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.     

Mucoactive agents for chronic,non‐cystic fibrosis lung disease: A systematic review and meta‐analysis

Inhaled mucoactive agents are used in respiratory disease to improve mucus properties and enhance secretion clearance. The effect of mannitol, recombinant human deoxyribonuclease/dornase alfa (rhDNase) and hypertonic saline (HS) or normal saline (NS) are not well described in chronic lung conditions other than cystic fibrosis (CF). The aim of this review was to determine the benefit and safety of inhaled mucoactive agents outside of CF. We searched Medline, Embase, CINAHL and CENTRAL for randomized controlled trials investigating the effects of mucoactive agents on lung function, adverse events (AEs), health‐related quality of life (HRQOL), hospitalization, length of stay, exacerbations, sputum clearance and inflammation. There were detrimental effects of rhDNase in bronchiectasis, with average declines of 1.9–4.3% in forced expiratory volume in 1 s (FEV₁ ) and 3.7–5.4% in forced vital capacity (FVC) (n = 410, two studies), and increased exacerbation risk (relative risk = 1.35, 95% CI = 1.01–1.79 n = 349, one study). Some participants exhibited a reduction in FEV₁ (≥10–15%) with mucoactive agents on screening (mannitol = 158 of 1051 participants, rhDNase = 2 of 30, HS = 3 of 80). Most AEs were mild and transient, including bronchospasm, cough and breathlessness. NS eased symptomatic burden in COPD, while NS and HS improved spirometry, HRQOL and sputum burden in non‐CF bronchiectasis. Mannitol improved mucociliary clearance in asthma and bronchiectasis, while the effects of N‐acetylcysteine were unclear. In chronic lung diseases outside CF, there are small benefits of mannitol, NS and HS. Adverse effects of rhDNase suggest this should not be administered in non‐CF bronchiectasis.     

Pilot study of safety and tolerability of inhaled hypertonic saline in infants with cystic fibrosis

Inhaled hypertonic saline (HS) positively affects both lung function and pulmonary exacerbations in children and adults with cystic fibrosis (CF). Early initiation of treatment may potentially reduce lung function decline and improve outcome of CF patients. However, the safety and tolerability of HS have not been established in infants and young children. We conducted a prospective trial of inhaled HS in infants with CF. Raised volume rapid thoracoabdominal compression (RVRTC) maneuvers were performed at baseline, 10 min after salbutamol inhalation and 15 min after inhalation of a 7% HS solution. Oxygen saturation, respiratory rate, heart rate, and cough frequency were recorded during each inhalation. A clinically important change in lung function was defined a priori as a change in FEV 0.5 of > or =20%. Thirteen infants (5 female) aged 25-140 weeks were enrolled in the study. Overall, there was no difference between FEV(0.5) or FEF(25-75) at baseline, after bronchodilator or after HS. Respiratory and heart rate as well as oxygen saturation remained stable during inhalation of the HS. Three infants had cough during inhalation; one of the infants woke up due to cough but recovered within 5 min. No other side effects were observed during or immediately after inhalation. There was no difference in microbiologic yield between pre- and post-HS throat swabs. In this pilot study, inhalation of HS was well tolerated in CF infants. These results support a study of the efficacy of HS in this age group.     

Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: effect on lung function, health status and sputum

