The Evolution of Airway Function in Early Childhood Following Clinical Diagnosis of Cystic Fibrosis

Sarath C. Ranganathan, Janet Stocks, Carol Dezateux, Andrew Bush, Angie Wade, Siobhan Carr, Rosemary Castle, Robert Dinwiddie, Ah-Fong Hoo, Sooky Lum, John Price, John Stroobant, Colin Wallis, and The London Collaborative Cystic Fibrosis Group
Portex Anaesthesia, Intensive Therapy and Respiratory Medicine Unit; Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health; Department of Paediatric Respiratory Medicine, Royal Brompton Hospital; Department of Child Health, Royal London Hospital; Department of Paediatric Respiratory Medicine, Great Ormond Street Hospital; Department of Child Health, Kings College Hospital; Department of Child Health, University Hospital Lewisham; and Neonatal Unit, Homerton University Hospital, London, United Kingdom

This study aimed to investigate the evolution of airway function in infants newly diagnosed with cystic fibrosis (CF). FEV0.5 was measured soon after diagnosis (median age of 28 weeks) and 6 months later in subjects with CF and on two occasions 6 months apart (median ages of 7.4 and 33.7 weeks) in healthy infants, using the raised-volume technique. Repeated measurements were successful in 34 CF and 32 healthy subjects. After adjustment for age, length, sex, and exposure to maternal smoking, mean FEV0.5 was significantly lower in infants with CF both shortly after diagnosis and at the second test, with no significant difference in rate of increase in FEV0.5 with growth between the two groups. When compared with published reference data, FEV0.5 was reduced by an average of two z scores on both test occasions in those with CF, with 72% of individuals having an FEV0.5 of less than 1.64 z-scores (i.e., less than the fifth percentile) on one or both test occasions. On longitudinal analysis, subjects with CF experienced a mean (95% confidence interval) reduction in FEV0.5 of 20% (11, 28). Airway function is diminished soon after diagnosis in infants with CF and does not catch up during infancy and early childhood. These findings have important implications for early interventions in CF. Keywords: cystic fibrosis; respiratory function tests; infant; early intervention; forced expiration

diagnosis in infants with CF, even in the absence of any prior clinically recognized lower respiratory illness (6). Similarly, abnormalities of airway function were detected in 25% of those whose respiratory status was considered to be normal by a CF specialist (7). However, the natural history of these early lung function abnormalities is unclear, as few longitudinal studies exist (8). The aims of this study were to determine whether initial impairment in airway function noted in infants after a clinical diagnosis of CF persists despite treatment in specialist centers and if so whether this is independent of somatic growth impairment when compared both with repeated measurements made in a group of healthy infants without CF and with recently published cross-sectional reference data (9).

METHODS
Forty-seven infants and young children (less than 24 months) newly diagnosed with CF by sweat test and/or by positive genotype for CF mutations (10) were recruited between January 1999 and May 2001 from ve specialist centers in London as previously reported (7). Newborn screening was not available for infants who were managed in the collaborating centers for the duration of this study. Full details of methods of recruitment, eligibility criteria, and background characteristics of this cohort have been published previously (6, 7). Details of the mode of presentation before hospital admission or current or prior treatment with intravenous, inhaled, or oral antibiotics were obtained by inspection of medical records and parental report. A cough swab was taken approximately every 2 months and at each attendance for lung function tests. All past microbiological assessments were reviewed at the time of the test. Healthy infants were recruited as part of an ongoing epidemiologic study (11). Healthy infants in whom at least one prior lung function test had been performed were eligible for follow-up if less than 15 months of age. Parents of both CF and healthy subjects gave informed written consent. The study was approved by the North Thames Multicentre Research Ethics Committee and the Local Research Ethics Committees of the participating hospitals.

