterations in adult asthmatics,18 and there is evidence to suggest that the remodelling of asthmatic airways in (early) adulthood results in airways that are less distensible,69., 70., 71. which could even partly preserve lung function by counteracting any possible effects of airway narrowing. Similar studies in paediatric asthma are, however, lacking.

The hypothesis that early intervention in childhood asthma with anti-inflammatory treatment is beneficial for baseline lung function seems attractive, but the evidence for this rests on an extrapolation of the conclusions from adult studies59., 72., 73., 74. and one uncontrolled observational paediatric study75 that was somewhat uncritically accepted.76 There is one published long-term, randomised controlled trial study in asthmatic children in which a moderately high daily dose of inhaled corticosteroids (600μg budesonide) was administered with proof of good adherence to treatment; this study suggested that the forced expiratory volume in 1second after maximal bronchodilation could normalise completely even after correction for increased total lung capacity.48 The population size was, however, too small to consider this as proof of complete reversibility and it is also possible that measures of small airway patency would have proved more sensitive in demonstrating persisting airway obstruction.

It is simply unknown to what extent asthmatic inflammation and repair in children is comparable to that in adults, whether, and under what conditions, remodelling in childhood asthma is reversible, what the optimal treatment to achieve this is and what lung function parameters should be monitored to avoid false-negative results. It seems that we first need further evidence that early treatment is beneficial for long-term prognosis in terms of quality of life, morbidity and lung function, before modifying international guidelines for the treatment of asthmatic children.77., 78.

Infections of the lower respiratory tract

A few types of respiratory infection will be discussed below, infections with fungi and parasites being omitted.

Bacterial infections

There is a considerable amount of literature suggesting that pneumonia in early life is associated with lower adult lung function and it has been speculated that early lower respiratory tract infections are to some extent causally related to the development of COPD.79., 80. In one large epidemiological study, childhood pneumonia or pertussis infection was associated with reduced ventilatory function in adulthood.81 Intra-uterine influences that retard fetal weight gain may irrecoverably constrain the growth of the airways. Bronchitis, pneumonia or whooping cough in infancy further reduce adult lung function and retard infant weight gain. Consistent with this, death from chronic obstructive airways disease in adult life has been shown to be associated with a lower birthweight and weight at 1 year of age.82 Alternatively, it could be that reduced weight and lung size are themselves risk factors for developing more severe lower respiratory tract infections. The high prevalence of bronchiectasis among native Alaskan children has been attributed to the high rate of infant and childhood pneumonia.83

Cystic fibrosis can be regarded as the most extreme example of bacterial infection-induced progressive damage to the airways and lungs, being even more amplified by the associated reduced mucociliary clearance. Histological defects include massive airway inflammation, consolidation of the parenchyma and cystic/bronchiectatic scarring throughout the lung, while functional abnormalities demonstrate progressive airways obstruction, air trapping and decreased tolerance for exercise, including progressive ventilation/perfusion mismatch during exercise.84 Whether childhood empyema is associated with long-term effects on lung function is unclear. Mild obstructive abnormalities in lung function have been identified with equal frequency in children treated with and without chest tube drainage.85

Pertussis

A long-term follow-up, from childhood to adulthood, of lung function in subjects who had had pertussis in early childhood showed no abnormalities of lung function in some studies,80., 86., 87. although others found evidence for increased airways obstruction.88., 89. It appears that the development of bronchiectasis, appearing in a small minority of patients90., 91. and lung function abnormalities depends on the population studied, the severity of infection (only epithelial infection or complicated) and the interval between the infection and the assessments.

Viral infections

Viral lower airway infections may resolve completely, result in irreversible lung damage or even be fatal (Fig. 4). Adenovirus and RSV will be discussed as examples.

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Figure 4. Patterns of injury and repair following viral insults to the lung. (Reproduced with permission from ref. 124.)

Adenovirus

Adenovirus pneumonia is especially notorious for its rare but serious lifelong pulmonary sequelae and is one of the main causes of Swyer–James–McLeod syndrome (unilateral hyperlucent lung syndrome).92., 93. Constrictive bronchiolitis, in lung transplant patients also termed obliterative bronchiolitis, is also found as a rare complication of adenovirus, influenza type A and measles infections of the lung.94 The inflammation and fibrosis occur predominantly in the walls and contiguous tissues of the membranous and respiratory bronchioles, with resultant narrowing of the airway lumen.

