Rationale: The promise of newborn screening (NBS) for cystic fibrosis (CF) has not been fully realized, and the extent of improvement in respiratory outcomes is unclear. We hypothesized that significant lung disease was present at diagnosis.
Objectives: To determine the extent of lung disease in a geographically defined population of infants with CF diagnosed after detection by NBS.
Methods: Fifty-seven infants (median age, 3.6 mo) with CF underwent bronchoalveolar lavage and chest computed tomography (CT) using a three-slice inspiratory and expiratory protocol.
Measurements and Main Results: Despite the absence of respiratory symptoms in 48 (84.2%) of infants, a substantial proportion had lung disease with bacterial infection detected in 12 (21.1%), including Staphylococcus aureus (n = 4) and Pseudomonas aeruginosa (n = 3); neutrophilic inflammation (41. 4 × 103 cells/ml representing 18.7% of total cell count); proinflammatory cytokines, with 44 (77.2%) having detectable IL-8; and 17 (29.8%) having detectable free neutrophil elastase activity. Inflammation was increased in those with infection and respiratory symptoms; however, the majority of those infected were asymptomatic. Radiologic evidence of structural lung disease was common, with 46 (80.7%) having an abnormal CT; 11 (18.6%) had bronchial dilatation, 27 (45.0%) had bronchial wall thickening, and 40 (66.7%) had gas trapping. On multivariate analysis, free neutrophil elastase activity was associated with structural lung disease. Most children with structural lung disease had no clinically apparent lung disease.
Conclusions: These data support the need for full evaluation in infancy and argue for new treatment strategies, especially those targeting neutrophilic inflammation, if the promise of NBS for CF is to be realized.
There have been no previous population-based surveys of lung disease at diagnosis after newborn screening in infants with cystic fibrosis.
This study shows that infection, inflammation, and abnormal chest computed tomography findings are already present in a significant proportion of infants with cystic fibrosis at 3 months of age.
Lung disease may be present in infants within the first weeks of life (8–10), with abnormalities reported in lung function (10–12), pulmonary inflammation (13), and infection, including with Pseudomonas aeuginosa (11, 14, 15). The limited data available suggest that structural lung disease, as seen on chest computed tomography (CT), may be present in children as young as 10 weeks old (16–18). However, no systematic study has been conducted on the total population of infants diagnosed with CF after detection by NBS from a geographically defined region.
The pediatric CF clinics at Princess Margaret Hospital for Children (PMH), Perth, and Royal Children's Hospital (RCH), Melbourne, operate an early respiratory disease surveillance program aimed at early detection of lung disease. Children are referred to the CF clinics at PMH or RCH for diagnosis and/or assessment by the staff of the clinical genetics services responsible for the NBS program in each state. The majority of children are referred before 6 weeks of age for confirmation of diagnosis by sweat test. All children with CF detected in Western Australia are referred to PMH, and all children with CF detected in Victoria (apart from those originating from a small part of the southern metropolitan Melbourne region) are referred to RCH. Thus, the CF clinics at PMH and RCH care for a geographically defined population. The surveillance program is designed to assess children soon after diagnosis (approximately 3 mo old) and annually at times when the children are clinically stable and fit for general anesthetic. We report the results of a systematic prospective investigation of the presence of lung disease of all children diagnosed with CF within the relevant geographic regions after detection by NBS.
A more detailed description of the Methods is provided in the online supplement.
This report includes children diagnosed after detection by NBS in Western Australia and Victoria since 2005, with >95% of eligible children participating in the program. Children with equivocal sweat tests or whose diagnosis has not been confirmed were deemed ineligible. The surveillance program was approved by the ethics committee at each institution, and parents consented to each aspect separately.
Soon after diagnosis, infants had chest CT and bronchoalveolar lavage (BAL) under the same anesthetic. Details of the standard operating procedures for anesthesia, lung volume recruitment, chest CT, and BAL are provided in the online supplement. The aim was for the procedure to take place at approximately 3 months of age; however, in some children this was delayed until they attained a weight of 4 kg, and in others this was brought forward to enable microbiological assessment before commencing antibiotic therapy. BAL was performed after the CT.
