Power considerations for studies of lung function in cystic fibrosis

Observational studies and clinical trials in cystic fibrosis (CF) have largely been concerned with improving long-term survival. Lung function tests, in particular FEV(1), have proven to be reliable and objective measures for monitoring the course of CF lung disease. Over several decades, the variability and average rates of FEV(1) decline have been remarkably stable. In the past decade, specific treatments and management of CF have resulted in a more gradual rate of decline, so that large numbers of patients are needed to demonstrate a significant subgroup or treatment difference. New measures are needed that detect changes before lung function decline, and that reflect more subtle changes over time. As new measurement tools are developed, FEV(1) provides a model to show how age, sex, duration, and frequency of measurement are related to variability, sample size, and power in cross-sectional or longitudinal studies. Chest radiographs are a standard tool for clinical assessment of an individual patient. However, their use in clinical trials has been limited by the lack of an objective way of measuring the elements that characterize the disease process. The CT scan offers more specific measurements relating directly to the process of lung disease in CF. Computerized algorithms can provide objective scores, but it will be an ongoing challenge to confirm the validity of candidate measures and their relationship to CF lung disease.     

Disease-specific reference equations for lung function in patients with cystic fibrosis

RATIONALE: Forced expiratory volume in one second (FEV1), an important measure of pulmonary disease severity in patients with cystic fibrosis (CF), is frequently expressed as a percentage of a predicted value derived from a healthy reference population. There are limitations to comparing the lung function of a patient with CF to that of healthy control subjects, and potential advantages to comparing it to that of other patients with CF. OBJECTIVE: To estimate CF-specific percentiles of FEV1 as functions of height, age, and sex. METHODS: We used 287,108 FEV1 observations among more than 21,000 patients with CF in the CF Foundation National Patient Registry between 1994 and 2001. The percentiles were estimated using quantile regression methods. RESULTS: FEV1 percentile "growth grids" are presented, allowing comparison of an individual's FEV1 to that of patients with CF of the same sex, age, and height. Their potential uses in clinical practice and research are illustrated. CONCLUSIONS: CF-specific reference equations allow individual patients' FEV1 to be placed in the context of the distribution of lung function of their peers with CF, and should improve generalizability of CF clinical trials by setting entry criteria that are equitable across sex and age ranges. They may serve as a useful adjunct to conventional reference equations.     

Ventilation inhomogeneities in relation to standard lung function in patients with cystic fibrosis

Based on serial lung function measurements performed in 142 children (68 males; 74 females) with cystic fibrosis (CF), prospectively evaluated over an age range of 6 to 20 years, we attempted to determine whether the lung clearance index (LCI) as a measure of ventilation inhomogeneities could be a discriminating factor of disease progression. Annual follow-up lung function measurements featuring FRC determined by whole-body plethysmography and multibreath nitrogen washouts, effective specific airway resistance, flow-volume curves, LCI, and gas exchange characteristics were analyzed by linear mixed-model analysis and Kaplan-Meier statistics. The earliest occurring and strongest factor of progression was the LCI, followed by maximal expiratory flow (MEF(50)) and FRC determined by plethysmography (p < 0.0001). Associations between onset of chronic Pseudomonas aeruginosa infection and CF transmembrane conductance regulator (CFTR) genotype with FEV(1) (p = 0.027) and FVC (p = 0.007) were identified. The study shows that the LCI predicts earlier in life and represented much better functional progression than FEV(1). Moreover, there is no single functional predictor of progression in CF, but aside from risk factors, such as onset of chronic P. aeruginosa infection and genotype, pulmonary hyperinflation, airway obstruction, and ventilation inhomogeneities are important pathophysiologic processes that should be evaluated concomitantly as determinants of lung progression in CF.     

Improvements of lung function in cystic fibrosis

Improved care for patients with cystic fibrosis (CF) has led to their improved survival. We analyzed retrospectively whether improvements in lung function (LF) could be detected in our CF patients over the decade 1980-1990. In 72 patients, 153 LF measurements were performed in their first year of life (1980-1991), and then 189 LF measurements were performed again in 60 of those patients during their sixth year of life (1987-1997). Regression analysis was performed on LF parameters at age 6 years. When adjusting for weight, height, gender, and LF in the first year of life, the date of subsequent measurement was positively associated with FEV(1) (P < 0.01) and MEF(50%) (P < 0.05) and negatively with FRC(pleth) (P < 0.05). The proposed model predicts a child's FEV(1) at age 6 to be 75% of predicted if born in 1980, but 108% of predicted when born in 1990. Improved CF care is the most likely explanation for this observation.     

