Daniel Peckham, April, 2003. Airway inflammation [online]. Seacroft and St James's University Hospitals, Leeds, UK. Available from http://www.cysticfibrosismedicine.com

Introduction

Airway inflammation is recognised as a major factor in the pathogenesis of cystic fibrosis lung disease. While there appears to be no immune deficiency in patients with CF, the defect in CFTR and resulting abnormalities in ion transport appears to increase the susceptibility of the lungs to endobronchial infections by bacteria such as Pseudomonas aeruginosa. This results in an excessive airway inflammatory response and progressive lung damage (Heeckeren et al, 1997, Tirouvanziam et al, 2000).

There are several possible mechanism which explain this increased susceptible of CF lungs to pulmonary infection. Firstly the defect in the CFTR gene causes dehydration and reduced mucocillary clearance so that bacteria can't be removed from the airways as efficiently as normal. Secondly the thin layer of fluid which lines the airways (called airway surface liquid) has been found to have important antibacterial properties, which are reduced in CF (Smith et al, 1996, Bals et al, 2001). Thirdly the presence of CFTR mutations appears to cause an indirect increase in the adherence of bacteria such as Pseudomonas and Staphylococcus aureus to the airway epithelium, making it harder for the lungs to clear the organisms after an infection (Poschet et al, 2001; Imundo et al, 1995, Ratjen at al, 2003). Finally CFTR has been characterised as an important membrane receptor which is involved in the binding and killing of P.aeruginosa. In cystic fibrosis this process appears to be defective (Pier et al, 1996).

In the majority of patients, chronic infection with Pseudomonas aeruginosa is of the mucoid form. The bacterium produces large amounts of a polysaccharide (alginate) matrix and adheres to the damaged epithelial cell surfaces making the organism virtually impossible to eradicate.

Repeated infective exacerbations lead to chronic inflammation and further damage to the epithelial cell surface (Rayner et al, 1991). A vicious cycle is set up where the chronic presence of Pseudomonas aeruginosa results in a hyperimmune inflammatory response by the host's defences (Heeckeren et al, 1997; Venaille et al, 1998). Pulmonary secretions from CF patients colonised with Pseudomonas aeruginosa contain a large number of neutrophils as well as high levels of elastase and pro inflammatory mediators such as interleukins (Rayner et al, 1991, Amstrong et al, 1997; Tabary et al, 1997). A combination of a reduction in the lung's antiprotease defences and the host's hyperimmune response results in damage to the airways.

In infants the presence of chronic airway inflammation can be demonstrated in some clinically stable patients even in the absence of demonstrable infection (Armstrong et al, 1995; Armstrong et al, 1996; Armstrong et al, 1997; Kahn et al, 1995; Zahm et al, 1997). It is likely that a birth the lungs are sterile and normal in structure but after repeated and sometimes asymptomatic respiratory infections, persistent inflammation develops and eventually leads to lung damage. Importantly the inflammation associated with respiratory tract infections does improve when pathogens are eradication from the airways (Amstrong et al, 1997).

Drugs which can reduce the inflammatory response are available.These include the corticosteroids, high dose non steroidal anti inflammatory drugs, the macrolides and possibly leukotriene antagonists. The wide use of steroids and NSAID are limited by their side effects and further studies looking at the long term safety profile of macrolides are awaited.

Corticosteroids

Corticosteroids have a very complex but impressive anti-inflammatory action in a number of clinical situations. In CF they are well established as the treatment of choice for allergic bronchopulmonary aspergillosis (ABPA) (Simmonds et al, 1990). Corticosteroids should be of benefit if given long term to suppress the potentially damaging inflammatory response within the airways of the CF patient.