Cystic brosis (CF) is the most common lethal inherited disease affecting Northern European populations, with a birth prevalence of approximately 1:2,500. It is a multisystem disorder, with respiratory morbidity secondary to chronic inammation and infection being the leading cause of death. Recent survival data from both the United Kingdom and the United States indicate improving survival in successive birth cohorts (1, 2), suggesting that events in early life exert an important inuence on outcome. There has therefore been increased interest in the early natural history of CF lung disease and in interventions that might prevent or delay the progression of pulmonary disease. Recent studies have suggested that inammation in the CF lung develops very early in life, even in asymptomatic infants (35). We have reported diminished airway function soon after

Measurement of Airway Function

Both CF and healthy children were tested when well and clinically free from upper respiratory tract infections for at least 3 weeks. Measurements were made as soon as possible after diagnosis and 6 months later in those with CF and on two occasions, approximately 6 months apart, in healthy subjects. All measurements were performed by a single specialist team according to a standardized protocol as described previously (7, 11, 12). On the day of testing, subjects were weighed, and crownheel length was measured. Weight and length percentiles were calculated from standard UK growth reference data (13). Exposure to maternal smoking prenatally and postnatally was assessed from maternal report and current smoking habits conrmed by maternal salivary cotinine (14). All subjects were studied in the supine position after sedation with an oral dose of 60100 mg/kg of chloral hydrate or an equivalent dose of triclofos sodium. Full-forced expiratory maneuvers were performed using the raisedvolume rapid thoracoabdominal compression technique (7, 11, 12, 15)

(Received in original form September 30, 2003; accepted in final form January 25, 2004) Supported by the Cystic Fibrosis Trust UK, Portex Ltd., the Dunhill Medical Trust, and the Foundation for the Study of Sudden Infant Death (research at the Institute of Child Health and Great Ormond Street Hospital for Children National Health Service (NHS) Trust benefits from research and development funding received from the NHS Executive). Correspondence and requests for reprints should be addressed to Sarath Ranganathan, M.B.Ch.B., M.R.C.P., M.R.C.P.C.H., Ph.D., Portex Unit, 6th Floor, Cardiac Wing, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. E-mail: drsarath@clara.net
Am J Respir Crit Care Med Vol 169. pp 928933, 2004 Originally Published in Press as DOI: 10.1164/rccm.200309-1344OC on January 30, 2004 Internet address: www.atsjournals.org

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from which parameters of airway function similar to those obtained using spirometry in older subjects were measured. During the raised volume technique, expiration was forced from an ination pressure of 3 kPa. Maneuvers were repeated until a minimum of two (usually three) acceptable and reproducible ow-volume curves (sum of FVC and FEV0.5 being within 10% of each other) were obtained. FVC, FEV0.5, and forced expiratory ow when 75% of FVC had been expired (FEF75) were reported from the best ow-volume curve (dened as the technically acceptable maneuver with the highest sum of FVC and FEV0.5) (11, 12, 16).

Statistical Analysis
Although our group has reported FEV0.4 previously (12), currently, no reference data exist for this parameter. Therefore, we calculated FEV0.5 in this study to compare our results with published cross-sectional reference data for the raised-volume technique using similar equipment and technique (9). Thus, airway function for subjects with CF was compared directly with these reference data, using prediction equations incorporating coefcients for both age and length, in addition to the repeated measurements made in the healthy control subjects. Lung function parameters were reported in absolute terms, and z scores were calculated for FEV0.5, FVC, and FEF75 from the reference data. Values falling below 1.645 z scores (i.e., less than the 5th percentile) were considered to be unusually low (17). Multiple linear regression was used as previously described (6) to estimate the reduction in airway function in infants with CF on each of the two test occasions after accounting for differences in length, age, weight, sex, and exposure to maternal smoking. Multilevel modeling (MLWin version 1.10; Institute of Education, London, UK) was used to compare longitudinal trends in measurements after adjusting for the same factors. All parameters of airway function were log transformed before multilevel modeling. CF-length and CF-age interactions were assessed for evidence that proportionate growth in airway function differed between CF and healthy infants. Spearman correlation was used to assess whether the value of airway function expressed as a z score on the second test occasion was related to that obtained at the rst test. Paired t tests were used to assess changes in z scores between tests. Airway function at follow-up was thus assessed according to initial ranking to determine whether this position was maintained with growth (tracking).