Images were acquired on a Philips Brilliance 64TM (Philips Medical Systems, Eindhoven, The Netherlands) multi-slice CT scanner (Perth) and a Somatom Sensation 16 (Siemens Medical Solutions, Erlangen, Germany) (Melbourne). Three axial inspiratory (inflation pressure, 25 cm H2O) and three end-expiratory images were acquired evenly spaced above, at, and below the carina, with an exposure of 100 kV and a tube current of 100 to 200 mAs (40–80 mA) at PMH and exposure of 120 kV and a tube current of 70 mA at RCH. The maximum radiation dose was 0.28 to 0.4 mSv for combined inspiratory and expiratory scans.
Images were reported by an experienced pediatric thoracic radiologist (C.M.) blind to BAL results. Scans were read in batches, in random order, on a soft copy reporting station (Agfa ImpaxTM v. 5.2; Agfa-Gevaert, Mortsel, Belgium) using standard lung settings. Lungs were considered in six zones (upper, mid, and lower; right and left) corresponding to each axial slice. The presence of bronchial dilatation, bronchial wall thickening, and gas trapping was recorded in a binary fashion for each zone. The standard radiologic definition of bronchiectasis (bronchus to pulmonary artery diameter ratio >1 ) was used to define bronchial dilatation for the purpose of this study. Bronchial wall thickening was assessed subjectively. Gas trapping was defined as geographic foci of reduced density on the expiratory images (20) (Figure 1). The extent of each abnormality was graded by determining the proportion of each zone affected (<50% = 1; >50% = 2) and calculated by adding the scores (0,1) for each zone multiplied by the extent (1, 2) to give sums of 0 to 12 for bronchial dilatation, bronchial wall thickening, and gas trapping, respectively.
Total and differential cell counts were performed using identical protocols (11) at each center, with interoperator variability <10%. Inflammatory markers were performed in Perth to ensure consistency.
Variables were checked for normality and log-transformed before analysis where required. Data are presented as median (2–75% interval) or mean and SD as appropriate. t Tests (continuous variables) or Fisher's exact test (binary variable) were used to examine factors related to inflammation or to CT abnormalities, including respiratory symptoms, sex, presence of infection, and antibiotic prophylaxis. Ordinal logistic regression analyses were conducted to determine associations between extent of bronchial dilatation and inflammation, respiratory symptoms sex, infection, and antibiotic prophylaxis. Logistic regression was used to determine associations between the presence or absence of structural airway abnormalities and inflammation. Fisher's exact test was used to determine associations between structural abnormalities and inflammation considered as binary variables. Multivariate ordinal logistic analyses examined associations between inflammatory markers and structural abnormalities. No adjustment was made for multiple comparisons.
Fifty-seven infants (31 male infants, 54.4%) diagnosed with CF at a median age of 28 days had a chest CT and BAL performed at a median age of 3.6 months (Table 1). The mode of presentation and presence of clinically apparent disease at diagnosis are given in Table E1 (see the online supplement). At the time of assessment, 9 infants (15.8%) had respiratory symptoms, and 33 (57.9%) were receiving antistaphylococcal prophylaxis with amoxicillin clavulanate. Despite being diagnosed with CF after detection by NBS, 49 (86.0%) infants had pancreatic insufficiency and showed signs of inadequate nutrition, with a group mean body mass index (Z score) of −1.19 (25th to 75th percentile, −1.78 to −0.50).
