Six-minute walk test in children and adolescents with cystic fibrosis

The 6-min walk test is a simple, rapid, and low-cost method that determines tolerance to exercise. We examined the reproducibility of the 6-min walk test in 16 children with cystic fibrosis (11 female, 5 male; age range, 11.0 +/- 1.9 years). We related the distance walked and the work performed (distance walked x body weight) with nutritional (body mass index and respiratory muscle strength) and clinical (degree of bronchial obstruction and Shwachman score) status. Patients were asked to walk as far as possible upon verbal command on two occasions. There was no statistical difference between distances walked (582.3 +/- 60 and 598.2 +/- 56.8 m, P = 0.31), heart rate, respiratory rate, pulse oxygen saturation, arterial blood pressure, dyspnea, and percentage of maximal heart rate for age in the two tests. Distance walked correlated (Pearson) with maximal expiratory pressure (98.6 +/- 28.1 cmH2O, r = 0.60, P < 0.01), maximal heart rate (157.9 +/- 10.1 bpm, r = 0.59, P < 0.02), Borg dyspnea scale (1.7 +/- 2.4, r = 0.55, P < 0.03), and double product (blood pressure x heart rate; r = 0.59, P < 0.02). The product of distance walked and body weight (work) correlated (Pearson) with height (r = 0.83, P = 0.000), maximal expiratory pressure (r = 0.64, P < 0.01), systolic blood pressure (r = 0.56, P < 0.02), and diastolic blood pressure (r = 0.55, P < 0.03). We conclude that the 6-min walk test is reproducible and easy to perform in children and adolescents with cystic fibrosis. The distance walked was related to the clinical variables studied. Work in the 6-min walk test may be an additional parameter in the determination of physical capacity.     

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.     

六分钟步行试验对于慢性心力衰竭患者的临床应用

目的 探讨六分钟步行试验（6MWT）对于慢性心力衰竭（CHF）患者的心功能评估作用：采用6MWT定量研究CHF患者运动前后心率、血压的变化。方法218例受试对象按年龄段及美国纽约心脏病学会分级（NYHA分级）分别进行6MWT,同时记录六分钟步行距离（6MWD）及运动前后的血压和心率。结果不同年龄段组6MWD与NYHA分级呈高度负相关关系（P〈0．01）。正常对照组与NYHAI级组6MWD没有差别（P〉0．05）,其余各组均有显著差异（P〈0．01）;各年龄段组NYHA分级与心率变化值呈正相关关系,与收缩压变化值呈负相关关系（P〈0．01）。结论6MWT更适合评价轻、中度慢性心力衰竭患者的心功能;根据运动前后心率、血压的变化,6MWT可以为CHF患者运动锻炼提供指导。     

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.     

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.     

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.     

Comparison of gastrointestinal pH in cystic fibrosis and healthy subjects

The primary objective of this study was to define the pH conditions under which supplemental pancreatic enzyme preparations must function in the upper gastrointestinal tract. The hypothesis was that normal or greater gastric acid output in patients with cystic fibrosis (CF), combined with low pancreatic bicarbonate output, results in an acidic duodenal pH, compromising both dosage-form performance and enzyme activity. Gastrointestinal pH profiles were obtained in 10 CF and 10 healthy volunteers under fasting and postprandial conditions. A radiotelemetric monitoring method, the Heidelberg capsule, was used to continuously monitor pH. Postprandial duodenal pH was lower in CF than in healthy subjects, especially in the first postprandial hour (mean time greater than pH 6 was 5 min in CF, 11 min in healthy subjects,P<0.05). Based on the dissolution pH profiles of current enteric-coated pancreatic enzyme products, the duodenal postprandial pH in CF subjects may be too acidic to permit rapid dissolution of current enteric-coated dosage forms. However, the pH was above 4 more than 90% of the time on the average, suggesting that irreversible lipase inactivation in the duodenum is not likely to be a significant limitation to enzyme efficacy. Overall results suggest that slow dissolution of pH-sensitive coatings, rather than enzyme inactivation, may contribute to the failure of enteric-coated enzyme supplements to normalize fat absorption.This study was supported by a Rackham Faculty Award, National Institutes of Health grant M-01RR0042, and the Cystic Fibrosis Foundation.     