A four year double blind placebo controlled trial of alternate day prednisone (2mg/kg alternate days to a maximum dose of 60mg) suggested a beneficial effect on lung function, a reduction of respiratory infective exacerbations, lower IgG levels and improved nutrition in the treated patients (Auerbach et al, 1985). Unfortunately, the results have not been confirmed either by longer follow-up of those original patients or by subsequent studies (Donati et al, 1990). However, these initial results prompted a multicentre, 4-year, double-blind, placebo-controlled trial of alternate day prednisone. Either 2mg/kg, 1mg/kg of prednisone or placebo were given on alternate days. The 2mg/kg treatment arm was stopped as there were unacceptable side effects (Rosenstein & Eigen, 1991). The 1mg/kg alternate day group finished in August 1991. Side effects were common including diabetes and growth problems. The prednisone treated patients had better respiratory function (FVC) than controls after 4 years but the benefit was restricted to those who had chronic P.aeruginosa infection on entry. There was no evidence that the 2mg/kg was more effective than 1mg/kg on alternate days and side effects were less with the lower dose if treatment was only for 12 months. The height standard deviation scores were lower in both the treated groups than controls and there was no catch up 12 months after treatment was stopped (Eigen et al, 1995). Growth suppression induced by long term alternate day prednisone therapy (over 3 to 4 years) may be long-lasting, especially in males with CF, and especially when prednisone was taken before adolescence (Lai et al, 1999). A recent controlled trial of oral prednisolone for 12 weeks demonstrated improved respiratory function and reduced IgG and cytokine concentrations in treated patients (Greally et al, 1994).

We find that corticosteroids (oral soluble prednisolone, inhaled budesonide or fluticasone proprionate are helpful particularly in young patients who are wheezy and have associated asthma. There are surprisingly few trials of inhaled corticosteroids in CF patients as they are taken by approximately half the child and adult patients in many specialist centres. A randomised, controlled trial using budesonide (Pulmicort) 1600mcg/day for 6 weeks in CF patients with proven hyperresponsiveness showed no difference in spirometry, but there was a reduction in hyperreactivity in treated patients (Van Haren et al, 1995). Hospitalised CF patients showed greater improvement in respiratory function over 4 weeks when beclamethasone diproprionate was added to their usual antibiotic and physical therapy regimen (Nikolaizik & Schoni, 1996). A more prolonged study over 6 months showed significantly better respiratory function in the treated group (Romano et al, 1994). Even when patients with bronchial hyperreactivity were excluded, an advantage was apparent when inhaled budesonide was compared with placebo over 6 weeks (Bisgaard et al, 1994). A recent controlled trial of budesonide 800 mcg b.d. delivered as a dry powder by Turbohaler over two successive three month periods between courses of intravenous antibiotics, showed significantly slower deterioration of respiratory function in patients adhering to the steroid treatment (Bisgaard et al, 1997). However, a trial of inhaled fluticasone proprionate 500 mcg b.d. in adult patients with CF showed only minimal benefit (Neiman et al, 1996) and surprisingly, inhaled fluticasone proprionate 400mcg/day for 6 weeks in children had no effect on respiratory function or inflammatory markers in the sputum, (Balfour-Lynn et al, 1997). Nevertheless, there is increasing clinical evidence to support the theoretical prediction that inhaled steroids improve respiratory function in CF patients by suppressing the inflammatory response within the airways. A multicentre trial looking at the effect of withdrawing inhaled steroids is ongoing.

Patients on combination therapy of itraconazole and inhaled steroids should be monitored regularly for adrenal insufficiency as steroid clearance appears to be compromised by itraconazole's inhibition of cytochrome P450 enzymes (Main et al, 2002; Skov et al, 2002).

Corticosteroid treatment should be considered in adult patients with CF when other standard therapies have failed to control wheeze, when sputum production remains copious despite appropriate I.V. antibiotic treatment, or when inflammatory markers remain persistently elevated. Doses up to 20mg of prednisolone daily do not represent a contraindication to lung transplant.

Enteric-coated steroid preparations should be avoided as we have observed that they may be poorly absorbed by CF patients (Gilbert & Littlewood, 1986). It is common experience that oral steroids will frequently cause abnormalities of glucose metabolism in CF patients and precipitate diabetes mellitus. Urine and/or blood glucose levels should be monitored as appropriate.

