Lung Development and Early Origins of Childhood

7/28/2019 Lung Development and Early Origins of Childhood

http://slidepdf.com/reader/full/lung-development-and-early-origins-of-childhood 1/9

Lung development and early origins of childhoodrespiratory illness

Carol Dezateux* and Janet Stocks^*Department of Epidemiology and Biostatisttcs, Institute of Child Health, London, UK

^Portex Unit of Anaesthesia and Respiratory Medicine, Institute of Child Health, London, UK

In the last two decades, 5 cohort studies have been initiated to examine the association of infant respiratoryfunction with genetic and environmental risk factors, as well as with subsequent lower respiratory illness inearly childhood.While the current complexity of respiratory function tests in this age group precludes study samples withsufficient power to examine more complex issues, information from these studies has provided an excitingadjunct to that available from the larger cohort studies. Premorbid alterations in airway function or lungdevelopment increase the risk of wheezing lower respiratory illnesses during the preschool years and the risk ofimpaired airway function at 5—6 years of age. In addition, gender differences in airway function and theresponse to maternal smoking have been observed. Larger collaborative population-based studies are neededto explore the environmental, genetic and immunological mechanisms responsible, but will depend on the

development of less invasive tests of airway function appropriate for use in healthy infants.Correspondence to Dr Carol Dezateux, Department of Epidemiology and Bioitatistia, Imtitvte of Child Health, 30 Guilford Street, London

WON 1EH, UK

Childhood respiratory disease remains an important cause of mortality and morbidity, accounting

for one-third of general practitioner consultations, one-fifth of hospital admissions and one-

twentieth of deaths at all ages in childhood in England and Wales1. In the first 5 years of life, two-

thirds of respiratory deaths are due to lower respiratory tract infections1. A further dimension of the

public health importance of childhood respiratory disease lies in its potential contribution to chronic

respiratory disorders in adult life2. There is a growing body of evidence from epidemiological

studies confirming a link between childhood lower respiratory illness (LRI) and wheezing and the

development of adult chronic respiratory disease3"6. The nature of this link, the biologicalmechanisms which mediate it, and the genetic and environmental factors which influence its

expression have been the focus of a considerable research effort in recent years.

'Programming' in fetal and early postnatal lifeOne concept evoked to explain this association is that of 'programming'— the permanent alteration of the

structure and function of organs and tissues by factors operating during sensitive periods in fetal or early

postnatal life2. Factors implicated in 'programming' of the respiratory system include fetal nutrition 6"10, fetal

exposure to maternal smoking during pregnancy9'11'12, and exposure to environmental allergens13-14 or viral

respiratory infections15"19 during infancy. The issue of a genetic predisposition to asthma or atopy is also

pertinent14'20 and it is likely that, for childhood asthma at least, outcome is determined by a combinationof familial and environmental factors21. Some of these factors are also potential 'programmers' of the

developing immune system. It has been suggested that exposure to viral infections in early infancy in those

who are genetically susceptible to atopic disorders may favour dominance of TH-1 lymphocytes and reduce

the expression of atopic disorders as mediated by competing TH-2 lymphocyte populations17'19.



Developmental respiratory physiologyAs with other body tissues and organs, fetal and early postnatal life is a period of rapid growth and

development of the respiratory system22. Bronchial development and airway branching are mainly complete

by the 16th week of gestation and, thereafter, airways increase in size and complexity only 23. True alveoli do

not begin to develop until about 28 weeks gestation and increase rapidly in number, size and complexity

during the first 3—4 years of life23

. In a full term infant, lung volume doubles by 6 months and triples by 1year. These different growth patterns of the airways and parenchyma (i.e. dysanaptic growth) during fetal

and early life result m airways that are relatively large in relation to lung

volume at birth, when airway conductance may be higher than at 2-3 months of age22. The extent to which

gender differences in these growth patterns contribute to the increased incidence and severity of respiratory

