Infant Care Patterns at Epidemiologic Study of Cystic Fibrosis Sites That Achieve Superior Childhood Lung Function
OBJECTIVE. Previous analyses of the Epidemiologic Study of Cystic Fibrosis database revealed that sites with the highest average patient lung function monitor patients and treat with antibiotics more aggressively than those where average lung function is lowest. The aim of this study was to assess whether patterns of care for infants at cystic fibrosis sites with superior average lung function in 6- to 12-year-old children showed any differences from those at the lowest outcome sites.
METHODS. We divided cystic fibrosis sites with ≥20 patients who were 6 to 12 years of age into quartiles on the basis of median forced expiratory volume in 1 second of that age group in 2003 and compared demographic and clinical characteristics and treatment patterns during the first year of enrollment for patients who were aged 0 to 3 years at those sites in 1994 to 1999. The analysis included 755 infants from 12 upper quartile sites and 743 infants from 12 lower quartile sites.
RESULTS. Upper quartile sites had more infants whose disease was diagnosed by family history or newborn screening, fewer infants with symptoms at diagnosis, higher weight for age at enrollment, more white patients, and more ΔF508 homozygotes. Medical conditions and respiratory tract microbiology differed between sites. Infants at upper quartile sites had more office and sick visits; more respiratory tract cultures; and more frequent use of intravenous antibiotics, oral corticosteroids, mast cell stabilizers, and mucolytics; but they received less chest physiotherapy, inhaled bronchodilators, oral nutritional supplements, and pancreatic enzymes.
CONCLUSIONS. Both enrollment characteristics and infant care patterns are associated with lung function outcomes in later childhood. Our analysis suggests that pulmonary function of older children may be improved through specific interventions during the first 3 years of life.
The increasing use of newborn screening1 and prenatal screening2 has led to more frequent diagnoses of cystic fibrosis (CF) in early infancy. However, there are no published guidelines for care of infants with CF, and little information is available about specific interventions that might improve eventual outcomes. Because nutritional deficits may be observed before 2 months of age, early diagnosis and treatment can prevent malnutrition and improve long-term growth.3 The nutritional benefits of newborn screening for CF also are well established.4 Although growth and nutritional indices in early life seem to correlate with lung function later in childhood,5 the pulmonary benefits of newborn screening are less clear. This may be attributable, in part, to limited knowledge of which interventions during infancy might improve long-term pulmonary outcomes.
The Epidemiologic Study of Cystic Fibrosis (ESCF and ESCF II), a multicenter, longitudinal, observational study, was initiated in 1993 to collect treatment and outcomes data on patients with CF.6 Wide variation in treatment and outcomes has been observed across sites that participated in the ESCF,6,7 and a previous analysis of this database revealed that certain patterns of care were found more often in sites with better pulmonary function outcomes.8 Because early disease care is likely to have a long-term impact on pulmonary function, we attempted to discern “best practices” for respiratory care by comparing treatment that was prescribed to infants at ESCF sites with the highest median forced expiratory volume in 1 second (FEV1) in 6- to 12-year-old children with that given at sites with the lowest FEV1.
The ESCF database was used to establish 2 cross- sectional cohorts for this analysis: (1) an outcomes cohort of patients who were 6 to 12 years of age in 2003 and (2) an infant cohort of patients who were treated as infants between 1994 and 1999 at sites that were in the highest or lowest quartiles with respect to FEV1 in 2003. CF sites that were included in the outcomes cohort reported on at least 20 patients who were aged 6 to 12 years in 2003; 24 sites that participated in ESCF II met these criteria. The best FEV1 % predicted that was obtained in 2003 was determined for each patient, median FEV1 was calculated for each site, and those in the highest and lowest quartiles were identified. The infant cohort, aged 0 to 3 years, was used to compare demographics, clinical characteristics, and care patterns identified at upper (UQ) and lower quartile (LQ) sites. All patients who enrolled and participated in ESCF and ESCF II provided informed consent.
Data that were collected for each patient reflected the period from enrollment into the ESCF to 12 months after enrollment. The following demographic characteristics were collected: age, gender, race (non-Hispanic white or other), genotype, and method of CF diagnosis. Clinical characteristics included mean weight-for-age and height-for-age percentiles (during the first year of enrollment), signs and symptoms of lung disease (cough was described as none, occasional, or daily; and the presence of crackles, wheezing, and clubbing was identified using a check box), medical conditions (eg, asthma, sinusitis, elevated liver function results), microbiology and related variables, and nutritional status. The presence of asthma or sinusitis was based on the diagnostic determination of the individual physician. Practice patterns were defined by number of visits and use of parenteral antibiotics and routine therapies.