Respiratory syncytial virus bronchiolitis

Only approximately 2% of neonates and infants infected with RSV develop bronchiolitis requiring hospital admission. During the acute illness, there is inflammatory obstruction of the small airways with submucosal cellular infiltration, epithelial necrosis and mucous plugging; the functional residual capacity increases, and dynamic compliance falls. Following bronchiolitis, up to 75% of children have recurrent lower respiratory tract symptoms, many continuing to have hyperinflated lungs and bronchial hyperresponsiveness.95 The association between severity of viral lower respiratory tract infections and subsequent wheezing has been recognised by numerous studies.95., 96. Wheezing following RSV bronchiolitis may persist for over 5 years97 and is probably partly explained by pre-existing small airways.98 Whether or not measures of airway patency and airway responsiveness remain abnormal in later childhood may depend on the severity of the bronchiolitis.95., 99. Children genetically predisposed to atopy do not have an increased risk of developing bronchiolitis95 and it seems unlikely that RSV bronchiolitis is a cause of atopic asthma in later life.100

Infections in ciliary dyskinesia

Primary ciliary dyskinesia is accompanied by a progressive deterioration in lung function if it is misdiagnosed or undertreated but lung function can be maintained by early diagnosis and treatment.101 Once bronchiectasis is present, however, progressive lung damage and a decline of lung function are difficult to prevent.102 Hence, aggressive treatment of the lower airways infections in ciliary dyskinesia is required to avoid any worsening of respiratory symptoms and function.

Infections in the immunocompromised child

Children with immunodeficiencies are generally at risk of a more dramatic course of infections, of (subclinical) infections with less common pathogens and of a misdiagnosis of airway infections because their (acquired) immunodeficiency facilitates or masks these infections. Although the mechanisms involved may differ depending on the type of immunodeficiency, they all seem to produce an increased risk of developing bronchiectasis. Bronchiectasis may be progressive and associated with a gradual worsening of respiratory symptoms, lung function and radiological imaging. Development may be slow, and detection is best using high-resolution CT scans.103 Bronchiectasis has been observed in children with HIV/AIDS,104 in primary hypogammaglobulinaemia105 and after solid organ transplantations (P.J.F.M. Merkus, unpublished observations). Whether this is due to direct or indirect effects of immunosuppressive treatment is unknown; studies into the mechanisms and the micro-organisms responsible are needed. When the survival of the patients from their underlying illness is improving, quality of life and the prevention of chronic lung disease become especially important.

Aspiration

The aspiration of organic material such as milk or peanuts by pre-school children is associated with signs of air trapping and consolidation, and pneumonia when not treated early.106 In animal experiments, peanut aspiration induces immediate airway inflammation, with airway wall thickening present at 10 days and bronchial cartilage destruction with bronchiectasis at 30 days.107 Animal experiments also demonstrate that milk aspiration may lead to increased airway responsiveness, an influx of inflammatory cells and lung inflammation.108 The long-term pulmonary sequelae of the aspiration of organic material by children have not been investigated properly. In a small lung function study, it was concluded that the peripheral airways are permanently damaged following peanut aspiration in early childhood.109 The inhalation of foreign bodies is associated with scintigraphic alterations 6 months or more after removal of the foreign body, although chest X-rays may be normal.110., 111. Injury resulting from the inhalation of hydrocarbons is associated with persistent airway dysfunction112 and the development of pneumatoceles.113

Congenital abnormalities of the lungs, respiratory tract and diaphragm

There are a large number and variety of rare congenital abnormalities of the respiratory system that have not been systematically studied.114 Older studies into the long-term consequences of congenital lower respiratory tract malformations may be difficult to compare with more recent descriptive studies because the mortality from severe defects has decreased, at the expense of morbidity. Furthermore, the majority of children with significant respiratory distress undergo artificial ventilation, which may also compromise airway function in later life. They undergo thoracic surgery, often lobectomy, with subsequent compensatory lung growth when the procedure has been carried out in early life.114 Hence, the radiological and functional abnormalities are probably the net result of disease, its treatment and some catch-up lung growth.115 In general, mild-to-severe obstructive and/or restrictive lung function abnormalities have been observed, with enhanced airway responsiveness that may be largely explained by geometric factors rather than inflammation.115 Whether additional irreversible lung damage occurs depends mainly on complications such as recurrent pneumonia and aspiration and the development of bronchiectasis, or following neonatal ventilation. Some defects do not cause serious respiratory symptoms and do not require immediate surgery. On the other hand, compensatory growth following lobectomy will be less pronounced with advancing age.116