Total Population (n = 57)
|Absent (n = 48)||Present (n = 9)||P Value||Uninfected (n = 45)||Infected (n = 12)||P Value||No (n = 24)||Yes (n = 33)||P Value|
|Age at diagnosis, days||28 (18, 36)||29 (16, 36)||27 (22, 38)||0.74||25 (19, 32)||36 (8, 48)||0.10||31 (22, 38)||22 (12, 32)||0.045|
|Age at BAL, months||3.6 (2.3, 4.9)||3.6 (3.3, 4.8)||2.8 (2.5, 4.7)||0.33||3.6 (3.0, 4.8)||3.8 (2.9, 5.1)||0.70||3.6 (3.4, 4.8)||3.6 (2.8, 4.7)||0.81|
|Total cell count, ×103/ml*||242.0 (123.0, 467.2)||225.0 (130.0, 404.2)||450.8 (314.7, 618.1)||0.57||218.2 (96.7, 430.1)||360.0 (295.7, 515.7)||0.027||225.0 (101.8, 484.4)||262.8 (167.2, 450.3)||0.38|
|Neutrophils, ×103/ml*||41.4 (17.7, 117.0)||34.4 (16.5, 81.9)||127.8 (73.4, 285.3)||0.068||31.3 (11.3, 76.3)||169.0 (72.2, 208.5)||0.001||55.0 (9.8, 126.1)||40.2 (18.8, 91.5)||0.92|
|Neutrophils, %||18.7 (9.4, 35.7)||14.5 (9.0, 27.1)||39.7 (28.3, 65.0)||0.001||13.5 (8.3, 26.1)||35.7 (25.3, 44.7)||0.027||26.3 (11.3, 38.7)||15.3 (8.3, 28.3)||0.59|
|IL-8 detectable, n (%)||44 (77.2%)||40 (83.323%)||8 (88.9%)||0.66||36 (81.8%)||11 (91.7%)||0.410||21 (87.5%)||26 (81.3%)||0.53|
|IL-8, pg/ml*||320 (150, 845)||370 (173, 785)||170 (100, 880)||0.48||260 (128, 630)||770 (420, 2,120)||0.036||475 (243, 980)||245 (125, 860)||0.55|
|NE detectable, n (%)||17 (29.8%)||12 (25.0%)||5 (55.6%)||0.073||10 (22.7%)||7 (53.9%)||0.017||10 (41.7%)||7 (21.8%)||0.11|
|NE, ng/ml*†||100 (100, 270)||100 (100, 143)||100 (100, 2,025)||0.001||100 (100, 100)||350 (100, 1,330)||0.003||100 (100, 458)||100 (100, 100)||0.085|
The BAL inflammatory profile is shown in Table 1. The majority of infants (77.2%) had detectable levels of IL-8, and 17 (29.8%) had detectable NE activity. Infants with respiratory symptoms at the time of BAL had more neutrophils and more free NE activity (Table 1) but did not have a greater likelihood of being infected (33.3 vs. 19.0%; P = 0.38). There were no differences in inflammatory load or infection status between male and female infants (data not shown).
Pulmonary infection was detected in 12 (21.1%) infants, with the most common organism being Staphylococcus aureus (n = 4), followed by Escherichia coli (n = 4) and Haemophilus influenzae (n = 2). Three infants grew P. aeruginosa. Infants infected with any organism had higher cell counts, more neutrophils, higher levels of IL-8 and more free NE activity than uninfected infants (Table 1). The inflammatory profile of infants was not different if they were on antistaphylococcal prophylaxis (Table 1); neither was the overall prevalence of pulmonary infection (5/33, 15.2% vs. 7/24, 29.2%; P = 0.32). Respiratory symptoms did not correlate with pulmonary infection (P = 0.33), with only 3 of 12 (25.0%) of infected infants being symptomatic. One infant who grew P. aeruginosa had clinically significant respiratory symptoms; the other two infants were asymptomatic. There was no relationship between nutritional status and pulmonary inflammation (Table E5).
Forty-six (80.7%) infants had an abnormal chest CT, with bronchial dilatation present on 11 (18.6%), bronchial wall thickening present on 27 (45.0%), and gas trapping present on 40 (66.7%) (Table 2). The majority of infants with abnormal scans had no respiratory symptoms at the time of CT (Table 2). There was no relationship between nutritional status and abnormal lung structure (Table E6).