Steroids have many important side effects including growth retardation, osteoporosis and adrenal suppression. Patients receiving long term steroids for conditions such as allergic bronchopulmonary aspergillosis should be monitored closely and considered for appropriate osteoporosis prophylaxis.

The Macrolides

The macrolides are a group of antibiotics, which have been widely used for their antibacterial effect against diseases such as Mycoplasma pneumonia, Chlamydia pneumonia and legionella. More recently there has been growing interest in their potential role as anti-inflammatory agents in cystic fibrosis. This follows the success of long-term erythromycin in the treatment of diffuse pan-bronchiolitis (DPB), a condition that exhibits some similarities to cystic fibrosis in that it is associated with chronic sinusitis, mucoid pseudomonas aeuginosa (PA) colonisation and bronchiectasis (Hoiby, 1994; Kayama et al 1997; Jaffe et al, 2001). The introduction of erythromycin as a treatment for DPB had a dramatic impact on mortality increasing 10-year survival from 12.4-21.9% to over 90% in those colonised with P. aeruginosa (PA) (Hoiby, 1994; Black, 1997). Other macrolides such as clarithromycin and Azithromycin seem to be as equally effective.

There are several theoretical reasons why the macrolides could alter the disease process in cystic fibrosis. Firstly, several studies have suggested that the macrolides possess important anti-inflammatory activity, which appears to be mediated by an inhibition of neutrophil chemotaxis (attracting white cells), reduction of neutrophil elastase, and modification of pro-inflammatory cytokines with suppression of interleukin (IL)-1ß, IL-6, IL-8, and tumour necrosis factor (TNF)- production (Konstan et al, 1994; Kahn et al, 1995; Armonstrong et al, 1995; Black, 1997; Kayama et al, 1997; Bell et al, 2000; Jaffe et al, 2001; Bell et al, 2002). Secondly, they may reducing sputum viscoelasticity (thickness) and airway adhesion (stickiness) of P.aeruginosa and increase the killing of mucoid P.aeruginosa, a mechanism that may be mediated by their ability to disrupt the integrity of the protective biofilm and impair the transformation of non-mucoid P.aeruginosa to the more virulent mucoid phenotype (Yasuda et al, 1993; Kobayashi, 1995; Tai et al, 1999; Fisher et al, 1999; Jaffe et al, 2001).

Frederiksen et al carried out the first randomised, double blind, placebo controlled, crossover study of the effect of twice daily clarithromycin in cystic fibrosis (Frederiksen et al, 2001). Various parameters were measured including pulmonary function but, unexpectedly, 20 of 41 patients were excluded from the study so that no conclusions could be drawn. Importantly, failure to complete the study was not related to the active arm. More recently Hansen et al from the same group, reported a retrospective analysis of the effect of long-term azithromycin treatment in 50 patients (30 males) median age 30.1 years (range 18.1-53.8) with cystic fibrosis (Hansen et al, 2002). The median follow up time was 8 months (range 4-12). Azithromycin was associated with a small increase in lung function and weight and a fall in the number of sputum samples containing mucoid PA colonies. Similar results have been reported in children. In a non-randomised open labelled study Pirzada et al compared the effect of 250 mg azithromycin in 18 children with cystic fibrosis and 18 age and sex matched controls over a mean of 0.78 years (Pirzada et al, 1999). The azithromycin treated group showed significant improvement in lung function and weight gain. The drug was well tolerated and no significant side effects were observed. In an earlier study by Jaffe et al, 3 months of 250 mg azithromycin was also associated with a significant increase in lung function, although the study design was open making the results difficult to interpret (Jaffe et al, 1998).

