American Journal of Respiratory and Critical Care Medicine

Rationale: Better understanding of evolution of lung function in infants with cystic fibrosis (CF) and its association with pulmonary inflammation and infection is crucial in informing both early intervention studies aimed at limiting lung damage and the role of lung function as outcomes in such studies.

Objectives: To describe longitudinal change in lung function in infants with CF and its association with pulmonary infection and inflammation.

Methods: Infants diagnosed after newborn screening or clinical presentation were recruited prospectively. FVC, forced expiratory volume in 0.5 seconds (FEV0.5), and forced expiratory flows at 75% of exhaled vital capacity (FEF75) were measured using the raised-volume technique, and z-scores were calculated from published reference equations. Pulmonary infection and inflammation were measured in bronchoalveolar lavage within 48 hours of lung function testing.

Measurements and Main Results: Thirty-seven infants had at least two successful repeat lung function measurements. Mean (SD) z-scores for FVC were −0.8 (1.0), −0.9 (1.1), and −1.7 (1.2) when measured at the first visit, 1-year visit, or 2-year visit, respectively. Mean (SD) z-scores for FEV0.5 were −1.4 (1.2), −2.4 (1.1), and −4.3 (1.6), respectively. In those infants in whom free neutrophil elastase was detected, FVC z-scores were 0.81 lower (P = 0.003), and FEV0.5 z-scores 0.96 lower (P = 0.001), respectively. Significantly greater decline in FEV0.5 z-scores occurred in those infected with Staphylococcus aureus (P = 0.018) or Pseudomonas aeruginosa (P = 0.021).

Conclusions: In infants with CF, pulmonary inflammation is associated with lower lung function, whereas pulmonary infection is associated with a greater rate of decline in lung function. Strategies targeting pulmonary inflammation and infection are required to prevent early decline in lung function in infants with CF.

Scientific Knowledge on the Subject

Lung function is reduced in healthy infants with CF diagnosed by newborn screening compared with healthy control subjects. There are no published studies on the evolution of lung function in such infants diagnosed by newborn screening or on the role of pulmonary infection and inflammation in the process.

What This Study Adds to the Field

We demonstrate a decline in lung function over time in clinically well infants with CF that is associated with neutrophilic airway inflammation and pulmonary infection with Staphylococcus aureus and Pseudomonas aeruginosa detected by surveillance bronchoalveolar lavage. The deterioration in lung function during infancy occurs despite early diagnosis, management in a specialized center, and good nutritional status.

Early cystic fibrosis (CF) lung disease is characterized by reduced lung function, bacterial infection, airway inflammation, and structural changes as detected by computed tomography (15). Infants with CF diagnosed by clinical presentation have diminished lung function and continue to have reduced lung function relative to their peers during the preschool years, suggesting that early life events may have long-term consequences in CF (6, 7).

Newborn screening for CF has been widely adopted and results in improved nutrition in comparison to the prescreening era, but the impact on survival and lung function is unclear (14, 69). Early diagnosis provides an opportunity to introduce early nutritional support, microbiological surveillance of pulmonary infection, cohort segregation, airway clearance, and strategic use of antibiotics to manage infection (10). Despite the availability of such interventions, we previously reported that lung function appeared normal in infants diagnosed with CF after detection by newborn screening who were younger than 6 months, whereas older children had reduced lung function (11). In that predominantly cross-sectional study, we were unable to demonstrate an association between diminished lung function and either pulmonary infection or inflammation, but we did confirm decline in lung function in a subset of infants with repeated measurements. Other studies of lung function and pulmonary inflammation have either been inconclusive (12, 13) or point to a possible association between inflammation and lower lung function (14, 15). All these studies are limited by cross-sectional design. Therefore, the aim of this study was to investigate the evolution of lung function over time in infants with CF after detection by newborn screening and to investigate the association with pulmonary infection and inflammation.

We hypothesized that lung function declines over time in infants with CF diagnosed by newborn screening and that the decline in lung function is associated with pulmonary infection and inflammation.

Some of the results of this study have been previously reported in the form of an abstract (16).


