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Rapid lung function decline in adults with early-stage cystic fibrosis lung disease
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Original Article
Rapid lung function decline in adults with early-stage cystic fibrosis lung disease Elliott C. Dasenbrook a,∗, Aliza K. Fink b, Michael S. Schechter c, Don B. Sanders d, Stefanie J. Millar e, David J. Pasta e, Nicole Mayer-Hamblett f,g a
Respiratory Institute, Cleveland Clinic, Cleveland, OH, United States Cystic Fibrosis Foundation, Bethesda, MD, United States Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, VA, United States d Indiana University School of Medicine, Indianapolis, IN, United States e ICON Clinical Research, San Francisco, CA, United States f University of Washington, Seattle, WA, United States g Seattle Children’s Hospital, Seattle, WA, United States b c
a r t i c l e
i n f o
Article history: Received 25 June 2019 Revised 2 December 2019 Accepted 7 December 2019 Available online xxx Classification: 90 PULMONOLOGY Keywords: Cystic fibrosis Adult Risk factors Respiratory function tests Cohort studies
a b s t r a c t Rationale: The prevalence of adults living with cystic fibrosis (CF) who have early-stage lung disease is increasing. Objectives: Describe the prevalence and evaluate spirometric risk factors associated with the subgroup of patients with early-stage lung disease and FEV1 decline of ≥5% predicted/year. Methods: Retrospective cohort study of patients ≥18 years with FEV1 % predicted ≥80% included in the US CF Foundation Patient Registry from 2010–2013. Regression models were developed to estimate FEV1 rate of decline. Multivariable logistic analysis was used to assess if spirometric risk factors were associated with FEV1 decline. Measurements and main results: 3,029 subjects were in the study cohort. Approximately 15% of the cohort had a substantial decline in lung function ≥5% predicted/year. In multivariable models adjusted for confounders, FEV1 /FVC ratio <0.8 (Odds Ratio (OR) 1.63, 95% confidence interval (CI) 1.31 to 2.02) and history of FEV1 % predicted variability (OR 2.35,95%CI 1.74 to 3.18) were associated with rapid lung function decline. Conclusions: Even among adults with early-stage lung disease, approximately 15% are shown to progress and experience a large decline in lung function. This reinforces the concept that lung function in earlystage CF is not normal or mild. Rather, lung function decline may be delayed, but not avoided, in these individuals. Variability in FEV1 % predicted and airway obstruction as measured by FEV1/FVC ratio may identify individuals at increased risk of decline. Adults with early-stage lung disease should be followed in clinic to monitor for onset of decline. © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
1. Introduction The prevalence of adult cystic fibrosis (CF) patients with earlystage lung disease is increasing [1]. According to the US CF Foundation Patient Registry (CFFPR) report, the median forced expiratory volume in one second (FEV1 ) of 18 year olds increased from 66% to 83% over a 20 year period. A similar pattern was seen among
∗ Corresponding author at: The Cleveland Clinic Foundation, 9500 Euclid Avenue – A90, Cleveland, OH 44195, United States. E-mail address: [email protected] (E.C. Dasenbrook).
30 year olds as the median FEV1 increased from 49% to 61% over the same time period [1]. In the future, the prevalence of adults with early-stage lung disease in the United States will most likely continue to increase due to the wider availability of new medications that treat the basic defect [2], universal newborn screening [3], and increasingly proactive treatment such as early eradication of Pseudomonas aeruginosa [4]. The discussion between clinicians and adult individuals with CF about approach to treatment is complex, centering on the patients’ preferences regarding their care, effectiveness of various treatment options, and treatment burden [5]. The evidence base to support this discussion is scant as randomized clinical trials frequently do
https://doi.org/10.1016/j.jcf.2019.12.005 1569-1993/© 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
Please cite this article as: E.C. Dasenbrook, A.K. Fink and M.S. Schechter et al., Rapid lung function decline in adults with early-stage cystic fibrosis lung disease, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.12.005
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not include large numbers of individuals with early-stage lung disease and epidemiologic studies have largely been based on cohorts from previous treatment eras. It is known that patients with earlystage CF lung disease are at risk for increased rates of lung function decline [6,7]. In addition, Nick and colleagues have demonstrated that long-term survivors of CF (to age > 40 years) do not have “mild” lung disease, but rather they experience delayed onset of severe lung disease [8]. A natural conclusion is that earlyintervention may help prevent or ameliorate subsequent lung function decline; however, the decision about when and with whom to intervene is difficult since the timing of patients’ rapid decline is unknown. Morgan and colleagues have previously established that variability in FEV1 identifies risk of subsequent decline however was not specifically studied in those with early-stage lung disease [9]. Understanding risk factors for rapid progression of lung disease could provide patients with early-stage lung disease key information when balancing the benefits of using chronic CF medications against the large treatment burden individuals with CF endure. We hypothesize that among adult CF patients with early-stage lung disease many will experience a rapid decline and that two spirometric values, variability in FEV1 and the ratio of FEV1 to forced vital capacity (FVC), may be risk factors associated with this rapid increase in lung function decline. The advantage of spirometric based risk factors is that these are captured at each clinic visit and can easily be incorporated into a busy CF clinic. We utilized the United States CF Foundation Patient Registry to describe the clinical characteristics and rates of lung function decline of adults with early-stage lung disease and identify risk factors for the subgroup of patients who subsequently experience rapid lung function decline. 2. Methods The CFFPR contains demographic and clinical data collected at U.S. CF Foundation accredited centers using a standardized data collection form [10]. It has been estimated that the CFFPR captures 81%−84% of CF patients in the US [10]. Our analysis employed a retrospective cohort study design using longitudinal data from the approximately 120 care centers that entered data into the CFFPR from 2008 to 2013. Early-stage CF lung disease was defined as the first FEV1 ≥ 80% predicted at any point in 2010. Patients were included if they were ≥18 years of age and had forced expiratory volume in one second (FEV1 ) ≥ 80% predicted in 2010 (i.e., the index FEV1 ). In addition, patients had to have ≥ 3 FEV1 measurements spanning ≥6 months in the two years prior to index FEV1 and in the time period (2010–13) after the index FEV1 . Patients were excluded if they had previously had an organ transplant or had a missing forced vital capacity (FVC) measurement or weight value at the time of the index FEV1 . Patients who received a solid organ transplant during the study period or who were lost to follow-up were censored at that time point. Variables and their definitions are listed in Table 1 in the online supplement. The cohort was stratified a priori into groups by age at the index FEV1 : 18–21 years, 22–25 years, 26–29 years, 30–39 years, and ≥ 40 years. Age groupings were based on a combination of previous studies with inflection point in the slope of FEV1 decline at age 22[11] and clinical experience. FEV1 % predicted values were calculated using the Global Lung Function Initiative equations [12]. The FEV1 /FVC ratio was calculated using the FEV1 value in liters divided by the FVC value in liters. The mean FEV1 /FVC was approximately 0.8, so we compared <0.8 to >=0.8 in the analysis. Baseline variables were taken at the time of the index FEV1 except for CF related diabetes, positive respiratory cultures, and use of CF medications which were considered present if they were indicated
in the CFFPR at the index or in the year prior to the index. Visits, cultures, hospitalizations, and intravenous (IV) antibiotic event counts were also assessed in the year prior to (and including) the index date. FEV1 % predicted variability was defined as the median distance from the best FEV1 % predicted in the 2 years prior to the index date. For example, if the best FEV1 % predicted in the previous 2 years was 60 and the other measurements were 47, 50, 51, 52, 54, and 58 then the median distance would be 8% predicted [9]. A descriptive analysis was performed for all baseline variables by age group. Means and standard deviations were calculated for continuous variables, and counts and percentages were calculated for discrete variables. Due to the inclusion and exclusion criteria, the majority of variables did not contain any missing data and none of the variables had more than 5% of the data missing. As the inclusion criteria was age over 18, if a height value was missing, it was imputed using last observation carried forward. For the primary analysis, longitudinal change in FEV1 % predicted was assessed by developing mixed effects models to estimate rate of FEV1 decline. Rate of decline estimates did not include the index FEV1 measurement and were calculated within age group in the post-index period. The model included intercept and time as random effects within patient. Time was defined in years from the index FEV1 to each encounter in the post-index period. From these results, a rapid decline in FEV1 % predicted was defined as ≥ 5% predicted/year absolute decline during follow-up. This definition of rapid decline was decided a priori and was a value that was considered clinically significant by all the authors. Entry into the cohort required the first FEV1 ≥ 80% predicted at any point in 2010. Approximately 25% of study participants had all other FEV1 measurements < 80% in 2010. Sensitivity analyses were performed to evaluate the definition of early-stage CF lung disease defined as the first FEV1 ≥ 90% predicted at any point in 2010 and the first FEV1 ≥ 100% predicted at any point in 2010 and the results of the study were unchanged, thus the main results are presented. For the second analysis, multivariable logistic regression was used to assess if two risk factors calculated from spirometry were associated with ≥ 5% predicted/year absolute decline during follow-up. The two risk factors were FEV1 % predicted variability and the ratio of FEV1 to FVC. Next, we reviewed variables that may be associated with the relationship between these variables and rapid lung function decline [13]. Based on clinical experience we included the following confounders: age (categorical as 18–21 years and ≥ 22 years), female sex, insurance status, detection of Pseudomonas aeruginosa, detection of methicillin resistant Staphylococcus aureus, and detection of Burholderia cepacia complex [11]. We did not include treatment of exacerbations with intravenous antibiotics or measurements of weight as these are mediators in the relationship between the risk factors and rapid lung function decline. We also created a multivariable logistic regression model using backwards elimination as a sensitivity analysis. The results from both multivariable logistic regression models are consistent. The methods and results for the model created using backward stepwise analysis are presented in the online supplement (Online Supplement Figure E1). Statistical significance was defined as a 2-tailed α <0.05. Based on our large sample size, we had >80% power to detect clinically and statistically significant differences in lung function decline between age groups. We performed analyses using SAS Version 9.4 (SAS Institute, Inc.). Patients in the CFFPR (or guardians for minors) give informed consent for data to be used for research purposes. This specific study was reviewed and approved by the Cystic Fibrosis Foundation Patient Registry Committee and the institutional review board at Seattle Children’s Hospital (Protocol # 15263).
