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Risk Factors For Rate of Decline in Forced Expiratory Volume in One Second in Children and Adolescents with Cystic Fibrosis
Risk Factors For Rate of Decline in Forced Expiratory Volume in One Second in Children and Adolescents with Cystic Fibrosis MICHAEL W. KONSTAN, MD, WAYNE J. MORGAN, MD, STEVEN M. BUTLER, PHD, DAVID J. PASTA, MS, MARCIA L. CRAIB, MS, STEFANIE J. SILVA, MS, DENNIS C. STOKES, MD, MARY ELLEN B. WOHL, MD, JEFFREY S. WAGENER, MD, WARREN E. REGELMANN, MD, AND CHARLES A. JOHNSON, MBCHB, FOR THE SCIENTIFIC ADVISORY GROUP AND THE INVESTIGATORS AND COORDINATORS OF THE EPIDEMIOLOGIC STUDY OF CYSTIC FIBROSIS*
Objectives
To characterize the rate of decline of forced expiratory volume in 1 second (FEV1) in children and adolescents with cystic fibrosis and to identify and compare risk factors associated with FEV1 decline. Study design The rate of decline in FEV1% predicted over 3 to 6 years in 3 different age groups was determined. Risk factors for decline were identified and compared among and within age groups as a function of disease severity with repeatedmeasures, mixed-model regression. Results Mean (ⴞSD) baseline FEV1% predicted was 88.4% ⴞ 20.5% for 6- to 8-year-olds (n ⴝ 1811), 85.3% ⴞ 20.8% for 9- to 12-year-olds (n ⴝ 1696), and 78.4% ⴞ 22.0% for 13- to 17-year-olds (n ⴝ 1359). Decline in FEV1% predicted/year was ⴚ1.12, ⴚ2.39, and ⴚ2.34, respectively. High baseline FEV1 and persistent crackles were significant independent risk factors for decline across all age groups. Female sex, Pseudomonas aeruginosa infection, low weight-for-age, sputum, wheezing, sinusitis, pulmonary exacerbations treated with intravenous antibiotics, elevated liver test results, and pancreatic insufficiency were also identified as independent risk factors in some age See editorial, p 111 groups. Conclusions This study identifies risk factors for FEV1 decline in children and adoFrom the Department of Pediatrics, Rainlescents with cystic fibrosis. Clinicians should not be reassured by high lung function, bow Babies and Children’s Hospital and particularly in young children, because this factor, among others, is independently Case Western Reserve University School of Medicine, Cleveland, Ohio (M.K.); Deassociated with steeper decline in FEV1. (J Pediatr 2007;151:134-9)
he rate of decline in the forced expiratory volume in 1 second (FEV1) has been studied in patients with cystic fibrosis (CF) to better understand the progression of CF lung disease and to identify high-risk groups in whom aggressive therapy may be indicated,1-15 to assess therapeutic interventions,16-18 and to guide sample size estimations for use in designing clinical trials.19 Findings from previous studies suggest that FEV1 decline predicts death in CF7,11 and that therapeutic intervention can slow the decline in FEV1.17 Risk factors associated with FEV1 decline include, but are not limited to, young age,19 high lung function,1,9,19 sex,1,4,5,7-9 cystic fibrosis transmembrane conductance regulator genotype and modifier genes,7,8,13,14 pancreatic insufficiency,7,13 poor nutritional status,8,9,12 respiratory viral infections,2 infection with Pseudomonas aeruginosa or Burkholderia cepacia,3-5,12,13 and diabetes mellitus.10,13 Many of these findings were obtained from studies conducted at single treatment centers or with small numbers of patients, included adults in their analyses, or assessed only a limited number of potential risk factors. The Epidemiologic Study of Cystic Fibrosis (ESCF), a prospective encounter-based study designed to characterize the natural history of the pulmonary disease and growth in a large population of patients with CF (n ⫽ 24,863) in the United States and Canada,20 is a useful resource for the study of FEV1 decline in different age groups of patients. The objectives of this analysis were (1) to characterize the decline in FEV1 % predicted over
T
CF ESCF
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Cystic fibrosis Epidemiologic Study of Cystic Fibrosis
FEV1
Forced expiratory volume in 1 second
partment of Pediatrics and Physiology, University of Arizona, Tucson, Arizona (W.M.); Specialty Biotherapeutics, Genentech, Inc., South San Francisco (S.B., M.C., J.W., C.J.), and Ovation Research Group, San Francisco, California (D.P., S.S.); Department of Pediatrics, Children’s Hospital at Dartmouth and Dartmouth Medical School, Lebanon, New Hampshire (D.S.); Dept. of Pediatrics, Children’s Hospital and Harvard Medical School, Boston, Massachusetts (M.W.); Department of Pediatrics, The Children’s Hospital and University of Colorado School of Medicine, Denver, Colorado (J.W.); and Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (W.R.). Supported by Genentech, Inc., South San Francisco, Calif. Submitted for publication Jun 30, 2006; last revision received Dec 1, 2006; accepted Mar 5, 2007. Reprint requests: Michael W. Konstan, MD, Rainbow Babies and Children’s Hospital, 11100 Euclid Ave, Cleveland, OH 44106. E-mail: [email protected]. *List of members available at www.jpeds. com. 0022-3476/$ - see front matter Copyright © 2007 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2007.03.006
a 3- to 6-year period in children and adolescents with CF aged 6 to 8 years, 9 to 12 years, and 13 to 17 years; and (2) to identify and compare risk factors for the 3- to 6-year decline in FEV1% predicted in different age groups and among patients in each age group as a function of severity of lung disease. Some of the results of this analysis have been previously reported in abstract form.21
METHODS Patients 6 to 17 years old were included if they had at least 3 spirometry measurements obtained at times of clinical stability after enrollment in ESCF. The first measurement was defined as the baseline spirometry. A 1-year lead-in period followed, during which baseline clinical characteristics were assessed. The subsequent 5.5 years comprised the observation period. To ensure adequate long-term follow-up, spirometry must have been performed at times of clinical stability at least once during the first year of observation and again after 3 years. Of the 9410 patients aged 6 to 17 years in ESCF by December 1997, 4923 met these criteria. Written informed consent was obtained at institutions where required. To characterize the rate of decline in FEV1% predicted during the observation period, patients were categorized according to age at baseline spirometry (6-8 years, 9-12 years, and 13-17 years). To reduce bias caused by variation in the frequency of testing, the spirometry obtained during a time of clinical stability closest to the 6-month (⫾3 months) anniversary after the first test during the observation period was selected for each patient. The equations of Wang et al22 were used to calculate the percent of predicted FEV1. Repeatedmeasures, mixed-model regression analysis was used to estimate mean rate of change in FEV1% predicted within age groups and to explore baseline risk factors for decline in FEV1% predicted. Potential baseline risk factors included age at baseline spirometry; sex; baseline FEV1% predicted; growth indexes (including body mass index) at the last visit during lead-in; respiratory tract culture results for P aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Burkholderia cepacia, Stenotrophomonas maltophilia, other gram-negative organisms, Candida, and Aspergillus from the last culture during lead-in; signs and symptoms during lead-in consisting of daily cough, daily sputum production, hemoptysis, clubbing, crackles, and wheezing; medical conditions during lead-in consisting of asthma, allergic bronchopulmonary aspergillosis, sinusitis, nasal polyps, elevated liver tests, CF-related diabetes mellitus (insulin/oral hypoglycemic use), and pancreatic insufficiency (enzyme use); and the frequency of pulmonary exacerbations requiring treatment with intravenous antibiotics (exacerbations) during lead-in. For potential risk factors assessed throughout the 1-year lead-in period, patients were categorized as positive for each characteristic that was present on at least half of encounters during this period. To determine the most important independent risk factors, a multivariate, linear mixed-effects model of FEV1 %
predicted was developed separately for each age group. Risk factors were screened for univariate association with the rate of decline (P ⬍ .1); then a list of risk factors was created by use of multivariate models with backward selection, retaining those with P ⬍ .05. To allow comparison of all independent risk factors across age groups, factors retained in any age group were combined in the final multivariate model for each age group. Baseline FEV1% predicted was included as a continuous variable and as a 4-category variable interacted with time. Regression to the mean because of correlated errors was limited because baseline FEV1 was obtained 12 months before the beginning of the observation period. All analyses were performed with SAS Version 9.1 (Cary, NC).