This study was part of an early disease surveillance program conducted by the Royal Children's Hospital, Melbourne between May 2006 and April 2010 (11). Infants with CF were detected by newborn screening with an elevated immunoreactive trypsinogen (> 99th centile) and cystic fibrosis transmembrane regulator gene mutation analysis, with confirmation of the diagnosis by sweat chloride test as per guidelines (17). Infants diagnosed after a clinical presentation or prenatal diagnosis were also included in the study. Infants were excluded if they were born less than 36 weeks of gestation or had coexisting heart, lung, metabolic, bone, or neuromuscular disease.

We included all infants at the study inception who were less than 2 years of age. Infants were tested either within the first 6 months of life after the diagnosis, at 1 year of age, or around their second birthday. The infants were free of respiratory illness for at least 3 weeks before lung function testing. The schedule of assessments in the early surveillance program is shown in Figure E1 in the online supplement.

Clinical Data

At each visit a questionnaire-based history of current and past respiratory symptoms, antibiotic use, prior admissions, and all available microbiological results were recorded. Genotype was also recorded. A clinical examination was performed before lung function testing (N.P. and B.L.). Weight and crown–heel length were measured, and standard deviation scores (z-scores) for each measurement were calculated based on international growth reference data (18, 19).

Infant Lung Function Testing

Infant lung function was measured in a single, specialized infant lung function laboratory by the raised-volume rapid thoracoabdominal compression technique. The generic equipment used along with the data acquisition software has been described in earlier publications (11, 20, 21). The infants were sedated using chloral hydrate (60–100 mg/kg) and closely monitored according to the institution's sedation policy. The raised-volume technique was performed according to the joint guidelines of the American Thoracic Society/European Respiratory Society (ATS/ERS) (22). Repeated synchronized positive pressure inflation breaths were used to inflate the lungs to an inflation pressure of 30 cm H2O. An inflatable jacket was used to rapidly compress the thorax and abdomen, producing forced expiratory flow volume curves. A transmission pressure of at least 20 cm H2O at the airway opening was ensured according to the ATS/ERS guidelines. The jacket pressure was progressively increased until there was no further increase in forced expiratory flows; this indicating flow limitation had been achieved. The flow volume curves were carefully analyzed according to the ATS/ERS guidelines (22). The criteria for acceptable flow volume curves included acceptable transmission pressures at airway opening, a rapid rise to peak flow, expiration to residual volume, absence of glottic closure, and absence of flow transients. The lung function outcomes reported here are FVC, forced expiratory volume in the first 0.5 seconds (FEV0.5), and forced expiratory flow with 75% vital capacity expired (FEF75). Values are reported from the best curve defined as a technically acceptable curve with the greatest sum of FVC and FEV0.5, with at least one other curve within 10% of these values. The curves were analyzed by three of the investigators (N.P., B.L., and B.S.), with quality control provided by other investigators (S.R. and G.H.).

Bronchoalveolar Lavage

Bronchoalveolar lavage (BAL) was performed within 24 to 48 hours after the lung function measurements via a flexible videobronchoscope under general anesthesia induced and maintained by sevoflurane. The method for performing and processing the BAL is described in detail in previous publications (4, 11) and is also detailed in the online supplement. In short, the first lavage from the right middle lobe and the lingula were studied for infection defined as bacterial growth 104 or more colony-forming units per ml or the detection of respiratory viruses using immunofluorescence and/or viral tissue culture. The second and third lavages from the right middle lobe were tested for markers of inflammation. We measured total cell count, neutrophil count, and percentage of total cells, neutrophil elastase (NE), interleukin-1β, and IL-8.

Statistical Analysis

Lung function was reported as z-scores created from the raw lung function values using the reference equations published by Jones and colleagues (23). To investigate the change of lung function over time, marginal models of lung function z-scores were fitted using general estimating equations (GEE), adjusted for sex, age, and the interaction of sex and age. Length was not simultaneously included in the models due to the high correlation between length and age (sample correlation, 0.96). Results were similar when length, rather than age, was adjusted for.

The effect of genotype, mode of diagnosis, antistaphylococcal antibiotic prophylaxis, and current inflammation was investigated by adding covariates one at a time to the marginal models above, adjusted for age, sex, and their interaction. All measures of inflammation were log transformed and analyzed as continuous variables in relation to lung function. For the analysis, values for 50% of the lowest limits of detection were substituted where pulmonary inflammation was undetected in BAL. After back transformation of these data, we have reported the change in lung function associated with a doubling of each of the inflammatory markers. To investigate the effect of Pseudomonas aeruginosa or Staphylococcus aureus infection on lung function and also to investigate whether this infection is associated with a subsequent decline in lung function, an interaction between infection and time since first infection detected was included in the model. Change in weight and length z-scores over time were examined using a GEE linear model adjusted for sex. Robust standard errors were calculated in all GEE models. Estimated differences in lung function z-scores, with 95% confidence intervals (CIs), and Wald test P values are presented. All analyses were performed using Stata 10.1 (Stata Corporation, College Station, TX).