RESULTS
Sixty-three subjects less than 24 months of age were diagnosed with CF during the study. Sixteen infants were not recruited. The reasons for this included parental refusal (n 6), ventilation for respiratory failure (n 2), adverse social circumstances (n 1), distance from laboratory too great (n 1), associated ArnoldChiari malformation (n 1), and Pierre-Robin syndrome (n 1). Four infants were recruited but failed to attend for the initial lung function test on at least two occasions. There was no difference in the background characteristics of those who were and were not recruited (data not shown). Forty-seven infants with CF were therefore studied at a median (range) of 12 (1 to 37) weeks after diagnosis. Thirty-seven were restudied after a median

(interquartile range) interval of 29 (2632) weeks. The primary mode of presentation for these infants was recurrent chest infections (n 18), failure to thrive (n 5), meconium ileus (n 10), and meconium ileus with antenatal bowel pathology (n 4). Twenty two (60%) of the infants were homozygous for the F508 mutation. Of the 10 infants who were not followed, 2 were considered too old for sedation by the time the second test was due (i.e., more than 30 months). Two had moved out of the area, and the families of six infants (13%) either declined further assessments or failed to attend for follow-up. The background details of the 37 infants who were followed are shown in Table 1. There were no important differences in the distributions of sex, genotype, maternal smoking, age, body weight or length, or lung function measurements on rst test occasion in those who were and were not successfully followed (data not shown). Twenty ve (68%) of the 37 infants with CF who were followed had been admitted to hospital for a respiratory illness on a median (range) of two (18), occasions, and 24 of them had received between one to seven courses of intravenous antibiotics (median 1) at some time before the second lung function assessment. Thirteen received intravenous antibiotics before the rst test only, eight only in the interval between the lung function tests, and three both before the rst test and between the tests. Pseudomonas aeruginosa had been identied in eight (22%) infants by the time of the rst test and in an additional eight infants by the second test (i.e., total of 43%). Other organisms identied by the second lung function assessment were Staphylococcus aureus (n 5), methicillin-resistant S. aureus (2), Escheria coli (7), klebsiella sp. (4), Enterobacter sp. (2), Streptococcus pneumoniae (2), and Aspergillus species (1). In nine (24%) infants, no organisms had been cultured by the time of the second lung function test. Thirty-three healthy control infants had lung function tests repeated after a median (interquartile range) interval of 25 weeks (2042) weeks. Twenty eight of these subjects were included in the cohort of 138 infants whose airway function, measured on a single occasion, we reported previously (7). There were no important differences in the distributions of sex, age, body weight or length, or initial lung function measurements in those that were and were not asked to return for repeat testing (data not shown). There was a parental report of wheezing associated with lower respiratory illness in two control infants before the second test, but neither required hospitalization. None had crackles or wheeze on the day of test. The background details of the healthy infants are shown in Table 1, with anthropometric details at time of tests summarized in Table 2. At the time of the second test, infants with CF were older and slightly longer but of similar weight to healthy control subjects. When corrected for age and sex, by expressing as z scores (13), it can be seen that infants

TABLE 1. BACKGROUND DETAILS OF STUDY INFANTS

Cystic Fibrosis n Male, n (%) White n (%) Maternal smoking, n (%) Mean (SD) gestational age, wk Mean (SD) birthweight, kg Mean (SD) birthweight percentile Definition of abbreviations: CF * p 0.01. 37 14 36 12 38.8 3.03 42.1 cystic fibrosis; CI (38) (97) (32) (2.2) (0.58) (34.2) confidence interval. Control Subjects 33 16 32 7 39.9 3.37 44.7 (48) (97) (21) (1.2) (0.37) (23.7) Difference: CF control (95% CI) 11% ( 0.3% ( 11% ( 1.1 ( 0.34 ( 2.6 ( 36, 13) 2, 1) 13, 37) 2.0, 0.3)* 0.57, 0.10)* 16.8, 11.6)

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TABLE 2. MEASUREMENTS OF ANTHROPOMETRY AND AIRWAY FUNCTION ON EACH TEST OCCASION

