Three-minute step test to assess exercise capacity in children with cystic fibrosis with mild lung disease

The information obtained from a simple submaximal test (the 3-min step test) was compared with that from a maximal cycle ergometry study, in a group of children with CF with relatively mild abnormalities of lung function (FEV(1) > 50% predicted). Nineteen subjects with CF undertook both exercise tests on the same day. Measurements included heart rate (HR), oxygen saturations (SaO(2)), visual analogue score of perceived breathlessness (VAS), 15-count breathlessness score (15c), and peak oxygen consumption (VO(2)). There were significant differences in the median changes in HR and VAS during the cycle test compared to the step test, 78 vs. 46 beats per minute (P < 0.05) and 51 mm vs. 42 mm (P < 0.05), respectively. There were no differences between median changes in 15c and SaO(2), but 3 subjects had significant desaturations (>4%) during the cycle test only. Significant exercise desaturations may occur in mild CF lung disease and will not be detected by a 3-min step test. The 15c did not discriminate between a maximal and a submaximal test, and was less useful than VAS. Important information may be missed by the step test which is detected by more complex exercise tests.     

Quantitative air-trapping analysis in children with mild cystic fibrosis lung disease

The purpose of this study was to compare quantitative computed tomography air trapping (AT) and pulmonary function measurements between subjects with mild cystic fibrosis lung disease (MCF; forced expiratory volume in 1 sec (FEV1) > 70% predicted) and normal age-matched controls. Quantitative AT measurements at different levels of expiration were evaluated. Ten subjects from the MCF group and 10 normal subjects underwent inspiratory and expiratory spirometer-triggered chest high-resolution computed tomography (HRCT) and pulmonary function tests. Six matched CT images were obtained at full inflation and at a lung volume near residual volume (nRV). Quantitative measurements of AT were determined by evaluating expiratory CT lung density and by the percent of segmented lung which demonstrated AT on expiratory scans. Percent AT was evaluated for all lung slices combined (global AT), and also by regional assessment. Additional comparisons of lung density and percent air trapping were made in 10 CF subjects with three matched axial HRCT images at lung volumes corresponding to full inflation, near functional residual capacity (nFRC), and nRV. All measurements of expiratory lung density in CF subjects were significantly lower and % AT significantly higher than normal controls. Significant correlations for all subjects were observed between % global AT and RV/TLC as well as forced expiratory flow between 25-75% of forced vital capacity (FEF(25-75)) % predicted. Pulmonary density measurements and % AT better discriminated differences between groups than PFTs. Measurements made on expiratory scans near FRC showed significantly higher values for AT than those made near RV.     

Six-minute walking test in cystic fibrosis adults with mild to moderate lung disease: comparison to healthy subjects

The six-minute walking test (6MWT) has been widely utilized to evaluate global exercise capacity in patients with cystic fibrosis. The aim of this study was to assess the exercise capacity by 6MWT, measuring four outcome measures: walk distance, oxygensaturation and pulse rate during the walk, and breathlessness perception after the walk, in a group of cystic fibrosis adults with mild to moderate lung disease, and in healthy volunteers, as the control group. Moreover, the study examined the relationship between 6MWT outcome measures and pulmonary function in patients. Twenty-five adults (15 females, age range 18-39 years) with cystic fibrosis and 22 healthy volunteers (14 females, age range 20-45 years) performed a 6MWT following a standard protocol. Walk distance, oxygen saturation (SpO2) and pulse rate at rest and during walk, and breathlessness perception after walk assessed by visual analogue scale (VAS) were measured. Cystic fibrosis patients did notdiffer from healthy volunteers in walk distance (626 +/- 49 m vs. 652 +/- 46 m) and pulse rate. Patients significantly differed from healthy volunteers in SPO2 during the walk (mean SpO2) (P < 0.0001) and VAS (P < 0.0001). In patients, SPO2 during the walk significantly correlated with forced expiratory volume in 1 sec (FEV1) (P < 0.0001), residual volume (RV) (P < 0.001), resting SPO2 (base SpO2) (P < 0.001), and inspiratory capacity (IC) (P < 0.01). In addition, VAS significantly correlated with resting SPO2 (P < 0.01) and IC (P < 0.01).On the basis of regression equations by stepwise multiple regression analysis, SpO2 during walk was predicted by FEV1 (r2 = 0.60) and VAS by IC (r2 = 0.31), whereas walk distance was not reliably predicted by any assessed variables. This study showed that cystic fibrosis adults with mild to moderate lung disease covered a normal walk distance with unimpaired cardiac adaptation, but experienced a significant fall in oxygen saturation and an increased breathlessness perception during exercise. Resting pulmonary function was related to oxygen saturation and breathlessness perception during walk, but contributed significantly only tothe prediction of oxygen saturation. We suggest that 6MWT could be valuable for identifying patients who might experience oxygen desaturation and dyspnoea during demanding daily activities.     