The study was approved by the Ethics in Human Research Committee of the Royal Children's Hospital, Melbourne (EHRC no. 25054).

Repeat lung function measurements were attempted in 45 eligible infants and successful measurements obtained from 37 infants (22 boys and 15 girls). Fifteen children received the first and 1-year assessment, 9 received the 1-year and 2-year assessments, 6 received the first and 2-year assessments, and 7 received all three assessments described in Figure E1. The mean age of diagnosis was 4 weeks. Twenty-eight infants were diagnosed after detection by the newborn screening program. Five infants presented with meconium ileus and two infants were diagnosed by antenatal screening. One infant presented with duodenal atresia, and another infant was diagnosed after clinical presentation of failure to thrive at 11.6 weeks of age. Twenty-three (62%) were homozygous and 13 (35%) were heterozygous for the Phe508del mutation. Only two infants were pancreatic sufficient. There was a history of maternal smoking during pregnancy in four infants (10.8%). The most common reason for an unsuccessful lung function test was inadequate sedation (five sessions). Two sessions were unsuccessful because of equipment failure, whereas in another session the data were technically unacceptable for analysis. The anthropometric details and lung function measurements of the 37 infants are described in Table 1. Respiratory symptoms of cough, wheezing, or any breathing difficulty were reported by parents on 35% of assessments. There was a statistically significant increase in weight and height z-scores with time, which was independent of sex. For every 10 weeks of increment in age, weight increased by 0.10 z-scores (95% CI, 0.05–0.15; P < 0.001) and length increased by 0.08 z-scores (95% CI, 0.03–0.14; P = 0.004). These are shown in Figure 1.


1st Visit (N = 28)1-yr Visit (N = 31)2-yr Visit (N = 22)
Age. wk19.8 (15.5, 23.4)55.5 (51.5, 60.1)103.9 (102.5, 108.1)
Weight, kg6.5 (6.1, 6.7)9.7 (9.0, 10.4)12.7 (11.5, 13.5)
Length, cm64.2 (62.0, 66.4)77.5 (75.3, 79.0)89.8 (87.5, 90.7)
FVC, ml217.1 (189.0, 254.6)398.5 (352.7, 464.2)549.8 (499.7, 670.2)
FEV0.5, ml169.9 (138.6, 197.0)248.7 (221.2, 294.8)283.5 (233.8, 341.1)
FEF75, ml/s173.4 (131.3, 215.7)244.7 (211.4, 307.8)266.4 (205.5, 343.8)
Weight z-score−0.9 (0.7)−0.2 (0.8)0.0 (1.0)
Length z-score0.1 (1.0)0.7 (1.2)0.9 (0.8)
FVC z-score−0.8 (1.0)−0.9 (1.1)−1.7 (1.2)
FEV0.5 z-score−1.4 (1.2)−2.4 (1.1)−4.3 (1.6)
FEF75 z-score−1.3 (1.1)−1.6 (1.0)−2.6 (1.0)

Definition of abbreviations: FEF75 = forced expiratory flow at 75% of exhaled vital capacity; FEV0.5 = forced expiratory volume in 0.5 seconds.

Raw scores are expressed as median (1st, 3rd quartile); z-scores are summarized as mean (SD).

Markers of airway inflammation, such as NE, IL-8, IL-1β, total cell count, and neutrophil count, are reported in Table 2. Airway pathogens were detected in 37/84 (44%) of the BAL samples, as detailed in Table E1. S. aureus was isolated in BAL from nine infants during the course of the study. P. aeruginosa was isolated from five infants at some stage. P. aeruginosa persisted in one infant, despite an aggressive eradication regimen (see online supplement) instituted after its isolation. Respiratory viruses were detected on four occasions (Table E1).