Test 1 CF Mean (SD) Age, wk* Weight, kg* Weight z score Length, cm* Length z score FVC, mL FEV0.5, mL FEF75, ml s 1 FEV0.5/FVC% FVC z score FEV0.5 z score FEF75 z score FEV0.5/FVC z score 28.4 6.66 1.78 66.3 0.73 215 178 217 83 1.9 2.1 1.0 0.01 (16.643.0) (4.908.12) (1.42) (60.171.9) (1.6) (81) (65) (100) (10) (1.4) (1.8) (1.7) (1.2) Healthy Mean (SD) 7.4 4.82 0.11 57.5 0.37 162 144 210 91 0.33 0.18 0.04 0.25 (5.78.9) (4.455.61) (1.1) (55.360.1) (1.0) (60) (51) (87) (5) (1.3) (1.5) (1.3) (0.53) Difference: CF Healthy (95% CI) 13.3, 25.6 0.67, 2.45 2.2, 1.2 4.8, 11.4 1.7, 0.5 22 ( 44, 0.4) 30 ( 50, 9) 53 ( 97, 8) 4 ( 8, 0)|| 1.57 ( 2.2, 0.9) 1.6 ( 2.7, 1.1) 1.42 ( 1.7, 0.28) 0.26 ( 0.70, 0.20) CF Mean (SD) 59.0 8.90 0.97 75.1 0.18 365 267 305 74 1.5 2.0 1.0 0.49 (48.369.0) (8.1110.7) (1.4) (72.580.1) (1.5) (93) (64)** (126) (13) (1.3) (1.6) (1.7) (1.8) Test 2 Healthy Mean (SD) 33.7 8.72 0.44 71.4 1.1 367 299 389 83 0.37 0.13 0.23 0.51 (28.150.1) (8.189.13) (1.0) (70.076.1) (1.0) (84) (56) (109) (7) (1.3) (1.3) (1.0) (0.74) Difference: CF Healthy (95% CI) 13.1, 27.6 0.40, 1.05 1.8, 1.0 0.9, 4.9 1.9, 0.7 37* ( 71, 51 ( 77, 89 ( 147, 8 ( 13, 1.1 ( 1.8, 1.9 ( 2.5, 1.2 ( 1.9, 1.0 ( 1.7,

1) 25) 31) 3)|| 0.5) 1.1) 0.56) 0.31)

Definition of abbreviations: CF cystic fibrosis; CI confidence interval; FEF75 Data are expressed as mean (SD) except * median (interquartile range). p 0.05. p 0.01. p 0.001. Mean difference adjusted for length, sex and exposure to maternal smoking. || Mean difference adjusted for age, sex, and exposure to maternal smoking. ** n 34. n 32. n 31. Freeman and colleagues (13). Jones and colleagues (9).

forced expiratory flow when 75% of FVC had been expired.

with CF were signicantly lighter and shorter than the healthy control subjects on both test occasions. All infants had been free of symptoms of upper respiratory tract infection for at least 3 weeks on the day of test. However, crackles or wheeze were still identied on auscultation in eight (22%) infants with CF on at least one test occasion. Wheeze was present in ve infants with CF at the rst test. Four subjects with CF had wheeze at the second test, all of whom had been wheezy on the rst occasion.
Airway Function

Paired measurements of FEV0.5 were obtained in 32 of the 33 healthy infants and young children and in 34 of 37 subjects with CF. FVC and FEF75 were not reported in two of the subjects with CF in whom FEV0.5 was available because of early inspiration before residual volume had been attained. The association of airway function with length according to disease status for FVC, FEV0.5, and FEF75 is shown in Figure 1. FEV0.5 and FEF75 were signicantly diminished in male subjects (by 14% and 28%, respectively), and there was a 26% reduction in FEF75 among infants and young children exposed to maternal smoking (data not shown). These parameters were therefore included in the model when comparing CF with healthy subjects on each test occasion. The adjusted mean (95% condence interval) difference in airway function in infants and young children with CF assessed cross-sectionally on each test occasion after accounting for signicant factors (length, sex, and exposure to maternal smoking) by using multiple linear regression is shown in Table 2. FVC, FEV0.5, and FEF75 were signicantly diminished on both test occasions in those with CF when adjusted for such factors. FEV0.5/FVC was strongly dependent on age rather than on length. It was not signicantly reduced at the rst test in those with CF; however, a small but signicant reduction of 8% was identied at the time of the second test.