OBJECTIVE: Inhaled mannitol increases mucus clearance in patients with bronchiectasis by an unclear mechanism. The effect of mannitol on lung function, health status and sputum properties was investigated. METHODOLOGY: Nine patients with bronchiectasis inhaled 400 mg of mannitol once daily for 12 days. Health status was assessed using the St George's Respiratory Questionnaire (SGRQ). Sputum was analysed for viscosity, elasticity, spinnability, surface tension, contact angle, solids, mucociliary transportability (MCTR) on a frog palate, and cough transportability (CTR) on a simulated cough machine. RESULTS: Lung function was unchanged with treatment (baseline FEV1 82.0 +/- 16.2%) apart from an improvement in FEF from 85.4 +/- 13% (baseline) to 90.7 +/- 14.4% (P < 0.05; 12th treatment; visit 7). The total SGRQ score (mean +/- SD) of 49.3 +/- 13.8 at baseline, decreased by 12.4 +/- 10.2 (P < 0.01; visit 7) and 10.1 +/- 9.4 units (P < 0.02) 6-10 days after treatment cessation. The baseline subscores for symptoms (72.9 +/- 11.8), activity (44.7 +/- 20.9) and impact (44.4 +/- 14.3) were reduced by 0.8 +/- 9.1 (P > 0.7), 8.4 +/- 16.0 (P > 0.1) and 19.2 +/- 13.7 (P < 0.005) units, respectively (visit 7). Mannitol reduced the baseline (mean +/- SE) surface tension from 94.5 +/- 1.4 to 84.7 +/- 2.1 mN/m (P < 0.0001), contact angle from 51.1 +/- 2.8 to 33.2 +/- 2.4 degrees (P < 0.0001), spinnability from 11.6 +/- 0.4 to 10.0 +/- 0.2 mm (P < 0.005), and solids from 5.7 +/- 0.4 to 4.3 +/- 0.7% (P < 0.02), acutely (visit 7). Viscosity, elasticity and MCTR did not change significantly, while CTR was increased from 25.8 +/- 1.0 to 34.1 +/- 2.7 mm (P < 0.003). CONCLUSION: Mannitol significantly improved the health status over 12 days and this improvement was maintained for 6-10 days after cessation of treatment. In addition, mannitol reduced the tenacity, increased the hydration of mucus acutely and improved cough clearability in patients with bronchiectasis.     

The 24-h effect of mannitol on the clearance of mucus in patients with bronchiectasis

Study objective: To investigate the acute effect of mannitol on the clearance of mucus, and (1) the 24-h mucus retention, and (2) the mucus clearance rate and lung function 24 h after inhalation of a single dose of mannitol. DESIGN: Clearance of mucus was measured on 3 consecutive days using (99m)Tc-sulfur colloid radioaerosol and a gamma camera. INTERVENTIONS: Mannitol, 330 +/- 68 mg (mean+/- SD), was inhaled using a dry powder inhaler only on day 2. PATIENTS: Eight patients with bronchiectasis (age range, 29 to 70 years). Measurements and results: On each day, lung images were collected over 2 h and at 24 h. Key findings of the study are as follows: (1) the 24-h retention of mucus was reduced the day after mannitol had been inhaled, compared to the day without mannitol (day 1) in the whole right lung (57.6 +/- 6.2% vs 68.1 +/- 5.9%), central (47.5 +/- 6.7% vs 56.9 +/- 6.5%), intermediate (61.7 +/- 5.6% vs 73.8 +/- 5.5%), and peripheral regions (70.9 +/- 4.3% vs 86.6 +/- 4.6%)(p < 0.02); and (2) mannitol helped patients clear mucus within 2 h that might otherwise take up to 24 h, from the whole right lung and defined regions. However, clearance over 60 min measured 24 h after mannitol inhalation was not significantly different to baseline clearance without mannitol (8.7 +/- 1.9% on day 1 vs 9.7 +/- 3.7% 24 h after mannitol; p > 0.8). The patients maintained the same lung function the day before and after mannitol had been inhaled: FEV(1) (percent predicted), 79 +/- 5 on day 1 vs 80 +/- 5 on day 3; and forced expiratory flow, midexpiratory phase (percent predicted), 50 +/- 6 on day 1 vs 51 +/- 6 on day 3; p > 0.6). CONCLUSIONS: Mannitol inhalation acutely increases clearance of mucus, and this effect extends beyond the acute study period, resulting in decreased mucus retention at 24 h.     

Is significant cystic fibrosis‐related liver disease a risk factor in the development of bone mineralization abnormalities?