1st Visit (N = 28)1-yr Visit (N = 31)2-yr Visit (N = 22)
NE present12.0 (42.9)8.0 (29.6)5.0 (27.8)
NE, ng/ml*100 (100, 330)100 (100, 270)100 (100, 270)
IL-8 concentration, ng/ml425 (195, 1630)650 (420, 1,730)1,125 (270, 1,800)
IL-1β concentration, pg/ml10 (10, 49)10 (10, 41)10 (10, 36)
TCC, ×103/ml263 (147, 440)287 (127, 410)240 (152, 457)
NC, ×103/ml77 (20, 144)26 (9, 63)47 (8, 98)
Neutrophil, %29.3 (7.6, 54.7)9.1 (19.6, 21.9)19.6 (3.3, 40.8)

Definition of abbreviations: NC = neutrophil count; NE = neutrophil elastase; TCC = total cell count.

NE represented as frequency (%); the rest of markers of inflammation are shown as median (1st, 3rd quartile).

*Lower limit of detection of the assay is 200 ng/ml.

Lower limit of detection is 20 pg/ml.

Lung function data are expressed both as absolute values and z-scores in Table 1. In longitudinal analysis, lung function declined over time in this group of infants, with the most obvious decline observed in FEV0.5 compared with FVC and FEF75. The mean (SD) FEV0.5 z-scores at the first, first-year, and second-year visits were −1.4 (1.2), −2.4 (1.1), and −4.3 (1.6), respectively. The change in lung function over time for each individual infant is shown in Figure 2. Although FEF75 was lower in boys, lung function declined more rapidly over time in girls. FVC declined on average by 0.21 z-scores per 10 weeks in girls compared with 0.05 z-scores in boys. FEF75 was estimated to decline by 0.20 z-score in girls every 10 weeks compared with 0.10 z-score in boys (see Table 3).


CovariateDifference95% CIP ValueDifference95% CIP ValueDifference95% CIP Value
Male sex0.35(−0.19, 0.88)0.2010.25(−0.42, 0.91)0.4670.57(0.02, 1.12)0.042
Age (per 10 wk)
 Girls−0.21(−0.29, −0.12)<0.001−0.38(−0.51, −0.26)<0.001−0.20(−0.27, −0.13)<0.001
 Boys−0.05(−0.14, 0.04)0.275−0.31(−0.42, −0.20)<0.001−0.10(−0.17, −0.03)0.004
P-value for interaction0.0110.3970.046

Definition of abbreviations: CI = confidence interval; FEF75 = forced expiratory flow at 75% of exhaled vital capacity; FEV0.5 = forced expiratory volume in 0.5 seconds.

The association between lung function and pulmonary inflammation is shown in Table 4. The presence of detectable NE was associated with significantly worse lung function (Table 4). On average, FVC was 0.81 z-scores lower in those in whom NE could be detected (P = 0.003) and each doubling in the levels of NE was associated with a 0.55 reduction in FVC z-score. Similar associations were observed for FEV0.5 but not FEF75. There was no demonstrable association between other inflammatory markers or mode of diagnosis and measurements of lung function (Table 4).


CovariateDifference95% CIP ValueDifference95% CIP ValueDifference95% CIP Value
Mode of diagnosis0.34(−0.14, 0.82)0.1650.01(−0.67, 0.70)0.9660.21(−0.41, 0.82)0.509
Gene−0.16(−0.70, 0.38)0.557−0.42(−1.12, 0.27)0.234−0.57(−1.10, −0.04)0.036
NE binary−0.81(−1.35, −0.28)0.003−0.96(−1.51, −0.42)0.0010.02(−0.48, 0.52)0.943
NE (for a doubling)−0.55(−0.82, −0.27)<0.001−0.46(−0.77, −0.16)0.003−0.14(−0.48, 0.20)0.412
NC (for a doubling)−0.24(−0.55, 0.07)0.1340.03(−0.21, 0.27)0.801−0.04(−0.28, 0.19)0.716
IL-8 (for a doubling)−0.25(−0.58, 0.08)0.131−0.11(−0.45, 0.23)0.5320.03(−0.24, 0.29)0.834
IL-1β (for a doubling)−0.02(−0.45, 0.41)0.9380.15(−0.38, 0.69)0.5750.18(−0.21, 0.57)0.378
TCC (for a doubling)−0.34(−0.72, 0.03)0.071−0.06(−0.42, 0.30)0.742−0.18(−0.51, 0.16)0.305

Definition of abbreviations: CI = confidence interval; FEF75 = forced expiratory flow at 75% of exhaled vital capacity; FEV0.5 = forced expiratory volume in 0.5 seconds; NC = neutrophil count; NE = neutrophil elastase; TCC = total cell count. Statistically significant differences are shown in bold font.