Figure 2 shows the airway function of healthy children and those with CF on both test occasions in relationship to the published normal data of Jones and colleagues (9). When expressed as z scores, all parameters of lung function, except FEV0.5/FVC at the rst test, were signicantly lower among those with CF than both published normal values and those for the healthy infants and young children in this study. Among infants with CF, 14 (41%) had an FEV0.5 that was below 1.64 z scores on both test occasions (compared with only 6% of healthy subjects). Of 16 infants with CF in whom the z score for FEV0.5 was 1.96 or less (i.e., less than the 2.5 percentile) on the rst occasion, 10 also had an abnormally low z score at the second test. Z scores were reduced similarly for FVC and FEF75 (Table 2). Despite considerable within-subject variability in the rate of increase of airway function in relationship to somatic growth between the tests, especially among those with CF (Figure 1), there was demonstrable tracking between all parameters of airway function when differences in body size and growth were accounted for. Spearman correlations between airway function measured on the rst and second test occasion were 0.55, 0.66, and 0.80 for FVC, FEV0.5, and FEF75, respectively (p 0.001 for all), indicating a signicant correlation of ranking of airway function between the two test occasions. Mean z scores for FEV0.5 in healthy subjects were similar to predicted values on both test occasions, with no signicant change in these z scores between occasions (p 0.83) (Table 2). These data suggest that the ranking of lung function and an individuals z score are maintained when repeat measurements of airway function using the raised-volume technique are made during the rst 2 years of life. Mean z scores among those with CF also remained unchanged over the 6-month period, being 2.0 and 2.2 on the rst and second occasions, respectively (95% condence interval of difference between tests, 0.8, 0.4; p 0.50). There was no signicant change within subjects in z score for FVC, FEF75, or FEV0.5/ FVC between tests in either healthy subjects or those with CF.

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Figure 1. Association of (A ) FVC, (B ) FEV0.5, and (C ) forced expiratory flow when 75% of FVC had been expired (FEF75) with length. The dashed and solid lines indicate airway function of healthy infants and infants with cystic fibrosis (CF), respectively.

On multilevel (i.e., longitudinal) modeling, subjects with CF experienced an average (95% condence interval) reduction of 21% (12, 29), 20% (11, 28), and 30% (16, 42) in FVC, FEV0.5, and FEF75, respectively, compared with healthy subjects. Although absolute differences were thus greater for older and larger subjects with CF (e.g., a mean adjusted reduction in FEV0.5 of 51 ml at the second test compared with 30 ml at the rst), the proportionate difference (20%) was similar at each test. There was no signicant difference between groups with respect to the relative rate of increase in any parameter of airway function between tests (data not shown), with FVC, FEV0.5, and FEF75 increasing by a mean (95% condence interval) of 5.9% (5.2, 6.5), 5.8% (4.5, 7.0), and 4.0% (3.0, 4.6), respectively, per centimeter of growth in length after adjustment for age, sex, and smoking in both healthy infants and those with CF. The age at diagnosis, mode of presentation, isolation of P. aeruginosa at any stage before either the rst or second tests, cough on the day of test, history of hospitalization, and genotype did not appear to inuence airway function on either test occasion or the magnitude of change between tests in those with CF. However, the mean z score for FEV0.5 was lower for the ve infants who were wheezy at the rst test ( 4.6 vs. 1.8 in those

with and without wheeze respectively, p 0.06) and for four of these ve infants who were noted to be wheezy again at the second test ( 4.2 vs. 1.7, p 0.02). There was no difference in the change in FEV0.5 z score between tests in those subjects with CF who did or did not have evidence of wheeze on the day of test (p 0.7).