Effects of sildenafil on pulmonary hypertension and exercise tolerance in severe cystic fibrosis-related lung disease

Cystic fibrosis (CF) patients with advanced lung disease are at risk for developing pulmonary vascular disease and pulmonary hypertension, characterized by progressive exercise intolerance beyond the exercise-limiting effects of airways disease in CF. We report on a patient with severe CF lung disease who experienced clinically significant improvements in exercise tolerance and pulmonary hypertension without changing lung function during sildenafil therapy.     

Efficacy and safety of aerosolized tobramycin in cystic fibrosis

Aerosolized tobramycin has been extensively used in cystic fibrosis (CF) patients in order to directly deliver the antibiotic to the endobronchial site of infection, and decrease toxicity by limiting systemic absorption. Aerosolized tobramycin doses ranging from 80 mg twice or three times daily to 600 mg three times daily have been used in various clinical trials. At an 80-mg dose, preservation of pulmonary function with little or no improvement over the baseline was reported. Tobramycin, nebulized at 600 mg three times daily, significantly improved clinical and pulmonary functions and reduced the density of Pseudomonas aeruginosa in the sputum. No ototoxicity or nephrotoxicity was reported at either dose. TOBI, a tobramycin solution for inhalation, received Food and Drug Administration approval for maintenance treatment of P. aeruginosa lung infections in CF patients at least 6 years of age. Patients received TOBI nebulize 300 mg of tobramycin every 12 hr daily for 28 days, followed by 28 days off the drug in alternating cycles. In phase III trials, TOBI improved pulmonary function and decreased sputum density of P. aeruginosa compared to placebo. Serum creatinine was minimally, transiently elevated in both groups. More patients in the TOBI group reported voice alterations. All reports of tinnitus were in the TOBI group. An increased risk of emergence of resistant strains of P. aeruginosa was noted at all doses, after prolonged use.     

The six-minute walking test in children with cystic fibrosis: Reliability and validity

