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RATIONALE: Stenotrophomonas maltophilia is one of the more common multidrug-resistant organisms isolated from the respiratory tract of patients with cystic fibrosis (CF), but the effect of chronic S. maltophilia infection on CF lung disease is unknown. OBJECTIVES: To determine the impact of chronic S. maltophilia infection on lung disease in CF. METHODS: We developed a serologic assay specific for S. maltophilia and in a cross-sectional study, measured serum antibodies to S. maltophilia in patients with CF to determine if a definition of chronic S. maltophilia isolation based on culture results corresponded to an immunologic response (serologic study). We then used this validated definition to examine the effect of chronic S. maltophilia on the severity of lung disease in a retrospective cohort study using the Toronto CF Database from 1997-2008 (cohort study). MEASUREMENTS AND MAIN RESULTS: Serum antibody levels to S. maltophilia were measured in 179 patients with CF. Patients with chronic S. maltophilia had significantly higher mean antibody levels to S. maltophilia flagellin (P < 0.0001) and whole cell (P = 0.0004) compared with patients with intermittent or no S. maltophilia. The cohort study included 692 patients with an average follow-up of 8.3 years. In an adjusted log linear model, patients with chronic S. maltophilia infection had a significantly increased risk of pulmonary exacerbation requiring hospitalization and antibiotics compared with patients who had never had S. maltophilia (relative risk = 1.63; P = 0.0002). CONCLUSIONS: Chronic S. maltophilia infection in patients with CF is associated with a specific immune response to this organism and is an independent risk factor for pulmonary exacerbations. [ABSTRACT FROM AUTHOR]

Context: Azithromycin is recommended as therapy for cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infection, but there has not been sufficient evidence to support the benefit of azithromycin in other patients with CF.Objective: To determine if azithromycin treatment improves lung function and reduces pulmonary exacerbations in pediatric CF patients uninfected with P. aeruginosa.Design, Setting, and Participants: A multicenter, randomized, double-blind placebo-controlled trial was conducted from February 2007 to July 2009 at 40 CF care centers in the United States and Canada. Of the 324 participants screened, 260 were randomized and received study drug. Eligibility criteria included age of 6 to 18 years, a forced expiratory volume in the first second of expiration (FEV(1)) of at least 50% predicted, and negative respiratory tract cultures for P. aeruginosa for at least 1 year. Randomization was stratified by age of 6 to 12 years vs 13 to 18 years and by CF center.Intervention: The active group (n = 131) received 250 mg (weight 18-35.9 kg) or 500 mg (weight > or = 36 kg) of azithromycin 3 days per week (Monday, Wednesday, and Friday) for 168 days. The placebo group (n = 129) received identically packaged placebo tablets on the same schedule.Main Outcome Measures: The primary outcome was change in FEV(1). Exploratory outcomes included additional pulmonary function end points, pulmonary exacerbations, changes in weight and height, new use of antibiotics, and hospitalizations. Changes in microbiology and adverse events were monitored.Results: The mean (SD) age of participants was 10.7 (3.17) years. The mean (SD) FEV(1) at baseline and 168 days were 2.13 (0.85) L and 2.22 (0.86) L for the azithromycin group and 2.12 (0.85) L and 2.20 (0.88) L for the placebo group. The difference in the change in FEV(1) between the azithromycin and placebo groups was 0.02 L (95% confidence interval [CI], -0.05 to 0.08; P = .61). None of the exploratory pulmonary function end points were statistically significant. Pulmonary exacerbations occurred in 21% of the azithromycin group and 39% of the placebo group. Participants in the azithromycin group had a 50% reduction in exacerbations (95% CI, 31%-79%) and an increase in body weight of 0.58 kg (95% CI, 0.14-1.02) compared with placebo participants. There were no significant differences between groups in height, use of intravenous or inhaled antibiotics, or hospitalizations. Participants in the azithromycin group had no increased risk of adverse events, but had less cough (-23% treatment difference; 95% CI, -33% to -11%) and less productive cough (-11% treatment difference; 95% CI, -19% to -3%) compared with placebo participants.Conclusion: In children and adolescents with CF uninfected with P. aeruginosa, treatment with azithromycin for 24 weeks did not result in improved pulmonary function.Trial Registration: clinicaltrials.gov Identifier: NCT00431964. [ABSTRACT FROM AUTHOR]

Summary: Considerable advances in cystic fibrosis (CF) research have translated into improved patient care, reflected by a continuing trend of improving life expectancy in CF patients. This review summarises some of the major findings of CF research that have occurred in the past year. The review specifically focuses on those developments that have direct implications for patient care or those in which clinical trials suggest benefits that may impact on the treatment of CF patients in the near future. [Copyright &y& Elsevier]