RESULTS Of the 4923 patients who met the inclusion criteria, 4866 (98.8%) had data available for all of the final risk factors and were included in the final model. Baseline and lead-in year characteristics are shown in Table I. Progression of lung disease is evident on the basis of a cross-sectional analysis of baseline FEV1, which was highest in the 6- to 8-year-old group and lowest in the 13- to 17-year-old group. The percentage of patients with a positive respiratory tract culture for P aeruginosa at baseline increased from the youngest to the oldest age group, as did signs and symptoms of lung disease. Baseline nutritional status, indicated by weight for age, was best in the youngest children and worst in the adolescents. The mean duration of observation from the end of the lead-in year to the last spirometry measurement was 4.4 years (range 3.0-5.8). The median number of spirometry measures included per patient was 8. The final set of risk factors and associated P values for each age group are given in Table II. The annualized rate of FEV1 decline for each age group, unadjusted for other factors, is shown in Figure 1, upper left panel. Overall, the 6- to 8-year-old children exhibited a slower rate of decline compared with those aged 9 to 12 and 13 to 17 years. The line segments for the 3 age groups were estimated separately, and although they nearly connect exactly, they were not forced to do so. The most significant risk factors for decline in FEV1 were crackles, high baseline FEV1, and sex. The univariate association of each of these risk factors with decline in FEV1 is shown in the upper right, lower left, and lower right panels of Figure 1, presented as the estimated rate of decline for patients with and without each risk factor. This analysis does not include adjustment for other factors; for example, the decline for patients with crackles also reflects the presence of other risk factors in patients with crackles. In the lower left panel of Figure 1, the line for FEV1 ⬍40% predicted in the 6- to 8-year-old children is high because of regression to the mean in this small (n ⫽ 26) group. For most of the risk factors, the effect was in the same direction for all age groups. Sex is an exception; in the 6- to 8-year-old group, females demonstrated higher rates of decline, even though in 9- to 17-year-old children and adolescents, females showed lower rates of decline (Figure 1, lower right panel).
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Table I. Patient characteristics by age group Ages 6–8 n ⴝ 1811
Ages 9–12 n ⴝ 1696
Ages 13–17 n ⴝ 1359
Characteristic
n (%)
n (%)
n (%)
Age in years (mean ⫾ SD) Baseline FEV1 (mean ⫾ SD) Female P aeruginosa Weight-for-age percentile (mean ⫾ SD) Height-for-age percentile (mean ⫾ SD) Cough Sputum Clubbing Crackles Wheezing Sinusitis ⱖ2 IV exacerbations Elevated LFT Pancreatic enzyme use
7.2 ⫾ 0.9
10.9 ⫾ 1.2
15.2 ⫾ 1.4
88.4 ⫾ 20.5
85.3 ⫾ 20.8
78.4 ⫾ 22.0
883 (48.8) 777 (42.9) 37.4 ⫾ 26.9
820 (48.3) 991 (58.4) 30.2 ⫾ 26.2
660 (48.6) 942 (69.3) 26.7 ⫾ 24.9
33.1 ⫾ 26.7
29.8 ⫾ 26.0
31.2 ⫾ 27.2
831 (45.9) 398 (22.0) 1031 (56.9) 228 (12.6) 33 (1.8) 123 (6.8) 165 (9.1) 79 (4.4) 1772 (97.8)
1031 (60.8) 644 (38.0) 1135 (66.9) 359 (21.2) 53 (3.1) 99 (5.8) 226 (13.3) 78 (4.6) 1654 (97.5)
1019 (75.0) 710 (52.2) 955 (70.3) 392 (28.8) 67 (4.9) 82 (6.0) 258 (19.0) 50 (3.7) 1300 (95.7)
To show the multivariate model in the 3 age ranges and the impact of the 11 risk factors, we have displayed the data to demonstrate both the independent effect as a number and the predicted rate of decline associated with each risk factor as a plotted point (Figure 2). To determine the predicted risk of FEV1 decline for an individual patient with CF, the independent risk factors are added to the overall rate of decline (first row). For example, consider a 10-year-old boy with an FEV1 of 103% predicted, weight for age in the 20th percentile, with a positive culture for P aeruginosa, and either none or at most intermittent (less than half of encounters) sputum production, crackles, wheezing, and sinusitis. His liver enzymes are not elevated. He has not had a pulmonary exacerbation requiring intravenous antibiotics during the past year. He takes pancreatic enzymes. The estimated rate of decline for this patient would be calculated as ⫺2.39 (overall mean) ⫺0.61 (FEV1 ⱖ100% predicted) ⫺ 0.34 (male) ⫺ 0.22 (positive for P aeruginosa) ⫺ 0.14 (weight for age 10th-24th percentile) ⫹ 0.23 (no daily sputum) ⫹ 0.11 (no crackles) ⫺ 0.04 (no wheezing) ⫺0.02 (no sinusitis) ⫹ 0.17 (no intravenous exacerbations) ⫹ 0.04 (no elevated liver tests) ⫺ 0.01 (pancreatic enzyme use) ⫽ ⫺3.22 percent predicted points of expected FEV1 per year. Over a 4-year period, then, we could predict that this patient’s percent predicted FEV1 would drop by 13 percentage points (from 103% predicted to 90% predicted). A comparison of baseline FEV1 categories in the multivariate models for each age group shows that those patients with higher baseline FEV1 declined more rapidly than those with a lower FEV1, with adjustment for the other risk factors. The small number of patients aged 6 to 12 years with FEV1 136
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Table II. Statistical significance of factors in final multivariate model, by age group P value Ages 6–8 Ages 9–12 Ages 13–17 n ⴝ 1811 n ⴝ 1696 n ⴝ 1359
Factor Overall rate of decline* Baseline FEV1 Female P aeruginosa Weight-for-age percentile Sputum Crackles Wheezing Sinusitis IV exacerbations Elevated LFT Pancreatic enzyme use
.369 ⬍.001 ⬍.001 .002 .842 .111 .004 .524 .050 .006 .984 .023
.006 ⬍.001 ⬍.001 .007 .029 .003 .032 .009 .306 .159 .034 .721
.042 ⬍.001 .002 .398 .021 .003 .010 .066 .951 ⬍.001 .417 .041
*Relative to no decline.
⬍40% predicted did not substantially affect the results for this age group. Crackles were particularly significant for the 6- to 8-year-old group, where the observed rate of decline was ⫺1.86 points per year (⫺1.12 ⫺0.74 ⫽ ⫺1.86) for those with crackles compared with ⫺1.01 points per year (⫺1.12 ⫹ 0.11 ⫽ ⫺1.01) for those without. Other factors associated with rate of FEV1 decline were significant in some but not all age groups (Table II).
DISCUSSION In this analysis, we characterized the rate of FEV1 decline in children and adolescents with CF who participated in a large, prospective observational study. The rates of FEV1 decline that we estimated were either of the same magnitude or less than those previously published from studies assessing FEV1 decline in individuals with CF.1-19 Moreover, we identified many of the same risk factors for FEV1 decline. Both of these observations are reassuring because comparison of results from different studies is difficult because of many different factors, including the number of subjects, the age of subjects, the time period of the analysis (eg, 1970s vs 1990s), the length of observation in years, and inclusion of different clinical characteristics of the individuals. The observation that the rates of FEV1 decline in this analysis are less compared with previous studies may be related to improvements in CF care over time, although this is purely speculative. Our findings confirm earlier reports that higher FEV1, airway infection with P aeruginosa, female sex, and poorer nutritional status are among those factors associated with higher rates of FEV1 decline in individuals with CF.1,3-5,7-9,12,13 However, this analysis presents new information regarding the impact of these risk factors on the rate of FEV1 decline in children at different ages. Many of the previous studies included adults and did not separate children into different age categories. Moreover, our study included a larger number of potential risk factors than previous studies. Of all the risk The Journal of Pediatrics • August 2007
Figure 1. Estimated decline in FEV1% predicted by age group and selected risk factors. Upper left, Overall estimated average decline in percent predicted FEV1 for all patients, by age group. The line segments for the 3 age groups were estimated separately using all the available data; the segment is drawn only over the central 90% of the ages of each group to avoid overemphasizing the extreme values. Upper right, Estimated FEV1 decline for patients with and without crackles, by age group. Lower left, Estimated FEV1 decline by category of percent predicted FEV1 at baseline, by age group. Lower right, Estimated FEV1 decline by sex, by age group.
factors assessed, only 3 (high baseline FEV1, sex, and the presence of crackles) were significant across all 3 age groups. The effects of baseline FEV1 and crackles were quite striking and demonstrated that a factor commonly associated with a relatively healthy patient (high FEV1) and a factor more commonly associated with a sick patient (crackles) can predict a similarly steep decline in FEV1. The effect of other factors, such as the presence of P aeruginosa or daily sputum production, differed among age groups. Previous detection of P aeruginosa in a respiratory tract culture in children aged 6 to 8 years and 9 to 12 years was associated with a greater risk for FEV1 decline, but it was not significantly associated with FEV1 decline in 13- to 17-yearolds. Explanations for this finding might include that a large percentage of the adolescents (69%) had already acquired P aeruginosa, which limited the number of susceptible patients, or that P aeruginosa was present but undetected in the baseline culture and thus was already having an influence on FEV1.
