Anti inflammatory agents
The Leeds Method of Management. September 2008. Anti inflammatory agents [online]. Leeds Regional Adult and Paediatric Cystic Fibrosis Units, St James's University Hospital, Leeds, UK. Available from http://www.cysticfibrosismedicine.com
modulation of airway inflammation
Airway inflammation is a major factor in the pathology of CF lung disease. There is no immune deficiency in patients with CF, but the defect in the CFTR protein and the resulting abnormalities in ion transport increase the susceptibility of the lungs to endobronchial infections by bacteria such as Pseudomonas aeruginosa. Several mechanisms may explain this increased susceptibility of CF lungs to pulmonary infection;
• The abnormal CFTR gene results in dehydration and reduced mucociliary clearance so that the bacteria cannot be removed as efficiently as normal from the airways
• The thin layer of fluid which lines the airways (called airway surface liquid) has important antibacterial properties which are reduced in CF (Smith et al, 1996; Bals et al, 2001)
• CFTR mutations appear to cause an increase in the adherence of bacteria such as P. aeruginosa and Staphylococcus aureus to the airway epithelium. This makes it harder for the lungs to clear the infecting organisms (Imundo et al, 1995; Poschet et al, 2001; Ratjen & Doring, 2003)
• CFTR has been characterised as an important membrane receptor which is involved in the binding and killing of P. aeruginosa. In CF this process appears to be defective (Pier et al, 1996)
Endobronchial infection results in an excessive airway inflammatory response and progressive lung damage (Tirouvanziam et al, 2000). The severity of lung disease in adult patients correlates with CRP and immunoglobulin levels, both markers of active inflammation (Levy et al, 2007).
Although there is evidence that the lungs are sterile and normal in structure at birth, intermittent or chronic airway inflammation with free elastase activity in the airways can be demonstrated in some clinically stable infants even in the absence of demonstrable infection (Khan et al, 1995; Armstrong et al, 1996; Armstrong et al, 1997; Zahm et al, 1997). It is debated whether inflammation precedes infection or vice versa, although it is widely accepted that viral and bacterial infections can trigger sustained airway inflammation (Fayon, 2006). Importantly the inflammation associated with respiratory tract infections does improve when pathogens are eradicated from the airways (Amstrong et al, 1997), but neutrophilic inflammation is found in bronchoalveolar lavage samples independent of culture status (Rosenfeld et al, 2001).
In the majority of patients, chronic infection is with mucoid P. aeruginosa. These bacteria produce large amounts of a polysaccharide (alginate) matrix (mucus), adhere to the damaged epithelial cell surfaces and are 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 in which the chronic presence of P. aeruginosa results in a hyperimmune inflammatory response by the host's defences (Heeckeren et al, 1997; Venaille et al, 1998). Pulmonary secretions from patients with CF infected with P. 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, 1998). A combination of a reduction in the lung's antiprotease defences and the host's hyperimmune response results in damage to the airways.
Patients with Burkholderia cepcia complex (Bcc) infection have significantly higher levels of plasma and sputum neutrophil/elastase and alpha-1 antitrypsin (alpha-1AT) and appear to have increased neutrophil degranulation. Those who subsequenty die compared to those who survive show significantly higher inflammatory activity as registered by a number of markers (Downey et al, 2007). The poor outcome in patients with Bcc infection may reflect an excessive inflammatory response.
It is possible to reduce the excessive inflammatory response with a variety of drugs. These include corticosteroids, high dose non-steroidal anti inflammatory drugs (NSAIDs), macrolides and possibly leukotriene antagonists.
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 ABPA (Hanley-Lopez & Clement, 2000).
Corticosteroid treatment should be considered in patients with CF when other standard therapies have failed to control wheeze, when sputum production remains copious despite appropriate intravenous antibiotic treatment, or when inflammatory markers remain persistently elevated. Doses up to 10 mg of prednisolone daily do not represent a contraindication to lung transplant. Enteric-coated steroid preparations should be avoided as they may be poorly absorbed by patients with CF (Gilbert & Littlewood, 1986). Oral steroids will frequently cause abnormalities of glucose metabolism in patients and may precipitate diabetes mellitus. Urine and/or blood glucose levels should be monitored as appropriate to age of the patient (see The Glucose Tolerance Test and Cystic Fibrosis)..
Long term corticosteroids should theoretically suppress the potentially damaging inflammatory response within the airways but prolonged use is limited by important side effects including diabetes and growth problems. Clinical benefit may be restricted to patients with chronic P. aeruginosa infection (Eigen et al, 1995). Growth suppression induced by long term alternate day prednisolone therapy (over three to four years) may be long lasting, especially in males with CF, and especially if prednisolone is taken before adolescence (Lai et al, 2000). Short-term corticosteroid use may be beneficial. A controlled trial of oral prednisolone for 12 weeks improved respiratory function and reduced IgG (immunoglobulin G) and cytokine concentrations in treated patients (Greally et al, 1994). However, patients receiving repeated short courses of treatment are at risk of reducing their bone mineral density (Matsumoto et al, 2001). They and patients receiving long term steroids for conditions such as ABPA should be monitored closely and considered for appropriate osteoporosis prophylaxis.