Rationale: Nitric oxide formation is deficient in airways of patients with cystic fibrosis (CF). Since nitric oxide has bronchodilatory effects, nitric oxide deficiency may contribute to airway obstruction in CF. Objectives: We reasoned that inhalation of L-arginine, the precursor of enzymatic nitric oxide formation, could improve airway nitric oxide formation and pulmonary function in patients with CF. Measurements: Exhaled nitric oxide, pulmonary function, and peripheral oxygen saturation were measured before and after a single inhalation of nebulized l-arginine solution in patients with CF and in healthy subjects. A saline solution of similar osmolarity (1.7%) was used as control. Results: Nebulized L-arginine not only significantly increased exhaled nitric oxide concentrations but also resulted in a sustained improvement of FEV(1) in patients with CF. Oxygen saturation also increased significantly after the inhalation of L-arginine. Nebulized saline resulted in a small but significant increase in exhaled nitric oxide but a decrease in FEV(1) in patients with CF. In control subjects inhalation of L-arginine increased exhaled nitric oxide concentrations, but FEV(1) decreased. No effect of saline on exhaled nitric oxide, pulmonary function, or oxygen saturation was observed in healthy subjects. Conclusions: These data suggest that a single inhalation of L-arginine acutely and transiently improves pulmonary function in CF through the formation of nitric oxide. Augmentation of airway nitric oxide formation by inhalation of L-arginine is a promising therapeutic approach in patients with CF. [ABSTRACT FROM AUTHOR]

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 FEV[1] (r =-0.41, p = 0.01), as well as changes in arginase activity with percent change in FEV[1] during antibiotic therapy (r =-0.4, p < 0.01) in CF. Exhaled nitric oxide in CF was positively correlated to FEV[1] (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. [ABSTRACT FROM AUTHOR]

Summary:Bronchiolitis obliterans (BO) is a rare but serious complication of paediatric allogenic bone marrow transplantation (BMT). Currently, there is no clear evidence that therapeutic interventions have a positive impact on the course of the disease. We here report our experience with high-dose pulse methylprednisolone therapy in children after BMT. Nine patients fulfilling clinical and radiologic signs of BO were included in this analysis. The total amount of treatment cycles with pulse methylprednisolone therapy ranged from 1 to 6 cycles (median four cycles). Oxygen saturation increased significantly with normalization of oxygen saturation at the end of therapy in all individuals. Normal oxygen saturation was maintained in all but one patient during follow-up (mean follow-up period 42 {plus/minus} 20 months, range 19–67 months). Forced expiratory volume in 1 s (FEV1) was within the normal range prior BMT and significantly diminished at the time of BO diagnosis. Treatment led to stabilization of lung function, with a significant improvement of FEV1 after 2 months. In all, 7/9 patients remained in clinically stable condition without further deterioration of lung function during follow-up. These data would suggest that anti-inflammatory therapy may be a valuable treatment option in paediatric patients with bronchiolitis obliterans after BMT.Bone Marrow Transplantation (2005) 36, 135–138. doi:10.1038/sj.bmt.1705026 Published online 23 May 2005 [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) lung disease is primarily a disease of the small airways. We hypothesized that even in patients with normal lung function, a reduced surfactant function would be present and favor small airway obstruction. Bronchoalveolar lavages from 76 patients with CF (5-31 years, median 11) with well-conserved lung function (FEV1 94% predicted, range 78-121) and from 10 healthy control subjects were investigated. The deviation of the biophysical surfactant performance from normal, assessed in a bubble surfactometer, was small; however, the ability of the surfactant to maintain the patency of a narrow airway (% open) was significantly reduced. Surfactant protein (SP)-C level was increased, SP-B and SP-D were unchanged, whereas SP-A was decreased. Among the patients with CF, neutrophilic inflammation was modestly related to a poorer surfactant activity, but not to lung function. SP-D was reduced in proportion to the degree of inflammation and in the presence of bacteria. These findings in a large cohort of patients with CF with normal lung function show that the endobronchial airway inflammation is linked to early perturbations of the biophysical properties and immunologic components of pulmonary surfactant and opens fields for novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Chronic neutrophilic inflammation leads to oxidative damage, which may play an important role in the pathogenesis of cystic fibrosis lung disease. Bronchoalveolar lavage levels of the antioxidant glutathione are diminished in patients with cystic fibrosis. Here we evaluated the effects of glutathione aerosol on lower airway glutathione levels, lung function, and oxidative status. Pulmonary deposition of a radiolabeled monodisperse aerosol generated with a Pari LC Star nebulizer (Allergy Asthma Technology, Morton Grove, IL) connected to an AKITA inhalation device (Inamed, Gauting, Germany) was determined in six patients. In 17 additional patients bronchoalveolar lavage fluid was assessed before and after 14 days of inhalation with thrice-daily doses of 300 or 450 mg of glutathione. Intrathoracic deposition was 86.3 +/- 1.4% of the emitted dose. Glutathione concentration in lavage 1 hour postinhalation was increased three- to fourfold and was still almost doubled 12 hours postinhalation. FEV(1) transiently dropped after inhalation but increased compared with pretreatment values after 14 days (p < 0.001). This improvement was not related to the lavage content of oxidized proteins and lipids, which did not change with treatment. These results show that, using a new inhalation device with high efficacy, glutathione treatment of the lower airways is feasible. Reversion of markers of oxidative injury may need longer treatment, higher doses, or different types of antioxidants. [ABSTRACT FROM AUTHOR]