Please cite this article as: E.C. Dasenbrook, A.K. Fink and M.S. Schechter et al., Rapid lung function decline in adults with early-stage cystic fibrosis lung disease, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.12.005
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Table 1 Baseline characteristics at index FEV1 by age groupa . Characteristic
Female (n,%) Age at index (mean ± SD) FEV1 percent predicted (mean ± SD) FEV1 percent predicted variability - median distance from best (mean ± SD) FEV1 /FVC (mean ± SD) Weight (kg) (mean ± SD) BMI (mean ± SD) Genotype (n,%) F508del homozygous F508del heterozygous Mutation classification (n,%) 1–3 4–5 Insurance in 2010 (n,%) Non-Medicare Public Medicare Any Private None/Unknown MRSA (n,%) MSSA (n,%) Burkholderia cepacia complex (n,%) Pseudomonas aeruginosa (n,%) At least 50% encounters with P. aeruginosa (n,%) Stenotrophomonas maltophilia (n,%) Nontuberculosis mycobacteria (n,%) Tobramycin solution for inhalation (n,%) Dornase alfa (i.e. Pulmozyme) (n,%) Hypertonic saline (n,%) Azithromycin (n,%) Pancreatic enzymes (n,%) Diabetes (n,%) Number of visitsb baseline period (mean ± SD) Number of cultures performedb (mean ± SD) Number of IV exacerbationsb (mean ± SD) Number of hospitalizationsb (mean ± SD) At least 1 hospitalizationb (n,%) Number of home IV exacerbationsb (mean ± SD) Number of visits post-indexc (mean ± SD) Number of years of follow-upc (mean ± SD)
Age Group at Index 18–21 (N = 1377)
22–25 (N = 605)
26–29 N = 389)
30–39 (N = 421)
40–82 (N = 237)
624, 45.3% 19.51 ± 1.21 92.26 ± 9.96 8.90 ± 6.27
287, 47.4% 23.73 ± 1.14 91.99 ± 9.75 7.92 ± 5.77
197, 50.6% 27.83 ± 1.14 90.93 ± 8.56 7.43 ± 5.92
222, 52.7% 34.17 ± 2.98 89.60 ± 9.31 6.65 ± 5.12
126, 53.2% 48.84 ± 7.63 90.28 ± 9.28 6.67 ± 6.01
0.80 ± 0.08 63.01 ± 12.58 22.34 ± 3.43
0.78 ± 0.07 65.90 ± 12.47 23.29 ± 3.46
0.77 ± 0.07 67.65 ± 13.16 23.77 ± 3.56
0.75 ± 0.07 70.08 ± 15.29 24.74 ± 4.23
0.75 ± 0.07 74.36 ± 17.49 25.88 ± 4.90
688, 50.0% 499, 36.2%
294, 48.6% 230, 38.0%
201, 51.7% 129, 33.2%
178, 42.3% 179, 42.5%
51, 21.5% 133, 56.1%
1041, 75.6% 92, 6.7%
444, 73.4% 43, 7.1%
291, 74.8% 26, 6.7%
256, 60.8% 79, 18.8%
76, 32.1% 90, 38.0%
340, 24.7% 27, 2.0% 975, 70.8% 35, 2.5% 396, 28.8% 787, 57.2% 12, 0.9% 824, 59.8% 405, 29.4% 239, 17.4% 36, 2.6% 830, 60.3% 1157, 84.0% 652, 47.3% 778, 56.5% 1307, 94.9% 254, 18.4% 6.21 ± 3.54 4.01 ± 1.94 0.69 ± 1.13 0.63 ± 1.09 500, 36.3% 0.29 ± 0.69 15.91 ± 9.65 3.32 ± 0.58
106, 17.5% 37, 6.1% 442, 73.1% 20, 3.3% 128, 21.2% 281, 46.4% 5, 0.8% 391, 64.6% 244, 40.3% 84, 13.9% 16, 2.6% 361, 59.7% 478, 79.0% 297, 49.1% 382, 63.1% 571, 94.4% 125, 20.7% 5.45 ± 3.28 3.33 ± 1.88 0.73 ± 1.24 0.60 ± 1.10 205, 33.9% 0.34 ± 0.78 15.59 ± 9.04 3.44 ± 0.49
67, 17.2% 29, 7.5% 281, 72.2% 12, 3.1% 84, 21.6% 179, 46.0% 5, 1.3% 288, 74.0% 181, 46.5% 39, 10.0% 9, 2.3% 222, 57.1% 293, 75.3% 200, 51.4% 232, 59.6% 367, 94.3% 103, 26.5% 5.67 ± 3.22 3.44 ± 1.87 0.68 ± 1.07 0.49 ± 0.92 120, 30.8% 0.38 ± 0.78 15.35 ± 8.71 3.42 ± 0.52
37, 8.8% 45, 10.7% 332, 78.9% 7, 1.7% 87, 20.7% 166, 39.4% 5, 1.2% 290, 68.9% 176, 41.8% 37, 8.8% 12, 2.9% 213, 50.6% 292, 69.4% 217, 51.5% 240, 57.0% 377, 89.5% 124, 29.5% 5.44 ± 3.93 3.29 ± 2.18 0.55 ± 1.03 0.42 ± 0.87 106, 25.2% 0.34 ± 0.76 14.49 ± 8.49 3.39 ± 0.53
7, 3.0% 21, 8.9% 206, 86.9% 3, 1.3% 38, 16.0% 96, 40.5% 1, 0.4% 134, 56.5% 82, 34.6% 19, 8.0% 16, 6.8% 95, 40.1% 143, 60.3% 111, 46.8% 114, 48.1% 172, 72.6% 65, 27.4% 5.02 ± 2.75 3.00 ± 1.71 0.42 ± 0.87 0.30 ± 0.74 47, 19.8% 0.23 ± 0.54 13.96 ± 7.69 3.43 ± 0.50
Abbreviations: FEV1: forced expiratory volume in one second; FVC: forced vital capacity; kg: kilogram; BMI: body mass index; MRSA: methicillin resistant Staphylococcus aureus; MSSA: methicillin sensitive Staphylococcus aureus; P: Pseudomonas; IV: intravenous; SD: standard deviation. a Patients satisfied the following inclusion criteria: (1) ≥1 encounter in 2010 with age ≥18 years and FEV1 percent predicted ≥80%, (2) ≥3 FEV1 percent predicted values spanning ≥6 months in the 2 years prior to index, (3) nonmissing FVC percent predicted and weight at index, and (4) ≥3 FEV1 percent predicted values spanning ≥6 months post-index through last visit. b Characteristic assessed in baseline period (including index). c Characteristic assessed post-index.