Daily sputum production was not a significant risk factor in 6to 8-year-olds. However, 22% of the youngest patients reported daily sputum production compared with 52% of the older patients, which may partially explain why this factor did not attain statistical significance in the youngest group. Female sex had a negative impact on FEV1 decline among the 6- to 8-year-olds, but it had a positive influence at later ages when adjusted for other salient risk factors. A potential explanation for this finding may be that the females acquired P aeruginosa at an earlier age, as previously reported.5 Among the older children, there might have been a higher rate of new Pseudomonas infection in males. Interestingly, the presence of wheezing, which one might associate with more severe lung disease, was a significant risk factor in the univariate model; but after adjustment for other factors, it was associated with a lower decline in FEV1. Wheezing is easily identified by both patients and clinicians, and clinicians tend to treat wheezing. Given that all other factors are equal, this reduction in the rate of FEV1 decline might be the result of the increased clinical attention and intervention these patients received. However, a close examination of this possibility was beyond the scope of this analysis. Other factors that might potentially affect FEV1 decline, such as B cepacia infection and hemoptysis, were not found to be significant in this analysis, perhaps because they are relatively rare in children. We also recognize that there are many other possible risk factors that could not be assessed in this analysis because we were limited to the variables collected in the ESCF. Nevertheless, this is the most comprehensive analysis of risk factors for FEV1 decline in children that has been performed to date. Our study differs from previous analyses of risk factors associated with FEV1 decline in that it provides clinicians with a method for estimating the rate of FEV1 decline in an individual patient. The example we provided highlights the striking effect of the various risk factors on FEV1 in patients who are commonly cared for by CF clinicians. Surprisingly, high FEV1 was the risk factor with the most significant impact across all ages. This finding should alert clinicians to devote as much attention to this group of patients as they would to patients considered to be sicker on the basis of their pulmonary function values. Evidence from bronchoalveolar lavage and high-resolution computed tomography studies demonstrates the presence of lung disease in patients with minimal pulmonary function abnormalities.23,24 It is inevitable that disease progression will occur in these “well-appearing” patients, and therapeutic interventions initiated during more stable periods might slow their loss of lung function. Because risk factors are additive, clinicians should exercise particular vigilance with patients who have multiple risk factors for increased loss of lung function; such patients might benefit the most from earlier, aggressive intervention. Identifying and understanding the impact of risk factors associated with disease progression, as measured by the rate of decline of the FEV1, is critical not only to the clinical care of
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Figure 2. Results of multivariate models of decline in FEV1% predicted by age group. The first column lists risk factors. The subsequent columns give the number of patients (N) and the estimated effect (EST) of each risk factor in each of the 3 age groups. These effect values can be added to the overall rate of decline (first row) to estimate the rate of FEV1 decline for an individual with various characteristics (see example provided in the text). The graphical display shows the estimated effect of each variable (the dot), with 95% confidence intervals that include the error in the mean (indicated by the line segment).
patients with CF but also has important implications in the design and analysis of clinical trials to assess new therapies for CF. For example, assuming that the rate of FEV1 decline is an outcome measure in a clinical trial, a therapy targeted at patients with a high rate of decline is more likely to demonstrate a significant effect than one targeted at a group of patients with a low rate of decline. This observation has important implications for sample size calculations, because fewer subjects are required to show an effect if the treatment difference is greater. Although this has been demonstrated for high FEV1 in a previous report,19 our analysis includes other 138
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risk factors that might affect sample size calculations. These same risk factors could be considered in randomization schemes and should be considered as covariates in data analysis. Thus identification of risk factors for FEV1 decline has important implications for both clinical care and the design of clinical trials. The authors gratefully acknowledge the participation of the more than 400 site investigators and coordinators in ESCF in collecting this comprehensive database, and the helpful discussions with members of the Scientific Advisory Group for ESCF and the The Journal of Pediatrics • August 2007
editorial assistance of Jill Luer, PharmD, in the preparation of this manuscript.
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12. Steinkamp G, Wiedemann B. Relationship between nutritional status and lung function in cystic fibrosis: cross sectional and longitudinal analyses from the German CF quality assurance (CFQA) project. Thorax 2002;57:596-601. 13. Schaedel C, de Monestrol I, Hjelte L, Johannesson M, Kornfalt R, Lindblad A, et al. Predictors of deterioration of lung function in cystic fibrosis. Pediatr Pulmonol 2002;33:483-91. 14. Drumm ML, Konstan MW, Schluchter MD, Handler A, Pace R, Zou F, et al. Gene modifiers of lung disease in cystic fibrosis. N Engl J Med 2005;353:1443-53. 15. Schluchter MD, Konstan MW, Drumm ML, Yankaskas JR, Knowles MR. Classifying severity of lung disease in cystic fibrosis patients using longitudinal pulmonary function measurements. Am J Respir Crit Care Med 2006;174:780-6. 16. Reisman JJ, Rivington-Law B, Corey M, Marcotte J, Wannamaker E, Harcourt D, Levison H. Role of conventional physiotherapy in cystic fibrosis. J Pediatr 1988;113:632-6. 17. Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 1995;332:848-54. 18. Schneiderman-Walker J, Pollock SL, Corey M, Wilkes DD, Canny GJ, Pedder L, Reisman JJ. A randomized controlled trial of a 3-year home exercise program in cystic fibrosis. J Pediatr 2000;136:304-10. 19. Davis PB, Byard PJ, Konstan MW. Identifying treatments that halt progression of pulmonary disease in cystic fibrosis. Pediatr Res 1997;41:161-5. 20. Morgan WJ, Butler SM, Johnson CA, Colin AA, FitzSimmons SC, Geller DE, Konstan MW, et al. Epidemiologic study of cystic fibrosis: design and implementation of a prospective, multicenter, observational study of patients with cystic fibrosis in the U.S. and Canada. Pediatr Pulmonol 1999;28:231-41. 21. Konstan MW, Butler S, Stoddard M, Zheng B, Morgan WJ. The Epidemiologic Study of Cystic Fibrosis: risk factors for FEV1 decline in children and adolescents with CF. Pediatr Pulmonol 2001(suppl 22):322. 22. Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG Jr. Pulmonary function between 6 and 18 years of age. Pediatr Pulmonol 1993;15:75-88. 23. Konstan MW, Hilliard KA, Norvell TM, Berger M. Bronchoalveolar lavage findings in cystic fibrosis patients with stable, clinically mild lung disease suggest ongoing infection and inflammation. Am J Respir Crit Care Med 1994;150:448-54. 24. de Jong PA, Nakano Y, Lequin MH, Mayo JR, Woods R, Pare PD, Tiddens HA. Progressive damage on high resolution computed tomography despite stable lung function in cystic fibrosis. Eur Respir J 2004;23:93-7.