Wolter et al investigated the effect of 3 months of 250 mg daily azithromycin versus placebo in 49 adults with cystic fibrosis. (Wolter et al, 2002). In this study treatment with azithromycin was associated with significantly fewer courses of intravenous antibiotics, maintenance of lung function, reduction in median C reactive protein (CRP) levels, and improvement in quality of life scores. A study by Equi et al investigated the effect of 250 mg (<40 kg) or 500 mg (>40 kg) azithromycin versus placebo in 41 children with cystic fibrosis (age 8-18 years) (Equi et al, 2002). The study had a randomised double blind, placebo controlled, and crossover design and was carried out over 15 months and included a 6 months treatment period. Importantly 17 out of the 41 patients who completed the study did not culture P aeruginosa from sputum. While the use of azithromycin was associated with a significant but modest (5.4%) group response in FEV1, 5/41 had a clinically important deterioration. Treatment was also associated with the use of fewer oral antibiotic and full benefit appeared to be delayed, occurring after 2-4 months after the commencement of therapy. Interestingly, individuals who were not on concurrent rhDNase showed better response and begs the question as to whether or not azithromycin inhibits rhDNAse in vivo (Ripoll et al, 1996).

At the Sixteenth Annual North American Cystic Fibrosis Conference, the preliminary result of a US study were presented (Plenary session Sixteenth Annual North American Cystic Fibrosis Meeting, 2002). This was a multicentre, placebo controlled trial and included individuals with an age greater than 6 years old, FEV1 > 30% predicted and chronic infection with PA. The dose of azithromycin was titrated to weight (500mg or 250 mg 3 times a week if weight was greater or less than 40kg respectively) and routine therapies such as Pulmozyme, TOBI and high dose Brufen were continued for the duration of the trial. A total of 185 patients were studied with 87 patients received AZT and 98 Placebo. Treatment with azathioprine resulted in a relative change in % predicted FEV1 and body weight of 6.2% and 0.8kg respectively. The improvement in FEV1 was seen in the 1st 28 days and sustained but declined to baseline levels after discontinuation. AZT also impacted the number of pulmonary exacerbations as indicated by a 40% reduction in the number of courses of intravenous antibiotic courses and a 47% reduction in the number of hospital days. Trends towards improvement in quality of life were seen in the AZT treated group. There was a mean reduction in PA density from baseline to end of treatment period although there was no significant differences in sputum microbiology at baseline and no difference in acquisition of resistant organisms during the treatment period. While the drug was well tolerated symptoms occurred more frequently in AZT group (nausea, diarrhoea and wheeze).

There is now growing evidence to support the short term use of macrolides in cystic fibrosis with Azithromycin providing a beneficial effect in a proportion of patients. Studies have shown a modest improvement in lung function, weight gain and a reduction in the number of pulmonary exacerbations. In addition patients seem to experience some improvement in quality of life. Further trials are needed to assess the long-term benefit and safety of this group of drugs in patients with cystic fibrosis.

Non-steroidal anti-inflammatory drugs (NSAID)

High doses, non steroidal anti-inflammatory agents such as Ibuprofen can inhibit neutrophil migration and adherence, and inhibit the release of lysosomal enzymes. In rat studies Ibuprofen has been demonstrated to significantly reduce lung inflammation. Getting the dose right is likely to be important as there is some evidence to suggest that the use of low drug concentrations could increase the influx of neutrophils into the lungs.

In a four year double blind placebo controlled study, Konstan et al demonstrated that high dose oral Ibuprofen reduced the decline of lung function, weight and chest radiographic scores in patients with cystic fibrosis (Konstan et al, 1995). Patients in this study had mild lung disease and a drug effect was only evident in patients who were initially less than 13 years old. Follow up data from this study suggests that the improvement in lung function has persisted and that the greatest benefit remains in the 5 - 12 year age group.

The major disadvantage of the NSAID relates to their narrow treatment window and high side effect profile. Close monitoring of plasma levels is mandatory to ensure both a potential therapeutic effect and to prevent toxicity. Results from an ongoing Canadian study are awaited.

