Bronchopulmonary Disease in Children with Cystic Fibrosis after Early or Delayed Diagnosis

Abstract

Section:

Although early diagnosis of cystic fibrosis (CF) can lead to nutritional benefits, there has been uncertainty about pulmonary outcomes. Using a randomized controlled trial with unique unblinding/surveillance, we evaluated patients with CF who received similar treatment after being assigned to an early diagnosis (screened) group or to a standard diagnosis (control) group. When the youngest patient was 7 years of age, we compared outcomes using pulmonary function data and quantitative chest radiology. In the screened group (56 patients), diagnosis was made at a younger age of 12.4 weeks, compared with the diagnosis in control group (47 control patients) at the age of 95.8 weeks, but included a significantly greater proportion of patients with ΔF508 genotypes and pancreatic insufficiency. The first chest radiograph showed significantly fewer abnormalities in the screened group; but, over time, the two groups converged, and after 10 years of age the screened patients showed worse chest X-ray scores associated with earlier acquisition of Pseudomonas aeruginosa. No differences were detected in any measure of pulmonary dysfunction, which was generally mild in each group. Although CF neonatal screening provides a potential opportunity for better pulmonary outcomes, it appears that respiratory infections and pancreatic status are the dominant factors in pulmonary prognosis.

Keywords:

cystic fibrosis; newborn; screening; pulmonary disease; Pseudomonas aeruginosa

Although cystic fibrosis (CF) generally shows characteristic signs or symptoms during infancy (1–3), diagnostic delays are common so that the median and mean ages of recognition in the United States are 0.5 and 3 years (3, 4), respectively, with the former skewed by patients with meconium ileus or a positive family history and the latter by adult patients with pancreatic sufficiency. When diagnosis was made by traditional methods that rely on suspicion and a sweat test, nearly half the patients showed severe malnutrition (3) and many were suffering from chronic respiratory disease (1, 2, 4). Early diagnosis through neonatal screening became possible after 1979 when Crossley and coworkers (5) determined that measurement of immunoreactive trypsinogen on dried blood specimens from newborns could be used to identify infants with CF. A variety of studies conducted during the past two decades have demonstrated that nutritional benefits are achievable with early diagnosis (6–11). On the other hand, pulmonary outcomes after screening have been less certain and are a source of controversy (12). Observational studies (8–11, 13), however, suggest that potentially milder bronchopulmonary disease is present in screened patients compared with those diagnosed by traditional methods. In addition, research associated with the Colorado screening program has demonstrated conclusively that CF respiratory disease with recurrent infection/inflammation often develops early during infancy (1, 2), despite histologically normal lungs at birth (14).

The Wisconsin Cystic Fibrosis Neonatal Screening Project was established in 1984 as a randomized, controlled trial to assess the benefits, risks, and costs of CF neonatal screening (15) and the epidemiology of childhood CF. Our data demonstrated nutritional benefits by Year 10 of the study (6), particularly in patients without meconium ileus (7), and randomization was therefore stopped, whereas longitudinal evaluations continued. Pulmonary outcomes, however, have proved more difficult to evaluate because CF lung disease has a variable onset in children, with multiple risk factors and problematic evaluation methods in young children. The diagnostic tools for quantitating pediatric lung disease were especially limiting when we began this randomized trial in 1985, although better methods such as high-resolution computed tomography have become available since then. In addition to these challenges, we experienced unexpected confounders when some postrandomization group imbalances emerged (7) and a subgroup of screened patients acquired Pseudomonas aeruginosa prematurely during 1985 to 1990 at an old clinic of one of Wisconsin's two CF Centers collaborating in this investigation (16). When all the children in this study reached 7 years of age and could perform adequate pulmonary function tests (PFTs), we analyzed the quantitative pulmonary outcome measures such as spirometry data and chest X-ray scores and now report important findings about the course of bronchopulmonary disease in CF as related to the age at diagnosis and other variables.

METHODS

Section:

Design of a Randomized Trial of CF Neonatal Screening

The design of the Wisconsin Cystic Fibrosis Neonatal Screening Project is described in detail elsewhere (15). In summary, we performed an assessment of the potential benefits of early diagnosis through neonatal screening in two concurrent groups of randomly identified children with CF who were managed prospectively with the same protocol. The two groups of patients with CF were selected through a 1985-to-1994 randomization process, proven statistically valid (7), in which newborns' blood specimens were assigned either to an early diagnosis (screened) group or to a standard diagnosis (control) group (15). To avoid selection bias, a unique unblinding/surveillance system (12) was used to identify all the control patients by approximately 4 years of age (7). Other methods, described in detail elsewhere (15), were also used to ensure an unbiased assessment of outcomes. A sweat chloride level of 60 mEq/L or greater at one of Wisconsin's two CF Centers was required to establish the diagnosis. This investigation was approved by the institutional review boards at the University of Wisconsin and at the Childrens' Hospital of Wisconsin. Patients included in this assessment were those in whom diagnosis was made through newborn screening and those not having meconium ileus, those randomized to the control group, with of signs or symptoms other than meconium ileus, and those with a positive family history.

Pulmonary Outcome Assessments

Patients were seen every 3 months in Madison (Center A) or Milwaukee (Center B) and assessed by an Evaluation and Treatment Protocol (15) developed in 1984 and reviewed regularly by personnel of the two CF Centers. After diagnosis, each patient was placed on similar treatment and had the same systematic evaluations performed. Designations of “screened” or “control” group were avoided to ensure that the same care would be provided irrespective of group identity. Outcome assessments included Shwachman–Kulczycki clinical scores (16); serial cultures of respiratory secretions obtained during coughing either as expectorated sputum or as oropharyngeal swabs (17); and longitudinal quantitative chest radiology (18) and PFTs when children were old enough to perform spirometry and/or body plethysomography, as described elsewhere (19). Original chest films obtained at the time of diagnosis and annually were scored (18, 20) independently and blindly by a pediatric pulmonologist and radiologist to obtain either total scores or subscores reflecting components of disease such as hyperinflation. PFTs were generally begun when children reached 4 years of age, and spirometry was obtained every 6 months. The quality of data was ensured using a new method (19) referred to as the Pediatric Alternate Spirometry System.