Continuous variables are presented as means ± SD, and categorical variables are presented as number (%). Two-tailed χ2 tests (for categorical variables) and t tests (for continuous variables) were performed to identify any differences between UQ and LQ sites. These variables were examined further by means of multivariable logistic regression modeling, controlling for quartile, genotype, non-Hispanic race, and age. All statistical analyses and summaries were performed using SAS 9.1 (SAS Institute, Cary, NC). P < .05 was considered to be significant.
Quartiles were established from an outcomes cohort of 837 children who were aged 6 to 12 years; 525 of these patients also were included in the infant cohort to evaluate clinical characteristics and practice patterns. A total of 1498 infants were included in the analysis of practice patterns: 755 patients from UQ sites and 743 patients from LQ sites. Figure 1 shows the distribution and overlap of infants and children who were evaluated in the analysis.
Demographic and clinical characteristics for both cohorts are summarized in Table 1. In the outcomes cohort, no differences were observed in mean age or gender distribution between UQ and LQ sites. Median FEV1 in 2003 was 107.1 ± 3.7% and 89.0 ± 6.5% predicted for UQ and LQ sites, respectively. UQ sites cared for a significantly higher proportion of non-Hispanic white patients (P < .0001) and patients whose CF was diagnosed by newborn screening (P < .0001). UQ sites had fewer infants whose CF was diagnosed by the presence of clinical symptoms (P < .0001). The distribution of other demographic and clinical characteristics was similar between UQ and LQ sites in both their infant and outcomes cohorts.
A significantly higher percentage of patients at the LQ sites exhibited cough (P = .001) at ≥75% of clinic visits (Table 2). The incidence of clubbing was similar between groups. The difference in incidence of crackles could not be assessed because of the small number of affected patients.
No difference was observed between UQ and LQ sites in the diagnosis of asthma. However, at UQ sites, fewer infants demonstrated abnormal results on liver function tests (P = .003), but more infants received a diagnosis of sinusitis (P < .0001; Table 3).
UQ sites performed airway cultures in a greater proportion of their infants and did more cultures per individual infant than LQ sites (P < .0001 for both). Infants at UQ sites were more likely to have positive cultures for Staphylococcus aureus (P < .0001) and other Gram-negative bacilli (P < .05) and less likely to have positive cultures for Pseudomonas aeruginosa (P < .003; Table 4).
Infants at UQ sites exhibited both higher weight-for-age and height-for-age percentiles (P < .0001) compared with patients at the LQ sites (Fig 2), but these differences were not large. The mean weight-for-age percentiles at the UQ and LQ sites were 28.4 and 22.6, respectively, and the mean height-for-age percentiles at the UQ and LQ sites were 31.7 and 25.9, respectively.
Office Visits and Hospitalizations
Infants who received care at UQ sites had more frequent office visits (6.4 ± 3.3 vs 5.9 ± 3.1; P = .009) and sick visits (1.2 ± 1.9 vs 1.0 ± 1.7; P = .014) but a similar number of hospital admissions (0.5 ± 0.9 vs 0.5 ± 1.0) in the 12 months after enrollment (Fig 3).
Univariate analyses showed that patients who were cared for at UQ sites received more intravenous antibiotics at home (P < .05), oral corticosteroids (P < .0001), mast cell stabilizer therapies (P < .0001), mucolytics (excluding dornase alfa; P < .0001), and supplemental oxygen (P = .002; Table 5). In contrast, patients from the LQ sites received more airway clearance therapies/chest physiotherapy (P < .0001), inhaled bronchodilators (P = .0001), oral nutritional supplements (P < .05), and pancreatic enzymes (P < .0001). These differences generally were confirmed by multivariable analysis with adjustment for age, race, and genotype. The borderline result for intravenous antibiotics at home (P = .028) no longer was significant after adjustment (P = .059). No differences were noted between groups regarding the use of chronic therapies, including inhaled or oral antibiotics, inhaled corticosteroids, enteral nutrition, or dornase alfa.
This analysis compares the demographics, clinical characteristics, and medical care received during the first 12 months after enrollment at ESCF sites in the highest and lowest quartiles for FEV1 % predicted in 2003. We found that sites where patients had the best lung function at ages 6 to 12 years had fewer infants with risk factors (nonwhite race, symptomatic diagnosis, P aeruginosa airway infection) compared with sites with lower lung function and that infants who attended these sites had slightly better height and weight percentiles. Some of the risk factors, such as ethnicity and genotype, are not modifiable. Others, including symptomatic diagnosis, cannot be modified at the time of an individual patient's diagnosis but can be changed in future patient populations with specific interventions. Importantly, specific patterns of patient monitoring and treatment at sites in the highest quartile were significantly different from those at the lower quartile sites.