All models adjusted for age, sex, and their interaction with the characteristics entered singly.

There was no evidence that infection with either S. aureus or P. aeruginosa was associated with lower lung function at the time of detection (Table 5), but both these organisms resulted in more rapid decline in FEV0.5 after detection. Infection with S. aureus was associated with a mean (95% CI) greater decline in FEV0.5 of −0.25 z-score (−0.45 to −0.04; P = 0.018) for each 10 weeks after its isolation in BAL and P. aeruginosa with a greater decline in FEV0.5 z-score of −0.38 (−0.71 to −0.06; P = 0.021), respectively, compared with infants in whom these infections were not detected (Table 5). Neither CF genotype nor antistaphylococcal antibiotics were associated with lung function (data not shown). Our findings were unchanged when analysis was restricted to the 30 infants diagnosed after newborn and antenatal screening.


CovariateDifference95% CIP ValueDifference95% CIP ValueDifference95% CIP Value
Infection with Staphylococcus aureus−0.13(−0.54, 0.27)0.522−0.12(−0.59, 0.35)0.615−0.06(−0.69, 0.58)0.864
 Interaction with age (per 10 wk)−0.09(−0.21, 0.04)0.170−0.25(−0.45, −0.04)0.0180.02(−0.16, 0.20)0.862
Infection with Pseudomonas aeruginosa0.20(−0.48, 0.88)0.5640.29(−0.47, 1.06)0.4510.41(−0.08, 0.90)0.097
 Interaction with age (per 10 wk)−0.12(−0.39, 0.14)0.359−0.38(−0.71, −0.06)0.021−0.11(−0.27, 0.05)0.184

Definition of abbreviations: CI = confidence interval; FEF75 = forced expiratory flow at 75% of exhaled vital capacity; FEV0.5 = forced expiratory volume in 0.5 seconds; NC = neutrophil count; TCC = total cell count.

In this longitudinal study of infants with CF diagnosed predominantly after newborn screening, we have demonstrated that lower lung function was associated with neutrophilic airway inflammation detected in BAL. We have also shown that lower respiratory infection with either S. aureus or P. aeruginosa was associated with a greater subsequent decline in lung function during infancy. These changes were demonstrated despite nutritional status improving at each time point.

We previously reported that lung function was normal in infants with CF measured soon after diagnosis but was diminished in older infants (11). The strength of our current study lies in the fact that this is a prospective longitudinal study of early CF lung disease in infancy, where lung function has been studied in relation to pulmonary infection and inflammation detected by BAL. Most of our subjects were diagnosed by 4 weeks of age by either newborn screening or with meconium ileus. Our first measurements were within 6 months of age for most subjects. All lung function tests were performed in a single center by experienced investigators using internationally recognized, standardized techniques (22). As long as infant lung function tests are performed in specialized centers with experienced operators they can be reliable end points for clinical investigation (24).

The raised-volume technique has been shown to be as sensitive as other methods in detecting abnormal lung function in infants with CF (25, 26). Using the raised-volume technique, the London CF collaboration showed that lung function in clinically diagnosed infants (median age at diagnosis, 10 wk) was diminished shortly after diagnosis compared with healthy control subjects without CF (3). They also showed that when lung function was measured 6 months later, there was no catch-up in lung function (7). These infants were followed up at age 3 to 5 years with repeat lung function assessments using incentive spirometry. Reduced lung function in infancy tracked into the preschool years (6). The isolation of P. aeruginosa at any stage was associated with lower lung function during the preschool years (6). The infants from the London cohort were diagnosed after a clinical presentation and were significantly malnourished both at diagnosis and follow-up compared with the infants in our study. They also reported a higher prevalence of maternal smoking (27.7 vs. 10.8% in our subjects). Because we based this on maternal report alone and not on assessments of infant urinary cotinine, it is possible that we underestimated its true prevalence. Although we found no effect of maternal smoking on lung function (data not shown), the numbers are too small to merit meaningful comparisons. The London group also reported a higher rate of P. aeruginosa acquisition (22%) compared with our cohort. We found that both infection with P. aeruginosa (irrespective of successful subsequent eradication) and S. aureus were associated with greater decline in lung function. Because both these organisms can be detected in the lower respiratory tract of asymptomatic infants (4), and in the case of S. aureus is commonly found incidentally in the upper airways even in healthy children, these data lend support to the use of surveillance BAL in early CF and the need to monitor progress using lung function. Bronchoscopy with BAL appears safe in young children with CF (27).