3. Results Among all accredited pediatric and adult CF centers in the United States in 2010, there were 9,434 individuals with CF ≥ 18 years of age who had not received an organ transplant including 3,795 meeting our definition of early-stage lung disease, defined as an FEV1 ≥ 80% predicted. Of these, 3,060 had at least 3 FEV1 values spanning at least a 6-month period in the 2 years prior to the index FEV1 and in the time period (2010–13) after the index FEV1 in order to calculate lung function decline. After excluding patients for missing data, there were 3,029 subjects in the study cohort (Fig. 1). Approximately 15% of the study cohort (n = 475) experienced a rapid decline in lung function that was ≥ 5% predicted per year. The median follow-up for the cohort was 3.6 years per patient (interquartile range 3.2 years to 3.8 years). The baseline characteristics of the study cohort according to age groups are shown in Table 1. The mean index FEV1 % predicted was similar between age groups and ranged from 89.6% predicted to 92.3% predicted. FEV1 % predicted variability, which was defined as the median distance from the best FEV1 % predicted in the 2 years
prior to the index FEV1 ranged from 6.7% predicted to 8.9% predicted. The mean BMI for the 18–21 age group was 22.3 kg/m2 while the 40 and above age group had a mean BMI of 25.9 kg/m2. Class 4–5 mutations were noted in approximately 7% of patients < 30 years of age while 19% of patients aged 30–39 years and 38% of patients ≥ 40 years of age had class 4–5 mutations. The cohort was largely prior to the availability of modulators and 130 (4.3%) individuals had the G551D mutation. From 29% to 47% of patients had at least half of their cultures positive for Pseudomonas aeruginosa within the year of the index visit. Dornase alpha use was recorded in 84% of those aged 18–21 years and 60% of those aged greater than 40. The prevalence of CF-related diabetes was 18% in those aged 18–21 years and peaked at 30% in those aged 30–39 years. At least one hospitalization in the 12 months prior to the index visit was noted in 36% of patients aged 18–21 years, while only 20% of patients 40 and over had at least one hospitalization. Online supplement Table 2 presents characteristics of the study cohort and those excluded from the study population. Excluded patients are those who had at least a single percent predicted FEV1 greater than 80% in 2010 but did not satisfy other study criteria. In general,
Please cite this article as: E.C. Dasenbrook, A.K. Fink and M.S. Schechter et al., Rapid lung function decline in adults with early-stage cystic fibrosis lung disease, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.12.005
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Fig. 1. Study flow Abbreviations: FEV1: forced expiratory volume in one second; FVC: forced vital capacity.
Table 2 Spirometric risk factors associated with ≥ 5% predicted/year decline in follow-up. Characteristic
Univariate OR (95% CI)
Multivariate OR (95% CI)
FEV1 percent predicted variability - median distance from besta 10+ vs <4 3.00 (2.25 – 4.01) 2.35 (1.74 – 3.18) FEV1 /FVCa <0.8 vs ≥0.8 1.41 (1.15 – 1.73) 1.63 (1.31 – 2.02) Abbreviations: FEV1: forced expiratory volume in one second; FVC: forced vital capacity; OR: odds ratio; CI: confidence interval. a The multivariate models were adjusted for the following variables: Age,sex, insurance status, CF related diabetes, Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus, and Burkholderia cepacia complex.
the excluded population tended to have less severe clinical characteristics. In comparison to the study cohort, the excluded population had > 10% absolute difference in variables such as mutation class 4–5 (23% vs 11%), diagnosis after year 20 0 0 (30% vs 12%), sweat chloride greater than 90 (52% vs 70%), methicillin-resistant Staphylococcus aureus (12% vs 24%), Pseudomonas aeruginosa (39% vs 64%) and were less likely to use chronic CF medications. A sensitivity analysis with the assumption that all individuals excluded because they did not have data to calculate decline, would not experience a significant decline in lung function was performed. In this analysis, the overall prevalence of decline in the cohort only drops from 16% to 14%, which does not change the significance of the finding. The estimated intercept and slope of FEV1 % predicted for all patients are shown in the forest plot in Fig. 2. The mean intercept for the cohort was 87% predicted and within each age group at least 40% of the patients have an index FEV1 that is above 90% predicted (data not shown). The mean overall decline in the post index FEV1 period for adult patients with early-stage lung disease was −1.88 FEV1 % predicted/year [95% confidence interval (CI) −2.01 to −1.74]. The most rapid decline was noted in those aged
18–21 years (−2.50 FEV1 % predicted/year, (95% CI −2.70 to −2.30)) and this decline was significantly more rapid compared to those aged ≥ 22 years (difference −1.20 FEV1 % predicted/year, 95% CI −1.48 to −0.92) (data not shown). The annualized FEV1 % predicted decline was categorized in to 4 subgroups (≤ −5% predicted/year, −5% predicted/year < slope ≤ −2% predicted/year, −2% predicted/year < slope < 0% predicted/year, slope ≥ 0% predicted/year) in Fig. 3. Among those aged 18–21 years, approximately a quarter of the subjects fell into each of the slope categories. In contrast, among those over the age of 30 years, approximately 10% had rapid lung function decline while approximately a third actually had an improvement in lung function. For each age group, a substantial number of subjects had a positive slope in the post index period (range 27.0% to 36.7%). Overall, there were 475 (16%) subjects that developed rapid lung function decline defined as a post index decline ≤ −5% predicted per year. In unadjusted analyses, FEV1 % predicted variability (>10% predicted vs < 4% predicted) (OR 3.00, 95% CI 2.25 to 4.01) and FEV1 /FVC (L) less than 0.8 (OR 1.41, 95% CI 1.15 to 1.73) were associated with rapid lung function decline (Table 2). Even after adjustment for confounders, the multivariable model suggested both spirometric risk factors were associated with subsequent rapid lung function decline: FEV1 % predicted variability (>10% predicted vs < 4% predicted) (OR 2.35, 95% CI 1.74 to 3.18) and FEV1 /FVC (L) less than 0.8 (OR 1.63, 95% CI 1.31 to 2.02) (Table 2). The results from the sensitivity analysis using a backward stepwise analysis is presented in the online supplement (Figure E1). 4. Discussion We performed a cohort study among 3,029 individuals with early-stage CF lung disease to determine the prevalence and if there were spirometric risk factors for subsequent rapid lung function decline during a median of 3.6 years of follow-up. We found
Please cite this article as: E.C. Dasenbrook, A.K. Fink and M.S. Schechter et al., Rapid lung function decline in adults with early-stage cystic fibrosis lung disease, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.12.005
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Fig. 2. Estimated intercepts (FEV1 % predicted) and decline in FEV1 % predicted by baseline age group Abbreviations: FEV1 : forced expiratory volume in one second.
Fig. 3. Distribution of mean annual decline in FEV1 % predicted by age group Abbreviations: FEV1 : forced expiratory volume in one second.
Please cite this article as: E.C. Dasenbrook, A.K. Fink and M.S. Schechter et al., Rapid lung function decline in adults with early-stage cystic fibrosis lung disease, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.12.005
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that 16% of the cohort had a rapid decline defined as a post-index slope ≤ −5% predicted per year. In contrast, approximately 25% of individuals in this cohort actually had no change or an increase in FEV1 during the same time period. Thus, a global strategy of targeting all individuals with early-stage lung disease may not be warranted. A significant finding from this study is that two simple measures calculated from spirometry were associated with subsequent lung function decline. Variability in FEV1 % predicted and evidence of obstruction as measured by the FEV1 to FVC ratio may be useful risk factors in identifying a subgroup of patients at greater risk for subsequent lung function decline [9]. Variability in FEV1 can be quickly gleaned by reviewing FEV1 measurements over the last 2 years in graphical format with a “saw tooth” pattern of FEV1 potentially identifying more variability in lung function. In addition to variability in FEV1 over the previous two years, the ratio of FEV1 to FVC was also identified as a potential risk factor for subsequent rapid lung function decline. Among patients with a ratio < 0.8, the risk for subsequent lung function decline increases. This ratio is a reflection of airway obstruction and could be another marker of subtly advancing lung disease even though FEV1 is in the “normal” range. Future studies validating these risk factors in an independent population are needed. A second important finding is that CF adults with early-stage lung disease in the youngest age group, 18–21 years, are particularly vulnerable as compared to those aged ≥ 22 years. This is not unexpected given that these individuals are at higher risk of progression of lung disease when they are transitioning to adult centers, going away to college and/or leaving home [14,15]. Further study to evaluate if variability in FEV1 is predictive in the youngest age group as another way to identify poor adherence, lack of aggressiveness of care, and/or frequent pulmonary exacerbations would be informative [9]. While the younger age group did have the highest prevalence of subsequent lung function decline, all age groups had a significant number of individuals experiencing big drops in their lung function, including those over age 40 years. As detailed by Nick and colleagues, our data also reinforces the important point that adults with early-stage lung disease may not have permanently “mild” disease [8]. Rather these adults may be experiencing a delay in manifestations of lung disease and will eventually experience worsening lung function as has previously been detailed in individuals with the R117H mutation [16]. Our study builds upon these observations and identifies two spirometric factors that may help identify higher risk patients. It is imperative that these older patients continue to be seen at regular intervals by a team with expertise in the care of adults with CF to monitor lung function decline and intervene as appropriate. In the backward stepwise analysis presented in the online supplement, there were other risk factors for subsequent lung function decline. An advantage to this model is allowing the evaluation of other confounders and see if the models are consistent with what has been previously found in observational studies in cystic fibrosis. As has been previously noted in CF patients of all stages of lung disease, history of pulmonary exacerbations is associated with subsequent decline [17]. We found a similar association in our cohort with early-stage lung disease. Insurance status and presence of CF related diabetes were also associated with subsequent lung function decline. Infection with Pseudomonas aeruginosa was not in the final model, however the use of inhaled antibiotics was associated with rapid lung function decline. The modeling approach was not designed to evaluate the effectiveness of treatments, but given the potential for confounding, this variable is most likely a marker for the presence of Pseudomonas aeruginosa. Finally, female sex, which has previously been noted as a risk factor for worse outcomes in CF [18], was not a risk factor in our analysis. The prevalence of female
