Macrolides in cystic fibrosis: is there a role?

A spectrum of anti-inflammatory properties, evidence of anti-infective action against Pseudomonas aeruginosa at sub-inhibitory concentrations and positive clinical experience in patients with diffuse panbronchiolitis, a disease with features in common with cystic fibrosis (CF), has prompted research to evaluate the role of macrolide therapy in patients with CF. Newer macrolides such as azithromycin have the advantage of improved tolerability and a prolonged intracellular half-life requiring an infrequent dosing regimen. Results from initial studies suggest a benefit from several months of macrolide therapy in patients with CF. An improvement in lung function was initially shown in a small open study in children, while maintenance of lung function compared with placebo, reduced acute respiratory exacerbations, and reduced systemic markers of inflammation were demonstrated in a randomized, placebo-controlled study of macrolide therapy in adult patients with CF. Additional controlled studies are required to determine optimal drug, dosage, and duration of therapy, and long-term adverse effects of prolonged therapy with macrolides in patients with CF. The potential, with long-term use, to induce resistance against other bacteria colonizing the upper respiratory tract e.g. pneumococci has not been explored. Measurement of cytokines and inflammatory mediators from the sputum of patients with CF is technically difficult and does not correlate with disease activity. There is a need for easily measurable, reproducible and clinically meaningful end-points for evaluation of new therapies in CF. The choice of appropriate outcome measures, apart from lung function, to monitor disease activity needs careful consideration in clinical trials determining the efficacy of macrolides in patients with CF. Evidence-based recommendations for the use of macrolides in the treatment of CF are not expected for some years although macrolides are already being prescribed for long-term use in some centers. There is a need for further research into mechanisms of anti-inflammatory action of macrolides in the lungs of patients with CF and whether or not such therapy may be beneficial in the long term.     

Can mucoid Pseudomonas aeruginosa be eradicated in children with cystic fibrosis?

Pseudomonas aeruginosa (PsA) is the most common pathogen to cause chronic lung infection in children with cystic fibrosis (CF), and is associated with an increase in both morbidity and mortality. Whilst the non‐mucoid strain can be eradicated, it is believed that mucoid PsA is difficult, if not impossible, to eradicate. We hypothesized that with modern and aggressive antibiotic regimes, mucoid PsA can be eradicated in children with CF. We investigated this hypothesis through a retrospective review of respiratory tract cultures of children with CF at The Royal Brompton Hospital, London. Children aged under 16 with a confirmed diagnosis of CF and mucoid PsA on respiratory tract culture during a defined 9‐year period were eligible for inclusion. Respiratory tract culture results were followed up for each patient to establish whether children remained infected with mucoid PsA and specifically to identify clearance of infection. Factors which may have been associated with persistence or clearance were also sought. One hundred sixteen children had the minimum dataset, and of these patients 67 (58%) cleared mucoid PsA for more than 1 year. Of the 67 patients who cleared mucoid PsA for more than 1 year, 38 (57%) patients remained clear of mucoid PsA at the last available culture (median 30, range 2–106 clear cultures, and median 55, 12–103 months clear). We conclude that isolation of mucoid PsA does not necessarily equate to lifelong infection. We suggest that trials of eradication of mucoid PsA at first isolation are required. Pediatr Pulmonol. 2010; 45:566–568. © 2010 Wiley‐Liss, Inc.     

Does deficiency of arylsulfatase B have a role in cystic fibrosis?