There is a need to judge general exercise tolerance in children with cystic fibrosis (CF) under normal daily activity conditions and—when more extensive testing is required—in an exercise laboratory in a specialized center. We investigated the reproducibility, validity, and criterion for a 6-minute walking test, which simulates normal childhood activities. In Part A, we evaluated the reproducibility of a 6-minute walking test in 23 children (12 girls and 11 boys; ages 11.1 ± 2.2 years; range, 8.2 15.6 years) with mild symptoms of CF [forced expiratory volume in 1 second (FEV₁) 94.4 ± 16.5% of predicted values (range, 60.6–129.7); body weight Z-score −0.71 ± 0.81 (range, −1.73–0.93)]. The subjects performed two standardized 6-minute walking tests with 1 week between tests. There was no significant difference between the two walking distances reached (737 ± 85 versus 742 ± 90 meters; P = 0.56), and there was a strong correlation between the two walking distances reached by the individuals (r = 0.90, P < 0.0001). In Part B, the validity of the walking test was evaluated in 15 children (6 girls and 9 boys; ages 14.5 ± 2.0 years; range, 10.2–16.9 years) with moderate symptoms of CF [FEV₁ = 58 ± 16.0% of predicted values, (range, 41.1–89.4); RV/TLC ratio = 46.3 ± 6.5% (range, 31.6–57.2); body weight Z-score: −1.29 ± 0.60 (range, −2.20–0.14)]. They underwent standardized maximum incremental exercise testing on a cycle ergometer and a 6-minute walking test. Postexertional lactate values exceeded threshold values (as described in the literature) in all patients but one. Correlation analysis (Pearson) showed a significant correlation between the walking distance reached (WD = 697 ± 104 meters), and the maximum workload (W_max = 118 ± 44 Watt; r = 0.76, P < 0.001) or the maximum oxygen uptake (1,688 ± 495 ml; r = 0.76, P < 0.001), the latter two being determined on a cycle ergometer. RV/TLC% showed a significant negative correlation (r = −0.72, P < 0.01) with WD. Stepwise multiple regression analysis showed a multiple regression coefficient of R = 0.84 (P < 0.001) for W_max and RV/TLC % as the independent variables vs. WD as the dependent variable. We conclude that the 6-minute walking test is a valid and useful test in children with mild to moderate symptoms of CF to assess their exercise tolerance and endurance. Exercise test results correlated negatively with pulmonary hyperinflation expressed by the RV/TLC ratio. Pediatr Pulmonol. 1996;22:85–89. © 1996 Wiley-Liss, Inc.     

Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition

As part of the ongoing Wisconsin Cystic Fibrosis (CF) Neonatal Screening Project, we had the unique opportunity to study the longitudinal relationship between Pseudomonas aeruginosa (Pa) acquisition and infection and developing lung disease in children with CF. The primary objective was to determine whether acquisition of Pa was associated with a measurable change in the progression of lung disease. Two outcome measures were used to study 56 patients who were diagnosed through newborn screening: 1) Wisconsin additive chest radiograph score (WCXR), based on the average of scores from a pulmonologist and a radiologist, and 2) the highest forced expired volume in 1 sec (FEV(1))/forced vital capacity (FVC) ratio. We used two measures of Pa acquisition: 1) time of first positive protocol-determined oropharyngeal (with cough) culture, and 2) the magnitude of antibody titer detected by ELISA assays, using as antigen a crude cell lysate, purified exotoxin A, or an elastase toxoid prepared from three Pa strains. Other predictor variables included age, pancreatic status, height-for age, and weight-for-age-percentiles. The best regression model for predicting changes in the WCXR included time to first positive culture and antibody titer for Pa elastase. Prior to Pa acquisition, WCXR worsened by 0.45 points/year (P > 0.25); after Pa acquisition, the rate of worsening increased significantly (P < 0.001) to 1.40 points/year. Each antibody titer level (log base 2) increased the score by 0.48 points (P < 0.001). The best regression model for predicting change in the FEV(1)/FVC included only time to first positive culture. Prior to Pa acquisition, the FEV(1)/FVC ratio declined by 1.29%/year; after Pa infection, the rate of decrease significantly accelerated to 1.81%/year (P = 0.001). Our data show that Pa acquisition is associated with declining pulmonary status in children with CF, and that this effect is probably gradual rather than precipitous. Because these patients were diagnosed and treated aggressively, our estimates of the effects of Pa acquisition may be conservative. We also conclude that the WCXR appears to be more sensitive than FEV(1)/FVC in detecting early changes in lung disease associated with CF.     