Comparisons of site outcomes must consider the baseline characteristics of patients who attended those sites, which may not be modifiable by treatment, and differences in treatment approach. Nonmodifiable differences between UQ and LQ sites were seen in this analysis. Fewer ethnic minorities were seen at UQ sites. Minority ethnicity is associated with a lower socioeconomic status in the United States, which, in turn, is associated with poorer pulmonary function in patients with CF.9 Because socioeconomic data were not available for this analysis, it is not possible to evaluate the impact of socioeconomic status separately. Fewer pancreatic-insufficient patients, as identified by pancreatic enzyme use, were seen at UQ sites. Pancreatic insufficiency is associated with increased disease severity.10,11
Some of the risk factors that were seen at LQ sites can be modified in future populations of infants with CF. Infants from LQ sites demonstrated a greater severity of illness and a lower weight for age at enrollment. Both weight for age and severity of illness during the first year after diagnosis affect morbidity and mortality in children with CF.12,13 These risk factors can be modified by widespread implementation of newborn screening programs. Observational and randomized studies have demonstrated that early diagnosis and treatment improve long-term nutritional status and lung health12,14 and are the basis for the Centers for Disease Control and Prevention and the Cystic Fibrosis Foundation consensus for routine newborn screening for CF.15 In the United Kingdom, infants whose CF is diagnosed by newborn screening require less intensive therapies than those whose CF is diagnosed clinically.16 Our data show that ESCF sites whose 6- to 12-year-old patients have the highest pulmonary function had more infants whose CF was diagnosed by newborn screening or family history than sites with the lowest pulmonary function. These infants also seem to require less intensive therapy, because less frequent prescription of airway clearance therapy, inhaled bronchodilators, and enteral supplemental feedings were seen at UQ sites. There are no randomized, controlled studies of these therapies in CF, and the association between use of these therapies in infants and outcomes cannot be assessed adequately with the current analysis.
More patients from the LQ sites had sputum cultures positive for P aeruginosa, which is associated with greater airway inflammation and poorer lung function in ensuing years. In contrast, UQ sites performed more cultures per patient, which might be expected to allow earlier detection and treatment. Infection control practices and early intervention for P aeruginosa infection could reduce the frequency of positive P aeruginosa cultures in the population and further improve outcomes.
For achievement of the best health outcomes for infants whose CF is diagnosed without clinical symptoms and for improvement of outcomes for those whose CF is diagnosed with symptoms, it is essential to recognize and apply monitoring and treatment strategies that may improve subsequent health status. Although significant information indicates that important physiologic aberrations occur early in CF, very few data give the clinician insight into the best treatment strategies. For example, there is evidence for early airway infection and inflammation in infants and young children with CF,17,18 and structural airway abnormalities are apparent on high-resolution computed tomography scan in infants and young children with CF.19 Abnormalities that are seen on high-resolution computed tomography are prevalent even in a cohort of children with normal lung function,20 the conventional marker of lung health. Furthermore, early malnutrition has deleterious effects on cognitive function in children with CF; minimizing the duration of vitamin E deficiency may be associated with better cognitive function.21 Therefore, early diagnosis and prompt care, including close attention to growth and vitamin status, of infants with CF are expected to improve long-term outcomes. We do not know, however, which interventions might prevent bronchiectasis or slow its progression or whether specific strategies for nutrition in infants and young children could improve further later nutrition.
Although our analysis showed that sites with the highest FEV1 had a lower proportion of high-risk infants, it is important and most useful to examine the differences in treatment approaches that were used during infancy. In older children, significant differences in care patterns and outcomes have been noted at ESCF sites.7 More visits to the site, more frequent respiratory tract cultures, and more frequent use of intravenous antibiotics have been documented at UQ versus LQ sites. The present analysis shows that these specific care patterns also are seen in the care of the youngest patients at sites that later demonstrate the best pulmonary function outcomes. Despite lesser severity of illness, infants in the UQ sites were evaluated more frequently (office and sick visits), cultured more frequently, and treated more often with intravenous antibiotics (at home), oral corticosteroids, mast cell stabilizers, and mucolytics than those at LQ sites. Increased use of anti-inflammatory therapies in young children in UQ sites suggests consideration of evaluating the benefits of these agents in prospective, controlled clinical trials. Also surprising was the finding that patients at UQ sites received supplemental oxygen more frequently than those at LQ sites; given that UQ patients had a lower risk for severe lung disease, this finding might represent a variability in prescribing practices. The more frequent diagnosis of sinusitis at the UQ sites (P < .001) may be a marker for more frequent antibiotic therapy, leading to better lung function in subsequent years. The significance of this finding is difficult to determine because case report forms captured physician-diagnosed sinusitis but did not give specific criteria for this diagnosis.