Pancreatic exocrine function in patients with cystic fibrosis

Pancreatic insufficiency in cystic fibrosis (CF) is associated with more severe disease and requires replacement therapy. Outcome measures such as growth and number of stools, frequency of abdominal pain, and flatulence have often been used to identify pancreatic-insufficient patients and to adjust the dose of replacement enzymes. Unfortunately, some patients with CF are misclassified, and approximately 9% do not receive therapy appropriate for their pancreatic exocrine functional status. Growth, number of stools, frequency of abdominal pain, and flatulence cannot be used to adjust enzyme doses.     

Respiratory muscle function in patients with cystic fibrosis

Respiratory muscle function in patients with cystic fibrosis (CF) can be assessed by measurement of maximal inspiratory pressure (Pi_max), maximal expiratory pressure (Pe_max), and pressure–time index of the respiratory muscles (PTI_mus). We investigated the differences in maximal respiratory pressures and PTI_mus between CF patients with no gross hyperinflation and healthy controls and described the effects of pulmonary function and nutrition impairment on respiratory muscle function in this group of CF patients. Forced expiratory volume in 1 sec (FEV₁), forced vital capacity (FVC) and maximal expiratory flow between 25% and 75% of VC (MEF_25–75), body mass index (BMI), upper arm muscle area (UAMA), Pi_max, Pe_max, and PTI_mus were assessed in 140 CF patients and in a control group of 140 healthy subjects matched for age and gender. Median Pi_max and Pe_max were significantly lower in CF patients compared to the controls [Pi_max = 74 (57–94) in CF vs. 84 (66–102) in controls, P = 0.009], [Pe_max = 71 (50–95) in CF vs. 84 (66–102) in controls, P < 0.001]. Median PTI_mus in CF patients compared to controls was significantly increased [PTI_mus = 0.110 (0.076–0.160) in CF vs. 0.094 (0.070–0.137) in controls, P = 0.049] and it was significantly higher in CF patients with impaired pulmonary function. In CF patients, PTI_mus was significantly negatively related to upper arm muscle area (r = 0.184, P = 0.031). These findings suggest that CF patients with no severe lung disease compared to healthy subjects exhibit impaired respiratory muscle function, while CF patients with impaired pulmonary function and nutrition indices exhibit higher PTI_mus values. Pediatr Pulmonol. 2013; 48:865–873. © 2012 Wiley Periodicals, Inc.     

Muscular strength and function in patients with cystic fibrosis

BACKGROUND: For 20 years, physical activity has been an important component in the treatment of cystic fibrosis (CF) patients in Sweden. Data concerning physical performance in terms of muscular strength in these patients are limited OBJECTIVE: To compare muscular strength and function in patients with CF with those aspects in a healthy control group (CG). DESIGN: Thirty-three patients with CF (16 women) aged 16 to 35 years and 20 healthy individuals matched for age and gender were included in the study. All participants had undertaken regular physical training two to three times per week. The following tests were performed: vertical jumping ability; hand-grip strength; abdominal strength; arm/shoulder strength; quadriceps muscle strength; and a functional test of leg muscle endurance. RESULTS: Patients with CF showed decreased muscle strength and function compared to control subjects (women: maximal hand-grip strength in the right [p = 0.02] and the left hand [p = 0.001]; sustained hand-grip strength in the left hand [p = 0.002]; and in leg muscle endurance [p = 0.02]; men: the number of sit-ups performed within 30 s [p = 0.03]; and left leg isokinetic quadriceps strength at 180 degrees per second [p = 0.02]). The differences were not related to pancreatic or pulmonary function. There was no significant difference between the CF group and the CG in any other test results. CONCLUSIONS: Our study showed few differences in muscular performance between patients with CF and healthy control subjects. Both groups had regular moderate-to-high activity levels. Further studies are needed to evaluate whether the small but significant differences might be related to metabolic abnormalities in skeletal muscles in CF patients.     