Statistical Analyses

The pulmonary outcomes of patients without meconium ileus were analyzed using data collected between April 1985 and 2002, including Brasfield chest X-ray (BCXR) scores (20), Wisconsin Additive chest X-ray (WCXR) scores and subscores (18) as continuous or dichotomous variables, and serial PFTs compared with reference values of Wang and coworkers (21). Sequential analyses have included three group comparisons with α levels of 0.005, 0.01, and 0.035 during the years 2000, 2001, and 2002, respectively. For the last analysis, there were 746 chest films scored and 539 PFTs. Generalized estimating equations (GEE) were used for repeated measures of radiographic scores and PFTs, adjusting for various covariates with the identity link for continuous outcomes and the logit link for dichotomous outcomes (22). A variety of GEE models was assessed, and two were found to be especially useful. Model I was a GEE model with patient group and other balanced factors, CF Center and sex as well as age. Model II was a GEE model with patient group, CF Center, sex, and age, plus genotype, pancreatic status, and indicators of P. aeruginosa infection. Model I was used because first we attempted to detect any differences in the major outcome measures (PFTs and WCXR) between the screened and the control groups. Log-rank tests were used for comparing time to P. aeruginosa acquisition between groups. χ² tests of homogeneity were used for discrete variables, and t tests were used for continuous variables at individual time points (23).

RESULTS

Section:

Age at Diagnosis and Clinical Characteristics

Table 1

TABLE 1. Characteristics of the enrolled patients with cystic fibrosis
		Screened patients, n (%)	Control Subjects, n (%)	p Value
Number of patients	Total = 103	56	47
Center	Madison (A)	28 (50)	26 (55)
	Milwaukee (B)	28 (50)	21 (45)	0.59
Sex	Female	21 (38)	17 (36)
	Male	35 (63)	30 (64)	0.89
Genotype	ΔF508/ΔF508	32 (57)	21 (45)
	ΔF508/Other	23 (41)	15 (32)
	Other/Other	1 (2)	11 (23)	0.003^†
Pancreatic status*	PI/PPI	49 (88)	31 (66)
	PS/PPS	5 (9)	13 (28)	0.029^†
P. aeruginosa acquisition	Yes (%)	45 (80)	28 (60)	0.021
	No (%)	11 (20)	19 (40)
Age at diagnosis, wk (mean ± SEM)^‡		12.4 ± 4.9	95.8 ± 16.7	<0.001

^*There are two patients with unknown pancreatic status in the screened group and three among the control group. Pancreatic status was generally determined by 3-day fat absorption studies, i.e., computation of dietary fat intake and quantitation of fecal fat excretion (6).

^†The disproportion in genotype and pancreatic status between the two groups has been reported previously (6).

^‡There were five false-negative patients in the screened group, as described in results.

Definition of abbreviations: P. aeruginosa = Pseudomonas aeruginosa; PI = pancreatic insufficiency; PPI = probable pancreatic insufficiency; PPS = probable pancreatic sufficiency; PS = pancreatic sufficiency.

There were another 29 patients with meconium ileus (13 in the screened group and 16 in the control group).

lists the age at diagnosis and characteristics of patients identified and enrolled from the onset (April 1985) of randomized screening to the completion (April 1998) of the unblinding and surveillance efforts. The unblinding method enabled us to identify and include in this analysis 11 control subjects (23%) in whom diagnosis was yet to be made on the basis of positive family history, signs, or symptoms of CF (7). The mean age at diagnosis based on a positive sweat test was 12.4 weeks in the screened group and 95.8 weeks in the control group (p < 0.001). Included in the screened group were four patients with false-negative screening tests in whom diagnosis was made by a positive family history or by symptoms at 7, 8, 21, and 281 weeks and another screened patient who had an initial negative sweat test following a high immunoreactive trypsinogen level but in whom diagnosis was made at 21 months because of symptoms and a subsequent positive sweat test. Similar patient distributions were found when comparing center and sex; however, apparently by chance (7), there were significant differences in genotype and pancreatic status between groups, despite randomizing 650,341 newborns (6). Specifically, as identified in previous analyses (7), we found a greater proportion of ΔF508-containing genotypes in the screened group and significantly more subjects with pancreatic sufficiency or probable pancreatic sufficiency (6) in the control group (Table 1).

Pulmonary Function Data

PFT results are shown in Figure 1

Figure 1. Comparisons of pulmonary function tests (PFTs) as related to age between the screened and control groups after the age of 7 years. (A) % Predicted FEV₁/FVC. (B) % Predicted FEV₁. (C) % Predicted mean forced expiratory flow during the middle half of the FVC (FEF_25–75). (D) Lung volumes as residual volume:total lung capacity (RV:TLC) ratio. p Values shown were obtained from generalized estimating equation (GEE) model adjusting for cystic fibrosis (CF) Center, sex, and age. The dashed lines show the lower limits of normal at 89.25, 82.4, and 67.9%, as suggested by Wang and coworkers (21). The average upper or lower 95% confidence intervals are represented by vertical bars.