It is intriguing that airway clearance and the administration of bronchodilators, interventions that the majority of CF care providers initiate early and consider to be effective, were used more frequently at the LQ than the UQ sites. It is possible that providers at UQ sites do not prescribe these therapies in asymptomatic or minimally symptomatic infants. It also is possible that UQ sites more frequently diagnose CF by newborn screening and that these patients receive less intense treatment.16 Alternatively, this finding may be explained by the variability in defining actual versus prescribed care. The case report forms were designed to capture prescribed therapy, but because case reports are extracted from the medical chart, it is possible that intended treatment, rather than actual treatment, has been captured and that parents of asymptomatic or minimally symptomatic infants are less likely to adhere to airway clearance regimens. This issue might be investigated further through a detailed survey of CF care provider practices.
It is impossible to determine fully the influence of care in previous years versus more recent or current care on pulmonary function outcomes. However, given the early onset of inflammation and bronchiectasis in CF and the progressive nature of CF lung disease, it is compelling to consider the benefits of frequent monitoring and more frequent use of antibiotics in infants and young children as strategies for improving long-term health outcomes. Our study design is limited by the use of 2 cross-sectional cohorts at identical sites rather than a true longitudinal assessment of individual patients. However, 64% of the 6- to 12-year-old patients who were used to define the outcomes cohorts were part of the infant cohort at the same care site. Nonetheless, we believe that our findings are valid. A longitudinal cohort study would be confirmatory, and multivariable analysis then would allow the ascertainment of the relative contribution of patient risk factors and treatment patterns in relation to pulmonary outcomes.
It is important to realize that an epidemiologic study can identify only associations and, as such, does not define cause and effect but rather points out opportunities for future evaluation. In the present study, observation of better lung function at ESCF sites in patients who were aged 6 to 12 years is associated with specific patient characteristics and clinical care patterns in infants in previous years. Although some patient characteristics are not modifiable, others can be modified through currently available strategies such as widespread implementation of newborn screening. Higher FEV1 is associated with specific practice patterns, including more frequent visits, more sputum cultures, and more frequent antibiotic therapy. The correlations between these practices and improved outcomes generate hypotheses for prospective research and suggest specific strategies that can be implemented in quality improvement initiatives. Frequent monitoring and use of antibiotics may preserve long-term lung health in CF.
This study was supported by Genentech, Inc.
This study was conducted with the ESCF database.
We acknowledge the contributions of the North American Scientific Advisory Group; the investigators and study coordinators of the ESCF; and Jill Luer, PharmD, for editorial assistance.
- Accepted September 18, 2006.
- Address correspondence to Raj Padman, MD, Division of Pulmonology, Alfred I. duPont Hospital for Children, PO Box 269, Wilmington, DE 19899. E-mail:
Financial Disclosure: Drs Padman, Schechter, and Ren are consultants for Genentech, Inc; Dr McColley is a consultant and member of the speakers bureau for Genentech, Inc; Dr Miller is employed by Ovation Research Group, which receives research funding from Genentech, Inc; Dr Konstan has received research support from and is a consultant for Genentech, Inc, Novartis, Axcan-Scandipharm, and Digestive Care Inc; Dr Morgan is an advisory board member for Genentech, Inc; and Dr Wagener is an employee and shareholder of Genentech, Inc.
- ↵National Newborn Screening & Genetics Resource Center (NNSGRC). U.S. National Screening Status Report. Austin, TX: NNSGRC. Available at: http://genes-r-us.uthscsa.edu/nbsdisorders.htm. Accessed September 14, 2006
- ↵Oestreich C, Teicher J, Miller W, Lerner B. After the ACOG Guidelines: obstetrician-gynecologist's current practices on carrier screening. Abstracts from the twenty-second Annual Education Conference of the National Society of Genetic Counselors (Charlotte, NC, September 2003). J Genet Couns.2003;12 :531– 532
- ↵Farrell PM, Kosorok MR, Rock MJ, et al. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Wisconsin Cystic Fibrosis Neonatal Screening Study Group. Pediatrics.2001;107 :1– 13
- ↵Corey M, Gaskin K, Durie P, Levinson H, Fostner G. Improved prognosis in CF patients with normal fat absorption. J Pediatr Gastroenterol Nutr.1984;3(suppl 1) :S99– S105
- ↵Waters DL, Wilcken B, Irwig L, et al. Clinical outcomes of newborn screening for cystic fibrosis. Arch Dis Child Fetal Neonatal Ed.1999;80 :F1– F7
- ↵Campbell PW, White TB. Newborn screening for cystic fibrosis: an opportunity to improve outcomes. J Pediatr.2005;147(suppl) :S2– S5
- ↵Nixon GM, Armstrong DS, Carzino R, et al. Early airway infection, inflammation, and lung function in cystic fibrosis [published correction appears in Arch Dis Child. 2003;88:946]. Arch Dis Child.2002;87 :306– 311
- ↵Koscik RL, Farrell PM, Kosorok MR, et al. Cognitive function of children with cystic fibrosis: deleterious effect of early malnutrition. Pediatrics.2004;113 :1549– 1558
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