50 Years Ago in The Journal of Pediatrics OBSTRUCTION
TO LEFT ATRIAL OUTFLOW BY A SUPRAVALVULAR STENOSING RING
Johnson NJ, Dodd K. J Pediatr 1957;51:190-3
Johnson and Dodd describe a girl who died at 11 years of age of supervalvular mitral stenosis. Diagnostic modalities at the time did not allow for premortem diagnosis. This article consisted of a 3-page case presentation in which the progression of congestive heart failure and severe pulmonary hypertension was painfully described. The authors comment that had the diagnosis been made before death, surgery could have been attempted but might not have been successful. Fifty years later, the diagnosis of a supervalvular mitral ring would have been made in the first several weeks of life when this girl presented with difficulty breathing and a poor appetite. Surgical correction of a simple, isolated supervalvular mitral ring is very successful, even in the tiny infant. If the mitral valve is abnormal, palliation is often performed with anticipated complete mitral valve replacement later in childhood. Despite the complications that occur with that operation (anticoagulation, etc), these children now enjoy full and healthy lives. In the future, with fetal echocardiography and fetal heart surgery, these defects may be repaired before the infant is even born. Reginald L. Washington, MD Pediatrix Medical Group Pediatric Cardiology University of Colorado School of Medicine Denver, Colorado 10.1016/j.jpeds.2007.02.028
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APPENDIX North American Scientific Advisory Group: Wayne Morgan (Chair), Michael Konstan (Co-Chair), Andrew Colin, Stacey FitzSimmons, David Geller, Charles Johnson, Michael Light, Ted Liou, Bruce Marshall, Susanna McColley, Ann McMullen, Alexandra Quittner, Harvey Rabin, Warren Regelmann, Clement Ren, Michael Schechter, Daniel Schidlow, Dennis Stokes, Jeff Wagener, Mary Ellen Wohl, Marlyn Woo. ESCF Investigators: Alabama — Dana Brasfield, Raymond Lyrene, Lawrence Sindel; Alaska — Dion Roberts; Arkansas — John Carroll, Robert Warren, Louay Nassri, Paula Anderson; Arizona — Mark Brown, Amy Silverthorn, Peggy Radford, Gerald Gong, Gregory Legris; California — Gerald Greene, Reddivalam Sudhakar, Arnold Platzker, Bruce Nickerson, Karen Hardy, Ivan Harwood, Gregory Shay, Bryon Quick, Allan Lieberthal, Richard Moss, Chris Landon, Yvonne Fanous, Jay Lieberman, Eugene Spiritus, Bradley Chipps, Ruth McDonald, Mark Pian, Gerd Cropp, Nancy Lewis, Dennis Nielson, Bertrand Shapiro; Colorado — Jeff Wagener, Frank Accurso, Milene Saavedra; Connecticut — Karen Daigle, Jacob Hen, Regina Palazzo; Delaware — Kathryn Dodds, Raj Padman, John Goodill; District of Columbia — Glenna Winnie, Lea Davies; Florida — Tony Kriseman, Jorge Sallent, Joseph Chiaro, Martin Kubiet, Sue Goldfinger, Morton Schwartzman, Carlosenrique Diaz, Kevin Maupin, Eduardo Riff, David Geller, Floyd Livingston, Kunjana Mavunda, Jose Birriel, Jr., Luis Faverio, David Rosenberg, David Schaeffer, James Sherman, Mary Wagner, Michael Light, Bruce Schnapf; Georgia — Gary Montgomery, Kevin Kirchner, Mark Weatherly, Daniel Caplan, Margaret Guill, Valera Hudson; Illinois — Javeed Akhter, Donald Davison, Steven Boas, Susanna McColley, Youngran Chung, Rennee Latner, Gabriel Aljadeff, Youngran Chan, Jerome Kraut, Arvey Stone, John Lloyd Still, Girish Sharma, Lanie Eagleton, Patricia Hopkins, Umesh Chatrath, Lucille Lester, Young-Jee Kim; Indiana — Veena Anthony, Howard Eigan, Michelle Howenstine, Pushpom James, Edward Gergesha, James Harris, Robert Plant; Iowa — Veljko Zivkovich, Angela Collins, Edward Nassif, Richard Ahrens; Kansas — Daniel Doornbos, Joseph Kanarek, Richard Leff, Pamela Shaw, Elanor Demoss, Maria Riva, Leonard Sullivan; Kentucky — Michael Anstead, Jamshed Kanga, Nemr Eid, Ron Morton; Louisana — Bettina Hilman, Kim Jones, Scott Davis; Maine — Ralph Harder, Tom Lever, Anne Marie Cairns, Edgar Caldwell, Jonathan Zuckerman; Maryland — Peter Mogayzel, Beryl Rosenstein, John McQuestion, Donna Perry, Samuel Rosenberg; Massachusetts — Robert Gerstle, Andrew Colin, Mary Ellen Wohl, Allan Lapey, William Yee, Brian O’Sullivan, Robert Zwerdling; Michigan — Ibrahim Abdulhamid, Adrian O’Hagan, John Schuen, Lawrence Kurlandsky, Richard Honicky, Douglas Homnick, John Marks, Bohdan Pichurko, Norma Maxvold, Samya Nasr, Richard Simon, Wan Tsai, Dana Kissner; Minnesota — John McNamara, Nancy Henry, Stephen Marker, Michael Pryor, Warren Regelmann, Lynn Walker; Mississippi — Jim Woodward, Louis Mizell, Suzanne Miller; Missouri — Daniel 139.e1
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Rosenbluth, Philip Black, Michael McCubbin, Alan Cohen, Thomas Ferkol, George Mallory, Anthony Rejent, Bruce Rubin, Gavin Graff, Peter Konig; Nebraska — John Colombo, Peter Murphy; New Hampshire — William Boyle, H. Worth Parker; New Jersey — Chandler Patton, Robert Zanni, Arthur Atlas, Nelson Turcios, Lourdes Laraya-Cuasay, Dorothy Bisberg, Helen Aguila; New Mexico — Sarah Allen, David James, Elizabeth Perkett, Marsha Thompson; Nevada — Sonia Budhecha, Ruben Diaz; New York — Jonathan Rosen, Robert Kaslovsky, Ronald Percciacante, Drucy Borowitz, Joseph Cronin, Colin McMahon, Lynne Quittell, Robert Giusti, Rubin Cohen, Joan DeCelie-Germana, Jack Gorvoy, Kalpan Patel, Meyer Kattan, Allen Dozor, Emily DiMango, Maria Berdella, Ran Anbar, Debra Ianuzzi, James Sexton, Catherine Tayag-Kier, John McBride, Clement Ren, Karen Voter, Mary Dimaio; North Carolina — Gerald Georgitis, Joseph Marc Majure, Maria Martinez, J. Clarke McIntosh, Margaret Leigh, Michael Schechter, Hugh Black; North Dakota — James Hughes, Anand Kantak; Ohio — Robert Wilmott, Gregory Omlor, Robert Stone, Karen McCoy, James Acton, Carl Doershuk, Michael Konstan, Robert Fink, Michael Steffan, Pierre Vauthy, Patricia Joseph; Oklahoma — Santiago Reyes, John Kramer, James Royall; Oregon — Jay Eisenberg, Michael Wall; Pennsylvania — Stanley Fiel, Thomas Scanlin, Shroti Phadke, Glenna Winnie, Joel Weinberg, William Sexauer, Stephen Wolf, Douglas Holsclaw, Debra Klein, W. Stuart Warren, Robert Kinsey, Carlos Perez, Muttiah Ganeshanathan, James Shinnick, Howard Panitch, Laurie Varlotta, Cynthia Robinson; Puerto Rico — Jose Rodriguez Santana; Rhode Island — Mary Ann Passero; South Carolina — Jane Gwinn, Robert Baker, C. Michael Bowman, Patrick Flume, Daniel Brown, Roxanne Marville; South Dakota — James Wallace, Rodney Parry; Tennessee — Don Ellenburg, John Rogers, Ricky Mohon, Joel Ledbetter, Aram Hanissian, Robert Schoumacher, Preston Campbell, Christopher Harris, Bonnie Slovis, Dennis Stokes; Texas — Kathryn Hale, Marcia Katz, Dan Seilheimer, Marianne Sockrider, Allan Frank, James Daniel, James Cunningham, Iley Browning, John Bray, Amanda Dove, J. Fernando Mandujano, Larry Tremper, Martha Morse, Donna Willey-Courand, Steven Copenhaver, John Pohl, Bennie McWilliams, Marie Martine-Logvinoff, Marsh Wallace, Robert Klein, Rodolfo Amaro, Leslie Couch, Michael Brown, Claude Prestidge, Stephen Inscore, Andrew Lipton; Utah — Barbara Chatfield, Theodore Liou, Bruce Marshall; Virginia — Karl Karlson, Ignacio Ropoll, Thomas Rubio, Joel Schmidt, David Thomas, John Osborn, Deborah Froh, Benjamin Gaston, Greg Elliott; Vermont — Thomas Lahiri, Donald Swartz, Laurie Whittaker; Washington — Ronald Gibson, Bonnie Ramsey, Michael McCarthy, Lawrence Larson, David Ricker, Mark Robbins, Moira Aitken, Julia Emerson; Wisconsin — Julie Biller, Mark Splaingard, Bradley Sullivan, Paul Pritchard, Stu Adair, Peter Holzwarth, Guillermo Dopico, Keith Meyer, Christopher Green, Michael Rock; West Virginia — Stephen Aronoff, Kathryn Moffett. The Journal of Pediatrics • August 2007
Objectives
To characterize the rate of decline of forced expiratory volume in 1 second (FEV1) in children and adolescents with cystic fibrosis and to identify and compare risk factors associated with FEV1 decline. Study design The rate of decline in FEV1% predicted over 3 to 6 years in 3 different age groups was determined. Risk factors for decline were identified and compared among and within age groups as a function of disease severity with repeatedmeasures, mixed-model regression. Results Mean (ⴞSD) baseline FEV1% predicted was 88.4% ⴞ 20.5% for 6- to 8-year-olds (n ⴝ 1811), 85.3% ⴞ 20.8% for 9- to 12-year-olds (n ⴝ 1696), and 78.4% ⴞ 22.0% for 13- to 17-year-olds (n ⴝ 1359). Decline in FEV1% predicted/year was ⴚ1.12, ⴚ2.39, and ⴚ2.34, respectively. High baseline FEV1 and persistent crackles were significant independent risk factors for decline across all age groups. Female sex, Pseudomonas aeruginosa infection, low weight-for-age, sputum, wheezing, sinusitis, pulmonary exacerbations treated with intravenous antibiotics, elevated liver test results, and pancreatic insufficiency were also identified as independent risk factors in some age See editorial, p 111 groups. Conclusions This study identifies risk factors for FEV1 decline in children and adoFrom the Department of Pediatrics, Rainlescents with cystic fibrosis. Clinicians should not be reassured by high lung function, bow Babies and Children’s Hospital and particularly in young children, because this factor, among others, is independently Case Western Reserve University School of Medicine, Cleveland, Ohio (M.K.); Deassociated with steeper decline in FEV1. (J Pediatr 2007;151:134-9)