DISCUSSION
We have reported previously that airway function, as measured by the raised-volume technique, is diminished soon after clinical diagnosis in infants with CF (6, 7). In this follow-up study performed 6 months after clinical diagnosis and management in specialist centers, this diminution in airway function persisted, reecting the fact that airway function increased at a similar but not greater rate in infants and young children with CF compared with healthy subjects; in other words, there was no catch-up growth in lung function. This was evident in comparison to both the healthy control group and previously published reference data. This nding is consistent with previous reports of reduced airway function in infants with CF early in the course of disease (6, 7). There was strong evidence of tracking of airway function in both healthy subjects and those with CF; that is, those with

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Figure 2. Association of FEV0.5 with length for healthy subjects (open square, occasion one; closed square, occasion two) and infants with CF (closed inverted triangles, occasion one; closed triangles, occasion two) in this study and that of the cross-sectional reference population of Jones and colleagues (9) (open circles).

lowest lung function initially tended to maintain this position with growth. To our knowledge, this is the rst study to use the raisedvolume technique to perform repeated measurements of airway function in healthy infants and young children and those with CF. Longitudinal studies of airway function that have been reported (18, 19) used techniques that are now considered less discriminative than the raised-volume technique for identifying diminished airway function in infants with CF (7) and did not recruit a healthy control group prospectively. Hence, it is somewhat difcult to relate these results to those from previous studies (8). Although comparison of our results with cross-sectional published reference data (9) provided additional evidence that in CF airway function failed to improve during infancy and early childhood, comparing measurements obtained in subjects with CF directly with those measured longitudinally in a healthy population of infants using identical methods and equipment remains a more powerful approach. The infants with CF recruited into this study were typical of those followed at the ve collaborating centers. Twenty-two percent had evidence of P. aeruginosa infection by the rst test and 43% by the second test at median ages of 28 and 59 weeks, respectively. Sixty-ve percent had received intravenous antibiotics at some point before the second test, and evidence for signicant proteinenergy malnutrition was present at diagnosis. These factors suggest that our cohort had relatively severe disease and may not be representative of those diagnosed by neonatal screening or following clinical diagnosis with milder disease at other centers. Repeating such a study in a cohort after a diagnosis made by neonatal screening and before the onset of clinical disease would improve our understanding of the early pathophysiology of CF. A number of aspects of study design merit discussion. The interval between tests was selected for practical reasons. Although a shorter interval might have permitted more than two measurements to be made before the age limit for infant lung

function tests was exceeded, this might also have precluded identication of changes associated with growth and treatment between tests. In contrast, a longer interval might have increased the likelihood of demonstrating change in airway function but would have also limited the number of infants in whom tests could be repeated. Selection of suitable healthy control subjects posed problems as matching for age or crownheel length would have resulted in the control group being longer or younger, respectively, as many infants with CF are growth retarded and have reduced length for age. Although there appeared to have been some catch-up growth in those with CF, a similar trend was noted among healthy control subjects, particularly with respect to length. This suggests that published growth charts may be underestimating body size in healthy infants (and potentially underestimating any growth retardation among those with disease) and emphasizes the importance of a prospective control group. Although the healthy subjects were younger on average than those with CF, their lengths, which accounted for the highest proportion of the variance in lung function between infants, were broadly similar. However, the differences in age range between healthy infants and those with CF in this study could potentially confound interpretation of the results, particularly with respect to rate of change. For example, developmental changes in lung maturation and growth might not be linearly related to body size even if airway function is. For this reason, we also calculated z scores for the infants with CF by comparing measurements of airway function with published reference data for healthy subjects whose ages spanned the range of our entire cohort. Our healthy infants had airway function similar to that predicted from the reference population, but z scores were signicantly lower on each test occasion in those with CF (Figure 2) after length, age, and sex were accounted for when calculating the z scores. There was no signicant change in z score between tests for individuals with CF for any of the parameters of airway function measured in this study. This pattern of reduction in z scores of our CF cohort on both test occasions in relationship to the reference population provides further evidence that airway function does not catch up during infancy and early childhood. The primary cause of morbidity and mortality in patients with CF is progressive obstructive lung disease associated with infection and an intense neutrophilic inammation. Inammation has been identied in infants as young as 4 weeks of age using bronchoalveolar lavage (35, 20, 21). Inammation could cause airway obstruction as a result of airway wall thickening, airway wall destruction leading to increased airway wall compliance, increased airway tone caused by increased smooth muscle mass or caused by attenuation of the airwayparenchymal tetherings, or obstruction secondary to intraluminal mucus. In our centers, bronchoalveolar lavage is rarely undertaken to identify pulmonary inammation in asymptomatic infants with CF, and thus, we are unable to comment on the association between inammation and diminished lung function in this cohort of infants. However, in a recent study, an inverse correlation was demonstrated between either infection or inammation and specic respiratory system compliance, and a positive correlation demonstrated with hyperination in children with CF of mean age 25 months, suggesting that infection and inammation impact on lung function early in CF (22). In our study, FEV0.5/FVC was reduced at the second test in infants and young children with CF compared with the healthy control subjects and could be considered as evidence that airway obstruction is present. However, interpretation of changes in FEV0.5/FVC during the rst year of life is notoriously difcult because of the negative age dependency of this parameter, making it difcult to distinguish effects of disease from those of growth and development (12). The longer-term implications of early diminution in airway