In order to assess the effects of significant cystic fibrosis-related liver disease (CFLD) on bone health, we compared the bone mineral status of older children and adolescents with CFLD to those with cystic fibrosis (CF) alone. Thirteen children (age range, 10-19 years) from our clinical CF services were identified with significant CFLD (9 of these 13 patients had clinical and radiological evidence of portal hypertension). This cohort was then matched by age, gender, and anthropometric measurements with equal numbers of patients with CF alone. All patients had a dual-energy X-ray absorptiometry (DEXA) scan to determine bone mineral content (BMC), bone area (BA), bone mineral density (BMD), and bone mineral apparent density (BMAD) in the region of the lumbar spine. Blood was drawn to determine serum vitamin A, D, E, and K status and liver function tests. The best forced expired volume in 1 sec (FEV1) for each patient in the 12 months around the time of the scan was also documented. Patients with CFLD had slightly worse FEV1 (82 +/- 20% vs. 91 +/- 16%, P = 0.05) and significantly higher alanine aminotransferase (65.5 +/- 35 IU/l vs. 30 +/- 20 IU/l, P = 0.01) than those with CF alone. The mean lumbar spine BA, BMC, BMD, and BMAD were not different between children with CFLD and CF. In conclusion, the presence of significant liver disease in children with CF does not appear to be an additional risk factor for the development of abnormal bone mineralization.     

Effects of hyperglycemia and mannitol infusions on renal hemodynamics in normal subjects

Early diabetes mellitus is characterized by an increase in glomerular filtration rate and effective renal plasma flow which may initiate and potentiate glomerular injury which ultimately results in diabetic nephropathy. To investigate the role of hyperglycemia per se in mediating these hemodynamic changes, eight healthy adults had inulin clearance, creatinine clearance, and para-aminohippurate (PAH) clearance after steady state conditions of hyperglycemia were achieved (549 +/- 86). Clearances were repeated during equivalent osmotic diuresis with Mannitol. Euvolemia was maintained by quantitative fluid and electrolyte replacement of urinary losses. Mean inulin clearances were 87 +/- 6, 87 +/- 5, and 81 +/- 4 ml/min during control, glucose, and mannitol periods (p = ns). Creatinine clearance overestimated inulin clearance by 15-32% but there were no differences between control glucose and mannitol periods. PAH clearance fell from control values of 595 +/- 29 to 340 +/- 22 ml/min during hyperglycemia (p less than .05). During osmotic diuresis with mannitol PAH, clearance rose to control values. In vitro studies excluded the possibility that conjugation between glucose and PAH can explain the clearance results. These results in normal subjects documenting renal vasoconstriction with hyperglycemia are of particular interest in view of recent experimental data suggesting that failure to vasoconstrict characterizes the hemodynamics of early diabetes.     

Effect of a short course of rhDNase on cough and mucociliary clearance in patients with cystic fibrosis

The aim of the study was to measure the effect of a short course of recombinant human deoxyribonuclease I (rhDNase) on ciliary and cough clearance in a group of cystic fibrosis patients, using a radioaerosol and gamma camera technique. Patients were initially randomized to receive either rhDNase (2.5 mg qd) or placebo. Following the measurement of baseline clearance, patients were given a 7-day course of either rhDNase or placebo. The patient then returned on the seventh day for follow-up clearance measurements. This was followed by a 2-week washout period before the whole process was repeated with the alternative inhalation solution. On each of the study days, mucociliary clearance was initially measured for a period of 60 min (IC). This was followed by cough clearance (CC) measurements for 30 min, during which patients were requested to cough a total of 120 times. Post-cough clearance (PCC) was then measured for a further 60 min. Thirteen patients completed the study. Patients' age ranged between 18-38 years, and they had baseline values of FEV(1) of 27-103% of predicted values. Following completion of the course of rhDNase, there was a mean percent increase from baseline of 7.5% for FEV(1) and 5.4% for FVC% (P = 0. 03). There was a small, nonsignificant increase in IC (6.2 +/- 3.6%) on the rhDNase arm compared with the placebo arm (-2.3 +/- 2.9%), P = 0.1. No changes were seen in either CC (1.0 +/- 3.2% [rhDNase] vs. 1.9 +/- 2.4% [placebo], P = 0.9) or PCC (-0.7 +/- 1.5% [rhDNase] vs. 0.9 +/- 1.7% [placebo], P = 0.3). Patients who achieved a 10% or greater improvement in FEV(1) (n = 5) in response to rhDNase did not show any greater change in clearance than nonresponders. In conclusion, we were unable to demonstrate any improvements in either ciliary or cough clearance in response to a short course of rhDNase. The mechanism of action of this drug in vivo remains uncertain.     