Download Figure | Download Powerpoint

[More] [Minimize]

for 7- to 16-year-old patients, as related to age using all Pediatric Alternate Spirometry System “acceptable” (19) data. These results were analyzed using either % predicted values or absolute values, and the same conclusions were reached. The % predicted FEV₁/FVC results at 7 years of age for the screened and control groups were not statistically different (94 ± 1.8% vs. 95 ± 1.3%; p = 0.54). In addition, there were no differences over time between the groups in % predicted FEV₁/FVC (p = 0.32) or in % predicted FEV₁ (p = 0.18), nor were the absolute values different (e.g., FEV₁, p = 0.58). It should be pointed out, however, that the opportunity to detect differences in pulmonary function is limited by the fact that 88 and 75% of the observations in 7-year-old screened and control patients, respectively, were within the normal limits (21) at 89% predicted or greater (p = 0.30). Figure 1 shows that the PFT data demonstrated relatively mild pulmonary dysfunction in both groups throughout the evaluation. Even the most sensitive measures such as mean forced expiratory flow during the middle half of the FVC (FEF_25–75) and residual volume (RV)/total lung capacity (19, 24) showed very little deterioration with age. The comparisons of FEF_25–75 (p = 0.37) and RV/total lung capacity (p = 0.25) also revealed no group differences. In addition, using all acceptable data obtained after 4 years of age, there were no statistically significant differences in any of the PFT measures analyzed.

Chest Imaging Results at Diagnosis

Quantitative chest radiography was more useful than PFTs in assessing bronchopulmonary disease. Table 2

TABLE 2. Initial chest radiographic scores* in wisconsin cystic fibrosis neonatal screening project
	Screened Group	Control Group	p Value
Number of patients*	49	40
Age at diagnosis, wk	13.1 ± 6	107 ± 19	< 0.001
Age at first CXR, wk	14.3 ± 6	108 ± 19	< 0.001
WCXR scores (mean ± SEM)	4.2 ± 0.5	7.2 ± 1.0	0.012
WCXR scores, age adjusted^†	4.2 ± 0.7	7.0 ± 0.9	0.014
WCXR scores adjusted for age, genotype, and pancreatic status^†	4.3 ± 0.7	7.2 ± 0.9	0.013
BCXR scores^†	21.7 ± 0.3	20.6 ± 0.4	0.022
WCXR scores > 5, %	33	50	0.097
BCXR scores < 21, %	24	45	0.042

^*There are seven patients in the screened group and seven in the control group who do not have a score for chest radiograph within the first 6 months of diagnosis.

^†Because some measures may be age dependent and the mean ages of the two groups at the time of diagnosis were significantly different, the mean values were recalculated for each group after adjustment for age at the time of diagnosis. The age-adjusted means for the two groups were compared with an analysis of covariance.

Definition of abbreviations: BCXR = Brasfield chest X-ray; CXR = chest X-ray; WCXR, Wisconsin chest X-ray.

WCXR scores (18) range from 0 (normal) to 100 (most severe), whereas the corresponding BCXR scores (20) are 25 (normal) to 3 (most severe). Both methods quantitate a combination of hyperinflation measures associated with airways obstruction and indicators of infection such as peribronchial thickening and bronchiectasis. Table includes mean ± SEM.

presents the results of the initial chest radiographs available in 49 screened patients compared with 40 control patients. At an average age of 14.3 weeks compared with 108 weeks (p < 0.001), the screened group showed better WCXR and BCXR mean scores. After adjusting these data for age (or for age, genotype, and pancreatic status), the differences remain significant (Table 2). Using discriminators of potentially irreversible lung disease described elsewhere (19) (i.e., WCXR ⩾ 5 and BCXR ⩽ 21), we found that approximately half the number of the control patients had reached this stage of radiographic lesions compared with about one-fourth the number of the screened patients (Table 2). The group differences were especially prominent in the subscores that evaluate structural airways abnormalities, reflecting apparent lower respiratory tract infection, i.e., peribronchial thickening and bronchiectasis (18, 19). Thus, significant differences were found in the summation subscores of these two components (p = 0.022), whereas measures of hyperinflation were not different (p = 0.85). In other words, after a delay in diagnosis averaging just over 2 years, half of the control group had developed structural changes by chest imaging that reflect permanent bronchopulmonary abnormalities, and this is twice the proportion in the screened group.

Longitudinal Assessment of Chest Radiographic Abnormalities

Other differences emerged in two groups as they aged and were assessed with quantitative chest radiology. Examining only the data recorded after 5 years of age to avoid selection bias and a GEE Model (I) that included patient group, CF Center, sex, and age, our analysis revealed worse scores over time in the screened group (p = 0.017 for WCXR, and p = 0.041 for BCXR); however, if genotype, pancreatic status, and indicators of P. aeruginosa infection were also included (Model II), there were no significant differences (p = 0.10 for WCXR, and p = 0.20 for BXCR). Using all available quantitative chest radiology data, we found that GEE analysis with Model I revealed apparently worse scores in the screened group (p = 0.027 for WCXR, and p = 0.089 for BCXR), but again, if genotype, pancreatic status, and P. aeruginosa-culture results are added, the significant difference disappears (p = 0.081 for WXCR, and p = 0.21 for BXCR). Thus, although there were apparent differences in chest X-ray scores during the longitudinal period analyzed, it is evident that confounders clearly influence the outcomes.

Association of Bronchopulmonary Disease Progression with Respiratory Infections

Inspection of WCXR scores as related to age (Figure 2)

Figure 2. Comparison of Wisconsin chest X-ray (WCXR) scores as related to age between the screened and control groups. The p value for group comparison is 0.017 when the generalized estimating equation (GEE) Model I includes patient group, Cystic Fibrosis (CF) Center, sex, and age, whereas the p value for group comparison is 0.10 when the GEE Model II includes the covariates described previously and adjustments for the risk factors, i.e., genotype, pancreatic status, and Pseudomonas aeruginosa acquisition. The numbers of observations, i.e., patients at each age are indicated above the line for the screened group and below the line for the control group. The dashed line at WCXR = 5 shows the value that discriminates potentially irreversible, although still mild, lung disease (19). For WCXR, a high score indicates greater chest radiograph abnormalities. The average upper or lower 95% confidence intervals are represented by the vertical bars.