Inhaled mannitol improves lung function in cystic fibrosis

BACKGROUND: The airways in patients with cystic fibrosis (CF) are characterized by the accumulation of tenacious, dehydrated mucus that is a precursor for chronic infection, inflammation, and tissue destruction. The clearance of mucus is an integral component of daily therapy. Inhaled mannitol is an osmotic agent that increases the water content of the airway surface liquid, and improves the clearance of mucus with the potential to improve lung function and respiratory health. To this end, this study examined the efficacy and safety of therapy with inhaled mannitol over a 2-week period. METHODS: This was a randomized, double-blind, placebo-controlled, crossover study. Thirty-nine subjects with mild-to-moderate CF lung disease inhaled 420 mg of mannitol or placebo twice daily for 2 weeks. Following a 2-week washout period, subjects were entered in the reciprocal treatment arm. Lung function, respiratory symptoms, quality of life, and safety were assessed. RESULTS: Mannitol treatment increased FEV(1) from baseline by a mean of 7.0% (95% confidence interval [CI], 3.3 to 10.7) compared to placebo 0.3% (95% CI, - 3.4 to 4.0; p < 0.001). The absolute improvement with mannitol therapy was 121 mL (95% CI, 56.3 to 185.7), which was significantly more than that with placebo (0 mL; 95% CI, - 64.7 to 64.7). The forced expiratory flow in the middle half of the FVC increased by 15.5% (95% CI, - 6.5 to 24.6) compared to that with placebo (increase, 0.7%; 95% CI, - 8.3 to 9.7; p < 0.02). The safety profile of mannitol was adequate, and no serious adverse events related to treatment were observed. CONCLUSIONS: Inhaled mannitol treatment over a period of 2 weeks significantly improved lung function in patients with CF. Mannitol therapy was safe and well tolerated. TRIAL REGISTRATION: (ClinicalTrials.gov) Identifier: NCT00455130.     

Lung function decline in cystic fibrosis patients and timing for lung transplantation referral

STUDY OBJECTIVES: To determine risk factors associated with an accelerated decline in lung function in cystic fibrosis (CF), and whether longitudinal changes in FEV(1) would be a better predictor of the need for referral for lung transplantation than any single value for FEV(1.) DESIGN: The rate of decline in pulmonary function was determined by standard linear regression from each patient's calendar year's best percentage of predicted FEV(1) (%FEV(1)) over at least 4 years, and patients were classified into three cohorts based on their rate of decline. Differences between groups in age, weight-for-age z score, gender, genotype, pancreatic status, diabetes, and the presence of various lung microbial isolates were analyzed. A subset of 30 patients referred for lung transplantation were further analyzed, and a prediction model for lung transplantation referral was created using the patient's rate of decline in lung function, the mean waiting time for donor organs, and the average level of lung function of patients prior to lung transplantation. PATIENTS: One hundred fifty-three patients with CF followed up at the Washington University Adult Cystic Fibrosis Center. RESULTS: Younger age, malnutrition, and concurrent infection with both Pseudomonas aeruginosa and Staphylococcus aureus were significant (p < 0.05) risk factors for rapidly declining lung function. Among patients with rapidly declining lung function, referral for lung transplantation would have occurred 8.4 months earlier than actual referral age (p < 0.05) if the prediction model had been used, possibly resulting in additional patient salvage in several cases. CONCLUSIONS: Rate of decline in lung function should be routinely evaluated in patients with CF, and a prediction model utilizing the rate of decline in %FEV(1), and the median regional waiting period for donor lungs for patients with CF may assist in the timing of referral for lung transplantation and more rapidly declining lung function.     

Interpretation of lung function in infants and young children with cystic fibrosis

The last decade has seen a significant advance in understanding about early lung disease in cystic fibrosis (CF). As studies that have measured lung function in preschool years are conducted in association with surveillance of infection, inflammation and early structural changes, and emerging longitudinal data become available, a better insight into the very early onset and nature of such lung disease is emerging. Interventions during the preschool years are increasingly viewed as being crucial to delaying and minimizing disease progression as this is the most important period of postnatal life in terms of lung development and airway remodelling. Lung function measurement in CF is potentially an important assessment tool and is used in routine clinical practice in several centres already. Results of studies from lung function tests that, on the basis of their underpinning physiology, are viewed as being best suited currently for the early detection of lung disease in CF are reviewed.     