Inhaled mannitol changes the sputum properties in asthmatics with mucus hypersecretion

BACKGROUND AND OBJECTIVES: Most asthmatics with mucus hypersecretion have difficulty in clearing their secretions so that mucus plugs and airway obstruction are commonly present. Inhaled mannitol facilitates clearance of mucus. This study investigated the changes in the physical properties of sputum in response to mannitol in asthmatics with chronic cough and sputum production. METHOD: Sputum was collected from 12 asthmatics (26-73 year), lifelong non-smokers, at baseline, after eformoterol (24 mug) and after mannitol on each of four visits. Inhaled mannitol doses were: 635 mg (Visit 1), 240 mg (Visit 2), 360 mg (Visit 3) and 360 mg in the presence of montelukast (Visit 4). Eformoterol was inhaled before mannitol on each visit to prevent bronchoconstiction. Sputum measurements included viscosity, elasticity, surface tension, contact angle-glass and percentage solids. RESULTS: There were no significant differences between the sputum properties at baseline and after eformoterol. Mannitol (360 mg) reduced the baseline (mean +/- SEM) elasticity from 29.9 +/- 4.5 to 15.1 +/- 1.4 Pa (P < 0.0001), viscosity from 18.4 +/- 3.2 to 8.1 +/- 1.2 Pa (P < 0.0001) at 1 rad/ s, surface tension from 92.1 +/- 2.2 to 81.9 +/- 2.5 mN/m (P < 0.0001), contact angle-glass from 57.5 +/- 3.2 to 49.6 +/- 2.0 degrees (P < 0.0001), and percentage solids from 6.9 +/- 0.7 to 5.7 +/- 0.4% (P < 0.0001). All doses of mannitol reduced the sputum properties similarly and no property was further reduced by montelukast (P > 0.4). CONCLUSION: Inhaled mannitol reduced the viscoelasticity, surface tension, contact angle and the solids content of sputum in asthmatics with chronic cough and sputum production, consistent with the osmotic effect of mannitol causing water efflux in the airway lumen.     

Effect of albuterol on maximal exercise capacity in cystic fibrosis

BACKGROUND: Inhaled, short-acting beta-adrenergic agonists (SAbetaAs) are widely prescribed in cystic fibrosis (CF) subjects, despite a lack of convincing data for efficacy and the potential for these agents to result in airway instability. We tested the hypothesis that inhaled albuterol would improve maximal exercise performance in CF subjects with airflow obstruction, as a result of acute bronchodilation. METHODS: Randomized, double-blind, placebo-controlled crossover study of the effect of inhaled albuterol on maximal exercise performance in 20 stable adult CF patients (mean +/- SD age, 23.3 +/- 6.1 years; FEV(1), 57.65 +/- 17.13% of predicted). RESULTS: Ventilatory limitation to exercise was demonstrated in 16 subjects (80%). Significant bronchodilation occurred with exercise alone (end-exercise FEV(1), 2.24 +/- 0.8 L; vs preexercise FEV(1), 2.09 +/- 0.77 L; p < 0.0001), but albuterol resulted in significantly greater exercise-induced bronchodilation than placebo (change in FEV(1), 0.3 +/- 0.15 L vs 0.15 +/- 0.11 L; 95% confidence interval [CI], + 0.07 to + 0.23; p < 0.001). However, there was no difference in maximal workload achieved (albuterol, 158 +/- 46 W; vs placebo, 158 +/- 45 W; 95% CI, - 4.41 to + 4.71; p = 0.95), nor any other measure of exercise performance including maximal oxygen uptake. CONCLUSIONS: Despite causing significant acute bronchodilation, inhaled albuterol did not improve maximal exercise performance in ventilatory-limited CF adults, adding to the body of literature that fails to show any clinical benefit of SAbetaAs in CF subjects. The current results provide further evidence to question the widespread use of these agents, although the potential for adrenergic beta-agonists to instead improve submaximal exercise performance merits further investigation.     