he rate of decline in the forced expiratory volume in 1 second (FEV1) has been studied in patients with cystic fibrosis (CF) to better understand the progression of CF lung disease and to identify high-risk groups in whom aggressive therapy may be indicated,1-15 to assess therapeutic interventions,16-18 and to guide sample size estimations for use in designing clinical trials.19 Findings from previous studies suggest that FEV1 decline predicts death in CF7,11 and that therapeutic intervention can slow the decline in FEV1.17 Risk factors associated with FEV1 decline include, but are not limited to, young age,19 high lung function,1,9,19 sex,1,4,5,7-9 cystic fibrosis transmembrane conductance regulator genotype and modifier genes,7,8,13,14 pancreatic insufficiency,7,13 poor nutritional status,8,9,12 respiratory viral infections,2 infection with Pseudomonas aeruginosa or Burkholderia cepacia,3-5,12,13 and diabetes mellitus.10,13 Many of these findings were obtained from studies conducted at single treatment centers or with small numbers of patients, included adults in their analyses, or assessed only a limited number of potential risk factors. The Epidemiologic Study of Cystic Fibrosis (ESCF), a prospective encounter-based study designed to characterize the natural history of the pulmonary disease and growth in a large population of patients with CF (n ⫽ 24,863) in the United States and Canada,20 is a useful resource for the study of FEV1 decline in different age groups of patients. The objectives of this analysis were (1) to characterize the decline in FEV1 % predicted over
T
CF ESCF
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Cystic fibrosis Epidemiologic Study of Cystic Fibrosis
FEV1
Forced expiratory volume in 1 second
partment of Pediatrics and Physiology, University of Arizona, Tucson, Arizona (W.M.); Specialty Biotherapeutics, Genentech, Inc., South San Francisco (S.B., M.C., J.W., C.J.), and Ovation Research Group, San Francisco, California (D.P., S.S.); Department of Pediatrics, Children’s Hospital at Dartmouth and Dartmouth Medical School, Lebanon, New Hampshire (D.S.); Dept. of Pediatrics, Children’s Hospital and Harvard Medical School, Boston, Massachusetts (M.W.); Department of Pediatrics, The Children’s Hospital and University of Colorado School of Medicine, Denver, Colorado (J.W.); and Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (W.R.). Supported by Genentech, Inc., South San Francisco, Calif. Submitted for publication Jun 30, 2006; last revision received Dec 1, 2006; accepted Mar 5, 2007. Reprint requests: Michael W. Konstan, MD, Rainbow Babies and Children’s Hospital, 11100 Euclid Ave, Cleveland, OH 44106. E-mail: [email protected]. *List of members available at www.jpeds. com. 0022-3476/$ - see front matter Copyright © 2007 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2007.03.006
a 3- to 6-year period in children and adolescents with CF aged 6 to 8 years, 9 to 12 years, and 13 to 17 years; and (2) to identify and compare risk factors for the 3- to 6-year decline in FEV1% predicted in different age groups and among patients in each age group as a function of severity of lung disease. Some of the results of this analysis have been previously reported in abstract form.21
METHODS Patients 6 to 17 years old were included if they had at least 3 spirometry measurements obtained at times of clinical stability after enrollment in ESCF. The first measurement was defined as the baseline spirometry. A 1-year lead-in period followed, during which baseline clinical characteristics were assessed. The subsequent 5.5 years comprised the observation period. To ensure adequate long-term follow-up, spirometry must have been performed at times of clinical stability at least once during the first year of observation and again after 3 years. Of the 9410 patients aged 6 to 17 years in ESCF by December 1997, 4923 met these criteria. Written informed consent was obtained at institutions where required. To characterize the rate of decline in FEV1% predicted during the observation period, patients were categorized according to age at baseline spirometry (6-8 years, 9-12 years, and 13-17 years). To reduce bias caused by variation in the frequency of testing, the spirometry obtained during a time of clinical stability closest to the 6-month (⫾3 months) anniversary after the first test during the observation period was selected for each patient. The equations of Wang et al22 were used to calculate the percent of predicted FEV1. Repeatedmeasures, mixed-model regression analysis was used to estimate mean rate of change in FEV1% predicted within age groups and to explore baseline risk factors for decline in FEV1% predicted. Potential baseline risk factors included age at baseline spirometry; sex; baseline FEV1% predicted; growth indexes (including body mass index) at the last visit during lead-in; respiratory tract culture results for P aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Burkholderia cepacia, Stenotrophomonas maltophilia, other gram-negative organisms, Candida, and Aspergillus from the last culture during lead-in; signs and symptoms during lead-in consisting of daily cough, daily sputum production, hemoptysis, clubbing, crackles, and wheezing; medical conditions during lead-in consisting of asthma, allergic bronchopulmonary aspergillosis, sinusitis, nasal polyps, elevated liver tests, CF-related diabetes mellitus (insulin/oral hypoglycemic use), and pancreatic insufficiency (enzyme use); and the frequency of pulmonary exacerbations requiring treatment with intravenous antibiotics (exacerbations) during lead-in. For potential risk factors assessed throughout the 1-year lead-in period, patients were categorized as positive for each characteristic that was present on at least half of encounters during this period. To determine the most important independent risk factors, a multivariate, linear mixed-effects model of FEV1 %
predicted was developed separately for each age group. Risk factors were screened for univariate association with the rate of decline (P ⬍ .1); then a list of risk factors was created by use of multivariate models with backward selection, retaining those with P ⬍ .05. To allow comparison of all independent risk factors across age groups, factors retained in any age group were combined in the final multivariate model for each age group. Baseline FEV1% predicted was included as a continuous variable and as a 4-category variable interacted with time. Regression to the mean because of correlated errors was limited because baseline FEV1 was obtained 12 months before the beginning of the observation period. All analyses were performed with SAS Version 9.1 (Cary, NC).
RESULTS Of the 4923 patients who met the inclusion criteria, 4866 (98.8%) had data available for all of the final risk factors and were included in the final model. Baseline and lead-in year characteristics are shown in Table I. Progression of lung disease is evident on the basis of a cross-sectional analysis of baseline FEV1, which was highest in the 6- to 8-year-old group and lowest in the 13- to 17-year-old group. The percentage of patients with a positive respiratory tract culture for P aeruginosa at baseline increased from the youngest to the oldest age group, as did signs and symptoms of lung disease. Baseline nutritional status, indicated by weight for age, was best in the youngest children and worst in the adolescents. The mean duration of observation from the end of the lead-in year to the last spirometry measurement was 4.4 years (range 3.0-5.8). The median number of spirometry measures included per patient was 8. The final set of risk factors and associated P values for each age group are given in Table II. The annualized rate of FEV1 decline for each age group, unadjusted for other factors, is shown in Figure 1, upper left panel. Overall, the 6- to 8-year-old children exhibited a slower rate of decline compared with those aged 9 to 12 and 13 to 17 years. The line segments for the 3 age groups were estimated separately, and although they nearly connect exactly, they were not forced to do so. The most significant risk factors for decline in FEV1 were crackles, high baseline FEV1, and sex. The univariate association of each of these risk factors with decline in FEV1 is shown in the upper right, lower left, and lower right panels of Figure 1, presented as the estimated rate of decline for patients with and without each risk factor. This analysis does not include adjustment for other factors; for example, the decline for patients with crackles also reflects the presence of other risk factors in patients with crackles. In the lower left panel of Figure 1, the line for FEV1 ⬍40% predicted in the 6- to 8-year-old children is high because of regression to the mean in this small (n ⫽ 26) group. For most of the risk factors, the effect was in the same direction for all age groups. Sex is an exception; in the 6- to 8-year-old group, females demonstrated higher rates of decline, even though in 9- to 17-year-old children and adolescents, females showed lower rates of decline (Figure 1, lower right panel).