illnesses observed in boys is unclear. Although some remodelling of the lung may occur during the first year

of life following prenatal and perinatal challenges, there appears to be considerable tracking of respiratory

function from the end of the first year of life to late childhood 22. The somatic growth that occurs during the

first year of life is accompanied by major developmental changes in respiratory physiology 22, including

changes in the shape, compliance, and deformability of the rib cage. The highly compliant chest wall of the

newborn infant gradually stiffens during the first year of life. Infants also modulate expiratory flow in order

to dynamically elevate functional residual capacity (FRC) above the level passively determined by the

outward recoil of the chest wall and the inward recoil of the lung, an important strategy to establish andmaintain an adequate lung volume in the presence of a highly compliant chest wall. Transition to a more

relaxed pattern of expiratory flow occurs between 6-12 months of age. Another consequence of a highly

compliant chest wall is an increased tendency of the small peripheral airways to close during tidal breathing

in early infancy, which results in impaired gas exchange in the dependent parts of the lung. This, together

with the small absolute size of the airways, increases susceptibility to airway obstruction in the infant and

young child22. While there is clear evidence that airway responsiveness is present from birth, the contribution

of pre-existing alterations in airway geometry and lung mechanics or pathologic changes such as airway

oedema and mucus hypersecretion to wheezing LRIs may be of greater importance. Smooth muscle tone is

modulated by a balance between slowly adapting receptors (SARs), which normally evoke smooth muscle

relaxation, and rapidly adapting receptors (RARs) and pulmonary C fibres, which normally promote cough

and bronchoconstriction22. In newborn infants, the coupling between smooth muscle and SARs is influenced

by the mechanical properties of the cartilage of the large airways, elastic recoil of the lung-chest wall system,as well as the relatively reduced number of RARs. Any given increase in airway resistance may reflect

differing combinations of airway smooth muscle shortening and relative thickness of the airway wall. Thus,

airway inflammation will increase and potentiate the effect of smooth muscle shortening on airway

resistance, although the overall effect may vary with airway generation, being counteracted in the small

airways by elastic lung recoil. Thus, in infants, the balance between central airway compliance, peripheral

airway resistance and lung recoil may differ from that of older children and adults, resulting in different

patterns of airflow limitation. Adverse influences during this period may operate by diminishing airway or

alveolar growth and hence maximal lung and airway size attained24, by increasing airway responsiveness to

allergens, viruses and air pollutants in later childhood or adult life19, by impairing collagen and elastin

development in the lung parenchyma with secondary effects on airway function, or by some combination of

all three. Finally, the agerelated decline in respiratory function which commences in mid adult life may be

more rapid or reach a critical threshold at an earlier age in those in whom maximal fetal and early childhood

growth potential has not been achieved24. Reduced forced expiratory flows have been identified in young

school age children in whom pneumonia, bronchitis and other lower respiratory

illnesses have been documented prospectively25'26.

However, the relevance of these objective changes in early childhood to lung health in adult life

remains unclear. The most recent follow up of the 1946 British birth cohort suggests that early

childhood respiratory illness remains a significant risk factor for respiratory symptoms in later

life27. While ventilatory function in early childhood appears to be normal in asthmatic children who

have outgrown their wheezing by early adult life, it is impaired in those whose symptoms persist to

adult life, particularly if wheezing commenced before 7 years of age28. Further deterioration in

spirometry throughout adolescence appears to be related to both persistence and duration of

symptoms. Shaheen and Barker have highlighted the need for more information about patterns of early lung growth, their determinants and their relation to subsequent morbidity and respiratory



function2. Cohort studies in which respiratory function has been assessed before the onset of any

LRI are required to resolve the question of whether reduced expiratory flow precedes or follows the

initial episode of LRI in early childhood, and to clarify whether persistence and duration of

symptoms are associated with subsequent impaired development of airway and lung function28-29.