sex increased with each group (45.3% in the youngest to 53.2% in the oldest age group). Our study cohort only includes individuals with early-stage lung disease which may explain the difference compared to previous studies which included a larger range of CF lung disease severity. Interestingly, approximately one quarter of individuals with early-stage lung disease had no change in lung function or an improvement in lung function over the course of the study. This phenotype, which was approximately twice as common as rapid lung function decline, may be responsible for providing the notion to members of the CF team that early-stage lung disease have “mild” or “normal” lung function. Specific understanding of this group was not the focus of this study, however, we did note that in general, use of medications for maintenance of lung health among individuals with early-stage lung disease was high. This patient phenotype deserves more study. The CFFPR is a valuable source for clinical research but also has limitations [19]. The study design required that adults have multiple spirometric measurements in the two years prior to the index FEV1 and multiple measurements after the index FEV1, thus our results may not be generalizable to patients with infrequent follow-up. Approximately 20% of the cohort was excluded for this reason. The clinical characteristics of those excluded are generally similar to the included population (Online Supplement Table 2) except there was a greater prevalence of class 4–5 mutations in the excluded group and less chronic infections and less use of chronic medications. A possible explanation is that patients were doing well and did not attend clinic. If so, excluding these patients would actually weaken the association with the spirometric risk factors and suggest our associations are conservative estimates. Finally, a sensitivity analysis with the assumption that all individuals excluded because they did not have data to calculate decline, would not experience a significant decline in lung function, then the overall prevalence of decline in the cohort only drops from 16% to 14%, which does not change the significance of the finding. We only looked at the two years prior to the index FEV1 , thus we do not know what happened in the years prior to entry and if this is indeed their “first” rapid decline. Given our conservative definition of rapid decline of ≤ −5% predicted per year over a median follow-up of 3.6 years, this is not likely to be a significant factor. The overall amount of missing data (<5%) was minimal and would not be expected to bias the results. This study was conducted prior to the wide availability of modulators. The impact of modulators on delaying subsequent rapid lung function decline among those with early-stage lung disease is unknown. There is no standard definition of early-stage lung disease in adults. We chose FEV1 80% predicted since this is frequently interpreted as the lower limit of “normal” in spirometric reports and the CF patient registry reports FEV1 % predicted ≥ 70% as “normal/mild”1 . A priori defined sensitivity analyses using FEV1 % predicted ≥ 100% were consistent with the main results and thus we report results with FEV1 % predicted ≥ 80% . We did not examine details specifically related to transition which may have differentially impacted the 18–21 year old age group in comparison to other age groups. However, FEV1 variability as a risk factor for subsequent decline is still valid and may be even more important in this younger age group. In conclusion, even among adults with early-stage lung disease, approximately 15% may experience substantial declines in their lung function. The variability in FEV1 over the previous two years may be important in identifying patients at risk for subsequent rapid lung function decline and should be validated in an independent cohort. This study reinforces the concept that adults with early-stage lung disease do not have “normal lungs” or mild lung disease and the CF community should give strong consideration to no longer using these terms. The onset of decline in lung disease may be delayed, rather than absent, and this cohort
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should be followed in the Adult CF clinic to identify the onset of decline. All authors meet the 4 criteria for authorship below: •
•
• •
Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND Drafting the work or revising it critically for important intellectual content; AND Final approval of the version to be published; AND Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
5. Grant support Drs. Dasenbrook (DASENB17A0) and Sanders (SANDERS16Y5) were supported by grants from the Cystic Fibrosis Foundation. Declaration of Competing Interest DJP and SJM are employees of ICON Clinical Research, which was paid by The Cystic Fibrosis Foundation for providing analytical services for this study. ECD has received honoraria from Gilead Sciences and Vertex Pharmaceuticals. DBS has received honoraria from Vertex Pharmaceuticals. Acknowledgements The authors would like to thank the Cystic Fibrosis Foundation for the use of CF Foundation Patient Registry data to conduct this study. Additionally, we would like to thank the patients, care providers, and clinic coordinators at CF Centers throughout the United States for their contributions to the CF Foundation Patient Registry. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jcf.2019.12.005.
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[2] Boyle MP. The evidence for long-term benefits of restoration of CFTR function continues to grow. Am J Respir Crit Care Med Oct 1 2015;192(7):774–6. [3] VanDevanter DR, Pasta DJ, Konstan MW. Improvements in lung function and height among cohorts of 6-year-olds with cystic fibrosis from 1994 to 2012. J Pediatr Dec 2014;165(6):1091–7 e1092. [4] Mogayzel PJ Jr, Naureckas ET, Robinson KA, et al. Cystic fibrosis foundation pulmonary guideline. pharmacologic approaches to prevention and eradication of initial pseudomonas aeruginosa infection. Ann Am Thorac Soc Dec 2014;11(10):1640–50. [5] Sawicki GS, Sellers DE, Robinson WM. High treatment burden in adults with cystic fibrosis: challenges to disease self-management. J Cyst Fibros Mar 2009;8(2):91–6. [6] Konstan MW, Wagener JS, Vandevanter DR, et al. Risk factors for rate of decline in FEV1 in adults with cystic fibrosis. J Cyst Fibros Sep 2012;11(5):405–11. [7] VandenBranden SL, McMullen A, Konstan MW, et al. Characteristic changes in lung function decline from adolescence to young adulthood. Pediatr Pulmonol 20 07;42(S30):365–6 10/3/20 07. [8] Nick JA, Chacon CS, Brayshaw SJ, et al. Effects of gender and age at diagnosis on disease progression in long-term survivors of cystic fibrosis. Am J Respir Crit Care Med Sep 1 2010;182(5):614–26. [9] Morgan WJ, VanDevanter DR, Pasta DJ, et al. Forced expiratory volume in 1 Second variability helps identify patients with cystic fibrosis at risk of greater loss of lung function. J Pediatr Feb 2016;169:116–21 e112. [10] Knapp EA, Fink AK, Goss CH, et al. The cystic fibrosis foundation patient registry: design and methods of a national observational disease registry. Ann Am Thorac Soc Apr 14 2016. [11] Dasenbrook EC, Merlo CA, Diener-West M, Lechtzin N, Boyle MP. Persistent methicillin-resistant Staphylococcus aureus and rate of FEV1 decline in cystic fibrosis. Am J Respir Crit Care Med 2008;178(8):814–21 10/15/2008. [12] Quanjer PH, Stanojevic S, Cole TJ, et al. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J Dec 2012;40(6):1324–43. [13] Lederer DJ, Bell SC, Branson RD, et al. Control of confounding and reporting of results in causal inference studies. Guidance for authors from editors of respiratory, sleep, and critical care journals. Ann Am Thorac Soc Jan 2019;16(1):22–8. [14] Sawicki GS, Ostrenga J, Petren K, et al. Risk factors for gaps in care during transfer from pediatric to adult cystic fibrosis programs in the United States. Ann Am Thorac Soc Feb 2018;15(2):234–40. [15] Tuchman LK, Schwartz LA, Sawicki GS, Britto MT. Cystic fibrosis and transition to adult medical care. Pediatrics Mar 2010;125(3):566–73. [16] Wagener JS, Millar SJ, Mayer-Hamblett N, et al. Lung function decline is delayed but not decreased in patients with cystic fibrosis and the R117H gene mutation. J Cyst Fibros Jul 2018;17(4):503–10. [17] Heltshe SL, Goss CH, Thompson V, et al. Short-term and long-term response to pulmonary exacerbation treatment in cystic fibrosis. Thorax Mar 2016;71(3):223–9. [18] Harness-Brumley CL, Elliott AC, Rosenbluth DB, Raghavan D, Jain R. Gender differences in outcomes of patients with cystic fibrosis. J Women’s Health Dec 2014;23(12):1012–20. [19] Dasenbrook EC, Sawicki GS. Cystic fibrosis patient registries: a valuable source for clinical research. J Cyst Fibros Mar 16 2018.
References [1] Cystic Fibrosis Foundation. Patient registry 2016 annual data report, MD: Bethesda; 2017. 2017.