Defensins and cathelicidins

Anti microbial peptides called defensins and cathelicidins are innate immune factors present in airway surface liquid and make up part of the lung's natural defences (Bals et al, 1998; Bals et al, 1998; Singh et al, 1998). These peptides are produced by several different cell types including airway epithelial cells, macrophages and neutrophils. The defensins appear to be present in equivalent or higher concentrations in cystic fibrosis lungs as compared to controls. In cystic fibrosis their ability to kill bacteria may be impaired by the presence of abnormally high sodium concentrations within airway surface fluids (Bals et al, 1998; Bals et al, 1998, Goldman et al, 1998). Cathelicidin peptides also appear to have a wide range of antimicrobial activity although they may be under expressed in cystic fibrosis airways. The development of topically administered antimicrobial peptides may have a future role in the treatment of cystic fibrosis

Leukotriene receptor antagonists

The leukotrienes are biologically active compounds formed from arachidonic acid and are released as part of the inflammatory response to lung infections. They are present in high levels in the CF sputum. Several small studies looking at the potential role of leukotriene antagonists (inhibitors) have been carried out in patients with cystic fibrosis. Conway et al reported the effect of 4 month treatment of Zafirlukast in 25 non asthmatic adult patients with CF and found that treatment was associated with the use of less antibiotics, lower inflammatory markers, dyspnoea and symptoms and higher well-being scores (Conway et al, 2001). However the study was small and the differences did not reach statistical significance. In a double-blind, randomized, crossover study, Schmitt and colleagues evaluated the anti-inflammatory and clinical effects of montelukast in 16 children with CF (Schmitt-Grohe et al, 2002). The study was of short duration and although montelukast had little effect on clinical symptoms it reduces eosinophilic inflammation.

Following a marked improvement in symptoms and peak expiratory flow rate in a patient with cystic fibrosis, Morris et al performed an open label study in 11 adult patients with CF (Morice et al, 2001). They found a significant improvement in subjective symptoms score, exercise tolerance and a reduction in the variability of morning PEFR.

More recently, preliminary studies looking at the potential therapeutic role of BIIL 284 BS, a specific LTB4 receptor antagonist, have been completed and results are pending. Studies looking at the clinical efficacy of this compound are planned in the near future.

Alpha-1-antitrypsin and secretory leukoprotease inhibitor (SLPI)

Two natural defences which protect the lung against the destructive impact of the enzyme elastase, released by the neutrophil dominated inflammatory infiltrate in the lung tissue, are alpha-1-antitrypsin (a -1AT) (PPL Therapeutics Ltd, Scotland, UK) and secretory leukoprotease inhibitor (SLPI). These anti-proteases can be administered by aerosol to supplement the inadequate amount of anti-proteases present in the cystic fibrosis airway (Vogelmeier et al, 1996; McElvaney et al, 1991; Allen, 1996). A phase II trial to assess the clinical efficacy of transgenic alpha-1-antitrypsin as an effective treatment of cystic fibrosis showed a trend towards improvement in terms of time to first pulmonary exacerbation and total number of exacerbations when treatment groups were compared to placebo. There were no differences in the reported adverse events in the different treatment groups and placebo and the product were well tolerated. In this small study of nebulised transgenic alpha-1-antitrypsin in CF there were indications of clinical benefit warranting further investigation (Bilton et al, 1999). Although anti-proteases remain therapeutically promising much research needs to be completed in this area and their efficacy and safety needs to be fully established before they will become available in routine clinical use.

References

Armstrong DS, Grimwood K, Carzino R, Carlin JB, Olinsky A, Phelan PD. Lower respiratory tract infection and inflammation in infants with newly diagnosed cystic fibrosis. BMJ 1995; 310: 1571-1572

Armstrong DS, Grimwood K, Carlin JB, Carzino A, Phelan PD. Bronchoalveolar lavage and oropharyngeal cultures to identify lower respiratory pathogens in infants with cystic fibrosis. Pediatr Pulmonol 1996; 21: 267-275

Allen ED. Opportunities for the use of aerosolised a 1 anti-trypsin for the treatment of cystic fibrosis. Chest 1996; 110: 256S-260S

Armstrong DS, Grimwood K, Carlin JB et al. Lower airway inflammation in infants and young children with cystic fibrosis. Am J Resp Crit Care Med 1997;156:1197-204.