Evaluation of ventilation maldistribution as an early indicator of lung disease in children with cystic fibrosis.

Many children with cystic fibrosis (CF), receiving modern, aggressive CF care, have normal spirometry results. This study aimed to see if homogeneity of ventilation distribution is impaired early in the course of CF lung disease, and if ventilation inhomogeneity is a more frequent finding than abnormal spirometry in children benefiting from modern CF care. The study compared spirometry findings to two indices of ventilation inhomogeneity (mixing ratio (MR) and lung clearance index (LCI)) from multiple-breath inert gas washout in 43 children with CF, aged 3-18 yrs, and 28 healthy children. In total, 10/43 CF subjects (23%) had reduced forced expiratory volume in one second (FEV1) and 14/34 (41%) showed abnormal maximum expiratory flow at 25% of forced vital capacity (MEF25). In contrast, MR was abnormal in 31/43 (72%) and LCI in 27/43 (63%). MR was abnormal in 22/33 CF subjects with normal FEV1, versus 0/28 controls (p<0.001), and abnormal MR was found in 10/20 CF subjects with normal MEF25, versus 0/22 controls (p<0.001). Nine of the 10 CF subjects with reduced FEV1 and 12/14 with abnormal MEF25 showed abnormal MR. Inert gas washout discloses airway dysfunction in the majority of children with cystic fibrosis with normal lung function judged by spirometry. These findings suggest that multiple-breath inert gas washout is of greater value than spirometry in detecting early cystic fibrosis lung disease.     

Mucus properties in children with primary ciliary dyskinesia: comparison with cystic fibrosis

OBJECTIVE: It has been assumed that cystic fibrosis (CF) lung disease is due in part to abnormal airway mucus. Primary ciliary dyskinesia (PCD) is a form of bronchiectasis that is similar to CF in many ways but is caused by congenital defects in mucociliary clearance. Our objective was to compare the biophysical and transport properties of CF and PCD sputa in subjects matched for age and degree of lung function impairment. DESIGN, SETTING, PARTICIPANTS: PCD patients (n = 19; mean age, 9.5 +/- 3.0 years [+/- SD]; FEV1, 65.0 +/- 7.8 L) were recruited from the clinic at the Royal Brompton Hospital. Patients with CF (n = 30, mean age, 10.8 +/- 2.6 years; FEV1, 61.8 +/- 22.8 L) were identified from the Wake Forest University School of Medicine CF Center. Pulmonary function testing and sputum collection were performed as part of routine, scheduled clinic visits. MEASUREMENTS: Pulmonary function was measured by spirometry, and sputum was collected during the pulmonary function test maneuver. Some patients were longitudinally assessed at visits during the course of 3 years. Sputum properties measured were dynamic viscoelasticity, wettability, cohesivity, interfacial (surface) tension, solids composition, DNA and interleukin (IL)-8 concentration, in vitro mucociliary transportability, and cough transportability. RESULTS: Inflammation as measured by IL-8 concentration was three times greater in the PCD sputa (p < 0.0001). There were no significant differences in the sputum biophysical or transport properties comparing CF with PCD sputum. CONCLUSIONS: It is unlikely that established CF lung disease is principally due to abnormal sputum properties, and it is more likely that the biophysical and transport properties reflect disease severity regardless of whether bronchiectasis is due to CF or PCD.     

Reduced bone density in cystic fibrosis: DeltaF508 mutation is an independent risk factor.