Association of body composition and lung function in children with cystic fibrosis

Survival in cystic fibrosis has improved significantly in the last 30 years, with major therapeutic goals of delaying the progressive loss of pulmonary function and maintaining normal growth. Dual-energy X-ray absorptiometry (DEXA) was performed in children with cystic fibrosis (CF) to assess both bone mineral density and body composition. We hypothesised that there would be an association between body composition and pulmonary function in children with CF. Fifty subjects with CF (28 males), mean age 12.7 years, participated in the study. Body composition was determined by DEXA. Body mass index (BMI) was calculated from the ratio of weight/height2 (kg/m2). Lung function was assessed by spirometry. Most patients (78%) had mild lung disease. The mean forced expired volume in 1 sec percent predicted (FEV1% predicted) for the 50 patients was 79.2% (range, 24-117%). There was a strong association between FEV1% predicted and BMI (R=0.59, P=0.0001). Fat-free mass had positive association with pulmonary function tests (R=0.30, P=0.03). Although fat mass showed a positive correlation with pulmonary function, this association did not reach statistical significance. In our group of children with CF and mild lung disease, pulmonary function was more strongly associated with BMI than with fat and fat-free mass.     

Correlation between sinus and lung cultures in lung transplant patients with cystic fibrosis

Background

Lung transplantation has revolutionized the treatment of end‐stage pulmonary disease due to cystic fibrosis. However, infection of the transplanted lungs can lead to serious complications, including graft failure and death. Although many of these patients have concurrent sinusitis, it is unclear whether bacteria from the sinuses can infect the allograft.

Methods

This is a single‐institution retrospective study of all patients who underwent lung transplantation for cystic fibrosis from 2005 to 2015 at Duke University Hospital. Pre‐ and posttransplant nasal and pulmonary cultures obtained via nasal endoscopy and bronchoalveolar lavage (BAL), respectively, were analyzed.

Results

A total of 141 patients underwent 144 lung transplants. Sinus cultures were available for 76 patients (12 pretransplant, 42 posttransplant, 22 both pre‐ and posttransplant). Pretransplant BAL cultures were available for 139 patients, and posttransplant BAL cultures were available for all patients. Pseudomonas aeruginosa (PsA) and methicillin‐resistant Staphylococcus aureus (MRSA) were the most common organisms cultured. There was a significant correlation between pretransplant sinus and posttransplant BAL cultures for PsA (p = 0.003), MRSA (p = 0.013), and Burkholderia cepacia (p = 0.001).

Conclusion

There was a high correlation between pretransplant sinus cultures and posttransplant BAL cultures for PsA, MRSA, and Burkholderia sp. This suggests that the paranasal sinuses may act as a reservoir for allograft colonization in patients with cystic fibrosis. Further studies are needed to determine whether treatment of sinusitis affects allograft colonization and transplant outcomes.

     

GI complications after lung transplantation in patients with cystic fibrosis

STUDY OBJECTIVE: Lung transplantation is now available for patients with cystic fibrosis (CF) and end-stage lung disease. While pulmonary graft function is often considered the major priority following transplantation, the nonpulmonary complications of this systemic disease also continue. We examined the GI complications in a cohort of patients who underwent transplantation. DESIGN: This was a retrospective study of all patients with CF who underwent transplantation between March 1988 and December 1998 in Toronto. Medical records were reviewed, and a short questionnaire was mailed to patients who were alive as of December 1998. RESULTS: There were 80 bilateral lung transplants performed in 75 patients. The questionnaire was distributed to 43 patients, of whom 27 patients (63%) responded. Pancreatic insufficiency requiring enzyme intake was evident in 72 of 75 patients (96%) at the time of surgery. Of three pancreatic-sufficient patients (4%), pancreatic insufficiency was diagnosed in two patients later. Biliary cirrhosis was diagnosed in three patients prior to transplantation. Distal intestinal obstruction syndrome (DIOS) was recorded for 15 patients (20%). Ten patients had a single episode, of which eight episodes occurred early in the postoperative period. Five patients had recurrent episodes. All were medically treated, except for two patients who underwent surgery. Other complications included cholecystitis (n = 3), mucocele of the appendix (n = 1), peptic ulcer disease (n = 3), and colonic carcinoma (n = 1). CONCLUSION: GI complications after lung transplantation are common in patients with CF, and attention should be paid to the risk for DIOS in the early postoperative period. Prevention and early medical treatment are important in order to avoid acute surgery. Close collaboration with the CF clinic, in order to diagnose and treat CF-related complications, is recommended.