Total Population (n = 57)
|Absent (n = 48)||Present (n = 9)||P Value||Uninfected (n = 45)||Infected* (n = 12)||P Value||No (n = 24)||Yes (n = 33)||P Value|
|Present, n (%)||11 (18.6)||5 (10.2)||6 (60.0)||0.003||5 (10.9)||6 (46.2)||0.004||4 (16.7)||7 (20.6)||1.00|
|Extent, median (25%, 75%)||0 (0, 0)||0 (0, 0)||1 (0, 2)||0.001||0 (0, 0)||0 (0, 1)||0.001||0 (0, 0)||0 (0, 0)||0.86|
|Bronchial wall thickening|
|Present, n (%)||27 (45.0)||20 (40.8)||7 (63.6)||0.27||20 (42.6)||7 (53.9)||0.35||13 (54.2)||14 (40.0)||0.30|
|Extent, median (25%, 75%)||0 (0, 3)||0 (0, 2)||5 (0, 6)||0.066||0 (0, 3)||1 (0, 6)||0.16||1 (0, 3)||0 (0, 3)||0.46|
|Present, n (%)||40 (66.7)||32 (65.3)||8 (72.7)||0.25||29 (61.7)||11 (84.6)||0.30||18 (75.0)||21 (60.0)||0.40|
| Extent, median (25%, 75%)||1 (0, 3)||1 (0, 3)||2 (1, 4)||0.11||1 (0, 3)||2 (1, 4)||0.29||1 (1, 4)||1 (0, 4)||0.75|
Bronchial dilatation was more likely to occur in infants with respiratory symptoms at the time of the CT (60.0 vs. 10.2%; P = 0.003) and in those with any respiratory infection (46.2 vs. 10.9%; P = 0.004) (Table 2). All infants infected with P. aeruginosa and two of the four children with S. aureus had bronchial dilatation. Treatment with antistaphylococcal prophylaxis did not influence the incidence of bronchial dilatation (20.6 vs. 16.7%) (Table 2). The absence of respiratory symptoms or pulmonary infection did not exclude the presence of bronchial dilatation (Table 2). Significant associations were seen between the presence of bronchial dilatation and cellular inflammation (total cell count and number of neutrophils) and the levels of NE and IL-8 (Table 3). Bronchial dilatation was more extensive in infants with pulmonary infection (P = 0.001; Table 2) and was associated with cellular inflammation and the presence and levels of NE (Table 3). Bronchial dilatation was more common (P = 0.019) and more extensive in female infants (data not shown; P = 0.021). On multivariate analysis, NE activity was significantly related to the presence of bronchial dilatation (P = 0.047) and to the extent of bronchial dilatation (P = 0.001).
Bronchial Wall Thickening
|Presence/ absence||Extent||Presence/ absence||Extent||Presence/ absence||Extent|
|OR* (95% CI)||P Value||OR (95% CI)||P Value||OR (95% CI)||P Value||(95% CI)||P Value||OR (95% CI)||P Value||OR (95% CI)||P Value|
|Total cell count, ×103/ml†||13.9 (1.2–165.5)||0.037||25.1 (1.7–378.3)||0.020||1.1 (0.4–3.0)||0.83||1.4 (0.6–3.6)||0.45||1.9 (0.7–5.2)||0.24||1.7 (0.7–3.9)||0.26|
|Neutrophils, ×103/ml†||17.3 (2.0–148.7)||0.009||33.8 (3.1–363.2)||0.004||1.7 (0.7–4.3)||0.23||2.2 (0.9–5.5)||0.094||1.4 (0.6–3.4)||0.41||1.6 (0.7–3.5)||0.23|
|Neutrophils, %||1.0 (0.99–1.06)||0.10||1.03 (0.99–1.06)||0.066||1.02 (0.99–1.05)||0.15||1.02 (0.99–1.04)||0.17||0.99 (0.97–1.02)||0.71||1.00 (0.98–1.02)||0.93|
|IL-8 detectable, n (%)||‡||1.0||2.1 (0.2–18.5)||0.52||‡||0.48||2.2 (0.5–9.5)||0.28||‡||1.0||0.6 (0.2–2.2)||0.47|
|IL-8, pg/ml†||3.7 (1.0–13.5)||0.047||3.3 (1.0–11.5)||0.056||1.4 (0.6–3.5)||0.47||1.7 (0.7–4.0)||0.27||1.3 (0.5–3.5)||0.58||0.9 (0.4–2.1)||0.87|
|NE detectable, n (%)||‡||0.001||16.8 (3.0–93.1)||0.001||‡||0.001||11.6 (3.6–37.3)||0.001||‡||0.005||10.1 (3.2–31.6)||0.001|
|NE, ng/ml†§||10.9 (2.5–46.7)||0.001||10.8 (3.0–38.8)||0.001||9.4 (1.7–52.3)||0.01||4.3 (1.7 –10.7)||0.002||14.4 (0.9–240.1)||0.063||3.9 (1.6–9. 9)||0.004|
The presence of bronchial wall thickening was associated with increased NE activity (Table 3) but not with any index of cellular inflammation (Table 3) or with pulmonary infection (Table 2). Bronchial wall thickening was more extensive in infants with increased NE (Table 3). There were no sex differences in the presence or extent of bronchial wall thickening (data not shown). On multivariate analysis, NE activity (P = 0.018) was significantly related to the presence of bronchial wall thickening and to the extent of bronchial wall thickening (P = 0.016).