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Table I. Patient characteristics by age group Ages 6–8 n ⴝ 1811
Ages 9–12 n ⴝ 1696
Ages 13–17 n ⴝ 1359
Characteristic
n (%)
n (%)
n (%)
Age in years (mean ⫾ SD) Baseline FEV1 (mean ⫾ SD) Female P aeruginosa Weight-for-age percentile (mean ⫾ SD) Height-for-age percentile (mean ⫾ SD) Cough Sputum Clubbing Crackles Wheezing Sinusitis ⱖ2 IV exacerbations Elevated LFT Pancreatic enzyme use
7.2 ⫾ 0.9
10.9 ⫾ 1.2
15.2 ⫾ 1.4
88.4 ⫾ 20.5
85.3 ⫾ 20.8
78.4 ⫾ 22.0
883 (48.8) 777 (42.9) 37.4 ⫾ 26.9
820 (48.3) 991 (58.4) 30.2 ⫾ 26.2
660 (48.6) 942 (69.3) 26.7 ⫾ 24.9
33.1 ⫾ 26.7
29.8 ⫾ 26.0
31.2 ⫾ 27.2
831 (45.9) 398 (22.0) 1031 (56.9) 228 (12.6) 33 (1.8) 123 (6.8) 165 (9.1) 79 (4.4) 1772 (97.8)
1031 (60.8) 644 (38.0) 1135 (66.9) 359 (21.2) 53 (3.1) 99 (5.8) 226 (13.3) 78 (4.6) 1654 (97.5)
1019 (75.0) 710 (52.2) 955 (70.3) 392 (28.8) 67 (4.9) 82 (6.0) 258 (19.0) 50 (3.7) 1300 (95.7)
To show the multivariate model in the 3 age ranges and the impact of the 11 risk factors, we have displayed the data to demonstrate both the independent effect as a number and the predicted rate of decline associated with each risk factor as a plotted point (Figure 2). To determine the predicted risk of FEV1 decline for an individual patient with CF, the independent risk factors are added to the overall rate of decline (first row). For example, consider a 10-year-old boy with an FEV1 of 103% predicted, weight for age in the 20th percentile, with a positive culture for P aeruginosa, and either none or at most intermittent (less than half of encounters) sputum production, crackles, wheezing, and sinusitis. His liver enzymes are not elevated. He has not had a pulmonary exacerbation requiring intravenous antibiotics during the past year. He takes pancreatic enzymes. The estimated rate of decline for this patient would be calculated as ⫺2.39 (overall mean) ⫺0.61 (FEV1 ⱖ100% predicted) ⫺ 0.34 (male) ⫺ 0.22 (positive for P aeruginosa) ⫺ 0.14 (weight for age 10th-24th percentile) ⫹ 0.23 (no daily sputum) ⫹ 0.11 (no crackles) ⫺ 0.04 (no wheezing) ⫺0.02 (no sinusitis) ⫹ 0.17 (no intravenous exacerbations) ⫹ 0.04 (no elevated liver tests) ⫺ 0.01 (pancreatic enzyme use) ⫽ ⫺3.22 percent predicted points of expected FEV1 per year. Over a 4-year period, then, we could predict that this patient’s percent predicted FEV1 would drop by 13 percentage points (from 103% predicted to 90% predicted). A comparison of baseline FEV1 categories in the multivariate models for each age group shows that those patients with higher baseline FEV1 declined more rapidly than those with a lower FEV1, with adjustment for the other risk factors. The small number of patients aged 6 to 12 years with FEV1 136
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Table II. Statistical significance of factors in final multivariate model, by age group P value Ages 6–8 Ages 9–12 Ages 13–17 n ⴝ 1811 n ⴝ 1696 n ⴝ 1359
Factor Overall rate of decline* Baseline FEV1 Female P aeruginosa Weight-for-age percentile Sputum Crackles Wheezing Sinusitis IV exacerbations Elevated LFT Pancreatic enzyme use
.369 ⬍.001 ⬍.001 .002 .842 .111 .004 .524 .050 .006 .984 .023
.006 ⬍.001 ⬍.001 .007 .029 .003 .032 .009 .306 .159 .034 .721
.042 ⬍.001 .002 .398 .021 .003 .010 .066 .951 ⬍.001 .417 .041
*Relative to no decline.
⬍40% predicted did not substantially affect the results for this age group. Crackles were particularly significant for the 6- to 8-year-old group, where the observed rate of decline was ⫺1.86 points per year (⫺1.12 ⫺0.74 ⫽ ⫺1.86) for those with crackles compared with ⫺1.01 points per year (⫺1.12 ⫹ 0.11 ⫽ ⫺1.01) for those without. Other factors associated with rate of FEV1 decline were significant in some but not all age groups (Table II).
DISCUSSION In this analysis, we characterized the rate of FEV1 decline in children and adolescents with CF who participated in a large, prospective observational study. The rates of FEV1 decline that we estimated were either of the same magnitude or less than those previously published from studies assessing FEV1 decline in individuals with CF.1-19 Moreover, we identified many of the same risk factors for FEV1 decline. Both of these observations are reassuring because comparison of results from different studies is difficult because of many different factors, including the number of subjects, the age of subjects, the time period of the analysis (eg, 1970s vs 1990s), the length of observation in years, and inclusion of different clinical characteristics of the individuals. The observation that the rates of FEV1 decline in this analysis are less compared with previous studies may be related to improvements in CF care over time, although this is purely speculative. Our findings confirm earlier reports that higher FEV1, airway infection with P aeruginosa, female sex, and poorer nutritional status are among those factors associated with higher rates of FEV1 decline in individuals with CF.1,3-5,7-9,12,13 However, this analysis presents new information regarding the impact of these risk factors on the rate of FEV1 decline in children at different ages. Many of the previous studies included adults and did not separate children into different age categories. Moreover, our study included a larger number of potential risk factors than previous studies. Of all the risk The Journal of Pediatrics • August 2007
Figure 1. Estimated decline in FEV1% predicted by age group and selected risk factors. Upper left, Overall estimated average decline in percent predicted FEV1 for all patients, by age group. The line segments for the 3 age groups were estimated separately using all the available data; the segment is drawn only over the central 90% of the ages of each group to avoid overemphasizing the extreme values. Upper right, Estimated FEV1 decline for patients with and without crackles, by age group. Lower left, Estimated FEV1 decline by category of percent predicted FEV1 at baseline, by age group. Lower right, Estimated FEV1 decline by sex, by age group.
factors assessed, only 3 (high baseline FEV1, sex, and the presence of crackles) were significant across all 3 age groups. The effects of baseline FEV1 and crackles were quite striking and demonstrated that a factor commonly associated with a relatively healthy patient (high FEV1) and a factor more commonly associated with a sick patient (crackles) can predict a similarly steep decline in FEV1. The effect of other factors, such as the presence of P aeruginosa or daily sputum production, differed among age groups. Previous detection of P aeruginosa in a respiratory tract culture in children aged 6 to 8 years and 9 to 12 years was associated with a greater risk for FEV1 decline, but it was not significantly associated with FEV1 decline in 13- to 17-yearolds. Explanations for this finding might include that a large percentage of the adolescents (69%) had already acquired P aeruginosa, which limited the number of susceptible patients, or that P aeruginosa was present but undetected in the baseline culture and thus was already having an influence on FEV1.