Auerbach HS, William M, Kirkpatrick JA, Catten HR. Alternate day prednisone reduces morbidity and improves pulmonary function in cystic fibrosis. Lancet 1985; ii: 686-688

Balfour-Lynn IM, Klein NJ, Dinwiddie R. Randomised controlled trial of inhaled fluticasone proprionate in cystic fibrosis. Arch Dis Child 1997; 76: 38-40

Bisgaard H, Nielson KG, Skov M, Mosfeldt E, Bjerre B, Pedersen SS et al. Inhaled steroid treatment of CF patients with chronic Pseudomonas aeruginosa (Pa) lung infection. Paediat Pulmonol 1994; Suppl 10: Poster 3959

Bisgaard H, Pederson SS, Neilson KG, Skov M, Laursen EM, Kronborg G et al. Controlled trial of inhaled budesonide in patients with cystic fibrosis and chronic bronchopulmonary Pseudomonas aeruginosa infection. Am J Crit Care Med 1997; 156: 1190-1196

Bals R, Goldman MJ, Wilson JM. Mouse beta-defensin 1 is a salt-sensitive antimicrobial peptide present in epithelia of the lung and urogenital tract. Infect Immun 1998; 66: 1225-1232

Bals R, Wang X, Zasloff M, Wilson JM. The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface. Proceedings of the National Academy of Sciences of the United States of America 1998; 95: 9541-9546

Bals R, Wang X, Wu Z et al. Human beta-defensin 2 is a salt-sensitive peptide antibiotic expressed in human lung. J Clin Invest 1998; 102: 874-880

Bals R, Weiner DJ, Meegalla RL et al. Salt-independent abnormality of antimicrobial activity in cystic fibrosis airway surface fluid. Am J Respir Cell Mol Biol 2001;25:21-25

Bell SC, Wolter JM, Seeney SL, et al. Azithromycin reduces TNF- release from lipopolysaccharide (LPS) in cystic fibrosis (abstract). Pediatr Pulmonol 2000;Suppl 20:261.

Bell SC, Seeney S, Walmsley K et al. Long term treatment with Azithromycin results in reduced ex-vivo inflammatory cytokine production in adults with cystic fibrosis (abstract). Pediatr Pulmonol 2002. Supp 24:289

Black PN. Anti-inflammatory effects of macrolide antibiotics. Eur Respir J 1997;10:971-2.

Bilton D, Ellborn S, Conway S, Edgar J, Redmond A. Phase II trial to assess the clinical efficacy of transgenic alpha-1-antitrypsin as an effective treatment of cystic fibrosis. Pediatr Pulmonol 1999; Suppl 19: 246.

Conway SP, Etherington C, Peckham DG, Whitehead A. Zafirlukast (Accolate) as additional therapy in non astmatic, non-ABPA adult patients with cystic fibrosis. 24TH European Cystic Fibrosis Conference, Vienna, Austria 2001; P71

Donati MA, Haver K, Gerson W, Klein M, McLaughlin FJ, Wohl MEB. Long term alternate day prednisone therapy in cystic fibrosis. Pediatr Pulmonol 1990; Suppl 5; poster 322, p277

Eigen H, Rosenstein BJ, Fitzsimmons S, Schidlow DV. Cystic Fibrosis Foundation Prednisone Trial Group. A multicenter study of alternate day prednisone therapy in patients with cystic fibrosis. J Pediatr 1995; 126: 515-523

Equi A, Balfour-Lynn, Bush A et al. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet 2002;360:978-84.

Fisher JJ, Baumon U, Gudowius P, et al. Azithromycin reduces epithelial adherence of P aeruginosa in patients with cystic fibrosis (abstract). Pediatr Pulmonol 1999;Suppl 19:265.

Frederiksen B, Koch C, Hoiby N. Antibiotic treatment at time of initial colonisation with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration in pulmonary function in patients with cystic fibrosis. Pediatr Pulmonol 1997;23:330-5.