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Contents lists available at ScienceDirect
Journal of Cystic Fibrosis journal homepage: www.elsevier.com/locate/jcf
Original Article
Rapid lung function decline in adults with early-stage cystic fibrosis lung disease Elliott C. Dasenbrook a,∗, Aliza K. Fink b, Michael S. Schechter c, Don B. Sanders d, Stefanie J. Millar e, David J. Pasta e, Nicole Mayer-Hamblett f,g a
Respiratory Institute, Cleveland Clinic, Cleveland, OH, United States Cystic Fibrosis Foundation, Bethesda, MD, United States Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, VA, United States d Indiana University School of Medicine, Indianapolis, IN, United States e ICON Clinical Research, San Francisco, CA, United States f University of Washington, Seattle, WA, United States g Seattle Children’s Hospital, Seattle, WA, United States b c
a r t i c l e
i n f o
Article history: Received 25 June 2019 Revised 2 December 2019 Accepted 7 December 2019 Available online xxx Classification: 90 PULMONOLOGY Keywords: Cystic fibrosis Adult Risk factors Respiratory function tests Cohort studies
a b s t r a c t Rationale: The prevalence of adults living with cystic fibrosis (CF) who have early-stage lung disease is increasing. Objectives: Describe the prevalence and evaluate spirometric risk factors associated with the subgroup of patients with early-stage lung disease and FEV1 decline of ≥5% predicted/year. Methods: Retrospective cohort study of patients ≥18 years with FEV1 % predicted ≥80% included in the US CF Foundation Patient Registry from 2010–2013. Regression models were developed to estimate FEV1 rate of decline. Multivariable logistic analysis was used to assess if spirometric risk factors were associated with FEV1 decline. Measurements and main results: 3,029 subjects were in the study cohort. Approximately 15% of the cohort had a substantial decline in lung function ≥5% predicted/year. In multivariable models adjusted for confounders, FEV1 /FVC ratio <0.8 (Odds Ratio (OR) 1.63, 95% confidence interval (CI) 1.31 to 2.02) and history of FEV1 % predicted variability (OR 2.35,95%CI 1.74 to 3.18) were associated with rapid lung function decline. Conclusions: Even among adults with early-stage lung disease, approximately 15% are shown to progress and experience a large decline in lung function. This reinforces the concept that lung function in earlystage CF is not normal or mild. Rather, lung function decline may be delayed, but not avoided, in these individuals. Variability in FEV1 % predicted and airway obstruction as measured by FEV1/FVC ratio may identify individuals at increased risk of decline. Adults with early-stage lung disease should be followed in clinic to monitor for onset of decline. © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
1. Introduction The prevalence of adult cystic fibrosis (CF) patients with earlystage lung disease is increasing [1]. According to the US CF Foundation Patient Registry (CFFPR) report, the median forced expiratory volume in one second (FEV1 ) of 18 year olds increased from 66% to 83% over a 20 year period. A similar pattern was seen among
∗ Corresponding author at: The Cleveland Clinic Foundation, 9500 Euclid Avenue – A90, Cleveland, OH 44195, United States. E-mail address: [email protected] (E.C. Dasenbrook).
30 year olds as the median FEV1 increased from 49% to 61% over the same time period [1]. In the future, the prevalence of adults with early-stage lung disease in the United States will most likely continue to increase due to the wider availability of new medications that treat the basic defect [2], universal newborn screening [3], and increasingly proactive treatment such as early eradication of Pseudomonas aeruginosa [4]. The discussion between clinicians and adult individuals with CF about approach to treatment is complex, centering on the patients’ preferences regarding their care, effectiveness of various treatment options, and treatment burden [5]. The evidence base to support this discussion is scant as randomized clinical trials frequently do
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Please cite this article as: E.C. Dasenbrook, A.K. Fink and M.S. Schechter et al., Rapid lung function decline in adults with early-stage cystic fibrosis lung disease, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.12.005
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not include large numbers of individuals with early-stage lung disease and epidemiologic studies have largely been based on cohorts from previous treatment eras. It is known that patients with earlystage CF lung disease are at risk for increased rates of lung function decline [6,7]. In addition, Nick and colleagues have demonstrated that long-term survivors of CF (to age > 40 years) do not have “mild” lung disease, but rather they experience delayed onset of severe lung disease [8]. A natural conclusion is that earlyintervention may help prevent or ameliorate subsequent lung function decline; however, the decision about when and with whom to intervene is difficult since the timing of patients’ rapid decline is unknown. Morgan and colleagues have previously established that variability in FEV1 identifies risk of subsequent decline however was not specifically studied in those with early-stage lung disease [9]. Understanding risk factors for rapid progression of lung disease could provide patients with early-stage lung disease key information when balancing the benefits of using chronic CF medications against the large treatment burden individuals with CF endure. We hypothesize that among adult CF patients with early-stage lung disease many will experience a rapid decline and that two spirometric values, variability in FEV1 and the ratio of FEV1 to forced vital capacity (FVC), may be risk factors associated with this rapid increase in lung function decline. The advantage of spirometric based risk factors is that these are captured at each clinic visit and can easily be incorporated into a busy CF clinic. We utilized the United States CF Foundation Patient Registry to describe the clinical characteristics and rates of lung function decline of adults with early-stage lung disease and identify risk factors for the subgroup of patients who subsequently experience rapid lung function decline. 2. Methods The CFFPR contains demographic and clinical data collected at U.S. CF Foundation accredited centers using a standardized data collection form [10]. It has been estimated that the CFFPR captures 81%−84% of CF patients in the US [10]. Our analysis employed a retrospective cohort study design using longitudinal data from the approximately 120 care centers that entered data into the CFFPR from 2008 to 2013. Early-stage CF lung disease was defined as the first FEV1 ≥ 80% predicted at any point in 2010. Patients were included if they were ≥18 years of age and had forced expiratory volume in one second (FEV1 ) ≥ 80% predicted in 2010 (i.e., the index FEV1 ). In addition, patients had to have ≥ 3 FEV1 measurements spanning ≥6 months in the two years prior to index FEV1 and in the time period (2010–13) after the index FEV1 . Patients were excluded if they had previously had an organ transplant or had a missing forced vital capacity (FVC) measurement or weight value at the time of the index FEV1 . Patients who received a solid organ transplant during the study period or who were lost to follow-up were censored at that time point. Variables and their definitions are listed in Table 1 in the online supplement. The cohort was stratified a priori into groups by age at the index FEV1 : 18–21 years, 22–25 years, 26–29 years, 30–39 years, and ≥ 40 years. Age groupings were based on a combination of previous studies with inflection point in the slope of FEV1 decline at age 22[11] and clinical experience. FEV1 % predicted values were calculated using the Global Lung Function Initiative equations [12]. The FEV1 /FVC ratio was calculated using the FEV1 value in liters divided by the FVC value in liters. The mean FEV1 /FVC was approximately 0.8, so we compared <0.8 to >=0.8 in the analysis. Baseline variables were taken at the time of the index FEV1 except for CF related diabetes, positive respiratory cultures, and use of CF medications which were considered present if they were indicated
in the CFFPR at the index or in the year prior to the index. Visits, cultures, hospitalizations, and intravenous (IV) antibiotic event counts were also assessed in the year prior to (and including) the index date. FEV1 % predicted variability was defined as the median distance from the best FEV1 % predicted in the 2 years prior to the index date. For example, if the best FEV1 % predicted in the previous 2 years was 60 and the other measurements were 47, 50, 51, 52, 54, and 58 then the median distance would be 8% predicted [9]. A descriptive analysis was performed for all baseline variables by age group. Means and standard deviations were calculated for continuous variables, and counts and percentages were calculated for discrete variables. Due to the inclusion and exclusion criteria, the majority of variables did not contain any missing data and none of the variables had more than 5% of the data missing. As the inclusion criteria was age over 18, if a height value was missing, it was imputed using last observation carried forward. For the primary analysis, longitudinal change in FEV1 % predicted was assessed by developing mixed effects models to estimate rate of FEV1 decline. Rate of decline estimates did not include the index FEV1 measurement and were calculated within age group in the post-index period. The model included intercept and time as random effects within patient. Time was defined in years from the index FEV1 to each encounter in the post-index period. From these results, a rapid decline in FEV1 % predicted was defined as ≥ 5% predicted/year absolute decline during follow-up. This definition of rapid decline was decided a priori and was a value that was considered clinically significant by all the authors. Entry into the cohort required the first FEV1 ≥ 80% predicted at any point in 2010. Approximately 25% of study participants had all other FEV1 measurements < 80% in 2010. Sensitivity analyses were performed to evaluate the definition of early-stage CF lung disease defined as the first FEV1 ≥ 90% predicted at any point in 2010 and the first FEV1 ≥ 100% predicted at any point in 2010 and the results of the study were unchanged, thus the main results are presented. For the second analysis, multivariable logistic regression was used to assess if two risk factors calculated from spirometry were associated with ≥ 5% predicted/year absolute decline during follow-up. The two risk factors were FEV1 % predicted variability and the ratio of FEV1 to FVC. Next, we reviewed variables that may be associated with the relationship between these variables and rapid lung function decline [13]. Based on clinical experience we included the following confounders: age (categorical as 18–21 years and ≥ 22 years), female sex, insurance status, detection of Pseudomonas aeruginosa, detection of methicillin resistant Staphylococcus aureus, and detection of Burholderia cepacia complex [11]. We did not include treatment of exacerbations with intravenous antibiotics or measurements of weight as these are mediators in the relationship between the risk factors and rapid lung function decline. We also created a multivariable logistic regression model using backwards elimination as a sensitivity analysis. The results from both multivariable logistic regression models are consistent. The methods and results for the model created using backward stepwise analysis are presented in the online supplement (Online Supplement Figure E1). Statistical significance was defined as a 2-tailed α <0.05. Based on our large sample size, we had >80% power to detect clinically and statistically significant differences in lung function decline between age groups. We performed analyses using SAS Version 9.4 (SAS Institute, Inc.). Patients in the CFFPR (or guardians for minors) give informed consent for data to be used for research purposes. This specific study was reviewed and approved by the Cystic Fibrosis Foundation Patient Registry Committee and the institutional review board at Seattle Children’s Hospital (Protocol # 15263).