We found that forced expiratory flows were lower in boys, a finding that replicates several previous reports (3, 2830) but is not universal (26). However, we identified a greater decline in lung function in girls compared with boys (Table 3). The numbers in our study are small, and further investigation of the association between sex differences and lung function decline is required in both healthy infants and those with CF.

Airway inflammation, especially neutrophilic inflammation, is believed to be a key pathogenic mechanism in CF lung disease (31). Whether this altered inflammation is primary or secondary is still not clear. When studying inflammation in BAL from children with CF, one of the difficulties is the paucity of data in healthy infants without CF with which to compare samples from infants with CF (32, 33). Free NE activity is indicative of the amount of NE present in the BAL that has exceeded the antiprotease binding capacity in the lung (34). This is believed to be responsible for much of the destruction of the CF airway and parenchyma. Work from our center has previously shown that in infants with CF, pulmonary inflammation is characterized by increased neutrophil counts, elevated IL-8 concentration, and free NE, and associated with airway infection (2, 35, 36). An earlier study showed the presence of inflammation in the absence of infection (37). The differences between these studies might well be due to the BAL methodology involved and the extent and regions of the lungs that were sampled. Although pulmonary inflammation in CF is considered progressive, neutrophil counts were greatest at the first visit in our study (Table 2) compared with subsequent visits. It is possible that improved nutrition during this period together with antibiotic prophylaxis resulted in decreased inflammation. We also treated asymptomatic infections aggressively (see online supplement), which may also have contributed to reduced neutrophilic inflammation. We used standardized BAL protocols based on guidelines developed by the European Respiratory Society (33, 38). Such protocols allow collaboration between centers and meaningful comparisons of data. In support of the role of infection-driven neutrophilic inflammation, the AREST CF program has reported a link between the detection of free NE and early structural lung disease detected by surveillance CT scans (4). Now we provide evidence that free NE is associated with worse lung function in infants with CF. Free NE indicates that the antiproteinase mechanisms have been overwhelmed, exposing proteins associated with the basal lamina, extracellular matrix, and cell-associated glycocalyxes to hydrolyzation.

There are some limitations of this study. We used historical published reference equations rather than recruiting healthy infants without CF. These reference equations were derived from a cross-sectional study of 155 infants aged 3 to 149 weeks (23) and have been used extensively in other studies reporting lung function in infants with and without CF (7, 39). There are currently no longitudinal reference data available for the raised-volume technique. Cross-sectional reference data used in longitudinal studies may result in either under- or overestimation of changes over time. The z-scores for FVC, FEF75, and FEV0.5 in this study were similar to those identified in prior cross-sectional studies that did recruit healthy infants (7, 40) but lower than another large multicenter study in US children with CF that used the same reference data as we did (24). When we previously calculated z-scores for FEV0.5 during the first few months of life using an inflation pressure of 20 cm H2O, we demonstrated normal FEV0.5 compared with our own healthy control subjects (11). In the current study we used an inflation pressure of 30 cm H2O as recommended (22) and identified much lower z-scores compared with the reference data. We therefore acknowledge that the actual degree of reduction and decline in lung function needs confirmation by recruiting healthy infants to future longitudinal studies. The ethics of this will be challenging given the requirement for sedation when using the raised-volume technique to measure lung function and the increased difficulty associated with repeating these tests to obtain longitudinal data. However, we do not believe that this limitation alters our important finding that pulmonary inflammation was associated with lower lung function and pulmonary infection associated with greater decline in lung function in infants with CF.