Frederiksen B, Koch C, Hoiby N, et al. Clinical efficacy of clarithromycin in CF patients with chronic lung infection. Abstracts of the 24th European Cystic Fibrosis Conference, Vienna, Austria 2001:P208.

Gilbert J, Littlewood JM. Enteric coated prednisolone in cystic fibrosis. Lancet 1986; ii: 1167-1168

Greally P, Hussain MJ, Vergani D, Price JF. Interleukin-1A, soluble interleukin-2 receptor, and IgG concentrations in cystic fibrosis treated with prednisolone. Arch Dis Child 1994; 71: 53-39

Goldman MJ, Anderson GM, Stolzenberg ED et al. Human beta-defensin-I is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Chemtracts 1998; 11(10): 770-776

Hansen CR, Pressler T, Lanng S et al. Effects of long term azithromycin treatment of patients with CF and chronic P. aeruginosa infection (abstract). Pediatr Pulmonol 2002. Supp 24:287

Heeckeren A, Walenga R, Konstan MW, Bonfield T, Davis PB, Ferkol T. Excessive inflammatory response of cystic fibrosis mice to bronchopulmonary infection with Pseudomonas aeruginosa. J Clin Invest 1997; 100: 2810-2815

Hoiby H. Diffuse panbronchiolitis and cystic fibrosis: East meets West. Thorax 1994;49:531-2.
Imundo L, Barasch, Prince A et al. Cystic Fibrosis epithelial cells have a rteceptor for pathogenic bacteria on their apical surface. Proc Natl Acad Sci USA 1995;92:3019-23.

Jaffe A, Jackie F, Rosenthal M, et al. Long-term azithromycin may improve lung function in children with cystic fibrosis. Lancet 1998;351:420.

Jaffe A, Bush A. Anti-inflammatory effects of macrolides in lung disease. Pediatr Pulmonol 2001;31:464-73.

Kahn TZ, Wagener JS, Bost T, Martinez J, Accurso FJ, Richer DWH. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 1995; 151: 1075-1082.

Koyama H, Geddes DM. Erythromycin and diffuse panbronchiolitis. Thorax 1997;52:915-8.

Kahn TZ, Wagener JS, Bost T, et al. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 1995;151:1075-82.

Kobayashi H. Biofilm disease: its clinical manifestation and therapeutic possibilities of macrolides. Am J Med 1995;99:26-30.

Kobayashi O, Moser C, Jensen PO, et al. Azithromycin treatment inhibits induction of mucoid phenotype in susceptible BALB/c mice with chronic Pseudomonas aeruginosa lung infection (abstract). In: Proceedings of XIIIth International Cystic Fibrosis Congress, Stockholm, Sweden 2000:164.

Konstan MW, Hilliard KA, Norvell TM, et al. Bronchoalveolar lavage findings in cystic fibrosis patients with stable, clinically mild lung disease suggest ongoing infection and inflammation. Am J Respir Crit Care Med 1994;150:448-54.

Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 1995; 331: 848-854

Pirzada OM, Taylor CJ. Long-term macrolide antibiotics improve pulmonary function in cystic fibrosis (abstract). Pediatr Pulmonol 1999;Suppl 19:263.

Lai HC, Kosorok MR, Allen DB, FitzSimmons SC, Rosenstein BJ, Campbell PW et al. Longterm growth evaluation in children with CF with history of regular use of alternate-day prednisone therapy. Pediatr Pulmonol 1999; Suppl 19: 297

Main KM. Skov M. Sillesen IB. Dige-Petersen H. Muller J. Koch C. Lanng S.Cushing's syndrome due to pharmacological interaction in a cystic fibrosis patient. Acta Paediatrica 2002; 91(9):1008-11

McElvaney NG, Hubbard RC, Birrer P et al. Aerosol a 1 anti-trypsin for cystic fibrosis. Lancet 1991; 337: 392-394

Morice AH. Kastelik JA. Aziz I. Montelukast sodium in cystic fibrosis. Thorax.2001; 56(3):244-5.