Infant respiratory function testing in anepidemiological context—a challengeMeasurements of infant respiratory function were first described almost a century ago, but it is only

in the last 20 years that they have been more widely applied in the clinical setting 30-31. Although

automated methods and equipment are becoming increasingly available, most tests of infant

respiratory function remain time-consuming and require considerable patience, training and, in all

except the youngest infants, prior sedation. Thus, even though the last decade has witnessed their

increasing application to cohorts of healthy infants, the size of these studies has been limited by the

resources needed which are proportionately greater than comparable studies in older children and

adults, the low parental participation rate (18-30%) and the usual 2-3 h total duration of an

individual test. Furthermore, as this is a rapidly expanding field, tests have been applied before

standard methods of measurement, analysis and expression of results have been agreed31-32 andfrequently before their validity in relation to underlying functional pathology of the airways was

fully appreciated33-34. This complicates interpretation of, and comparison between, studies. With

these caveats, what studies have been initiated and what have they shown?

Studies of premorbid infant respiratory function andsubsequent respiratory illnessAt the time of writing, 5 cohort studies have been initiated which have included measurements of either

baseline infant respiratory function, airway responsiveness (AR) or both, made shortly after birth and prior

to any LRI.

The Harrow cohort study The earliest, and largest, of these studies was that reported by Colley in 197635, who measured crying

ventilatory capacity soon after birth and again at one year in 543 awake and spontaneously crying infants

with a simple face mask and flow measuring device. Neither crying peak inspiratory or expiratory flow, nor

their derived volume indices differed significantly between those who subsequently developed pneumonia or

bronchitis by their fifth birthday and those who did not. However, crying peak expiratory flow was

significantly reduced at 1 year of age in infants with pneumonia or bronchitis of onset during the

first year of life. This study had sufficient power to detect a 7.5% difference in respiratory function

and Colley concluded that either the test was insufficiently sensitive or that premorbid respiratory

function was not impaired.

The Tucson children's respiratory cohort study In 1988, Martinez and colleagues reported that diminished premorbid lung function predisposed to

wheezing LRI in the first year of life36. An index of tidal breathing — the time to peak tidal

expiratory flow as a proportion of total expiratory time (JFTEFÊ)37—was measured at 8 weeks of

age and prior to an LRI in 124 infants (58 boys), representing 33% of those eligible for testing and

10% of the entire cohort of 1246 children. Premorbid ?PTEF:Ê w a s significantly diminished in the 11

boys, but not the 13 girls, who subsequently developed wheezing during LRIs in the first year of

life. In contrast, girls, but not boys, with subsequent wheezing LRI were found to have significantly

diminished initial functional residual capacity, as assessed by helium dilution (FRCHE)- Respiratory

conductance (G^— the reciprocal of resistance), measured using the forced oscillation technique in

47 (38%) infants, was diminished in 11 with at least one wheezing LRI. Maximal flow at FRC

(VmaxFRC), obtained in 109 (88%) infants by partial forced expiration using the rapid thoraco-abdominal compression (RTC) technique, was only significantly reduced in the 8 infants with more



than one episode of wheezing LRI in the first year. Odds ratios comparing the risk of developing

subsequent wheezing in infants in the lower tercile with that of those in the upper two terciles were

significantly increased for ?PTEF:£E m boys, for FRCHE m girls a nd for Gre for both sexes.