Longitudinal data suggest that those with the lowest lung function in infancy tend to maintain their position relative to their peers when lung function is assessed during the subsequent preschool years (6). However, lung function tends to be in the normal range when first measured using spirometry. It is not clear whether this is because lung function improves or because spirometry is relatively insensitive. Newer techniques, such as multiple breath inert gas washout (MBW), show that school-aged children with CF have significant ventilation inhomogeneity even if spirometry is normal, suggesting that significant functional abnormalities can be missed using spirometry (41). There are no longitudinal studies to indicate that those with reduced or declining lung function in infancy have significantly poorer clinical outcomes or worse bronchiectasis in later life. Such studies are urgently required.

While performing BAL we sampled specific areas of the lung, such as the right middle lobe and the lingula, although it is recognized that CF lung disease is heterogeneous in nature (42). It is possible that we are either under- or overestimating pulmonary inflammation when we sample only selected areas in the lung. It is likely that we can only provide a snapshot of the true evolution of pulmonary infection and inflammation given the limited number of assessments that were undertaken. Due to the small numbers of infants with lower respiratory infection and our use of semiquantitative assessment of bacterial density on BAL, we are unable to comment on the association between bacterial density and decline in lung function in this study.

The deterioration in lung function during infancy occurred despite an early diagnosis, management in a specialized center, and improving nutritional status. Although the early diagnosis of CF by newborn screening is clearly associated with nutritional benefits (8, 43), there is currently limited evidence demonstrating improvements in pulmonary outcomes. Specific strategies to preserve lung structure and function deserve urgent attention. As lung function measured by the raised-volume technique changes in response to pulmonary inflammation and infection it appears to have a role in monitoring lung disease in infancy. Further studies are required to assess this role.

This longitudinal study reveals that lung function declines over time in infants with CF. Neutrophilic airway inflammation was associated with worse lung function in infancy, whereas infection with S. aureus and P. aeruginosa was associated with a greater decline in FEV0.5. Early and aggressive surveillance of CF lung disease is warranted. New strategies that target pulmonary inflammation and infection are required to prevent early decline in lung function in infants with CF.

The authors thank the children and the parents who participated in his study. They also acknowledge the contributions of the AREST CF members.

AREST CF members: Elizabeth Balding, Luke J. Berry, Dr. Siobhain Brennan, Professor John B. Carlin, Rosemary Carzino, Dr. Anne-Marie Ebdon, Professor Nick de Klerk, Dr. Tonia Douglas, Clara Foo, Dr. Catherine L. Gangell, Luke W. Garratt, Ms Anne-Marie Gibson, A/Professor Graham L. Hall, Dr. Joanne Harrison, Dr. Anthony Kicic, Dr. Ingrid A Laing, Dr Barry Linnane, Karla M Logie, A/Professor John Massie, Dr. Lauren S. Mott, Dr. David Mullane, Dr. Conor Murray, Faith Parsons, Dr. Naveen Pillarisetti, Dr. Srinivas R. Poreddy, A/Professor Sarath C. Ranganathan, Professor Colin F. Robertson, Professor Roy Robins-Browne, A/Professor Philip J. Robinson, Billy Skoric, Dr. Barbara Sheil, Professor Peter D. Sly, Dr. Manuel Soto, Professor Stephen M. Stick, Dr. Erika N. Sutanto, Dr. John Widger, and Dr. Elizabeth Williamson.

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Correspondence and requests for reprints should be addressed to Sarath Ranganathan, M.D., Ph.D., Department of Respiratory Medicine, Royal Children's Hospital Melbourne, Flemington Road, Parkville, 3052, Australia. E-mail:

Supported by grants from the United States Cystic Fibrosis Foundation, the National Health and Medical Research Council, Australia, and the Australian Cystic Fibrosis Research Trust; and by the Royal Children's Hospital Melbourne Cystic Fibrosis Research Trust (N.P.).

* A complete list of members may be found before the beginning of the References.

Author contributions: Conception and design of study: N.P., B.L.,C.F.R., P.S., S.S., and S.R. Acquisition of data, analysis, and interpretation: N.P., B.L., B.S., G.H., and S.R. Statistical analysis of data: E.W., N.P., and S.R. Writing of manuscript: N.P., E.W., and S.R. Revision of manuscript for intellectual content and approval before submission: N.P., E.W., B.L., B.S., C.F.R., P.R., J.M., G.H., P.S., and S.S.

This article has an online supplement, which is accessible from this issue's table of contents at

Originally Published in Press as DOI: 10.1164/rccm.201011-1892OC on April 21, 2011

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