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7. Ranganathan SC, Bush A, Dezateux C, Carr SB, Hoo AF, Lum S, Madge S, Price J, Stroobant J, Wade A, et al. Relative ability of full and partial forced expiratory maneuvers to identify diminished airway function in infants with cystic brosis. Am J Respir Crit Care Med 2002;166:1350 1357. 8. Gappa M, Ranganathan SC, Stocks J. Lung function testing in infants with cystic brosis: Lessons from the past and future directions. Pediatr Pulmonol 2001;32:228245. 9. Jones M, Castile R, Davis S, Kisling J, Filbrun D, Flucke R, Goldstein A, Emsley C, Ambrosius W, Tepper RS. Forced expiratory ows and volumes in infants. Am J Respir Crit Care Med 2000;161:353359. 10. Rosenstein BJ, Cutting GR. The diagnosis of cystic brosis: a consensus statement: Cystic Fibrosis Foundation Consensus Panel. J Pediatr 1998; 132:589595. 11. Lum S, Hoo AF, Dezateux C, Goetz I, Wade A, DeRooy L, Costeloe K, Stocks J. The association between birthweight, sex, and airway function in infants of nonsmoking mothers. Am J Respir Crit Care Med 2001;164:20782084. 12. Ranganathan SC, Hoo AF, Lum SY, Goetz I, Castle RA, Stocks J. Exploring the relationship between forced maximal ow at functional residual capacity and parameters of forced expiration from raised lung volume in healthy infants. Pediatr Pulmonol 2002;33:419428. 13. Freeman JV, Cole TJ, Chinn S, Jones PRM, White EM, Preece MA. Cross sectional stature and weight reference curves for the UK, 1990. Arch Dis Child 1995;73:1724. 14. Jarvis MJ, Tunstall-Pedoe H, Feyerabend C, Vesey C, Saloojee Y. Comparison of tests used to distinguish smokers from nonsmokers. Am J Public Health 1987;77:14351438. 15. Lum S, Hoo AF, Stocks J. Effect of airway ination pressure on forced expiratory maneuvers from raised lung volume in infants. Pediatr Pulmonol 2002;33:130134. 16. American Thoracic Society. Standardization of spirometry 1994 Update. Am J Respir Crit Care Med 1995;152:11071136. 17. Jones MH, Howard J, Davis S, Kisling J, Tepper RS. Sensitivity of spirometric measurements to detect airway obstruction in infants. Am J Respir Crit Care Med 2003;167:12831286. 18. Beardsmore CS, Bar-Yishay E, Maayan C, Yahav Y, Katznelson D, Godfrey S. Lung function in infants with cystic brosis. Thorax 1988; 43:545551. 19. Tepper RS, Montgomery GL, Ackerman V, Eigen H. Longitudinal evaluation of pulmonary function in infants and very young children with cystic brosis. Pediatr Pulmonol 1993;16:96100. ` 20. Armstrong DS, Grimwood K, Carlin JB, Carzino R, Gutierrez JP, Hull J, Olinsky A, Phelan EM, Robertson CF, Phelan PD. Lower airway inammation in infants and young children with cystic brosis. Am J Respir Crit Care Med 1997;156:11971204. 21. Muhlebach MS, Stewart PW, Leigh MW, Noah TL. Quantitation of inammatory responses to bacteria in young cystic brosis and control patients. Am J Respir Crit Care Med 1999;160:186191. 22. Dakin CJ, Numa AH, Wang H, Morton JR, Vertzyas CC, Henry RL. Inammation, infection, and pulmonary function in infants and young children with cystic brosis. Am J Respir Crit Care Med 2002;165:904910. 23. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ, Asthma and wheezing in the rst six years of life. N Engl J Med 1995;332:133138. 24. Young S, Arnott J, OKeeffe PT, Le Souef PN, Landau LI. The associa tion between early life lung function and wheezing during the rst 2 years of life. Eur Respir J 2000;15:151157. 25. Turner SW, Palmer LJ, Rye PJ, Gibson NA, Judge PK, Young S, Landau LI, Le Souef PN. Infants with ow limitation at 4 weeks: outcome at 6 and 11 years. Am J Respir Crit Care Med 2002;165:12941298. 26. Dezateux C, Stocks J, Wade AM, Dundas I, Fletcher ME. Airway function at one year: association with premorbid airway function, wheezing, and maternal smoking. Thorax 2001;56:680686. 27. FitzSimmons SC. The changing epidemiology of cystic brosis. J Pediatr 1993;122:19.