Download Figure | Download Powerpoint

[More] [Minimize]

reveals that before 10 years of age there was no obvious difference between the two groups, subsequently however the two groups diverged. By 12 years of age, the screened patients showed greater abnormalities compared with the control patients in WCXR (Figure 2; Table 3)

TABLE 3. Pulmonary outcomes and confounders by age and groups
Age (years)	Group (n)	% PI/PPI	% ΔF508	WCXR	BCXR
5	Screened (39)	90	97	7.6 ± 0.8	20.3 ± 0.3
	Control (29)	66	90	5.6 ± 0.7	20.9 ± 0.4
		(0.015*)	(0.40)	(0.081)	(0.26)
7	Screened (34)	91	97	10.3 ± 1.0	19.0 ± 0.4
	Control (32)	63	84	8.5 ± 0.9	19.6 ± 0.4
		(0.006)	(0.20)	(0.18)	(0.37)
10	Screened (29)	90	97	12.3 ± 1.8	18.5 ± 0.5
	Control (23)	70	78	13.3 ± 1.7	18.4 ± 0.7
		(0.068)	(0.094)	(0.69)	(0.87)
12	Screened (16)	81	100	20.7 ± 2.8	17.3 ± 0.8
	Control (20)	75	80	11.7 ± 1.9	19.5 ± 0.5
		(0.65)^†	(0.088)*	(0.009)	(0.023)
14	Screened (10)	80	100	23.71 ± 4.1	16.4 ± 1.1
	Control (12)	83	83	11.8 ± 2.3	19.5 ± 0.8
		(0.84)^†	(0.15)*	(0.015)	(0.025)

^*Numbers in parentheses are p values.

^†After age 12, significant differences in WCXR and BCXR scores between the screened group and control group were found, whereas there the differences in pancreatic status and genotype became less apparent. Thus, the significant differences in WCXR and BCXR after age 12 were mostly attributable to the P. aeruginosa infections, as demonstrated in Figure 4.

Definition of abbreviations: BCXR = Brasfield chest X-ray; PI = pancreatic insufficiency; PPI = probable pancreatic insufficiency; WCXR = Wisconsin chest X-ray.

. Further examination of subcomponents of WCXR scores reflecting structural airways changes revealed that the screened patients had significantly higher scores in measures of apparent infection (Figure 3)

Figure 3. Analysis of subcomponents of Wisconsin chest X-ray (WCXR) scores. The measure of apparent infection (i.e., sum of the scores of peribronchial thickening and bronchiectasis) from WCXR scores was compared between the two groups using generalized estimating equation (GEE) Model I (p = 0.003). The measure of airway obstruction (i.e., the score of hyperinflation) from WCXR scores was also compared between the two groups using GEE Model I (p = 0.83). The average upper or lower 95% confidence intervals are represented by the vertical bars.

Download Figure | Download Powerpoint

[More] [Minimize]

, such as peribronchial thickening and bronchiectasis (p = 0.003 with GEE Model I, and p = 0.042 with Model II). However, as shown in Figure 3, there was no difference in hyperinflation subscores (17–19) on the basis of either GEE Model I (p = 0.72) or Model II (p = 0.71). Therefore, the differences in WCXR scores were largely due to the indicators of apparent infection rather than to airway obstruction.

Differential Impact of P. aeruginosa Infection

Further evaluations of the two groups using t test are shown in Table 3 and revealed that at 12 and 14 years of age there were significant differences between the two groups in WCXR and BCXR scores. In our age-bracketed subgroup analyses, however, the differences in clinical characteristics became less significant with fewer patients. Consequently, factors such as genotype and pancreatic functional status that potentially influenced WCXR scores in the group comparisons before the age of 10 years were less influential in older patients, and the significant difference in WCXR scores after the age of 10 years appears to be mostly attributable to P. aeruginosa infection (the third factor in GEE Model II). However, the differences in WCXR scores at age 12 years were related in part to genotype status, especially ΔF508 homozygotes (p = 0.006), although this was not the case in the smaller subgroup at 14 years of age (p = 0.16). Analysis of covariance in the 36 patients at age 12 years revealed that P. aeruginosa infection explained more variability (i.e., 15%) than genotype (i.e., 6%) did on WCXR scores, although both are significant.

Figure 4

Figure 4. Comparison of Wisconsin chest X-ray (WCXR) scores as related to age among the four groups: screened group + No P. aeruginosa, screened group + P. aeruginosa, control group + No P. aeruginosa, and control group + P. aeruginosa. The p value for the overall four-group comparison is 0.006 using a generalized estimating equation (GEE) model adjusting for cystic fibrosis (CF) Center, sex, genotype, pancreatic status, and age. The p values for two-group comparisons are: 0.008 (screened + P. aeruginosa vs. screened + No P. aeruginosa), 0.19 (control group + P. aeruginosa vs. screened group + No P. aeruginosa), 0.31 (control group + No P. aeruginosa vs. screened group + No P. aeruginosa). The numbers of observations, i.e., patients at each age, are indicated above the lines for screened group + P. aeruginosa and control group + No P. aeruginosa groups and below the lines for screened + No P. aeruginosa, control group + P. aeruginosa groups. At 10 to 11 years of age, all screened patients shifted into the screened group + P. aeruginosa group. For WCXR, a higher score indicates greater abnormalities. The average upper or lower 95% confidence intervals are represented by the vertical bars.

Download Figure | Download Powerpoint

[More] [Minimize]

sheds more light on why the two groups' WCXR scores are diverging after 10 years of age. When WCXR scores were examined as a function of whether or not the patients had acquired P. aeruginosa at a younger age, we found that respiratory infections with this organism over time seem to largely explain the differences between the two groups. More specifically, it is the screened patients with P. aeruginosa infection who show increasing WCXR scores as they age. In the screened group, P. aeruginosa–positive status was clearly associated with rising WCXR scores (p = 0.008). In addition, we found that the screened group with P. aeruginosa had significantly higher scores than the control group with P. aeruginosa (p = 0.001). Further analyses revealed that screened patients had a much longer duration of P. aeruginosa infection. Specifically, patients in the screened group were culture positive for P. aeruginosa earlier than control patients (median time to culture positive status of 3.01 years, compared with 6.04 years; p = 0.007, Figure 5A)

Figure 5. Analysis of P. aeruginosa acquisition as patients age in the two groups and stratified by centers (A [Madison] or B [Milwaukee, where an old, small clinic was used from 1985 to 1989]) into four subgroups: screened group + Madison, control group + Madison, screened group + Milwaukee, and control group + Milwaukee. Time to first P. aeruginosa acquisition was compared using log-rank tests (p = 0.007 and p = 0.005, respectively).