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.     

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.     

Liver and lung transplantation in cystic fibrosis: an adult cystic fibrosis centre's experience

Liver disease develops in one‐third of patients with cystic fibrosis (CF). It is rare for liver disease to have its onset after 20 years of age. Lung disease, however, is usually more severe in adulthood. A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants. Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation.     

Metabolic abnormalities in adults with cystic fibrosis

Background and objective: Survival of patients with cystic fibrosis (CF) has improved, resulting in increased exposure of patients to cardiovascular risk factors. Diabetes mellitus is common in patients with CF; however, less is known about lipid abnormalities in this population. In this study, the prevalence of lipid abnormalities was investigated in a contemporary population of adults with CF. Methods: Clinical and laboratory data on 221 adult patients with CF were collected retrospectively. Fasting serum glucose levels and lipid profiles were recorded. The age‐specific values for healthy individuals, as reported by the National Health and Nutrition Examination Surveys, were used for comparison. Results: The mean age of the patients was 30 ± 10 years, 55.1% were men and the mean FEV₁% was 68 ± 25%. Sixty‐nine patients (31.2%) had CF‐related diabetes mellitus and 52 (23.5%) were receiving insulin therapy. In addition, 36 patients (16.3%) had impaired glucose tolerance. Triglyceride levels were similar to those of historical control subjects (mean ± SEM, 1.37 ± 0.05 and 1.39 ± 0.02 mmol/L, respectively, P = 0.75). However, in the 30–39 years age group of CF patients, triglyceride levels were increased relative to those of their control counterparts (1.79 ± 0.14 vs 1.38 ± 0.04 mmol/L, P = 0.006). Total cholesterol levels were lower in the CF patients compared with control subjects, across all age groups. Conclusions: Abnormalities of glucose metabolism are highly prevalent in CF patients, and are accompanied by hypertriglyceridaemia in the 30–39 years age group. Prospective studies are required to confirm lipid abnormalities and investigate possible cardiovascular complications in patients with CF.     

Antibiotic desensitization in adults with cystic fibrosis

OBJECTIVE: Allergic reactions to antibiotics occur in up to 30% of patients with cystic fibrosis (CF). Repeated antibiotic exposure and immune hyper-responsiveness increase the risk of allergic reactions and may limit antibiotic choice. Desensitization may allow the successful administration of an antibiotic despite previous allergy. We aimed to determine the success of antibiotic desensitization in patients with CF in an adult CF unit over a 7-year period. METHODOLOGY: A retrospective medical record review was performed on the 19 patients who had undergone antibiotic desensitization procedures. Data collected included drug allergy and intolerance profiles, nature of allergies, and the outcome of desensitization procedures. Desensitization procedures were performed in a ward setting according to published methods. RESULTS: Nineteen patients (13 females) reported 62 drug allergies with a mean of 3.3 per patient. Of the 71 desensitization procedures undergone by this group, 54 (76%) were successful. Fifteen of the 19 patients were allergic to two or more beta-lactam antibiotics. Over half of the patients were desensitized to more than one antibiotic. Nine different antibiotics were used in 31 different patient/drug combinations. A successful outcome was achieved in 18/31 (58%) combinations, with three requiring treatment for mild allergic reactions. Allergic reactions caused drug cessation in a total of 19 patient/drug combinations (three after initial successful desensitization and full courses of antibiotics). Over 50% of these reactions occurred on day 1. Desensitization failures were more common in patients with well-documented allergic reactions to a specific drug. CONCLUSION: This study demonstrates that multiple antibiotic allergies are common in adults with CF. Cross-reactivity between beta-lactam antibiotics may limit antibiotic choice for the treatment of pulmonary exacerbations. Antibiotic desensitization allows safe and successful treatment in the ward setting of many patients with previous allergies to an antibiotic. In many patients symptoms of allergy still occur and result in cessation of the antibiotics. Use of corticosteroids and antihistamines may improve the success rate of desensitization procedures.     

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.