The presence of gas trapping was associated with increased NE activity (Table 3) but not with any other index of cellular inflammation (Table 3) or with pulmonary infection (Table 2). Gas trapping was more extensive in infants with increased NE activity (Table 3). Gas trapping was more extensive in female infants (P = 0.014; data not shown). On multivariate analysis, NE activity (P = 0.001) was significantly related to the presence of gas trapping and to the extent of gas trapping (P = 0.004).
The results of the present study demonstrate that a substantial proportion of infants diagnosed with CF after detection by NBS have active pulmonary inflammation, 30% have detectable NE activity, 20% have pulmonary infection, and 80% have evidence of structural lung disease on chest CT at 3 months of age. Furthermore, although infants with respiratory symptoms are more likely to have lung disease, the majority with detectable lung disease are asymptomatic. The inflammatory marker most associated with structural lung disease was free NE activity, suggesting that new therapeutic approaches are required for preventing structural lung disease in infants with CF, including assessment of therapies, such as macrolides and intravenous antibiotics, that appear to be effective in older children.
The data from the present study may provide some explanation as to why a clear improvement in respiratory outcomes in populations with NBS has been difficult to demonstrate. In our population of infants, 21% had pulmonary infection, including four infected with S. aureus and three with P. aeruginosa; neutrophilic inflammation was common with raised neutrophil counts, and 30% had detectable levels of free NE in BAL. In addition, 80% had an abnormal chest CT, with 19% having bronchial dilatation, 45% having bronchial wall thickening, and 67% having gas trapping. These findings demonstrate that clinically significant lung disease is present very early in infants with CF in the absence of clinically apparent respiratory symptoms in the majority of infants.
There are some limitations to our study. First, we do not have comparative data from a control group of healthy 3-month-old children; there is a paucity of such data in the literature. We are aware of only one report of BAL findings in healthy children (21), in which neutrophil counts were reported from seven healthy infants with median (25%, 75%) absolute count of 32 (11.3, 46.5) × 103 cells per ml, representing 8% (4.0%, 11.5%) of the total cell count. No data are available on NE or proinflammatory cytokines; however, free NE activity is not expected in the lungs of healthy individuals (22). Thus, the levels of inflammation in the present study in uninfected children with CF are higher than expected. However, the levels of inflammation are similar to previous reports in children with CF, especially when not infected (8, 13, 14, 23, 24). In addition, we do not have chest CTs from healthy control children. Where chest CTs are performed for assessment of lung disease or for cancer staging, very different scanning protocols are used. Specifically, oncology or nonrespiratory chest CTs are performed with much higher radiation doses (in our institutions), so the resolution is very different. In addition, because airway dilatation or gas trapping are not usually the focus of the examination in other diseases, the controlled breathing maneuvers are not used, and expiratory images are not obtained. Finally, high-resolution scan protocols are generally used, and these protocols are not comparable to those used in our CF program. Another limitation of our CT data is that we have a single radiologist reporting the scans. Although a second independent report would be ideal, we were not able to achieve this. Instead, we have relied on the reports that we would receive clinically from a senior experienced thoracic radiologist.