Inflammatory markers of lung disease in adult patients with cystic fibrosis

BACKGROUND: Progressive pulmonary disease associated with chronic bacterial infection and inflammation is the major cause of morbidity and mortality in cystic fibrosis (CF) patients. Identifying markers of inflammation that correlate with lung injury may be useful in monitoring disease progression and response to therapy. We hypothesized that levels of serum biomarkers would correlate with clinical course of CF as defined by pulmonary function testing (FEV1). OBJECTIVE: To determine whether biomarkers of systemic inflammation correlate with lung function in adults with CF. METHODS: Retrospective cross-sectional analysis of 63 individuals > or = 30 years of age diagnosed with CF in childhood and followed at Children's Hospital, Boston. We collected data on demographics, CFTR genotype, percent predicted forced expiratory volume in 1 sec (FEV1), C-reactive protein (CRP), serum IgE nd IgG, alpha1-antitrypsin, total white blood cell and neutrophil counts, and percent neutrophils. We used univariate analyses and multivariate linear regression modeling to examine whether markers of systemic inflammation varied with FEV1 (% predicted). RESULTS: In two-covariate models including CRP and one other marker, CRP (P < 0.001) and IgG (P = 0.02) were significantly associated with FEV1 (% predicted). In the CRP and IgG model, percent predicted FEV1 decreased by 4.91% (P < 0.0001) for each twofold increase in CRP and by 1.56% (P = 0.02) for each 100 mg/dl increase in IgG. Results were unchanged by adjustment for number of DF 508 CFTR alleles. There was no association between any other marker and FEV1 (% predicted) after adjusting for CRP. CONCLUSION: Severity of lung disease in long surviving adult CF patients is correlated with CRP and IgG levels. Our findings relating CRP and IgG levels and lung function provide a foundation for subsequent longitudinal studies and consideration of novel disease mechanisms and outcome measurements.     

Effects of a supervised,outpatient exercise and physiotherapy programme in children with cystic fibrosis

Previous work suggests benefit from outpatient exercise and physiotherapy in children with cystic fibrosis (CF), namely improved exercise capacity and lung function measures, as well reduced intravenous (IV) antibiotic needs. Our study aim was to investigate the effect of a year‐long supervised outpatient exercise and physiotherapy programme in children with CF. Subjects with CF aged ≥10 years who had received ≥4 courses of IV antibiotics in 2009 were enrolled and seen fortnightly for supervised exercise and physiotherapy throughout 2010. In addition, they were expected to exercise three times weekly, and if unwell complete additional physiotherapy sessions extra to usual chest physiotherapy. Assessments of exercise capacity using the Modified Shuttle Test (MST) and quality of life (QOL; CFQ‐UK) were recorded at baseline and after 1 year. Regular spirometry was performed before and throughout the study. Data were collected on IV antibiotic days. 12 subjects (6 female) were enrolled with mean (95% CI) age of 13.3 (11.8–14.6) years at study entry. A significant reduction in IV antibiotic days from 60 (56–64) days in 2009 to 50 (44–56) in 2010 (P = 0.02) was noted, along with improved MST distance (m) [735 (603–867) vs. 943 (725–1,161), P = 0.04] and level attained [9.4 (8.4–10.5) vs. 11.1 (9.6–12.6), P = 0.04]. Significant improvements in CFQ‐UK scores for physical [59 (47–72) vs. 83 (74–92), P = 0.001], emotional [63 (55–72) vs. 84 (74–93), P < 0.001], treatment [41 (30–51) vs. 61 (48–73), P = 0.002], and respiratory [54 (42–66) vs. 76 (70–82), P = 0.002] domains were noted. The mean (95% CI) rate of change of FEV₁ was ?4 (?18, +10)% in 2009, but was +6 (?2, +13)% in 2010, although this did not reach statistical significance. Supervised, outpatient exercise and physiotherapy are associated with improvements in QOL and exercise tolerance, a reduction in IV antibiotic days, and a trend towards reducing lung function decline in children with CF. The cost of IV antibiotics was reduced by £66,384 ($104,000) in 2010 when compared with 2009. Such cost‐benefit may have implications for workforce planning and service provision. Pediatr Pulmonol. 2012; 47:1235–1241. © 2012 Wiley Periodicals, Inc.     