In a subsequent report38, infants with an initial wheezing LRI in the first year of life who also

experienced one or more subsequent episodes of LRI during their second and third years, had

significantly lower levels of premorbid ^PTEFÊ? VmaxFRC a nd Gra compared with those who hadbeen free of LRI throughout their first 3 years. It was calculated that 69% and 48% of all cases of

LRI recurring in the second and third years and preceded by a first wheezing LRI in the first year

were attributable to an initially diminished tprvt'-H or V^^RC respectively. Although 25 infants

(20% of the original sample of 124) were lost to follow up, biased conclusions were considered

unlikely since these infants had, if anything, higher levels of premorbid respiratory function than

those remaining free of LRI throughout. It was concluded that a reduction in the functional diameter

of the peripheral airways predisposed infants to develop signs of bronchial obstruction during viral

respiratory infections in early life. A recent report39 has examined the influence of early airway function on subsequent patterns of childhood

respiratory illness and, specifically, the risk of a diagnosis of childhood asthma by the age of 6, based on the

entire cohort of 1246 infants, of whom 826 (66%) had complete follow up data at 3 and 6 years of age, nowincluding the 124 infants with premorbid respiratory function. V^xFRC was measured from voluntary

maximalexpiratory flow manoeuvres in 526 children at 6 years of age. At the age of 6, children were

classified into one of four groups, according to the patterns of LRI observed in the first 6 years: (i) those

without prior wheezing LRI, comprising 51.5% of the cohort; (ii) those with transient early wheezing (i.e.

one or more wheezing LRIs before the 3rd birthday; 19.9%); (iii) those with late onset wheezing (i.e. after

the 3rd year of life; 15.0%); and (iv) those with persistent wheezing (i.e. wheezing LRI with onset in the first

3 years and recurring thereafter; 13.7%). Children with transient early wheezing had significantly lower

levels of Vn^FRC in infancy than those without prior or with late-onset wheezing, and continued to do so at

6 years of age. In contrast, those with persistent wheezing had similar values of Vn^FRC in infancy to those

without prior wheezing, but the lowest levels of all groups at 6 years of age. The associations with premorbid

tidal breathing parameters, respiratory conductance and FRCHE were not reported. Transient early wheezers

were also more likely to have mothers who smoked, whereas persistent wheezers were more likely to havemothers with asthma and elevated serum IgE at 9 months and 6 years of age. It was concluded that the

majority of infants with wheezing do not have increased risks for asthma or allergies later in life; that

transient early wheezing may reflect smaller airways in those exposed to maternal tobacco smoke; and that

children with reduced airway function at 6 years of age include those whose earlier symptoms have

apparently resolved. This raises many intriguing questions, including whether the diminished early airway

function associated with transient early wheezing LRI in early childhood is a risk factor for chronic

obstructive airway disease in adult life, and whether the longer duration of symptoms as experienced by

those with persistent wheezing may directly impair airway development and hence function28'29. The extent

to which other similar cohort studies can follow in the trail blazed by the Tucson cohort and confirm these

findings is thus of great interest, not least because Arizona appears to be an ecological niche as far as viral

and allergen exposures are concerned29. Preliminary analysis of data from our own cohort study in inner

London indicates that diminished premorbid airway function precedes wheezing LRI in infants living in anurban environment40.

The Perth longitudinal infant cohort study This third cohort, the Perth longitudinal infant cohort, consists of a group of 252 infants, enrolled during

pregnancy, in whom respiratory function and AR were assessed at 1, 6 and 12 months of age41. AR was

present at 4 weeks postnatal age in 58 of 63 infants42, being significantly increased in those with a family

history of asthma or parental smoking during pregnancy, who did not however differ with respect to initial

levels of V^FRC. On review of initial respiratory function for the entire cohort43, 19(8%; 12 boys) were

found to have marked flow limitation during tidal expiration, a pattern strongly suggestive of underlying

airway disease. All of these infants had a positive history of either parental asthma, parental atopy and/

or parental smoking, and, in comparison with infants from the same cohort without any of these risk factors,

or with those matched for sex, age and family history, significantly reduced VmaxFRC at 1 and 6 , but not 12,

months of age. Univariate analyses reported a significantly increased odds of developing physician

diagnosed asthma by the age of 2 in infants with a family history of asthma as well as in those with tidal flow



limitation prior to any LRI. However, 7 of the 19 flow-limited infants (37%) were lost to follow up.