Daily sputum production was not a significant risk factor in 6to 8-year-olds. However, 22% of the youngest patients reported daily sputum production compared with 52% of the older patients, which may partially explain why this factor did not attain statistical significance in the youngest group. Female sex had a negative impact on FEV1 decline among the 6- to 8-year-olds, but it had a positive influence at later ages when adjusted for other salient risk factors. A potential explanation for this finding may be that the females acquired P aeruginosa at an earlier age, as previously reported.5 Among the older children, there might have been a higher rate of new Pseudomonas infection in males. Interestingly, the presence of wheezing, which one might associate with more severe lung disease, was a significant risk factor in the univariate model; but after adjustment for other factors, it was associated with a lower decline in FEV1. Wheezing is easily identified by both patients and clinicians, and clinicians tend to treat wheezing. Given that all other factors are equal, this reduction in the rate of FEV1 decline might be the result of the increased clinical attention and intervention these patients received. However, a close examination of this possibility was beyond the scope of this analysis. Other factors that might potentially affect FEV1 decline, such as B cepacia infection and hemoptysis, were not found to be significant in this analysis, perhaps because they are relatively rare in children. We also recognize that there are many other possible risk factors that could not be assessed in this analysis because we were limited to the variables collected in the ESCF. Nevertheless, this is the most comprehensive analysis of risk factors for FEV1 decline in children that has been performed to date. Our study differs from previous analyses of risk factors associated with FEV1 decline in that it provides clinicians with a method for estimating the rate of FEV1 decline in an individual patient. The example we provided highlights the striking effect of the various risk factors on FEV1 in patients who are commonly cared for by CF clinicians. Surprisingly, high FEV1 was the risk factor with the most significant impact across all ages. This finding should alert clinicians to devote as much attention to this group of patients as they would to patients considered to be sicker on the basis of their pulmonary function values. Evidence from bronchoalveolar lavage and high-resolution computed tomography studies demonstrates the presence of lung disease in patients with minimal pulmonary function abnormalities.23,24 It is inevitable that disease progression will occur in these “well-appearing” patients, and therapeutic interventions initiated during more stable periods might slow their loss of lung function. Because risk factors are additive, clinicians should exercise particular vigilance with patients who have multiple risk factors for increased loss of lung function; such patients might benefit the most from earlier, aggressive intervention. Identifying and understanding the impact of risk factors associated with disease progression, as measured by the rate of decline of the FEV1, is critical not only to the clinical care of
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Figure 2. Results of multivariate models of decline in FEV1% predicted by age group. The first column lists risk factors. The subsequent columns give the number of patients (N) and the estimated effect (EST) of each risk factor in each of the 3 age groups. These effect values can be added to the overall rate of decline (first row) to estimate the rate of FEV1 decline for an individual with various characteristics (see example provided in the text). The graphical display shows the estimated effect of each variable (the dot), with 95% confidence intervals that include the error in the mean (indicated by the line segment).
patients with CF but also has important implications in the design and analysis of clinical trials to assess new therapies for CF. For example, assuming that the rate of FEV1 decline is an outcome measure in a clinical trial, a therapy targeted at patients with a high rate of decline is more likely to demonstrate a significant effect than one targeted at a group of patients with a low rate of decline. This observation has important implications for sample size calculations, because fewer subjects are required to show an effect if the treatment difference is greater. Although this has been demonstrated for high FEV1 in a previous report,19 our analysis includes other 138
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risk factors that might affect sample size calculations. These same risk factors could be considered in randomization schemes and should be considered as covariates in data analysis. Thus identification of risk factors for FEV1 decline has important implications for both clinical care and the design of clinical trials. The authors gratefully acknowledge the participation of the more than 400 site investigators and coordinators in ESCF in collecting this comprehensive database, and the helpful discussions with members of the Scientific Advisory Group for ESCF and the The Journal of Pediatrics • August 2007
editorial assistance of Jill Luer, PharmD, in the preparation of this manuscript.
REFERENCES 1. Corey M, Levison H, Crozier D. Five- to seven-year course of pulmonary function in cystic fibrosis. Am Rev Respir Dis 1976;114:1085-92. 2. Wang EE, Prober CG, Manson B, Corey M, Levison H. Association of respiratory viral infections with pulmonary deterioration in patients with cystic fibrosis. N Engl J Med 1984;311:1653-8. 3. Kerem E, Corey M, Gold R, Levison H. Pulmonary function and clinical course in patients with cystic fibrosis after pulmonary colonization with Pseudomonas aeruginosa. J Pediatr 1990;116:714-9. 4. Lewin LO, Byard PJ, Davis PB. Effect of Pseudomonas cepacia colonization on survival and pulmonary function of cystic fibrosis patients. J Clin Epidemiol 1990;43:125-31. 5. Demko CA, Byard PJ, Davis PB. Gender differences in cystic fibrosis: Pseudomonas aeruginosa infection. J Clin Epidemiol 1995;48:1041-9. 6. 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;50:712-8. 7. Corey M, Edwards L, Levison H, Knowles M. Longitudinal analysis of pulmonary function decline in patients with cystic fibrosis. J Pediatr 1997;131:809-14. 8. Zemel BS, Kawchak DA, Cnaan A, Zhao H, Scanlin TF, Stallings VA. Prospective evaluation of resting energy expenditure, nutritional status, pulmonary function, and genotype in children with cystic fibrosis. Pediatr Res 1996;40:578-86. 9. Zemel BS, Jawad AF, FitzSimmons S, Stallings VA. Longitudinal relationship among growth, nutritional status, and pulmonary function in children with cystic fibrosis: analysis of the Cystic Fibrosis Foundation National CF Patient Registry. J Pediatr 2000;137:374-80. 10. Milla CE, Warwick WJ, Moran A. Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline. Am J Respir Crit Care Med 2000;162(Pt 1):891-5. 11. Schluchter MD, Konstan MW, Davis PB. Jointly modeling the relationship between survival and pulmonary function in cystic fibrosis patients. Stat Med 2002;21:1271-87.
12. Steinkamp G, Wiedemann B. Relationship between nutritional status and lung function in cystic fibrosis: cross sectional and longitudinal analyses from the German CF quality assurance (CFQA) project. Thorax 2002;57:596-601. 13. Schaedel C, de Monestrol I, Hjelte L, Johannesson M, Kornfalt R, Lindblad A, et al. Predictors of deterioration of lung function in cystic fibrosis. Pediatr Pulmonol 2002;33:483-91. 14. Drumm ML, Konstan MW, Schluchter MD, Handler A, Pace R, Zou F, et al. Gene modifiers of lung disease in cystic fibrosis. N Engl J Med 2005;353:1443-53. 15. Schluchter MD, Konstan MW, Drumm ML, Yankaskas JR, Knowles MR. Classifying severity of lung disease in cystic fibrosis patients using longitudinal pulmonary function measurements. Am J Respir Crit Care Med 2006;174:780-6. 16. Reisman JJ, Rivington-Law B, Corey M, Marcotte J, Wannamaker E, Harcourt D, Levison H. Role of conventional physiotherapy in cystic fibrosis. J Pediatr 1988;113:632-6. 17. Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 1995;332:848-54. 18. Schneiderman-Walker J, Pollock SL, Corey M, Wilkes DD, Canny GJ, Pedder L, Reisman JJ. A randomized controlled trial of a 3-year home exercise program in cystic fibrosis. J Pediatr 2000;136:304-10. 19. Davis PB, Byard PJ, Konstan MW. Identifying treatments that halt progression of pulmonary disease in cystic fibrosis. Pediatr Res 1997;41:161-5. 20. Morgan WJ, Butler SM, Johnson CA, Colin AA, FitzSimmons SC, Geller DE, Konstan MW, et al. Epidemiologic study of cystic fibrosis: design and implementation of a prospective, multicenter, observational study of patients with cystic fibrosis in the U.S. and Canada. Pediatr Pulmonol 1999;28:231-41. 21. Konstan MW, Butler S, Stoddard M, Zheng B, Morgan WJ. The Epidemiologic Study of Cystic Fibrosis: risk factors for FEV1 decline in children and adolescents with CF. Pediatr Pulmonol 2001(suppl 22):322. 22. Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG Jr. Pulmonary function between 6 and 18 years of age. Pediatr Pulmonol 1993;15:75-88. 23. Konstan MW, Hilliard KA, Norvell TM, Berger M. Bronchoalveolar lavage findings in cystic fibrosis patients with stable, clinically mild lung disease suggest ongoing infection and inflammation. Am J Respir Crit Care Med 1994;150:448-54. 24. de Jong PA, Nakano Y, Lequin MH, Mayo JR, Woods R, Pare PD, Tiddens HA. Progressive damage on high resolution computed tomography despite stable lung function in cystic fibrosis. Eur Respir J 2004;23:93-7.