Download Figure | Download Powerpoint

[More] [Minimize]

. Detailed analyses on subgroups of the screened and control groups revealed that it was actually the screened patients in Center B who acquired P. aeruginosa much earlier than all other subgroups (2.04 vs. 5.27, 6.00, 6.50, years in median time) and that Center B had many more patients associated with an old, small clinic (17) than all other subgroups. Specifically, 19 of 28 patients in the screened B subgroup (contrasted with 0 of 28 for screened A, 7 of 21 for control B, and 0 of 28 for control A) received care in an old, small clinic setting that integrated young and old patients irrespective of their pulmonary status, as described previously (17). In addition, the age of P. aeruginosa acquisition is different between the ΔF508 patients in the screened and control groups (2.64 vs. 6.02 years, p = 0.033).

Other Pulmonary Outcome Assessments

We also used GEE analysis to assess longitudinal data on patients who were aged 5 years or older with the binary discriminators of WCXR and BCXR scores because this measure had proved in past analyses to be our most sensitive indicator of potentially irreversible lung disease (19). In comparing 54 screened patients with 44 control patients there was an apparent difference between groups (p = 0.024 for WCXR, and p = 0.055 for BCXR), but again, the difference diminished once the intrinsic risk factors (genotype and pancreatic status) and P. aeruginosa infection were considered (p = 0.19 for WCXR, and p = 0.18 for BCXR). In addition, Shwachman–Kulczycki clinical scores (16) were analyzed, including 1,253 total scores obtained from diagnosis up to 17 years of age. Using all the data, there were no differences in Shwachman–Kulczycki total scores between the two groups (p = 0.75 for GEE Model I, and p = 0.84 for Model II). Although using the data recorded when the patient was aged 5 years or older revealed that the screened group had significantly worse clinical scores than the control groups (p = 0.027), the significance disappeared again once the risk factors and P. aeruginosa infection were adjusted for in the model (p = 0.23).

DISCUSSION

Section:

Results from this randomized, controlled trial demonstrated previously that there are significant nutritional benefits associated with early diagnosis of CF through neonatal screening (6, 7). However, we recognized during the design phase, and subsequently as other CF screening studies were reported (1, 2, 8–11, 13), that greater difficulty would be encountered in assessing pulmonary outcomes. Comparison of screened and control patients has been complicated by center differences and dissimilar group characteristics such as genotype and pancreatic status, despite a large randomization process that was proven to be statistically valid (7). In an effort to avoid disproportions, all newborns were randomized into the screened or control group based strictly on the terminal digit (odd or even) of the laboratory number assigned to the first neonatal screening specimen and not on the basis of reason for diagnosis (15). For example, a patient in whom diagnosis of CF was made in early infancy because of positive family history or because of the presence of meconium ileus had an equal chance of being in the screened as in the control group. Conversely, a patient in whom diagnosis was made later in childhood due to symptoms could have been assigned to the screened group if the child had a false-negative screening test. Although most clinical and demographic characteristics were similar in the two groups (7), it should be emphasized that our control group has intrinsically less risk (19) of bronchopulmonary disease, especially with 28% of the patients having intact pancreatic function compared with 9% of screened patients. In addition, the patients' ages and duration of assessment varied markedly when this analysis was performed due to accrual over 13 years; in fact, only 57.1% of the screened group and 51.1% of the control group have been fully assessed thus far during the critical period of 10 to 14 years.

Another unexpected challenge we encountered is that the severity of lung disease has been less than anticipated at the onset of the study (25). Thus, PFT data revealed surprisingly mild degrees of pulmonary dysfunction throughout the evaluation period, and even the CXR scores are in the mild to moderate range of severity (18, 20). This is in accordance with the limited need both groups of patients showed for hospitalization (0.85 hospital days/patient/year), with no group differences either. Nevertheless, quantitative chest radiology, which has proved more sensitive than PFT data in our previous studies (19), enabled us to proceed with meaningful comparisons of the two randomly generated groups and to examine risk factors such as P. aeruginosa acquisition.

In summary, our radiographic data revealed two significant findings (1) screening provides a potential opportunity for a better pulmonary outcome in patients in whom diagnosis was made early because the initial chest radiograph was less severely affected and (2) the course of radiographically quantitated lung disease evolves predominately in relation to P. aeruginosa infection. The first point is especially significant because the lungs of patients with CF are histologically normal at birth (14) and therapies developed since this project began (26, 27) offer great potential to delay the onset of irreversible, progressive lung disease. Furthermore, there are newer and better modalities to monitor lung disease in young children with CF (28–30). In retrospect, methods such as high-resolution chest computed tomography imaging (29) and infant PFT assessment (30) would have added value to this study had they been available in 1985.

As identified previously (17, 28, 31, 32) and confirmed with these analyses, screened patients in whom diagnosis was made from 1985 to 1989 at one CF Center setting with a small, old clinic acquired P. aeruginosa at younger ages and therefore have had a longer duration of associated respiratory infection. We have also demonstrated that acquisition of P. aeruginosa accelerates radiographically quantitated lung disease (32) when there is no delay in diagnosis with an effect after age 10 years in this birth cohort. Thus, the results shown in Table 3 and Figure 3 indicate that P. aeruginosa infection had a stronger influence on measures of bronchopulmonary infection than did the age when diagnosis of CF was made in the case of patients followed longitudinally in this randomized trial.