Premorbid respiratory function was similar in 17 infants diagnosed with acute bronchiolitis during the first 2

years of life and the rest of the cohort44. Subsequently, a preliminary analysis of the first 22 children

followed to 6 years of age reported that the level of AR at 1 month is significantly associated with the level

observed at 6 years, and with physician diagnosis of asthma and eczema at 6 years45.

The maternal-infant lung study of the East Boston Neighbourhood Health Centre The initial objective of this fourth cohort study was to examine the influence of maternal smoking during

pregnancy on infant respiratory function measured shortly after birth46. Between March 1986 and October

1992, 1000 women were enrolled during pregnancy, of whom 848 continued to participate, with 159 (17.7%)

consenting to respiratory function testing in their infant. Maternal smoking during and after pregnancy has

been documented prospectively and in detail, together with biochemical validation of maternal report based

on maternal urinary cotinine. Mean VmaxFRC, but not FRCHE, was diminished when measured

before 50 weeks postconceptional age in infants whose mothers smoked continuously during pregnancy

compared to those whose mothers had never smoked, and was reported to be independent of postnatal

smoking exposure46. Maternal smoking during pregnancy was less prevalent (22%) among Hispanic

mothers, who comprised 40% of those consenting to infant respiratory function tests but 26% of

those declining, compared to white mothers (58%). Among never smoking mothers, VmaxFRCtended to be lower in infants of Hispanic compared to those of white origin46. Overall, 59 (61%)

had experienced a wheezing LRI before their first birthday, almost double that reported from

Tucson and these infants were more likely to have mothers who smoked during pregnancy, to be

white and to have mothers who reported wheezing themselves47. There were no significant

differences in premorbid FRCHE or VmaxFRC between those with subsequent LRI and those with

none, although girls whose mothers smoked and who developed LRI during the first year tended to

have diminished VmaxFRC. As only 5 Hispanic mothers were smokers, confounding by ethnic group

may have occurred. However, diminished Vn^FRC was also found in 6 infants with subsequent LRI

out of 20 born to white non-smoking mothers. It was concluded that level of lung function before 6

months of age was an important determinant of subsequent wheezing LRI before the first birthday

and was most pronounced in girls. The effect of maternal smoking during pregnancy on respiratory function during the first 18 months of life was examined in 159 infants in whom respiratory

function tests were obtained by October 199248. The prevalence of maternal smoking during

pregnancy was 50% among 66 white, and 16% among 88 Hispanic, mothers of infants with

respiratory function testing. Rates of growth of FRCHE, VQ^FRC and VmaxFRC/FRC were

diminished in infants whose mothers smoked during pregnancy, with no significant effect of

postnatal smoking after adjustment for smoking during pregnancy. While V'maxFRC was diminished

in both girls and boys whose mothers smoked during pregnancy, the percentage reduction, relative

to unexposed girls and boys respectively, was greatest in girls and most marked at birth, with a

tendency to become less marked by 1 year of age. It was concluded that maternal smoking in

pregnancy had a persistent but waning effect on lung and airway growth during the first 18 months

of life and that this was most marked in girls. It was suggested that the female airways had become

masculinised, with the normal higher flows expected in female infants reduced to levels found in

males of a comparable age, mediated perhaps by the presence of cortisone and

dehydroepiandosterone (a testosterone precursor) in the ammotic fluid of smoking mothers.