Neiman R, Williams S, Maden C, Knight R, Hodson M. A double blind placebo controlled study comparing the effects of the inhaled corticosteroid fluticasone propionate 500 mg bid with placebo in adults with cystic fibrosis. Am J Respir Crit Care Med 1996; 153: A72

Nikolaizik WJ, Schoni MH. Pilot study to assess the effects of inhaled corticosteroids on lung function of cystic fibrosis patients. J Pediatr 1996; 128: 271-274

Pier GB, Grout M, Zaida TS et al. Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections. Science 1996;271:64-67.

Poschet JF, Boucher JC, Tatterson L et al. Molecular basis for defective glycosylation and pseudomonas pathogenesis in cystic fibrosis lung. Proc Natl Acad Sci USA 2001;98:13972-77

Ratjen F, Doring G. Cystic Fibrosis.Lancet 2003;361:681-89

Rayner RJ, Wiseman WS, Cordon SM, Norman D, Hiller EJ, Shale DJ. Inflammatory markers in cystic fibrosis. Respir Med 1991; 85: 138-145

Rosenstein BE,Eigen H. Risks of alternate day prednisone in patients with cystic fibrosis. Pediatrics 1991; 87: 245-246

Ripoll L, Reinert P, Pepin LF et al. Interaction of macrolides with alpha dornase DNA hydrolysis. J Antimicrob Chemother 1996;37:987-91.

Saiman L. Plenary I session (oral presentation). Sixteenth Annual North American Cystic Fibrosis Conference, 2002.

Singh PK, Hong PJ, Wiles K et al. Production of beta-defensins by human airway epithelia. Proceedings of the National Academy of Sciences of the United States of America 1998; 95: 14961-14966

Smith JJ, Travis SM, Greenberg EP et al. Cystic Fibrosis airway epithelium fails to kill bacteria because of abnormal airway surface fluid. Cell 1996;85:229-36

Schmitt-Grohe S. Eickmeier O. Schubert R. Bez C. Zielen S. Anti-inflammatory effects of montelukast in mild cystic fibrosis. Ann Allergy Asthma Immunol. 2002; 89(6):599-605.

Skov M. Main KM. Sillesen IB. Muller J. Koch C. Lanng S.Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide. Eur Respir J 2002;20(1):127-33..

Tai S, Sudo E, Sun F, et al. Effect of azithromycin on sputum rheology in cystic fibrosis patients (abstract). Pediatr Pulmonol 1999;Suppl 19:264.

Tabary O, Zahm JM, Himrassky J et al. Selective upregulation of chemokine IL-8 expression in cystic fibrosis bronchial gland cells in vivo and in vitro. Am J Pathol 1998;153:921-30

Tirouvanziam R, De Bentzmann S, Hubeau C et al/ Inflammation and infection in naïve human cystic fibrosis airway grafts. 2000 Am J Respir Cell Mol Biol;23(2):121-127

Van Haren EHJ, Lammaers J-W J, Festen J, Heijerman HGM, Groot CAR, van Heerwaarden CLA. The effect of inhaled corticosteroid budesonide on lung function and bronchial hyper-responsiveness in adult patients with cystic fibrosis. Resp Med 1995; 89: 209--214

Vogelmeier C, Gillisen A, Buhl R. Use of secretory leukoprotease inhibitor to augment lung anti-neutrophil elastase activity. Chest 1996; 110: 261S-266S

Venaille TJ, Ryan G, Robinson BW. Epithelial cell damage is induced by neutrophil-derived, not pseudomonas-derived, proteases in cystic fibrosis sputum. Respir Med 1998; 92: 233-240

Wolter J, Seeney S, Bell S. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax 2002;57:212-6.

Yasuda H, Ajiki Y, Koga, T, et al. Interaction between biofilms formed by Pseudomonas aeruginosa and clarithromycin. AntimicrobAgents Chemother 1993;37:1749-55.

Zahm JM, Gaillard D, Dpuis F et al. Early alteration in airway mucociliary clearance and inflammation of the lamina propria in CF mice. Am J Physiol 1997;272:C853-59

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