Second, we have used a conventional microbiological diagnosis (>104 cfu/ml) to define pulmonary infection. Although we can be confident that those we define as infected are infected, it is more difficult to be certain that those we classify as uninfected are indeed free of infection. Tables E2 and E3 examine this issue in more detail by showing all bacterial counts and the associations of inflammation and structural lung disease with lower bacterial densities. The majority of children in the present study had a BAL performed in a single lobe only. Variations of infection, both the presence of and the infecting organism, have been reported in children with CF (25, 26). Although we did not see any differences in cultures in the 16 children with more than one lobe sampled (see the online supplement), we may be underestimating the true proportion of our population with pulmonary infection at diagnosis, and our data may represent a “best case” scenario.
In the present study, 33 (57.9%) of the infants were receiving anti-staphylococcal prophylaxis at the time of the BAL. These children were somewhat younger (22 vs. 31 d; P = 0.045) than those not on prophylaxis. According to clinic protocol, children with CF are given antistaphylococcal prophylaxis for the first 1 to 2 years of life; however, physician preference and consultation with the parents determines the practice in individual patients. There were no differences in cellular or cytokine profiles in the BAL between children on and children not on prophylaxis. These data need to be interpreted with caution; we were not able to determine retrospectively reasons why individual children were or were not on prophylaxis. Thus, a randomized clinical trial using BAL-based assessments of inflammation and infection needs to been performed to determine whether antistaphylococcal prophylaxis is of benefit in infants with CF.
The concept of significant lung disease early in life in CF is not new. Khan and colleagues (10) performed BAL on 16 infants (mean age, 6 mo) with CF and demonstrated increased levels of neutrophils, free NE activity, and IL-8 when compared with 11 disease-free control infants. Inflammation was present in infants without evidence of infection (n = 7) and in infants as young as 4 weeks old. Similar data have been reported by others (8, 9, 11, 13, 14, 24); however, the debate as to whether pulmonary inflammation can be a primary event or only follows infection has not been settled. The data from the present study are compatible with the notion that inflammation can be a primary event in the lungs of infants with CF. Although the level of inflammation is greater in infected infants, the levels of neutrophils, proinflammatory cytokines, and free NE activity in uninfected infants are greater than would be expected in the lungs of healthy infants. Unfortunately, our data cannot shed light on the mechanism(s) underlying inflammation in the absence of detectable infection.
Similarly, radiologic evidence of structural lung disease has been reported in children as young as 10 weeks old with CF (16–18). Long and colleagues (17), reporting data from HRCT performed in 34 children with CF (mean age, 2.4 y), demonstrated that the mean airway wall thickness and airway lumen diameter were greater than in scans from healthy control children. Davis and colleagues (16) performed HRCT in 17 children with CF (aged 2–44 mo) scheduled for bronchoscopy during respiratory exacerbations and used a modified Brody score (27) to characterize structural lung disease. Disease was greatest in the right lung; however, it is difficult to ascertain from their report whether all scans were abnormal (16). Scans were repeated after treatment with intravenous antibiotics. Using a modified Brody score, they demonstrated an improvement post treatment in the total score (18.2 pretreatment vs. 12.2 post-treatment; P < 0.01). The component subscores for bronchiectasis/bronchial dilatation and gas trapping improved, but those for mucous plugging and peribronchial thickening did not. These studies highlight that none of the current scoring systems used for assessing chest CTs is suitable for use in infants with mild, early lung disease. In the present study, we have used a binary classification (present:absent) for the three indicators of structural lung disease (bronchial dilatation, bronchial wall thickening, and gas-trapping). We have not attempted to create a total score by summing components because we do not believe that sufficient data are available to allow this to be done. Ours is the first study to describe structural changes in the lung in infants with CF soon after diagnosis by NBS. We chose to use the term “bronchial dilatation” even though the radiologic criterion used is in routine clinical practice to denote bronchiectasis. We took this stance because the term “bronchiectasis” generally implies permanent and irreversible airway damage. Longitudinal data are required from a cohort of children studied from early infancy through childhood before the implications of such early structural changes can be understood, in particular whether these early changes are predictive of bronchiectasis in later childhood.