The Hammersmith Hospital cohort study

This consists of infants with at least one atopic parent recruited neonatally from among those born

at the Hammersmith Hospital and a related maternity unit49'50 and has focused on neonatal AR as a risk factor for subsequent wheezing LRI. AR was measured at 1, 6 and 12 months of age. The effect of LRI

during the first 6 months of life on lung function and AR at 6 months was initially reported49. Vn^FRC, but

not AR, was significantly lower at 6 months in those with prior LRI, and the reduction was of similarmagnitude in both boys and girls. It was suggested that LRI symptoms are associated with reduced airway

caliber rather than bronchial responsiveness. However, different conclusions were reached when recruitment

was completed, and premorbid respiratory function was assessed in relation to parental report of wheezing

LRI in the first year of life50. Overall 24 of 73 (33%) of infants had wheezed by 1 year. As will be discussed

later, the most striking finding from this study related to the gender differences in baseline VmaxFRC. With

respect to boys within each group, median Vn^FRC was more than twice as high among girls with, and

almost 50% higher in those without, subsequent LRI. In addition, girls with subsequent wheezing LRI had

significantly increased AR, and infants of mothers with asthma significantly lower initial values of VmaxFRC.

Tidal breathing parameters were similar in those with and without subsequent LRI, and this was independent of gender.

Which exposures are relevant?Paneth has highlighted the recurring problems of lack of singularity of exposure and uncertainty about the

timing of exposure which bedevil studies assessing the impact of influences operating in fetal and early life

on the development of adult disorders51. Exposure to many environmental and social influences during fetal

and early postnatal life continues throughout later childhood and adult life and the potentially adverse effects

of earlier exposures may be difficult to disentangle from those occurring later. In addition, the effects

observed are not always a direct consequence of the exposure being examined since some exposures serve as

a marker of other exposures, operating both before and after birth, which may not have been measured or

may not be measurable directly. What do the data available from these 5 cohort studies show with respect to

factors which may 'programme' the respiratory system at a critical period of growth and development, andare

the findings consistent between studies? lender Gender differences in the prevalence of asthma and LRI52-53

in infantlung function54 and lung growth55 have been observed previously.

Males are more prone to develop severe LRI than girls and in later childhood have relatively

smaller airway calibre for a given lung volume than girls. Gender differences in premorbid

respiratory function in those developing subsequent LRI were initially reported from the Tucson

cohort36, with boys having reduced airway caliber and girls lower lung volumes. However,

subsequent analyses of this cohort38-39 reported no significant effect of gender on either initial

respiratory function or its association with subsequent LRI. While boys in the Boston cohort had

significantly lower initial VmaxFRC than girls46, subsequent analyses suggested that reductions in

forced flow were most marked in girls with subsequent LRI and exposure to maternal smoking in

utero*7 . Relative to the unexposed, smokingexposed infant girls in the Hammersmith cohort had

greater decrements in VmaxFRC throughout the first year of life than boys48, which may reflect

genetic or developmental gender differences in airway function and hence different mechanisms for

wheezing LRI between boys and girls50. In contrast, no significant gender differences in respiratory

function or AR at 1 month were reported from the Perth cohort42. Gender differences were not

required in the Harrow cohort35.

Fetal nutrition Small sample size and exclusion of preterm infants and those with perinatal problems have

precluded a detailed examination of hypotheses regarding fetal nutrition. Individualised birth

centiles and improved methods for assessing intra-uterine growth retardation are required, if the

extent of the latter is to be recognised and its effects assessed56. Although data on postnatal infant

body weight and crown-heel length have been collected for all cohorts, these are usually used tostandardize respiratory variables, rather than as an explanatory variable. With the exception of the

Hammersmith cohort, in which mean body weight of boys with subsequent LRI was 260 g greater



at 1 month compared to those with none50, birthweight and anthropometric measurements have not

been specifically examined in relation to respiratory function and later outcome.