function in those with CF are unclear as longitudinal studies are lacking. Although there are few longitudinal studies of airway function in healthy infants, those available suggest that infants with diminished airway function shortly after birth are at an increased risk of diminished lung function and subsequent respiratory morbidity in later childhood (2326). Thus, early impairment of airway function may have long-term consequences in a disease where the majority of patients die because of pulmonary involvement (27). The ndings of our study demonstrate that despite early treatment at specialist centers, airway function does not appear to improve in a population of infants with CF, not diagnosed by newborn screening, relative to healthy infants. Early detection of presymptomatic changes in lung function, together with the ability to assess response to treatment objectively, should strengthen our ability to evaluate the effectiveness of therapeutic interventions to minimize or prevent lung damage in infants with CF during a critical period of growth and development. This in turn could increase longevity and contribute to an improved quality of life for these children. In conclusion, we have shown that airway function is diminished soon after diagnosis in infants with CF and does not catch up during infancy and early childhood despite treatment in centers specializing in the management of CF. We have been able to address important questions about the natural history of airway function in infants with CF and have highlighted the value of such measurements for future clinical research.
Conflict of Interest Statement : S.C.R. has no declared conflict of interest; J.S. has no declared conflict of interest; C.D. has no declared conflict of interest; A.B. has no declared conflict of interest; A.W. has no declared conflict of interest; S.C. has no declared conflict of interest; R.C. has no declared conflict of interest; R.D. has no declared conflict of interest; A-F.H. has no declared conflict of interest; S.L. has no declared conflict of interest; J.P. has no declared conflict of interest; J.S. has no declared conflict of interest; C.W. has no declared conflict of interest. Acknowledgment : The authors thank the families who participated in this study and Dr. Colin Feyerabend for his analysis of the cotinine samples. The members of the London Collaborative Cystic Fibrosis Group are as follows: Beryl Adler, Ian Balfour Lynn, Andy Bush, Siobhan Carr, Rosie Castle, Kate Costeloe, Sarah Davies, Charlotte Daman-Willems, Jane Davies, Carol Dezateux, Robert Dinwiddie, Jackie Francis, Iris Goetz, Ah Fong Hoo, Jane Hawdon, Sooky Lum, Su Madge, John Price, Sarath Ranganathan, Mark Rosenthal, Gary Ruiz, Janet Stocks, John Stroobant, Angie Wade, Colin Wallis, and Hilary Wyatt.

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