Please cite this article as: E.C. Dasenbrook, A.K. Fink and M.S. Schechter et al., Rapid lung function decline in adults with early-stage cystic fibrosis lung disease, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.12.005
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Table 1 Baseline characteristics at index FEV1 by age groupa . Characteristic
Female (n,%) Age at index (mean ± SD) FEV1 percent predicted (mean ± SD) FEV1 percent predicted variability - median distance from best (mean ± SD) FEV1 /FVC (mean ± SD) Weight (kg) (mean ± SD) BMI (mean ± SD) Genotype (n,%) F508del homozygous F508del heterozygous Mutation classification (n,%) 1–3 4–5 Insurance in 2010 (n,%) Non-Medicare Public Medicare Any Private None/Unknown MRSA (n,%) MSSA (n,%) Burkholderia cepacia complex (n,%) Pseudomonas aeruginosa (n,%) At least 50% encounters with P. aeruginosa (n,%) Stenotrophomonas maltophilia (n,%) Nontuberculosis mycobacteria (n,%) Tobramycin solution for inhalation (n,%) Dornase alfa (i.e. Pulmozyme) (n,%) Hypertonic saline (n,%) Azithromycin (n,%) Pancreatic enzymes (n,%) Diabetes (n,%) Number of visitsb baseline period (mean ± SD) Number of cultures performedb (mean ± SD) Number of IV exacerbationsb (mean ± SD) Number of hospitalizationsb (mean ± SD) At least 1 hospitalizationb (n,%) Number of home IV exacerbationsb (mean ± SD) Number of visits post-indexc (mean ± SD) Number of years of follow-upc (mean ± SD)
Age Group at Index 18–21 (N = 1377)
22–25 (N = 605)
26–29 N = 389)
30–39 (N = 421)
40–82 (N = 237)
624, 45.3% 19.51 ± 1.21 92.26 ± 9.96 8.90 ± 6.27
287, 47.4% 23.73 ± 1.14 91.99 ± 9.75 7.92 ± 5.77
197, 50.6% 27.83 ± 1.14 90.93 ± 8.56 7.43 ± 5.92
222, 52.7% 34.17 ± 2.98 89.60 ± 9.31 6.65 ± 5.12
126, 53.2% 48.84 ± 7.63 90.28 ± 9.28 6.67 ± 6.01
0.80 ± 0.08 63.01 ± 12.58 22.34 ± 3.43
0.78 ± 0.07 65.90 ± 12.47 23.29 ± 3.46
0.77 ± 0.07 67.65 ± 13.16 23.77 ± 3.56
0.75 ± 0.07 70.08 ± 15.29 24.74 ± 4.23
0.75 ± 0.07 74.36 ± 17.49 25.88 ± 4.90
688, 50.0% 499, 36.2%
294, 48.6% 230, 38.0%
201, 51.7% 129, 33.2%
178, 42.3% 179, 42.5%
51, 21.5% 133, 56.1%
1041, 75.6% 92, 6.7%
444, 73.4% 43, 7.1%
291, 74.8% 26, 6.7%
256, 60.8% 79, 18.8%
76, 32.1% 90, 38.0%
340, 24.7% 27, 2.0% 975, 70.8% 35, 2.5% 396, 28.8% 787, 57.2% 12, 0.9% 824, 59.8% 405, 29.4% 239, 17.4% 36, 2.6% 830, 60.3% 1157, 84.0% 652, 47.3% 778, 56.5% 1307, 94.9% 254, 18.4% 6.21 ± 3.54 4.01 ± 1.94 0.69 ± 1.13 0.63 ± 1.09 500, 36.3% 0.29 ± 0.69 15.91 ± 9.65 3.32 ± 0.58
106, 17.5% 37, 6.1% 442, 73.1% 20, 3.3% 128, 21.2% 281, 46.4% 5, 0.8% 391, 64.6% 244, 40.3% 84, 13.9% 16, 2.6% 361, 59.7% 478, 79.0% 297, 49.1% 382, 63.1% 571, 94.4% 125, 20.7% 5.45 ± 3.28 3.33 ± 1.88 0.73 ± 1.24 0.60 ± 1.10 205, 33.9% 0.34 ± 0.78 15.59 ± 9.04 3.44 ± 0.49
67, 17.2% 29, 7.5% 281, 72.2% 12, 3.1% 84, 21.6% 179, 46.0% 5, 1.3% 288, 74.0% 181, 46.5% 39, 10.0% 9, 2.3% 222, 57.1% 293, 75.3% 200, 51.4% 232, 59.6% 367, 94.3% 103, 26.5% 5.67 ± 3.22 3.44 ± 1.87 0.68 ± 1.07 0.49 ± 0.92 120, 30.8% 0.38 ± 0.78 15.35 ± 8.71 3.42 ± 0.52
37, 8.8% 45, 10.7% 332, 78.9% 7, 1.7% 87, 20.7% 166, 39.4% 5, 1.2% 290, 68.9% 176, 41.8% 37, 8.8% 12, 2.9% 213, 50.6% 292, 69.4% 217, 51.5% 240, 57.0% 377, 89.5% 124, 29.5% 5.44 ± 3.93 3.29 ± 2.18 0.55 ± 1.03 0.42 ± 0.87 106, 25.2% 0.34 ± 0.76 14.49 ± 8.49 3.39 ± 0.53
7, 3.0% 21, 8.9% 206, 86.9% 3, 1.3% 38, 16.0% 96, 40.5% 1, 0.4% 134, 56.5% 82, 34.6% 19, 8.0% 16, 6.8% 95, 40.1% 143, 60.3% 111, 46.8% 114, 48.1% 172, 72.6% 65, 27.4% 5.02 ± 2.75 3.00 ± 1.71 0.42 ± 0.87 0.30 ± 0.74 47, 19.8% 0.23 ± 0.54 13.96 ± 7.69 3.43 ± 0.50
Abbreviations: FEV1: forced expiratory volume in one second; FVC: forced vital capacity; kg: kilogram; BMI: body mass index; MRSA: methicillin resistant Staphylococcus aureus; MSSA: methicillin sensitive Staphylococcus aureus; P: Pseudomonas; IV: intravenous; SD: standard deviation. a Patients satisfied the following inclusion criteria: (1) ≥1 encounter in 2010 with age ≥18 years and FEV1 percent predicted ≥80%, (2) ≥3 FEV1 percent predicted values spanning ≥6 months in the 2 years prior to index, (3) nonmissing FVC percent predicted and weight at index, and (4) ≥3 FEV1 percent predicted values spanning ≥6 months post-index through last visit. b Characteristic assessed in baseline period (including index). c Characteristic assessed post-index.