Maternal smoking during pregnancy and postnatally

Evidence regarding the effects of maternal smoking during pregnancy derives largely from the

Boston study, which included biochemical validation of maternal report of smoking. Small samplesize, reliance on retrospective self-reporting without validation and confounding of preandpostnatal

exposure limit the interpretation of the reported effects of smoking during pregnancy from the other

studies. Among infants with mothers who smoked continuously during pregnancy in the Boston

cohort, there was a striking reduction in VnuxFRC measured shortly after birth46 and, in girls only,

in the subsequent increase in airway function and lung volume with age48. In the Tucson cohort,

maternal smoking was the only risk factor common to both those with transient early and persistent

wheezing at 6 years of age, suggesting that exposure to tobacco smoke in early life may have effects

other than those on airway growth in utero, for example on bronchial responsiveness39. In the Perth

study, AR was increased, but VmaxFRC similar, at 1 month of age in infants with one or both

parents smoking during pregnancy, compared to those with neither parent smoking42. Although AR

did not differ in infants with, and those without, a history of maternal smoking in the Hammersmithcohortso, only 16 (22%) of the cohort were thus exposed49. Further studies are required to confirm

the findings of the Boston cohort and to examine the effect of smoking on the development of

bronchial responsiveness in infancy and early childhood. While smoking cessation even in late

pregnancy may be associated with improved respiratory outcome60, the problem of distinguishing

the effects of exposure before and after pregnancy remains.

Family history of asthma and/or atopy In the absence of genetic markers, a familial or genetic atopic tendency has been assessed by

parental report of asthma or atopic conditions in first and second degree relatives, by measurement

of serum IgE in infant and/or parents, by skin tests to common allergens or by measurement of

airway responsiveness in one or more parents. Detailed pedigrees have been collected for thefamilies enrolled in the Perth cohort in whom genetic studies are proposed 41. While in this cohort

significant relationships were observed between parental asthma and level of infant AR at 1 month42

and between maternal serum and cord blood IgE, parental and infant AR were not significantly

related42, although preliminary analyses indicate that AR at 1 month may be predictive of asthma

and eczema at 6 years. At 6 years of age, maternal asthma and elevated serum IgE at 9 months and

6 years, but not cord blood IgE, were significant risk factors for persistent wheezing in the Tucson

cohort39. Infants of mothers with asthma had lower initial Vn^FRC in the Hammersmith cohort; this

effect was greater in boys than girls50. However, the influence of birth order, social class, and

burden of viral infections in early life — all potential mediators of early programming of the thymic

TH-2 lymphocytes — in relation to subsequent atopic disorders has not been examined in detail,

primarily due to the limitations imposed by small sample size.

Ethnic group and socio-economic status Although not strictly exposures, both ethnic group and socioeconomic status are significantly

related to respiratory illness in early childhood. The influence of ethnic group on the risk of

respiratory illness at all ages in life has been reviewed recently57. Ethnic differences in respiratory

illnesses and function in later childhood and adult life are well recognised52. Infants of Chinese and

African or Caribbean origin have lower total resistance and reduced nasal resistance58. However,

VmaxFRC, which is thought to be independent of nasal resistance, tends to be lower in infants with

Hispanic rather than white non-smoking mothers46 and, among healthy preterm infants, lower in

Caucasian infants compared to those of African or Caribbean origin59

. There may also be ethnicdifferences in risk factor and outcome prevalence: in the Boston studies, American women of

Hispanic origin were less likely to smoke and to have infants with subsequent LRI than their white

counterparts. Unfortunately other cohorts have either not examined the influence of ethnic group, or



have excluded those of minority ethnic status at the stage of enrolment or data analysis. Socio-

economic status has not been directly examined in these cohorts.

Respiratory function tests in infancy: what do they measure?In interpreting the findings of these studies, the sensitivity and specificity of the tests used as

measures of airway function is relevant. It has been suggested that VmaxFRC and fpj-Ep may be themost sensitive measures of bronchial responsiveness or induced airway obstruction available33, but

the 'best test' to assess changes in baseline airway function has yet to determined. Adler and

colleagues61 have concluded that £PTEF:Ê is less useful than VmaxFRC in investigating groups with

and without LRI and without clinically significant underlying disease. This may be due to the wider

intra-subject variability observed when such measurements are made within the first months of

life,62 as well as the fact that tpj^-.t^ probably reflects alterations in the control of breathing in