Randomized, double-blind, placebo-controlled, dose-escalating study of aerosolized interferon gamma-1b in patients with mild to moderate cystic fibrosis lung disease

Interferon gamma-1b (IFN-gamma1b) is a pleiotropic cytokine with immunomodulatory activities that could decrease bacterial burden, inflammation, and obstruction in patients with CF. Patients with CF (> or =12 years old, FEV1 > or =40% predicted) were randomly assigned to sequential dose cohorts inhaling 500 microg IFN-gamma1b, 1,000 microg IFN-gamma1b, or placebo by Respirgard II nebulizer thrice weekly for 12 weeks. Sputum bacterial density and spirometry were measured. Safety, antibiotic use, hospitalization, and sputum neutrophils, elastase, DNA, IL-8, and myeloperoxidase were also evaluated. Sixty-six patients (mean age, 24 years, with mean baseline FEV1 of 74 +/- 20 (SD) percent predicted) were studied. One patient had bronchospasm after the first dose of IFN-gamma1b; the overall withdrawal rate was 15% (5 in the placebo group, 2 in the 500-microg IFN-gamma1b group, and 3 in the 1,000 microg IFN-gamma1b group). The 500-microg IFN-gamma1b dose was well-tolerated, but the 1,000-mug dose cohort, who had a higher baseline bacterial density than placebo patients (mean difference, 1.2 log(10) CFU/g sputum, 95% confidence interval (CI), 0.1,2.8, P=0.04), had 24% more hospitalizations for exacerbation than placebo patients (95% CI, 2,45%, P=0.05). There was a 0.12-l difference between the 500-microg IFN-gamma1b and placebo groups with respect to the 12-week change in FEV1 (active group minus placebo group, 95% CI, -0.03,0.26, P=0.11), as compared to a 0.01-l difference between the 1,000-microg IFN-gamma1b and placebo groups (95% CI, -0.16,0.17, P=0.96). No effects of IFN-gamma1b were seen in sputum bacterial density or inflammatory biomarkers at 12 weeks. Aerosolized IFN-gamma1b did not improve pulmonary function, reduce sputum bacterial density, or affect inflammatory sputum markers in patients with mild-moderate lung disease.     

Randomized controlled study of in-hospital exercise training programs in children with cystic fibrosis

The aim of this study was to compare aerobic and resistance training in children with cystic fibrosis (CF) admitted to hospital with an intercurrent pulmonary infection with a control group. The subjects were randomized into three groups on the first day of admission. The fat-free mass (FFM) was calculated, using the skin fold thickness from four sites (biceps, triceps, subscapular, and iliac crest). Pulmonary function tests were performed within 36 hr of admission and repeated on discharge from the hospital, and again at 1 month after discharge. All subjects performed an incremental treadmill exercise test, using a modified Bruce protocol. Lower limb strength was measured using a Cybex dynamometer. An assessment of quality of life was made using the Quality of Well Being Scale, as previously reported. Activity levels were measured using a 7-day activity diary, and subjects also wore an accelerometer on their hips. There were no significant differences between the three groups in terms of disease severity, and length of stay in hospital. Subjects in all three groups received intravenous antibiotics and nutritional supplementation as determined by the physician. Children randomized to the aerobic training group participated in aerobic activities for five sessions, each of 30-min duration, a week. The children randomized to the resistance training group exercised both upper and lower limbs against a graded resistance machine. Subjects in the control group received standard chest physiotherapy. Our study demonstrated that children who received aerobic training had significantly better peak aerobic capacity, activity levels, and quality of life than children who received the resistance training program. Children who received resistance training had better weight gain (total mass, as well as fat-free mass), lung function, and leg strength than children who received aerobic training. A combination of aerobic and resistance training may be the best training program, and future studies to assess optimal training programs for CF patients are indicated.     