We have recently reported that lung function measured using the raised volume rapid thoracic compression technique (RVRTC) was normal in infants with CF in the first 6 months of life but became progressively abnormal after this time (28). Some of the infants in that earlier report are also in the present study population; however, there are too few to make a formal assessment of the relationship between lung function and lung structural abnormalities. Martinez and colleagues (18) measured lung function by RVRTC in 11 of 13 clinically stable children with CF aged 8 to 33 months and reported lower FEF (Z-scores: FEF50 = −2.0; FEF75 = −1.6) and FEV values (FEV0.5 = −2.1). In addition, they reported significant negative relationships between these variables and the ratio between airway wall thickness to airway lumen (FEF50: r2 = −0.66, P < 0.002; FEF75: r2 = −0.41, P < 0.002; FEV0.5: r2 = −0.40, P < 0.002). Reports from older children show a lack of association between measurements of forced expiration and structural abnormalities on CT (29). Thus, the true relationship between radiologic indications of structural lung disease and lung function, measured with tests of forced expiration or with other lung function tests, such as the lung clearance index or forced oscillation, remains to be determined.
A major finding of the present study is the association between structural lung disease and free NE activity in the BAL. It may be surprising that the percentage of neutrophils in the BAL is only weakly associated with bronchial dilatation. There is a relation between the number of neutrophils per milliliter of BAL fluid and the percentage of neutrophils; however, the absolute number of activated neutrophils and the products they release, such as NE, are more likely to be associated with tissue damage. Neutrophil elastase is a serine protease found mainly in azurophil granules in neutrophil cytoplasm that is capable of degrading a variety of proteins, including collagen, proteoglycans, fibronectin, and elastin, in the extracellular matrix and bacterial outer membrane proteins (22). When released from activated neutrophils, NE is “inactivated” by being bound to a variety of antiproteases, including α1 antitrypsin, secretory leukocyte protease inhibitor, monocyte/neutrophil protease inhibitor, and elafin/prelafin (22, 30). The assay used in the present study measures free NE activity, the presence of which implies that the amount of NE present in the BAL has exceeded the antiprotease binding capacity in the lung. The association of free NE activity with structural lung disease in infants warrants further investigation but suggests that new therapeutic approaches are required to prevent the onset of progressive lung damage and that such approaches need to be implemented in infancy.
The comprehensive early disease surveillance program run by AREST CF has the potential to contribute to the clinical management of individual patients in our clinics. Through this program, we have identified that the median age of acquisition of pulmonary infection with P. aeruginosa is approximately 26 months of age and that this infection can be eradicated by intensive treatment in approximately 80% of children (31). In addition, our routine practice is to prescribe antistaphylococcal prophylaxis for the first 12 to 24 months of life. This would normally be stopped for children with no evidence of structural abnormality of chest CT and no evidence of pulmonary infection on BAL. Conversely, children with radiologic or BAL evidence of established lung disease will be treated more aggressively, including earlier use of intravenous antibiotics for respiratory exacerbations.
In summary, we have presented data demonstrating that a substantial proportion of infants with CF diagnosed after detection by NBS have significant pulmonary inflammation, pulmonary infection, and radiologic evidence of structural lung disease at diagnosis. Although only 30% of infants had free NE activity detectable in BAL at 3 months of age, free NE activity was most strongly associated with bronchial dilatation. Although lung disease is greater in those with clinically significant respiratory symptoms, the absence of clinically apparent lung disease cannot be taken as an indication of “normal lungs.” The optimal treatment for preventing or delaying the onset of structural lung disease remains to be determined.
The authors thank the radiology, anaesthetic, and microbiology departments of Princess Margaret Hospital for Children, Perth and the Royal Children's Hospital Melbourne for their assistance with the CT/BAL procedures. The specific contribution of Dr. Britta von Ungern-Sternberg to developing the anaesthetic protocol is acknowledged.
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