The aim of this cross-sectional study was to determine the prevalence and identify determinants of reduced bone mineral density (BMD) in adults with cystic fibrosis (CF). Adults (88) with CF (mean+/-SD age 29.9+/-7.7 yrs; forced expiratory volume in one second (FEV1) 58.2+/-21.5% of the predicted value) were studied. BMD at the lumbar spine (LS) and femoral neck (FN) and body composition were measured using dual-energy X-ray absorptiometry. Blood and urine were analysed for hormones, bone turnover markers, and the cytokines tumour necrosis factor-alpha, and interleukin-6 and -1beta. FEV1 (% pred); CF genotype; malnutrition; history of growth, development or weight gain delays; and corticosteroid use were analysed. BMD Z-scores were -0.58+/-1.30 (mean+/-SD) at the LS and -0.24+/-1.19 at the FN. Z-scores of <-2.0 were found in 17% of subjects. Subjects who were homozygous or heterozygous for the DeltaF508 mutation exhibited significantly lower Z-scores than those with no DeltaF508 allele. Multiple linear regression showed that the DeltaF508 genotype and male sex were independently associated with lower BMD at both sites. Other factors also independently associated with lower BMD included malnutrition, lower 25-hydroxyvitamin D level, lower fat-free mass and lower FEV1 (% pred). In conclusion, reduced bone mineral density in cystic fibrosis is associated with a number of factors, including DeltaF508 genotype, male sex, greater lung disease severity and malnutrition.     

Lung volumes measured by the forced rebreathing technique in children with airways obstruction.

Forced rebreathings may recruit trapped gas into the mixing process. Therefore, we assessed the validity and reproducibility of measurements of residual volume (RVN2) by forced rebreathing in a closed circuit using N2 as indicator gas (N2FR) in children with airways obstruction. Validity was studied from measurements of RV obtained by N2FR, by helium dilution during resting ventilation, and by body plethysmograph at low panting frequency in young patients (8-18 yrs, 13 with asthma, forced expiratory volume in one second (FEV1) 93.0 +/- 22.8% pred; 12 with cystic fibrosis (CF), FEV1 80.4 +/- 16.4% pred). Reproducibility of RVN2 was assessed from duplicate measurements in 73 patients with asthma before and after bronchodilation (FEV1 81.4 +/- 13.7 and 99.6 +/- 11.5% pred, respectively), and in nine patients with CF; the total lung capacity (TLC) was unaffected by bronchodilation; 3,797 +/- 830 ml and 3,807 +/- 843 ml, respectively. Gas dilution methods gave comparable results in all subjects but gave lower values than plethysmography in patients with cystic fibrosis. Reproducibility was satisfactory, median differences between duplicate measurements of RVN2 and TLCN2 varying between 13 and 46 ml, respectively. We conclude that N2FR is quickly performed and well-tolerated. Lung volumes are highly reproducible and agree well with those obtained with the helium dilution method. Deep inspirations do not seem to overcome gas trapping in patients with CF.     

Sputum induction in young cystic fibrosis patients.

A culture from the lower airway secretions is the optimal sample to guide antibiotic therapy in cystic fibrosis (CF) lung disease. The authors therefore examined whether sputum induction is an efficient, safe and acceptable procedure in CF children without spontaneous expectorations. Nineteen patients were studied. Their mean age (range) was 8.6 yrs (4.3-15.2 yrs). Their mean forced expiratory volume in one second (FEV1) was 88% predicted (46-122%). NaCl solutions from 0.9-6% were inhaled, after baseline lung function tests before and after salbutamol. All patients did produce secretions. Alveolar macrophages were present in 16/19 induced samples. The procedure induced minor but significant bronchoconstriction: the mean change (range) in postsalbutamol FEV1 (% pred) was -7 (-24-16). Percutaneous oxygen saturation remained above 90% in all children. The test had to be discontinued in one child because of cough and wheeze. Acceptability of the procedure evaluated using a visual analogue scale from -7-7 showed a mean value (range) at the final concentration of -1.23 (-6.16-5.88). It is concluded that sputum induction is possible, safe and acceptable in cystic fibrosis children who do not expectorate spontaneously.     

Increased concentrations of iron and isoferritins in the lower respiratory tract of patients with stable cystic fibrosis.