3. Results Among all accredited pediatric and adult CF centers in the United States in 2010, there were 9,434 individuals with CF ≥ 18 years of age who had not received an organ transplant including 3,795 meeting our definition of early-stage lung disease, defined as an FEV1 ≥ 80% predicted. Of these, 3,060 had at least 3 FEV1 values spanning at least a 6-month period in the 2 years prior to the index FEV1 and in the time period (2010–13) after the index FEV1 in order to calculate lung function decline. After excluding patients for missing data, there were 3,029 subjects in the study cohort (Fig. 1). Approximately 15% of the study cohort (n = 475) experienced a rapid decline in lung function that was ≥ 5% predicted per year. The median follow-up for the cohort was 3.6 years per patient (interquartile range 3.2 years to 3.8 years). The baseline characteristics of the study cohort according to age groups are shown in Table 1. The mean index FEV1 % predicted was similar between age groups and ranged from 89.6% predicted to 92.3% predicted. FEV1 % predicted variability, which was defined as the median distance from the best FEV1 % predicted in the 2 years
prior to the index FEV1 ranged from 6.7% predicted to 8.9% predicted. The mean BMI for the 18–21 age group was 22.3 kg/m2 while the 40 and above age group had a mean BMI of 25.9 kg/m2. Class 4–5 mutations were noted in approximately 7% of patients < 30 years of age while 19% of patients aged 30–39 years and 38% of patients ≥ 40 years of age had class 4–5 mutations. The cohort was largely prior to the availability of modulators and 130 (4.3%) individuals had the G551D mutation. From 29% to 47% of patients had at least half of their cultures positive for Pseudomonas aeruginosa within the year of the index visit. Dornase alpha use was recorded in 84% of those aged 18–21 years and 60% of those aged greater than 40. The prevalence of CF-related diabetes was 18% in those aged 18–21 years and peaked at 30% in those aged 30–39 years. At least one hospitalization in the 12 months prior to the index visit was noted in 36% of patients aged 18–21 years, while only 20% of patients 40 and over had at least one hospitalization. Online supplement Table 2 presents characteristics of the study cohort and those excluded from the study population. Excluded patients are those who had at least a single percent predicted FEV1 greater than 80% in 2010 but did not satisfy other study criteria. In general,
Please cite this article as: E.C. Dasenbrook, A.K. Fink and M.S. Schechter et al., Rapid lung function decline in adults with early-stage cystic fibrosis lung disease, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.12.005
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Fig. 1. Study flow Abbreviations: FEV1: forced expiratory volume in one second; FVC: forced vital capacity.
Table 2 Spirometric risk factors associated with ≥ 5% predicted/year decline in follow-up. Characteristic
Univariate OR (95% CI)
Multivariate OR (95% CI)
FEV1 percent predicted variability - median distance from besta 10+ vs <4 3.00 (2.25 – 4.01) 2.35 (1.74 – 3.18) FEV1 /FVCa <0.8 vs ≥0.8 1.41 (1.15 – 1.73) 1.63 (1.31 – 2.02) Abbreviations: FEV1: forced expiratory volume in one second; FVC: forced vital capacity; OR: odds ratio; CI: confidence interval. a The multivariate models were adjusted for the following variables: Age,sex, insurance status, CF related diabetes, Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus, and Burkholderia cepacia complex.
the excluded population tended to have less severe clinical characteristics. In comparison to the study cohort, the excluded population had > 10% absolute difference in variables such as mutation class 4–5 (23% vs 11%), diagnosis after year 20 0 0 (30% vs 12%), sweat chloride greater than 90 (52% vs 70%), methicillin-resistant Staphylococcus aureus (12% vs 24%), Pseudomonas aeruginosa (39% vs 64%) and were less likely to use chronic CF medications. A sensitivity analysis with the assumption that all individuals excluded because they did not have data to calculate decline, would not experience a significant decline in lung function was performed. In this analysis, the overall prevalence of decline in the cohort only drops from 16% to 14%, which does not change the significance of the finding. The estimated intercept and slope of FEV1 % predicted for all patients are shown in the forest plot in Fig. 2. The mean intercept for the cohort was 87% predicted and within each age group at least 40% of the patients have an index FEV1 that is above 90% predicted (data not shown). The mean overall decline in the post index FEV1 period for adult patients with early-stage lung disease was −1.88 FEV1 % predicted/year [95% confidence interval (CI) −2.01 to −1.74]. The most rapid decline was noted in those aged
18–21 years (−2.50 FEV1 % predicted/year, (95% CI −2.70 to −2.30)) and this decline was significantly more rapid compared to those aged ≥ 22 years (difference −1.20 FEV1 % predicted/year, 95% CI −1.48 to −0.92) (data not shown). The annualized FEV1 % predicted decline was categorized in to 4 subgroups (≤ −5% predicted/year, −5% predicted/year < slope ≤ −2% predicted/year, −2% predicted/year < slope < 0% predicted/year, slope ≥ 0% predicted/year) in Fig. 3. Among those aged 18–21 years, approximately a quarter of the subjects fell into each of the slope categories. In contrast, among those over the age of 30 years, approximately 10% had rapid lung function decline while approximately a third actually had an improvement in lung function. For each age group, a substantial number of subjects had a positive slope in the post index period (range 27.0% to 36.7%). Overall, there were 475 (16%) subjects that developed rapid lung function decline defined as a post index decline ≤ −5% predicted per year. In unadjusted analyses, FEV1 % predicted variability (>10% predicted vs < 4% predicted) (OR 3.00, 95% CI 2.25 to 4.01) and FEV1 /FVC (L) less than 0.8 (OR 1.41, 95% CI 1.15 to 1.73) were associated with rapid lung function decline (Table 2). Even after adjustment for confounders, the multivariable model suggested both spirometric risk factors were associated with subsequent rapid lung function decline: FEV1 % predicted variability (>10% predicted vs < 4% predicted) (OR 2.35, 95% CI 1.74 to 3.18) and FEV1 /FVC (L) less than 0.8 (OR 1.63, 95% CI 1.31 to 2.02) (Table 2). The results from the sensitivity analysis using a backward stepwise analysis is presented in the online supplement (Figure E1). 4. Discussion We performed a cohort study among 3,029 individuals with early-stage CF lung disease to determine the prevalence and if there were spirometric risk factors for subsequent rapid lung function decline during a median of 3.6 years of follow-up. We found
Please cite this article as: E.C. Dasenbrook, A.K. Fink and M.S. Schechter et al., Rapid lung function decline in adults with early-stage cystic fibrosis lung disease, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.12.005
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Fig. 2. Estimated intercepts (FEV1 % predicted) and decline in FEV1 % predicted by baseline age group Abbreviations: FEV1 : forced expiratory volume in one second.
Fig. 3. Distribution of mean annual decline in FEV1 % predicted by age group Abbreviations: FEV1 : forced expiratory volume in one second.
Please cite this article as: E.C. Dasenbrook, A.K. Fink and M.S. Schechter et al., Rapid lung function decline in adults with early-stage cystic fibrosis lung disease, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.12.005
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that 16% of the cohort had a rapid decline defined as a post-index slope ≤ −5% predicted per year. In contrast, approximately 25% of individuals in this cohort actually had no change or an increase in FEV1 during the same time period. Thus, a global strategy of targeting all individuals with early-stage lung disease may not be warranted. A significant finding from this study is that two simple measures calculated from spirometry were associated with subsequent lung function decline. Variability in FEV1 % predicted and evidence of obstruction as measured by the FEV1 to FVC ratio may be useful risk factors in identifying a subgroup of patients at greater risk for subsequent lung function decline [9]. Variability in FEV1 can be quickly gleaned by reviewing FEV1 measurements over the last 2 years in graphical format with a “saw tooth” pattern of FEV1 potentially identifying more variability in lung function. In addition to variability in FEV1 over the previous two years, the ratio of FEV1 to FVC was also identified as a potential risk factor for subsequent rapid lung function decline. Among patients with a ratio < 0.8, the risk for subsequent lung function decline increases. This ratio is a reflection of airway obstruction and could be another marker of subtly advancing lung disease even though FEV1 is in the “normal” range. Future studies validating these risk factors in an independent population are needed. A second important finding is that CF adults with early-stage lung disease in the youngest age group, 18–21 years, are particularly vulnerable as compared to those aged ≥ 22 years. This is not unexpected given that these individuals are at higher risk of progression of lung disease when they are transitioning to adult centers, going away to college and/or leaving home [14,15]. Further study to evaluate if variability in FEV1 is predictive in the youngest age group as another way to identify poor adherence, lack of aggressiveness of care, and/or frequent pulmonary exacerbations would be informative [9]. While the younger age group did have the highest prevalence of subsequent lung function decline, all age groups had a significant number of individuals experiencing big drops in their lung function, including those over age 40 years. As detailed by Nick and colleagues, our data also reinforces the important point that adults with early-stage lung disease may not have permanently “mild” disease [8]. Rather these adults may be experiencing a delay in manifestations of lung disease and will eventually experience worsening lung function as has previously been detailed in individuals with the R117H mutation [16]. Our study builds upon these observations and identifies two spirometric factors that may help identify higher risk patients. It is imperative that these older patients continue to be seen at regular intervals by a team with expertise in the care of adults with CF to monitor lung function decline and intervene as appropriate. In the backward stepwise analysis presented in the online supplement, there were other risk factors for subsequent lung function decline. An advantage to this model is allowing the evaluation of other confounders and see if the models are consistent with what has been previously found in observational studies in cystic fibrosis. As has been previously noted in CF patients of all stages of lung disease, history of pulmonary exacerbations is associated with subsequent decline [17]. We found a similar association in our cohort with early-stage lung disease. Insurance status and presence of CF related diabetes were also associated with subsequent lung function decline. Infection with Pseudomonas aeruginosa was not in the final model, however the use of inhaled antibiotics was associated with rapid lung function decline. The modeling approach was not designed to evaluate the effectiveness of treatments, but given the potential for confounding, this variable is most likely a marker for the presence of Pseudomonas aeruginosa. Finally, female sex, which has previously been noted as a risk factor for worse outcomes in CF [18], was not a risk factor in our analysis. The prevalence of female