Cystic fibrosis (CF) is associated with mutation and abnormal function of the cystic fibrosis transmembrane conductance regulator (CFTR) that affects cellular chloride transport. Clinically, CF of the lung is associated with excessive accumulation of secretions, including the sulfated glycosaminoglycans, chondroitin sulfate and dermatan sulfate (DS), both of which contain sulfated N-acetylgalactosamine residues. The sulfatase enzymes, which are a highly conserved group of enzymes with high specificity for designated sulfate groups, include arylsulfatase B, a lysosomal enzyme. Arylsulfatase B, also known as N-acetyl galactosamine 4-sulfatase, can degrade DS and chondroitin-4 sulfate. Previously reported data demonstrated diminished activity of arylsulfatase B in lymphoid cell lines of patients with CF compared to normal control subjects. Frequent infections with Pseudomonas, a sulfatase-producing organism, occur in patients with CF, whereas infections with Mycobacterium tuberculosis, which lacks sulfatase activity, are infrequent. Additional investigation to determine if diminished function of arylsulfatase B is a consistent finding in cells of patients with CF may be informative, and may help to correlate the molecular, biochemical, and clinical characteristics of CF.     

Breath condensate pH in children with cystic fibrosis and asthma: a new noninvasive marker of airway inflammation?

STUDY OBJECTIVES: The noninvasive assessment and monitoring of airway inflammation could be important in respiratory disease. The pH of exhaled breath condensate (EBC) is a promising marker. Although pH has been measured in the EBC of adults with inflammatory airway diseases, no study has measured this in children. DESIGN: This study aimed to assess whether there is a change in pH in the EBC of children with cystic fibrosis (CF) and asthma, and to try to determine whether pH could be used as a marker of airway inflammation. Furthermore, the relationships among EBC pH, severity of disease, and oxidative stress were studied. PATIENTS AND METHODS: We studied 20 children with CF (mean [+/- SEM] age, 7 +/- 3 years), 20 children with asthma (mean age, 7 +/- 2 years), and 15 age-matched healthy children (mean age, 7 +/- 2 years). The pH of EBC was measured using a pH meter. MEASUREMENTS AND RESULTS: Lower pH values were observed in the EBC of children with CF and asthma compared to control subjects (mean pH, 7.23 +/- 0.03 and 7.42 +/- 0.01 vs 7.85 +/- 0.02, respectively). Furthermore, relationships among EBC pH, severity of asthma, and the presence of an infective exacerbation of CF was found. There was a negative correlation between exhaled pH and exhaled leukotriene B(4) concentrations (r = -0.5; p < 0.005). CONCLUSION: We conclude that the measurement of EBC pH may be useful in the evaluation of airway inflammation in children with asthma and CF.     

What is the role of virus vaccination in patients with asthma?

It is estimated that viruses play a role in 30% to 80% of asthma exacerbations. Thus, virus vaccination in patients with asthma could play an important role in preventing asthma exacerbations and other complications. Influenza is the only agent for which a routine vaccine is currently available. This article discusses whether influenza vaccination in patients with asthma, based on the available evidence, is justified. Cost-effectiveness of (influenza) vaccination for patients with asthma is questionable. For the other major viruses involved, the present state of affairs is described. Although progress is being made, a vaccine may be available in the near future only for respiratory syncytial virus (RSV). Meanwhile, clinicians and patients should aim for an optimal treatment with the currently available asthma medication.     

Aerosolized dornase alfa in cystic fibrosis: Is there a role in the management of patients with early obstructive lung disease?

Airway inflammation and infection are present in patients with mild lung disease in cystic fibrosis (CF), suggesting the need for early treatment. In a previously reported large multicenter trial, dornase alfa improved pulmonary function and decreased the need for hospitalization in patients with CF over 5 years of age and with forced vital capacity greater than 40% predicted. We report here preliminary results of a study of dornase alfa delivered by two different nebulizer systems to patients with mild lung disease in CF and near normal lung function. Even in this mild group dornase alfa improved pulmonary function. The delivery system with the smaller droplet size tended to provide greater improvement than the system with the larger droplet size, although this difference was not statistically significant. We have reviewed characteristics of nebulizers and patients' lung function that might affect efficacy of different nebulizer delivery systems. Our results indicate that treatment can improve pulmonary function in patients with mild lung disease in CF and illustrate the need for further studies in this group of patients. Pediatr. Pulmonol. 1997;24:155–158. © 1997 Wiley-Liss, Inc.