Reactive oxygen species may contribute to airway injury in patients with cystic fibrosis (CF) and iron catalyzes oxidant injury by promoting generation of highly reactive hydroxyl radicals. Iron in the lower respiratory tract may be free, ferritin bound (from which iron can be reductively mobilized), or transferrin bound (which generally prevents iron mobilization). Ferritin is composed of subunits that are heavy (H) or light (L), and H-rich ferritins have additional biologic effects including inhibition of lymphocyte proliferation and cell growth. To assess concentrations of iron and iron-binding proteins in the lower respiratory tract of patients with CF, we measured iron (ferrozine), L-ferritin, H-ferritin, and transferrin (enzyme-linked immunosorbent assay [ELISA]) in bronchoalveolar lavage (BAL) fluid recovered from stable patients with CF (n = 8), healthy nonsmokers (NS; n = 8), or heavy cigarette smokers (HS; n = 8). Iron was detected in BAL fluid from patients with CF and HS, but not NS, with higher iron concentrations in patients with CF (42.0 +/- 11.6 microgram/dl) than in HS (9.9 +/- 2.6 microgram/dl, p < 0.05). Ferritin was present in all BAL fluids, with higher total ferritin (L + H) in patients with CF (647 +/- 84 ng/ml) than in HS (181 +/- 25 ng/ml, p < 0.005) or NS (9 +/- 3 ng/ml, p < 0.0005). Ferritin recovered from HS and NS lungs was < 2% H type, whereas ferritin in CF lungs was > 40% H-type ferritin. Transferrin concentrations in BAL fluid were not different in any group. Tumor necrosis factor (TNF)-alpha was present only in BAL samples from patients with CF. To assess whether TNF-alpha contributed to H-ferritin accumulation in CF lungs, we treated lung epithelial cells (A549) with iron alone (FeSO(4), 10-40 microM) or with iron and TNF-alpha (5-20 ng/ml). Iron-treated A549 cells synthesized almost entirely L-ferritin whereas exposure to TNF-alpha with iron caused a dose-dependent increase in accumulation of H-type ferritin. These findings suggest that oxidant injury could be promoted in lungs of patients with cystic fibrosis by iron mobilized from extracellular ferritin and, in addition, that TNF-alpha-promoted accumulation of H-type ferritin may impair local immune function and cell growth.     

Increased arginase activity in cystic fibrosis airways

RATIONALE: Airway nitric oxide concentrations are reduced in cystic fibrosis (CF). Arginases compete for L-arginine, the substrate of nitric oxide synthesis. OBJECTIVES: We hypothesized that increased arginase activity may be one factor contributing to nitric oxide deficiency in CF. MEASUREMENTS: We therefore studied sputum arginase activity, exhaled nitric oxide, and pulmonary function in patients with cystic fibrosis. RESULTS: Mean (+/- SEM) sputum arginase activity was significantly higher in patients admitted for pulmonary exacerbation compared with patients with stable disease (1.032 +/- 0.148 vs. 0.370 +/- 0.091 U/mg protein, p = 0.004). Fourteen days of intravenous antibiotic treatment resulted in significantly decreased sputum arginase activity in all patients (p = 0.0002). However, arginase activity was still significantly (p = 0.0001) higher in CF sputum after treatment for exacerbation compared with induced sputum from healthy control subjects (0.026 +/- 0.006 U/mg protein). Negative correlations were found for sputum arginase activity at admission with FEV1 (r = -0.41, p = 0.01), as well as changes in arginase activity with percent change in FEV1 during antibiotic therapy (r = -0.4, p < 0.01) in CF. Exhaled nitric oxide in CF was positively correlated to FEV1 (r = 0.34, p = 0.007), and in patients admitted for pulmonary exacerbation negatively correlated to sputum arginase activity (r = -0.45, p = 0.03). CONCLUSIONS: These data suggest that increased sputum arginase activity contributes to nitric oxide deficiency in CF lung disease and may be relevant in the pathogenesis of CF airway disease.     

Symptoms, lactate and exercise limitation at peak cycle ergometry in adults with cystic fibrosis.