Recombinant human deoxyribonuclease (rhDNase) has been shown to improve lung function and reduce the number of pulmonary exacerbations in patients with cystic fibrosis (CF), but its long-term effect on airway inflammation remains unknown. In this study, we used bronchoalveolar lavage (BAL) to investigate the long-term effect of rhDNase on inflammation in patients with CF having mild lung disease. A total of 105 patients with CF (> or =5 years of age) having normal lung function were randomized to receive rhDNase (2.5 mg/day) or no rhDNase. Patients with a normal percentage of neutrophils in BAL fluid at baseline were not randomized and served as the control group. The percentage of neutrophils in the pooled BAL sample was similar in both randomized groups at baseline. A significant increase in neutrophils was observed over the 3-year study period in both untreated patients and control subjects, whereas neutrophils remained unchanged in patients treated with rhDNase. Elastase activities and interleukin-8 concentrations also increased in untreated patients and remained stable in patients on rhDNase. We conclude that in patients with CF, an increase in neutrophilic airway inflammation is found that is positively influenced by rhDNase treatment. [ABSTRACT FROM AUTHOR]

Variants in the genes encoding for the nitric oxide synthases may act as disease modifier loci in cystic fibrosis, affecting both an individual's nitric oxide level and pulmonary function. In this study, the 894G/T variant in exon 7 of the endothelial nitric oxide synthase gene was related to exhaled nitric oxide and pulmonary function in 70 cystic fibrosis patients who were aged 14.8 +/- 6.9 years (mean +/- SD), with a FEV1 of 69.4 +/- 24.8% predicted. Although there was no association between endothelial nitric oxide synthase genotypes and exhaled nitric oxide in males, nitric oxide levels were significantly higher in female cystic fibrosis patients with an 894T mutant allele, compared with female patients homozygous for the 894G wild-type allele (7.0 +/- 4.4 versus 3.6 +/- 1.9 parts per billion, p = 0.02). Furthermore, in female patients, colonization of airways with Pseudomonas aeruginosa was significantly (p < 0.05) less frequent when carrying an 894T mutant allele as compared with wild type. These data suggest that the 894T variant in the endothelial nitric oxide synthase gene is associated with increased airway nitric oxide formation in female cystic fibrosis patients, possibly affecting colonization of airways with P. aeruginosa. [ABSTRACT FROM AUTHOR]

Background: Matrix metalloproteinases (MMPs) are involved in the remodelling and degradation of extracellular matrix and may play a role in pulmonary tissue destruction in cystic fibrosis (CF).Methods: Bronchoalveolar lavage (BAL) fluid levels of MMP-8, MMP-9, and their natural inhibitor TIMP-1 were measured on two occasions within 18 months in 23 children with mild CF, 13 of whom were treated with DNase.Results: MMP-8 (39.3 (6.8) v 0.12 (0.01) ng/ml), MMP-9 (58.0 (11.4) v 0.5 (0.02) ng/ml), and the molar ratio of MMP-9/TIMP-1 (0.36 (0.05) v 0.048 (0.01)) were significantly higher in patients with CF than in control children without lung disease. Gelatine zymography showed the typical banding pattern of neutrophil derived MMP-9, including 130 kDa NGAL-MMP-9 complex and 92 kDa latent MMP-9 bands; 85 kDa bands (corresponding to active MMP-9) were seen in all patients. There was a close correlation between BAL fluid concentrations of MMPs and alpha(2)-macroglobulin, a marker of alveolocapillary leakage. After 18 months MMP levels were increased in untreated patients and decreased in patients treated with DNase.Conclusions: Uninhibited MMPs may contribute to pulmonary tissue destruction even in CF patients with mild lung disease that may be positively affected by treatment with DNase. [ABSTRACT FROM AUTHOR]

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