Our results also demonstrate the interaction of various risk factors that influence pulmonary prognosis. Clearly, genotype and pancreatic functional status are important intrinsic factors that predispose children with CF to chronic lung disease when they develop respiratory infections (19). Undoubtedly, prognosis in CF is determined by the interplay of multiple genetic, nutritional, and environmental determinants. In a randomized trial such as this, however, these factors can become confounders when unavoidable group imbalances occur.

Other reports on pulmonary outcomes associated with CF neonatal screening have been based exclusively on observational studies (1, 2, 8–11), but there are supportive epidemiologic data also (33). All published experience suggests that early diagnosis was beneficial, but the differences between screened patients and a variety of control groups are difficult to interpret. In Australia for instance, the screened patients compared with historic controls showed a higher % FEV₁ and % FVC at 5 and 10 years of age; however, the mean values were normal and chest radiograph scores were similar between the two groups (5). Observational studies in northeastern Italy (13) also revealed that better pulmonary outcomes were evident with early diagnosis compared with historic controls. In the Netherlands (8, 9), screened patients showed less of a decrease in % FEV₁ compared with a concurrent birth cohort that did not have access to CF screening. Finally, a recently completed 10-year observational study in Brittany (11) compared concurrent outcomes in the only nonscreening region (Loire-Atlantique) with data obtained on screened patients and found significantly worse BCXR scores in the former group but no differences in P. aeruginosa colonization or PFTs. Other assessments of P. aeruginosa acquisition compared with age at diagnosis have not revealed differences such as we report in this study, but these reports do not include complete information on extrinsic or intrinsic risk factors (34).

It has become increasingly clear that there are many potential risk factors for P. aeruginosa infection in children with CF. Our previous findings (17, 28) combined with other studies (35–37) incriminate long-term oral (non–P. aeruginosa) antibiotic administration, aerosol use, malnutrition, person-to-person exposures, and certain intrinsic characteristics such as pancreatic insufficiency. Although some of these factors are fundamentally iatrogenic, it should be recognized that at the time of diagnosis at a CF Center in the United States, nearly one-third of new patients registered with the CF Foundation already have acquired P. aeruginosa (38) and acquisition/infection can occur in early infancy (1, 2). In addition, our results show that in some clinic settings half the number of patients have P. aeruginosa by 2 years of age (Figure 5) and half the number of those identified by traditional methods already have irreversible lung disease at diagnosis (Table 2).

The deleterious effects of P. aeruginosa have been known for many years (39), but the quantitative impact of this pathogen on children with respect to morbidity and mortality has become more evident during the past decade (32, 35, 40–42). For instance, Emerson and coworkers (40) recently reported that P. aeruginosa-positive patients with CF have 2.6 times higher risk of death and significantly lower % FEV₁ values. Reduced survival to age 16 years was also reported by Wilmott and coworkers (43), whereas Hudson and coworkers (41) found higher mortality if P. aeruginosa was detected in cultures before 2 years of age. A recent epidemiologic assessment with P. aeruginosa molecular typing in Melbourne (44) identified cross-infection in ambulatory clinics and/or hospital wards as the key factor responsible for five unexpected deaths of children with CF who were less than 5 years old. This alarming experience with a virulent P. aeruginosa strain argues strongly for segregated clinics, as used in one of our ambulatory care settings (17, 31) and in Denmark (45). On the other hand, this issue remains controversial as arguments have been raised against P. aeruginosa–driven segregated care (46).

Among many potential advantages, CF neonatal screening provides a special opportunity to reorganize care (15) and emphasize proactive, preventive strategies such as eliminating malnutrition (7) and potentially eradicating P. aeruginosa when it first appears in young patients (26, 27, 47, 48). Fortunately, improved methods of P. aeruginosa surveillance (28) and more effective therapies are now available (26, 27, 47–49). Therefore, regions that are implementing or planning (50, 51) CF neonatal screening should give priority to enhancing care delivery methods because our results confirm that early diagnosis per se does not ensure a better outcome but only provides that important opportunity.

The authors thank the following investigators who have participated in the Wisconsin Cystic Fibrosis Neonatal Screening Project: University of Wisconsin Medical School, Madison—N. Fost, E. Mischler, M. Palta, A. Tluczek, M. Block, L. A. Davis, L. Feenan, D. Pfeil, K. Moucha, L. J. Wei, B. S. Wilfond, A. von Egmond, M. Weatherly, J. Sharp, L. Makholm, L. Loveland, and R. Brown; Medical College of Wisconsin, Milwaukee—W. T. Bruns, H. Colby, W. Gershan, C. McCarthy, L. Rusakow, M. E. Freeman, and K. Riley; and Wisconsin State Laboratory of Hygiene, Madison—G. Hoffman, D. J. Hassemer, and R. H. Laessig.

References

Section:

1.	Abman SH, Ogle J, Horbeck R, Butler-Simon N, Hammond K, Accurso F. Early bacteriological, immunologic and clinical courses of young infants with cystic fibrosis identified by neonatal screening. J Pediatr 1991;119:211–217. Crossref, Medline, Google Scholar
2.	Khan TZ, Wagener JS, Bost T, Martinez J, Accurso FJ, Riches DWH. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 1995;151:1075–1082. Abstract, Medline, Google Scholar
3.	Lai HC, Kosorok MR, Sondel SA, Chen ST, FitzSimmons SC, Green CG, Shen G, Walker S, Farrell PM. Growth status in children with cystic fibrosis based on the National Cystic Fibrosis Patient Registry data: evaluation of various criteria used to identify malnutrition. J Pediatr 1998;132:478–485. Crossref, Medline, Google Scholar
4.	Cystic Fibrosis Patient Registry. 2000: Annual Data Report. Bethesda, MD; 2001. Google Scholar
5.	Crossley JR, Elliott RB, Smith PA. Dried-blood spot screening for cystic fibrosis in the newborn. Lancet 1979;1:472–474. Medline, Google Scholar
6.	Farrell PM, Kosorok MR, Laxova A, Shen G, Koscik RE, Bruns T, Splaingard M, Mischler EH. Nutritional benefits of newborn screening for cystic fibrosis. N Engl J Med 1997;337:963–969. Crossref, Medline, Google Scholar
7.	Farrell PM, Kosorok MR, Rock MJ, Laxova A, Zeng L, Lai HC, Hoffman G, Laessig RH, Splaingard ML. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Pediatrics 2001;107:1–12. Crossref, Medline, Google Scholar
8.	Dankert-Roelse JE, te Meerman GJ. Long term prognosis of patients with cystic fibrosis in relation to early detection by neonatal screening and treatment in a cystic fibrosis centre. Thorax 1995;50:712–718. Crossref, Medline, Google Scholar
9.	Mérelle ME, Schouten JP, Gerritsen J, Dankert-Roelse JE. Influence of neonatal screening and centralized treatment on long-term clinical outcome and survival of CF patients. Eur Respir J 2001;18:306–315. Crossref, Medline, Google Scholar
10.	Waters DL, Wilcken B, Irwig L, Van Asperen P, Mellis C, Simpson JM, Brown J, Gaskin KJ. Clinical outcomes of newborn screening for cystic fibrosis. Arch Dis Child Fetal Neonatal Ed 1999;80:1–7. Crossref, Medline, Google Scholar
11.	Siret D, Bretaudeau G, Branger B, Dabadie A, Dagorne M, David V, de Braekeleer M, Moisan-Petit V, Picherot G, Rault G, et al. Comparing the clinical evolution of cystic fibrosis (CF) screened neonatally to that of CF diagnosed from clinical symptoms: a 10-years retrospective study in a French region (Brittany). Pediatr Pulmonol 2003;35:342–349. Crossref, Medline, Google Scholar
12.	Wagener JS, Farrell PM, Corey M. Commentary: a debate on why my state (province) should or should not conduct newborn screening for cystic fibrosis (14th Annual North American Cystic Fibrosis Conference). Pediatr Pulmonol 2001;32:385–396. Google Scholar
13.	Mastella G, Zanolla L, Castellani C, Altieri S, Furnari M, Giglio L, Lombardo M, Milano A, Sciuto C, Pardo F, et al. Neonatal screening for cystic fibrosis: long-term clinical balance. Pancreatol 2001;1:531–537. Crossref, Medline, Google Scholar
14.	Bedrossian CWM, Greenberg SC, Singer DB, Hansen J, Rosenberg H. The lung in CF: a quantitative study including prevalence of pathologic findings among different age groups. Hum Pathol 1976;7:195–204. Crossref, Medline, Google Scholar
15.	Farrell PM and the Wisconsin Cystic Fibrosis Neonatal Screening Study Group. Improving the health of patients with cystic fibrosis through newborn screening. Adv Pediatr 2000;47:79–115. Medline, Google Scholar
16.	Shwachman H, Kulczycki LL. Long-term study of one hundred five patients with cystic fibrosis. Am J Dis Child 1958;96:6–15. Crossref, Medline, Google Scholar
17.	Kosorok MR, Jalaluddin M, Farrell PM, Shen G, Colby CE, Laxova A, Rock MJ, Splaingard ML. Comprehensive analysis of risk factors for acquisition of Pseudomonas aeruginosa in young children with cystic fibrosis. Pediatr Pulmonol 1998;26:81–88. Crossref, Medline, Google Scholar
18.	Koscik RE, Kosorok MR, Farrell PM, Collins J, Peters ME, Laxova A, Green CG, Zen L, Rusakow LS, Hardie RC, et al. Wisconsin cystic fibrosis chest radiograph scoring system: validation and standardization for application to longitudinal studies. Pediatr Pulmonol 2000;29:457–467. Crossref, Medline, Google Scholar
19.	Farrell PM, Li Z, Kosorok MR, Laxova A, Green CG, Collins J, Lai HC, Makholm LM, Rock MJ, Splaingard ML. Longitudinal evaluation of bronchopulmonary disease in children with cystic fibrosis. Pediatr Pulmonol 2003;36:1–11. Crossref, Medline, Google Scholar
20.	Brasfield D, Hicks G, Song S, Tiller RE. The chest roentgenogram in cystic fibrosis: a new scoring system. Pediatrics 1979;63:24–29. Medline, Google Scholar
21.	Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG. Pulmonary function between 6 and 18 years of age. Pediatr Pulmonol 1993;15:75–88. Crossref, Medline, Google Scholar
22.	Liang KY, Zeger SK. Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13–22. Crossref, Google Scholar
23.	Pagano M, Gauvreau K. Principles of biostatistics, 2nd ed. Pacific Grove, CA: Duxbury; 2000. Google Scholar
24.	Davis PB. The decline and fall of pulmonary function in cystic fibrosis: new models, new lessons. J Pediatr 1997;131:789–790. Crossref, Medline, Google Scholar
25.	Blythe S, Farrell PM. Advances in the diagnosis and management of cystic fibrosis. Clin Biochem 1984;17:277–283. Crossref, Medline, Google Scholar
26.	Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, Vasiljev-K M, Borowirz D, Bowman CM, Marshall BC, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis: Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med 1999;340:23–30. Crossref, Medline, Google Scholar