Multicenter,open-label study of recombinant human DNase in cystic fibrosis patients with moderate lung disease

Cystic fibrosis is characterized by the accumulation of thick viscous purulent secretions. Recombinant human deoxyribonuclease I (rhDNase) breaks down extracellular DNA, which contributes to the increased viscosity of sputum. A multinational, open-label study was conducted in 974 cystic fibrosis patients with moderate lung disease [forced vital capacity (FVC) 40–70% of predicted values] to examine the safety and efficacy of aerosolized rhDNase, 2.5 mg, once daily over a period of at least 12 weeks. Patients were assessed under conditions reflecting routine clinical practice. During rhDNase therapy, at least one respiratory tract infection (RTI) requiring intravenous antibiotics was experienced by 29.5% of patients. Forced expiratory volume in 1 second (FEV₁) and FVC were significantly improved from baseline by a mean of 10.5% and 7.2%, respectively. Voice alteration and pharyngitis were the most frequent rhDNase-related adverse events, but only 2% of all patients discontinued treatment due to adverse events. The results obtained were similar to a subanalysis of data from the first 3 months of a placebo-controlled U.S. study. The patients in the present study had a similar frequency of RTIs and improvement in pulmonary function, and reported fewer rhDNase-related and cystic fibrosis–related adverse events than patients in the U.S. study. We conclude that administration of rhDNase is safe, well tolerated, and effective under conditions reflecting routine clinical practice in patients with cystic fibrosis and moderate lung disease. Pediatr Pulmonol. 1998;26:155–161. © 1998 Wiley-Liss, Inc.     

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.     

Regional differences in the evolution of lung disease in children with cystic fibrosis

Progression of lung disease is a major event in children with cystic fibrosis (CF), but regional differences in its evolution are unclear. We hypothesized that regional differences occur beginning in early childhood. We examined this issue by evaluating 132 patients followed in the Wisconsin Neonatal Screening Project between 1985 and 2010. We scored chest X-rays obtained every 1-2 years with the Wisconsin chest X-ray system, in which we divided the lungs into quadrants, and gave special attention to ratings for bronchiectasis (BX) and nodular/branching opacities. We compared the upper and lower quadrant scores, and upper right and left quadrant scores, as patients aged using a multivariable generalized estimation equation (GEE) model. We did a confirmatory analysis for a subset of 81 patients with chest computerized tomography (CT) images obtained in 2000 and scored using the Brody scoring system. The chest X-ray analysis shows that the upper quadrants have higher BX (P<0.001) and nodular/branching opacities (P<0.001) scores than the lower quadrants. CT analysis likewise reveals that the upper quadrants have more BX (P=0.02). Patients positive for mucoid PA showed significantly higher BX scores than patients with non-mucoid PA (P=0.001). Chest X-ray scoring also revealed that the upper right quadrant has more BX (P<0.001) than the upper left quadrant, and CT analysis was again confirmatory (P<0.001). We conclude that pediatric patients with CF develop more severe lung disease in the upper lobes than the lower lobes in association with mucoid PA infections and also have more severe lung disease on the right side than on the left side in the upper quadrants. A variety of potential explanations such as aspiration episodes may be clinically relevant and provide insights regarding therapies.     

Health-related fitness and trainability in children with cystic fibrosis

The objective of this study was to examine the effects of a supervised exercise training program performed during an in patient rehabilitation course on various attributes of health-related fitness, e.g., flexibility, balance and coordination. 286 patients with CF, age range 6-18 years (11.8 +/- 3.4 years), mean forced expiratory volume in 1 sec (FEV1 82.7 +/- 22.3% predicted) were included. Patients performed the modified Munich fitness test (mMFT) to assess flexibility, balance, strength and coordination. To assess aerobic capacity a 6-min walk-test (6MWT) was performed. In addition, some of the patients performed an incremental exercise test on a bicycle ergometer using the Godfrey protocol before and after the exercise training program. The supervised training program consisted of 4-6 weeks of different sports activities 5 times per week. After training, pulmonary function showed a significant (P < 0.05) increase. All test items of the mMFT improved significantly (P < 0.05). Compared to healthy children test scores achieved from children with CF in the mMFT were lower but within a normal range. Our children with CF had a lower walk distance in 6MWT (P < 0.05) compared to healthy. Our findings clearly demonstrated benefits of a systematic exercise training program on components of physical fitness in patients with CF, with improvements of test-tasks to predicted normal in some cases. The results from our study suggested that an exercise training program in CF should be focused on several aspects of physical fitness including all components of physical fitness, e.g. aerobic endurance, flexibility, balance and motor skills.