response to underlying mechanics, rather than airway size34, ^PTEFÊ and end expiratory airway

conductance are not significantly associated in healthy infants aged 3 months, in whom the pattern

of expiratory flow may reflect dynamic maintenance of FRC as much as a response to airway

calibre62'63. Similarly, £PTEF:Ê n a s been shown to be less sensitive than VmaxFRC in assessing

airway obstruction34'45-64'65. Clarke and Silverman have emphasised the problems of interpretingwhat is essentially a ratio and have suggested that tp^f may be of greater value34. Although RR,

measured with the single breath technique (SBT), and plethysmographic measurements of end-

expiratory airway resistance (Raw) have been found to be significantly higher in infants with prior

wheeze, the former technique may be of limited value in epidemiological studies as it has a high

failure rate66. Furthermore, the SBT technique does not detect dynamic changes in resistance

throughout the respiratory cycle66, and since it also includes chest wall and lung tissue components

of resistance, is rather a blunt tool for detecting subtle changes in airway

calibre.

There is increasing evidence to suggest that, despite the wide intersubject variability reported,

Vn^JRC is a sensitive indicator of small airway function43-48'61. However, inadequately high jacket

inflation pressures may result in failure to achieve flow limitation in infants without substantial

airway disease67. The most reliable and useful measurements in older children are derived from

flow-volume curves commencing at total lung capacity and a promising new technique to generate

and assess forced expiration from raised lung volume in infants has been described recently68.

While tests of airway responsiveness, assessed from inhaled agents such as histamine and

methachohne or from inhalation of cold air, have been successfully applied in a range of clinical

and epidemiological settings, they can only be reliably compared between children of a similar age

and size as it is difficult to ensure standardisation of the dose delivered to the lungs at differing

ages69. This may limit their application to longitudinal studies.

An additional consideration for future epidemiological studies is the optimal age at which these

tests should be performed. While assessment of premorbid respiratory function necessitates earlymeasurements before any LRI, within and between subject variation in tidal breathing and other

parameters may be very high within the first few months of life 62. Differences between cohorts in

the timing of premorbid tests may explain some of the different conclusions reached. Finally, the

feasibility of conducting large population-based studies will be determined by parental acceptance

of infant respiratory function tests, which usually require sedation of a healthy infant and the

relative inconvenience of attending a specialist laboratory. Like tests of crying vital capacity before

them, surface body measurements to estimate tidal breathing parameters in unsedated infants have

not realised their initial promise70 and a non-invasive yet sensitive test of airway function has yet to

be developed.



ConclusionIn the last two decades, 5 cohort studies have been initiated to examine the association of infant

respiratory function with genetic and environmental risk factors, as well as subsequent LRI in early

childhood. While the current complexity of respiratory function tests in this age group precludes a

sufficient sample size and study power to examine more complex issues, information from these

studies has provided an exciting adjunct to that available from the larger cohort studies. All providesome evidence to support the hypothesis that alterations in airway function or lung development are

present shortly after birth in infants who are at increased risk of wheezing LRI during the preschool

years and of impaired airway function at 5-6 years of age. Further research is required, in larger

samples of infants, to explore some of the environmental71-72, genetic and immunological

mechanisms which may mediate these observed associations. However, the feasibility of

sufficiently large population-based studies depends in part on the development of less invasive and

adequately sensitive tests of airway function appropriate for use in multicentre studies. A

multidisciphnary approach involving epidemiologic, physiologic, immunologic and genetic

expertise will be critical if further insights into the childhood origins of later respiratory disease are

to be gained73.

AcknowledgementsCarol Dezateux is supported by the Wellcome Trust and Janet Stocks by Portex Ltd. This work was

carried out while CD was a visiting associate professor in preventive medicine at the University of

Wisconsin, Madison, USA.

Documents

Lung Development and Early Origins of Childhood