Adult respiratory distress syndrome and sepsis

Structural and functional changes of the lung in the survivors of adult respiratory distress syndrome have not been extensively studied. The overdistension of non-dependent regions of the lung has been implicated in the development of lasting lung damage after recovery from severe protracted adult respiratory distress syndrome.117 The degree of lung and airway damage probably depends on the cause and duration of the disease, the ventilation strategy and the presence of pre-existing lung damage. The late stages may be described as restrictive lung disease with superimposed emphysema-like lesions.118 The development of desaturation during exercise following childhood sepsis may be explained by intra-vascular coagulation and vascular remodelling.119 Pneumothorax has been associated with a poorer outcome in children with cystic fibrosis120 but there is no evidence of any long-term structural or functional effects of pneumothoraces in other respiratory disorders.

Sickle cell anaemia

End stage chronic lung disease and cor pulmonale are the most frequent causes of death in young adult patients with sickle cell anaemia. Both perfusion and diffusion defects have been demonstrated, with generalised pulmonary fibrosis and disabling restrictive lung failure. In children and adolescents with sickle cell disease, obstructive lung function abnormalities have been reported in the majority of patients, probably preceding restrictive defects.121 Airways obstruction and transfer factor increased with the individual frequency of acute chest syndrome,122 which may imply a redistribution of pulmonary blood flow. Radiological abnormalities, consistent with scarring from episodes of infarction or infection, can be observed in most patients using CT scanning.123

CONCLUSIONS

Little appears to be known with certainty with respect to the long-term effects of early insults on the respiratory system, and we are left with much room for speculation and investigation. Prospective studies are required to provide a more adequate evaluation of the effects of disease on the development of the respiratory system but for most disorders, only cross-sectional studies are available, if indeed any reports exist. Another important limitation of most studies is that the reversibility of the functional and/or structural defects has not been adequately investigated. Hence, for some (or most?) disorders, there is still a distinct need for prospective studies that include and quantify the effect of optimal treatment. When the diagnosis, treatment and follow-up of paediatric respiratory diseases can be standardised and implemented internationally in a large number of patients, a valuable evaluation of lung function, respiratory symptoms and outcome is possible. A collaboration between large organisations such as the ERS and ATS is required, especially for rare diseases.

The developing respiratory system is exceptionally vulnerable to insults of various types. Even a subtle disturbance may be followed by incomplete repair, or an exaggerated response and scarring, resulting in chronic, lifelong respiratory morbidity, loss of quality of life and early death. Promoting or facilitating optimal lung growth in fetuses and infants, and reducing the incidence of lower respiratory tract infection in infancy, may reduce the incidence of chronic obstructive airways disease in the generations to come.

PRACTICE POINTS

•A significant proportion of adult lung disease can be attributed to insults to the lung during pregnancy and early childhood.

•Published outcome studies describing the net result of disease and treatment on lung function growth in childhood respiratory disease may be outdated due to altered treatment.

•The relationship between remodelling and functional changes in childhood respiratory diseases is largely unknown.

•The hypothesis that early anti-inflammatory treatment in childhood asthma favours long-term outcome seems attractive but remains unproven.

•Relevant parenchymal damage may precede abnormalities of routine lung function tests.

•High-resolution CT scans of the thorax have far better sensitivity in detecting structural changes of the peripheral airways and lung parenchyma than plain chest X-rays.

RESEARCH DIRECTIONS

•Improvement or development of convenient tests to evaluate inflammation and function of peripheral airways in young children.

•Prospective reversibility studies of airways obstruction in asthma involving sensitive test for small airway patency.

•International standardised diagnosis, treatment and follow-up of rare respiratory disorders to evaluate effects of treatment on long-term outcome.

•Prospective studies on the effects of aggressive treatment in early childhood respiratory disease on long-term outcome.

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Department of Paediatrics/Respiratory Medicine, Sophia Children’s Hospital, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands

Correspondence to: Peter J. F. M. Merkus. Tel.: +31-10-4636295; Fax: +31-10-4636772

PII: S1526-0542(02)00311-1

doi:10.1016/S1526-0542(02)00311-1

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