The purpose of this study was to investigate symptoms, lactate accumulation and limiting factors at peak exercise in cystic fibrosis (CF) patients. In total, 104 CF adults attending an adult CF centre and 27 controls performed progressive cycle ergometry to a symptom-limited maximum. Measurements taken at peak exercise included: heart rate, ventilation, oxygen uptake, carbon dioxide output, oxygen saturation and blood lactate. Symptom scores of perceived breathlessness and muscle effort were recorded using Borg scales. The CF subjects had a lower mean body mass index, forced expiratory volume in one second (FEV(1)) and peak oxygen uptake than controls. Peak lactate concentrations were very similar to controls (mean+/-sd 6.8+/-2.0 mmol x L(-1) versus 7.4+/-1.0 mmol x L(-1)). Symptom scores were no different to controls for either breathlessness (4.5+/-2.0 versus 4.3+/-1.0) or perceived muscle effort (6.1+/-2.0 versus 6.5+/-1.0), with higher scores for muscle effort than breathlessness in both groups. In addition, peak ventilation was lower than the predicted maximum, and high peak heart rates were recorded supporting nonpulmonary factors as important in limiting peak exercise. Peak oxygen uptake was correlated with FEV(1). Comparison of CF subjects with mild or moderate pulmonary disease and controls revealed similar exercise responses. In contrast, those CF patients with severe lung disease (FEV(1) <40% predicted) had significantly higher breathlessness, lower muscle effort scores, lower peak lactate, lower peak heart rate and a mean ventilation exceeding predicted, thus confirming that ventilation was the major factor limiting exercise. In conclusion, cystic fibrosis subjects have a reduced peak exercise capacity, but their exercise response is similar to controls in generating high blood-lactate concentrations and symptoms of muscle effort in excess of dyspnoea. Nonpulmonary factors influence peak performance more in those without severe disease.     

Anaerobic exercise in pediatric cystic fibrosis

Anaerobic fitness is important for daily functioning of children with cystic fibrosis (CF). The aim of this study was to assess the determinants of anaerobic performance in CF. Anaerobic performance was measured in 39 children with CF (mean age, 13.2 +/- 1.8 (SD) years, forced expired volume in 1 sec (FEV(1)) 81.6 +/- 22.1% predicted), using a Wingate anaerobic test. Significant associations were found for peak power (PP) and mean power (MP) with fat-free mass (FFM) body weight, body mass index, maximal isometric muscle force, and aerobic capacity. Pulmonary function was correlated with anaerobic indices when controlled for FFM. Multiple regression analysis indicated that FFM and FEV(1) accounted for 82% and 86% of the variability in PP and MP, respectively. Patients with moderate CF (FEV(1) < 80%), as compared to mild CF (FEV(1) >/= 80%), had higher PP (difference = 85 W, 95% CI = 27-144 W) and MP (difference = 53 W, 95% CI = 42-63 W) at equivalent FFM. Our results indicate that FFM and pulmonary function are important determinants of anaerobic exercise performance in children with CF. With progression of pulmonary disease, anaerobic performance may be enhanced.     

Low-dose methotrexate for advanced pulmonary disease in patients with cystic fibrosis

Inflammation is a hallmark in the pathogenesis of pulmonary destruction in cystic fibrosis (CF). There is no proven effective systemic anti-inflammatory treatment for CF patients with advanced pulmonary disease. Methotrexate (MTX) is known as an effective anti-inflammatory treatment in asthma and in juvenile rheumatoid arthritis. The question was: Is an improvement in pulmonary function achievable with low-dose MTX in patients with cystic fibrosis and advanced pulmonary disease.? METHODS: We treated five CF patients with advanced pulmonary disease, who deteriorated in spite of intensive conventional therapy on an individual basis with low-dose MTX. FEV1% and immunoglobulin G (IgG) serum levels were followed from the year before to the year after starting with MTX. RESULTS: In the year before starting with MTX, FEV1% decreased (median: 10% FEV1; range 9-15% FEV1; P<0.005) after starting with MTX, FEV1% increased (median: 9% FEV1; range: 2-15% FEV1; P<0.05). IgG changed (median: -2 g/l; range: 0.2 to -7.3 g/l) in the first year with MTX. CONCLUSION: These preliminary data suggest a beneficial effect of MTX even in advanced pulmonary disease in CF patients and supports the need for a controlled prospective study.