sex increased with each group (45.3% in the youngest to 53.2% in the oldest age group). Our study cohort only includes individuals with early-stage lung disease which may explain the difference compared to previous studies which included a larger range of CF lung disease severity. Interestingly, approximately one quarter of individuals with early-stage lung disease had no change in lung function or an improvement in lung function over the course of the study. This phenotype, which was approximately twice as common as rapid lung function decline, may be responsible for providing the notion to members of the CF team that early-stage lung disease have “mild” or “normal” lung function. Specific understanding of this group was not the focus of this study, however, we did note that in general, use of medications for maintenance of lung health among individuals with early-stage lung disease was high. This patient phenotype deserves more study. The CFFPR is a valuable source for clinical research but also has limitations [19]. The study design required that adults have multiple spirometric measurements in the two years prior to the index FEV1 and multiple measurements after the index FEV1, thus our results may not be generalizable to patients with infrequent follow-up. Approximately 20% of the cohort was excluded for this reason. The clinical characteristics of those excluded are generally similar to the included population (Online Supplement Table 2) except there was a greater prevalence of class 4–5 mutations in the excluded group and less chronic infections and less use of chronic medications. A possible explanation is that patients were doing well and did not attend clinic. If so, excluding these patients would actually weaken the association with the spirometric risk factors and suggest our associations are conservative estimates. Finally, a sensitivity analysis with the assumption that all individuals excluded because they did not have data to calculate decline, would not experience a significant decline in lung function, then the overall prevalence of decline in the cohort only drops from 16% to 14%, which does not change the significance of the finding. We only looked at the two years prior to the index FEV1 , thus we do not know what happened in the years prior to entry and if this is indeed their “first” rapid decline. Given our conservative definition of rapid decline of ≤ −5% predicted per year over a median follow-up of 3.6 years, this is not likely to be a significant factor. The overall amount of missing data (<5%) was minimal and would not be expected to bias the results. This study was conducted prior to the wide availability of modulators. The impact of modulators on delaying subsequent rapid lung function decline among those with early-stage lung disease is unknown. There is no standard definition of early-stage lung disease in adults. We chose FEV1 80% predicted since this is frequently interpreted as the lower limit of “normal” in spirometric reports and the CF patient registry reports FEV1 % predicted ≥ 70% as “normal/mild”1 . A priori defined sensitivity analyses using FEV1 % predicted ≥ 100% were consistent with the main results and thus we report results with FEV1 % predicted ≥ 80% . We did not examine details specifically related to transition which may have differentially impacted the 18–21 year old age group in comparison to other age groups. However, FEV1 variability as a risk factor for subsequent decline is still valid and may be even more important in this younger age group. In conclusion, even among adults with early-stage lung disease, approximately 15% may experience substantial declines in their lung function. The variability in FEV1 over the previous two years may be important in identifying patients at risk for subsequent rapid lung function decline and should be validated in an independent cohort. This study reinforces the concept that adults with early-stage lung disease do not have “normal lungs” or mild lung disease and the CF community should give strong consideration to no longer using these terms. The onset of decline in lung disease may be delayed, rather than absent, and this cohort
Please cite this article as: E.C. Dasenbrook, A.K. Fink and M.S. Schechter et al., Rapid lung function decline in adults with early-stage cystic fibrosis lung disease, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.12.005
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should be followed in the Adult CF clinic to identify the onset of decline. All authors meet the 4 criteria for authorship below: •
•
• •
Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND Drafting the work or revising it critically for important intellectual content; AND Final approval of the version to be published; AND Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
5. Grant support Drs. Dasenbrook (DASENB17A0) and Sanders (SANDERS16Y5) were supported by grants from the Cystic Fibrosis Foundation. Declaration of Competing Interest DJP and SJM are employees of ICON Clinical Research, which was paid by The Cystic Fibrosis Foundation for providing analytical services for this study. ECD has received honoraria from Gilead Sciences and Vertex Pharmaceuticals. DBS has received honoraria from Vertex Pharmaceuticals. Acknowledgements The authors would like to thank the Cystic Fibrosis Foundation for the use of CF Foundation Patient Registry data to conduct this study. Additionally, we would like to thank the patients, care providers, and clinic coordinators at CF Centers throughout the United States for their contributions to the CF Foundation Patient Registry. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jcf.2019.12.005.
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[2] Boyle MP. The evidence for long-term benefits of restoration of CFTR function continues to grow. Am J Respir Crit Care Med Oct 1 2015;192(7):774–6. [3] VanDevanter DR, Pasta DJ, Konstan MW. Improvements in lung function and height among cohorts of 6-year-olds with cystic fibrosis from 1994 to 2012. J Pediatr Dec 2014;165(6):1091–7 e1092. [4] Mogayzel PJ Jr, Naureckas ET, Robinson KA, et al. Cystic fibrosis foundation pulmonary guideline. pharmacologic approaches to prevention and eradication of initial pseudomonas aeruginosa infection. Ann Am Thorac Soc Dec 2014;11(10):1640–50. [5] Sawicki GS, Sellers DE, Robinson WM. High treatment burden in adults with cystic fibrosis: challenges to disease self-management. J Cyst Fibros Mar 2009;8(2):91–6. [6] Konstan MW, Wagener JS, Vandevanter DR, et al. Risk factors for rate of decline in FEV1 in adults with cystic fibrosis. J Cyst Fibros Sep 2012;11(5):405–11. [7] VandenBranden SL, McMullen A, Konstan MW, et al. Characteristic changes in lung function decline from adolescence to young adulthood. Pediatr Pulmonol 20 07;42(S30):365–6 10/3/20 07. [8] Nick JA, Chacon CS, Brayshaw SJ, et al. Effects of gender and age at diagnosis on disease progression in long-term survivors of cystic fibrosis. Am J Respir Crit Care Med Sep 1 2010;182(5):614–26. [9] Morgan WJ, VanDevanter DR, Pasta DJ, et al. Forced expiratory volume in 1 Second variability helps identify patients with cystic fibrosis at risk of greater loss of lung function. J Pediatr Feb 2016;169:116–21 e112. [10] Knapp EA, Fink AK, Goss CH, et al. The cystic fibrosis foundation patient registry: design and methods of a national observational disease registry. Ann Am Thorac Soc Apr 14 2016. [11] Dasenbrook EC, Merlo CA, Diener-West M, Lechtzin N, Boyle MP. Persistent methicillin-resistant Staphylococcus aureus and rate of FEV1 decline in cystic fibrosis. Am J Respir Crit Care Med 2008;178(8):814–21 10/15/2008. [12] Quanjer PH, Stanojevic S, Cole TJ, et al. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J Dec 2012;40(6):1324–43. [13] Lederer DJ, Bell SC, Branson RD, et al. Control of confounding and reporting of results in causal inference studies. Guidance for authors from editors of respiratory, sleep, and critical care journals. Ann Am Thorac Soc Jan 2019;16(1):22–8. [14] Sawicki GS, Ostrenga J, Petren K, et al. Risk factors for gaps in care during transfer from pediatric to adult cystic fibrosis programs in the United States. Ann Am Thorac Soc Feb 2018;15(2):234–40. [15] Tuchman LK, Schwartz LA, Sawicki GS, Britto MT. Cystic fibrosis and transition to adult medical care. Pediatrics Mar 2010;125(3):566–73. [16] Wagener JS, Millar SJ, Mayer-Hamblett N, et al. Lung function decline is delayed but not decreased in patients with cystic fibrosis and the R117H gene mutation. J Cyst Fibros Jul 2018;17(4):503–10. [17] Heltshe SL, Goss CH, Thompson V, et al. Short-term and long-term response to pulmonary exacerbation treatment in cystic fibrosis. Thorax Mar 2016;71(3):223–9. [18] Harness-Brumley CL, Elliott AC, Rosenbluth DB, Raghavan D, Jain R. Gender differences in outcomes of patients with cystic fibrosis. J Women’s Health Dec 2014;23(12):1012–20. [19] Dasenbrook EC, Sawicki GS. Cystic fibrosis patient registries: a valuable source for clinical research. J Cyst Fibros Mar 16 2018.
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Please cite this article as: E.C. Dasenbrook, A.K. Fink and M.S. Schechter et al., Rapid lung function decline in adults with early-stage cystic fibrosis lung disease, Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.12.005