27.	Koch C. Early infection and progression of cystic fibrosis lung disease. Pediatr Pulmonol 2002;34:232–236. Crossref, Medline, Google Scholar
28.	West SEH, Zeng L, Lee BL, Kosorok MR, Laxova A, Rock MJ, Splaingard ML, Farrell PM. Respiratory infections with Pseudomonas aeruginosa in children with cystic fibrosis: early detection by serology and assessment of risk factors. JAMA 2002;287:2958–2967. Crossref, Medline, Google Scholar
29.	Brody AS, Molina PL, Klein JS, Rothman BS, Ramogopal J, Swartz DR. High-resolution computed tomography of the chest in children with cystic fibrosis: support for use as an outcome surrogate. Pediatr Radiol 1999;29:731–735. Crossref, Medline, Google Scholar
30.	Beydon N, Amsallem F, Bellet M, Boulé M, Chaussain M, Denjean A, Matran R, Pin I, Alberti C, Gaultier C. Pulmonary function tests in preschool children with cystic fibrosis. Am J Respir Crit Care Med 2002;166:1099–1104. Abstract, Medline, Google Scholar
31.	Farrell PM, Shen G, Splaingard M, Colby CE, Laxova A, Kosorok MR, Rock MJ, Mischler EH. Acquisition of Pseudomonas aeruginosa in children with cystic fibrosis. Pediatrics 1997;100. URL:http//www.pediatrics.org/cgi/content/full/100/5/e2. Google Scholar
32.	Kosorok MR, Zeng L, West She, Rock MJ, Splaingard ML, Laxova A, et al. Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition. Pediatr Pulmonol 2001;32:277–287. Crossref, Medline, Google Scholar
33.	Wang SS, O'Leary LA, FitzSimmons SC, Khoury MJ. The impact of early cystic fibrosis diagnosis on pulmonary function in children. J Pediatr 2002;141:804–810. Crossref, Medline, Google Scholar
34.	Wang SS, FitzSimmons SC, O'Leary LA, Rock MJ, Gwinn ML, Khoury MJ. Early diagnosis of cystic fibrosis in the newborn period and risk of Pseudomonas aeruginosa acquisition in the first 10 years of life: a registry-based longitudinal study. Pediatrics 2001;107:274–279. Crossref, Medline, Google Scholar
35.	Burns JL, Gibson RL, McNamara S, Yim D, Emerson J, Rosenfeld M, Hiatt P, McCoy K, Castile R, Smith AL, et al. Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. J Infect Dis 2001;183:444–452. Crossref, Medline, Google Scholar
36.	Burns JL, Emerson J, Stapp JR, Yim DL, Krzewinski J, Louden L, Ramsey BW, Clausen CR. Microbiology of sputum from patients at cystic fibrosis centers in the United States. Clin Infect Dis 1998;27:158–163. Crossref, Medline, Google Scholar
37.	Ojeniyi B, Fredericksen B, Hoiby N. Pseudomonas aeruginosa cross-infection among patients with cystic fibrosis during a winter camp. Pediatr Pulmonol 2000;29:177–181. Crossref, Medline, Google Scholar
38.	FitzSimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr 1993;122:1–9. Crossref, Medline, Google Scholar
39.	Wood RE. Prognosis. In: Verlag CT, editor. Cystic fibrosis. New York: Thieme-Stratton, Inc.;1984. p. 434–460. Google Scholar
40.	Emerson J, Rosenfeld M, Mc Namara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol 2002;34:91–100. Crossref, Medline, Google Scholar
41.	Hudson VL, Wielinski CL, Regelmann WE. Prognostic implications of initial oropharyngeal bacterial flora in patients with cystic fibrosis diagnosed before the age of two years. J Pediatr 1993;122:854–860. Crossref, Medline, Google Scholar
42.	Nixon GM, Armstrong DS, Carzino R, Carlin JB, Olinsky A, Robertson CF, Grimwood K. Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis. J Pediatr 2001;138:699–704. Crossref, Medline, Google Scholar
43.	Wilmott RW, Tyson SL, Matthew DJ. Cystic fibrosis survival rates: the influences of allergy and Pseudomonas aeruginosa. Am J Dis Child 1985;139:669–671. Crossref, Medline, Google Scholar
44.	Armstrong DS, Nixon GM, Carzino R, Bigham A, Carlin JB, Robins-Browne RM, Grimwood K. Detection of a widespread clone of Pseudomonas aeruginosa in a pediatric cystic fibrosis clinic. Am J Respir Crit Care Med 2002;166:983–987. Abstract, Medline, Google Scholar
45.	Frederiksen B, Koch C, Hoiby N. Changing epidemiology of Pseudomonas aeruginosa infection in Danish cystic fibrosis patients (1974–1995). Pediatr Pulmonol 1999;28:159–166. Crossref, Medline, Google Scholar
46.	Ramsey BW. To cohort or not to cohort: how transmissible is Pseudomonas aeruginosa? Am J Respir Crit Care Med 2002;166:906–907. Abstract, Medline, Google Scholar
47.	Döring G, Conway SP, Heijerman HGM, Hodson ME, Høiby N, Smyth A, Touw DJ for the Consensus Committee. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J 2001;16:749–767. Google Scholar
48.	Valerius NH, Koch C, Høiby N. Prevention of chronic Pseudomonas aeruginosa colonization in cystic fibrosis by early treatment. Lancet 1991;338:725–726. Crossref, Medline, Google Scholar
49.	Wiesemann HG, Steinkamp G, Ratjen F, Bauernfeind A, Przyklenk B, Doring G, von der Hardt H. Placebo controlled, double blind, randomized study of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonization in patients with cystic fibrosis. Pediatr Pulmonol 1998;25:88–92. Crossref, Medline, Google Scholar
50.	Grosskopf C, Farriaux JP, Vidailhet M, Briard ML, Travert G, Belot V, Roussel P, Turck D, Navarro J, Bloch J. The French national screening program for CF. J Cystic Fibrosis 2002;1:S97. Google Scholar
51.	Bobadilla JL, Farrell MH, Farrell PM. Applying CFTR molecular genetics to facilitate the diagnosis of cystic fibrosis through screening. Adv Pediatr 2002;49:131–190. Medline, Google Scholar

Correspondence and requests for reprints should be addressed to Philip M. Farrell, M.D., Ph.D., University of Wisconsin Medical School, Room 1217 MSC, 1300 University Avenue, Madison, WI 53706-1532. E-mail: [email protected]

American Journal of Respiratory and Critical Care Medicine

Abstract

Abstract

Related