50 Years Ago in The Journal of Pediatrics OBSTRUCTION
TO LEFT ATRIAL OUTFLOW BY A SUPRAVALVULAR STENOSING RING
Johnson NJ, Dodd K. J Pediatr 1957;51:190-3
Johnson and Dodd describe a girl who died at 11 years of age of supervalvular mitral stenosis. Diagnostic modalities at the time did not allow for premortem diagnosis. This article consisted of a 3-page case presentation in which the progression of congestive heart failure and severe pulmonary hypertension was painfully described. The authors comment that had the diagnosis been made before death, surgery could have been attempted but might not have been successful. Fifty years later, the diagnosis of a supervalvular mitral ring would have been made in the first several weeks of life when this girl presented with difficulty breathing and a poor appetite. Surgical correction of a simple, isolated supervalvular mitral ring is very successful, even in the tiny infant. If the mitral valve is abnormal, palliation is often performed with anticipated complete mitral valve replacement later in childhood. Despite the complications that occur with that operation (anticoagulation, etc), these children now enjoy full and healthy lives. In the future, with fetal echocardiography and fetal heart surgery, these defects may be repaired before the infant is even born. Reginald L. Washington, MD Pediatrix Medical Group Pediatric Cardiology University of Colorado School of Medicine Denver, Colorado 10.1016/j.jpeds.2007.02.028
Risk Factors for Rate of Decline in Forced Expiratory Volume in One Second in Children and Adolescents with Cystic Fibrosis
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APPENDIX North American Scientific Advisory Group: Wayne Morgan (Chair), Michael Konstan (Co-Chair), Andrew Colin, Stacey FitzSimmons, David Geller, Charles Johnson, Michael Light, Ted Liou, Bruce Marshall, Susanna McColley, Ann McMullen, Alexandra Quittner, Harvey Rabin, Warren Regelmann, Clement Ren, Michael Schechter, Daniel Schidlow, Dennis Stokes, Jeff Wagener, Mary Ellen Wohl, Marlyn Woo. ESCF Investigators: Alabama — Dana Brasfield, Raymond Lyrene, Lawrence Sindel; Alaska — Dion Roberts; Arkansas — John Carroll, Robert Warren, Louay Nassri, Paula Anderson; Arizona — Mark Brown, Amy Silverthorn, Peggy Radford, Gerald Gong, Gregory Legris; California — Gerald Greene, Reddivalam Sudhakar, Arnold Platzker, Bruce Nickerson, Karen Hardy, Ivan Harwood, Gregory Shay, Bryon Quick, Allan Lieberthal, Richard Moss, Chris Landon, Yvonne Fanous, Jay Lieberman, Eugene Spiritus, Bradley Chipps, Ruth McDonald, Mark Pian, Gerd Cropp, Nancy Lewis, Dennis Nielson, Bertrand Shapiro; Colorado — Jeff Wagener, Frank Accurso, Milene Saavedra; Connecticut — Karen Daigle, Jacob Hen, Regina Palazzo; Delaware — Kathryn Dodds, Raj Padman, John Goodill; District of Columbia — Glenna Winnie, Lea Davies; Florida — Tony Kriseman, Jorge Sallent, Joseph Chiaro, Martin Kubiet, Sue Goldfinger, Morton Schwartzman, Carlosenrique Diaz, Kevin Maupin, Eduardo Riff, David Geller, Floyd Livingston, Kunjana Mavunda, Jose Birriel, Jr., Luis Faverio, David Rosenberg, David Schaeffer, James Sherman, Mary Wagner, Michael Light, Bruce Schnapf; Georgia — Gary Montgomery, Kevin Kirchner, Mark Weatherly, Daniel Caplan, Margaret Guill, Valera Hudson; Illinois — Javeed Akhter, Donald Davison, Steven Boas, Susanna McColley, Youngran Chung, Rennee Latner, Gabriel Aljadeff, Youngran Chan, Jerome Kraut, Arvey Stone, John Lloyd Still, Girish Sharma, Lanie Eagleton, Patricia Hopkins, Umesh Chatrath, Lucille Lester, Young-Jee Kim; Indiana — Veena Anthony, Howard Eigan, Michelle Howenstine, Pushpom James, Edward Gergesha, James Harris, Robert Plant; Iowa — Veljko Zivkovich, Angela Collins, Edward Nassif, Richard Ahrens; Kansas — Daniel Doornbos, Joseph Kanarek, Richard Leff, Pamela Shaw, Elanor Demoss, Maria Riva, Leonard Sullivan; Kentucky — Michael Anstead, Jamshed Kanga, Nemr Eid, Ron Morton; Louisana — Bettina Hilman, Kim Jones, Scott Davis; Maine — Ralph Harder, Tom Lever, Anne Marie Cairns, Edgar Caldwell, Jonathan Zuckerman; Maryland — Peter Mogayzel, Beryl Rosenstein, John McQuestion, Donna Perry, Samuel Rosenberg; Massachusetts — Robert Gerstle, Andrew Colin, Mary Ellen Wohl, Allan Lapey, William Yee, Brian O’Sullivan, Robert Zwerdling; Michigan — Ibrahim Abdulhamid, Adrian O’Hagan, John Schuen, Lawrence Kurlandsky, Richard Honicky, Douglas Homnick, John Marks, Bohdan Pichurko, Norma Maxvold, Samya Nasr, Richard Simon, Wan Tsai, Dana Kissner; Minnesota — John McNamara, Nancy Henry, Stephen Marker, Michael Pryor, Warren Regelmann, Lynn Walker; Mississippi — Jim Woodward, Louis Mizell, Suzanne Miller; Missouri — Daniel 139.e1
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Rosenbluth, Philip Black, Michael McCubbin, Alan Cohen, Thomas Ferkol, George Mallory, Anthony Rejent, Bruce Rubin, Gavin Graff, Peter Konig; Nebraska — John Colombo, Peter Murphy; New Hampshire — William Boyle, H. Worth Parker; New Jersey — Chandler Patton, Robert Zanni, Arthur Atlas, Nelson Turcios, Lourdes Laraya-Cuasay, Dorothy Bisberg, Helen Aguila; New Mexico — Sarah Allen, David James, Elizabeth Perkett, Marsha Thompson; Nevada — Sonia Budhecha, Ruben Diaz; New York — Jonathan Rosen, Robert Kaslovsky, Ronald Percciacante, Drucy Borowitz, Joseph Cronin, Colin McMahon, Lynne Quittell, Robert Giusti, Rubin Cohen, Joan DeCelie-Germana, Jack Gorvoy, Kalpan Patel, Meyer Kattan, Allen Dozor, Emily DiMango, Maria Berdella, Ran Anbar, Debra Ianuzzi, James Sexton, Catherine Tayag-Kier, John McBride, Clement Ren, Karen Voter, Mary Dimaio; North Carolina — Gerald Georgitis, Joseph Marc Majure, Maria Martinez, J. Clarke McIntosh, Margaret Leigh, Michael Schechter, Hugh Black; North Dakota — James Hughes, Anand Kantak; Ohio — Robert Wilmott, Gregory Omlor, Robert Stone, Karen McCoy, James Acton, Carl Doershuk, Michael Konstan, Robert Fink, Michael Steffan, Pierre Vauthy, Patricia Joseph; Oklahoma — Santiago Reyes, John Kramer, James Royall; Oregon — Jay Eisenberg, Michael Wall; Pennsylvania — Stanley Fiel, Thomas Scanlin, Shroti Phadke, Glenna Winnie, Joel Weinberg, William Sexauer, Stephen Wolf, Douglas Holsclaw, Debra Klein, W. Stuart Warren, Robert Kinsey, Carlos Perez, Muttiah Ganeshanathan, James Shinnick, Howard Panitch, Laurie Varlotta, Cynthia Robinson; Puerto Rico — Jose Rodriguez Santana; Rhode Island — Mary Ann Passero; South Carolina — Jane Gwinn, Robert Baker, C. Michael Bowman, Patrick Flume, Daniel Brown, Roxanne Marville; South Dakota — James Wallace, Rodney Parry; Tennessee — Don Ellenburg, John Rogers, Ricky Mohon, Joel Ledbetter, Aram Hanissian, Robert Schoumacher, Preston Campbell, Christopher Harris, Bonnie Slovis, Dennis Stokes; Texas — Kathryn Hale, Marcia Katz, Dan Seilheimer, Marianne Sockrider, Allan Frank, James Daniel, James Cunningham, Iley Browning, John Bray, Amanda Dove, J. Fernando Mandujano, Larry Tremper, Martha Morse, Donna Willey-Courand, Steven Copenhaver, John Pohl, Bennie McWilliams, Marie Martine-Logvinoff, Marsh Wallace, Robert Klein, Rodolfo Amaro, Leslie Couch, Michael Brown, Claude Prestidge, Stephen Inscore, Andrew Lipton; Utah — Barbara Chatfield, Theodore Liou, Bruce Marshall; Virginia — Karl Karlson, Ignacio Ropoll, Thomas Rubio, Joel Schmidt, David Thomas, John Osborn, Deborah Froh, Benjamin Gaston, Greg Elliott; Vermont — Thomas Lahiri, Donald Swartz, Laurie Whittaker; Washington — Ronald Gibson, Bonnie Ramsey, Michael McCarthy, Lawrence Larson, David Ricker, Mark Robbins, Moira Aitken, Julia Emerson; Wisconsin — Julie Biller, Mark Splaingard, Bradley Sullivan, Paul Pritchard, Stu Adair, Peter Holzwarth, Guillermo Dopico, Keith Meyer, Christopher Green, Michael Rock; West Virginia — Stephen Aronoff, Kathryn Moffett. The Journal of Pediatrics • August 2007