Approximately half the patients in many specialist centres are prescribed inhaled corticosteroids but there are few quality trials defining their efficacy. A randomised controlled trial using budesonide (Pulmicort) 1600 mcg/day for six weeks in patients with CF with proven hyperresponsiveness showed no differences in spirometry, but there was a reduction in hyperreactivity in treated patients (Van Haren et al, 1995). Hospitalised patients showed greater improvement in respiratory function over four weeks when beclomethasone diproprionate (Becotide) was added to their usual antibiotic and physical therapy regimen (Nikolaizik & Schoni, 1996). A more prolonged study over six 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 six weeks (Bisgaard et al, 1997). A controlled trial of budesonide 800 mcg twice daily, 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, 1994). However, a trial of inhaled fluticasone proprionate (Flixotide) 500 mcg bd in adult patients with CF showed only minimal benefit (Neiman et al, 1996). Inhaled fluticasone proprionate 400 mcg/day for six weeks in children had no effect on respiratory function or inflammatory markers in the sputum (Balfour-Lynn et al, 1997).
The theory that inhaled steroids should improve respiratory function in patients with CF by suppressing the inflammatory response in the airways was challenged in a recent multicentre, randomised, double-blind, placebo-controlled trial looking at the safety of withdrawal of inhaled corticosteroids in non atopic patients with CF (Balfour-Lynn et al, 2006). Patients already taking daily inhaled corticosteroid therapy received fluticasone for a two month run in period followed by six months of either fluticasone or placebo (fluticasone group: n = 84, placebo group: n = 87). The study found no difference in the time to the first exacerbation, change in lung function or difference in antibiotic or rescue bronchodilator use between the fluticasone and placebo groups. Fewer patients in the fluticasone group withdrew from the study due to lung-related adverse events (9% vs. 15%). This study suggests that inhaled steroids are not effective anti inflammatory agents in CF although long term studies are needed. Their only proven effect in CF care is in the treatment of airway hyperreactivity. The authors advised that treatment with inhaled steroids should be gradually withdrawn in stable patients down to the minimum dose needed (zero if possible) in line with the management of patients with asthma.
These conclusions should perhaps be tempered by consideration of patients not entered into the study because their doctors did not wish to chance withdrawing their corticosteroid treatment. We can only assume that these patients had had a positive response to inhaled corticosteroids.
Patients on combination therapy of itraconazole and inhaled steroids should be monitored regularly for adrenal insufficiency as steroid clearance may be compromised by itraconazole's inhibition of cytochrome P450 enzymes (Main et al, 2002; Skov et al, 2002).
In high doses NSAIDs such as ibuprofen can inhibit neutrophil migration and adherence and inhibit the release of lysosomal enzymes. In rat studies ibuprofen significantly reduces 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 and weight, and improved chest radiographic scores, in patients with CF (Konstan et al, 1995). Patients in this study had mild lung disease. The drug effect was only evident in patients who were initially less than 13 years old. Follow-up data suggests that the improvement in lung function persists and that the greatest benefit remains in the five to 12 year age group.
The major disadvantage of the NSAIDs 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. In Leeds it is felt that there is not sufficient evidence for their routine use.
Antimicrobial 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 CF lungs compared to controls. In CF 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; Hiemstra, 2007). Cathelicidin peptides also appear to have a wide range of antimicrobial activity although they may be under expressed in CF airways. The development of topically administered antimicrobial peptides may have a future role in the treatment of CF.
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 CF sputum. Several small studies looking at the potential role of leukotriene antagonists (inhibitors) have been carried out in patients with CF. Our study reported the effect of four months treatment with zafirlukast in 25 non-asthmatic adult patients with CF and found that treatment was associated with less antibiotic use, lower inflammatory markers, less dyspnoea and CF symptoms, and higher well-being scores (Conway et al, 2003). There was a significant improvement in a clinical score which included chest x-ray assessment, physical examination, presence or not of haemoptysis, sputum characteristics and general health measures such as appetite and exercise tolerance. However, the study was small and the differences in lung function did not reach statistical significance.
In a double-blind, randomised, crossover study, Schmitt-Grohe et al 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. Montelukast had little effect on clinical symptoms although it reduced eosinophilic inflammation. Following a marked improvement in symptoms and peak expiratory flow rate in a patient with CF, Morice et al performed an open label study in 11 adult patients (Morice et al, 2001). They found a significant improvement in a subjective symptom score and exercise tolerance, and a reduction in the variability of morning peak expiratory flow rate (PEFR). The leukotriene LTB4 is an important chemoattractant for neutrophils and therefore inhibiting its activity could reduce neutrophil influx into the airways. Unfortunately a recent multicentre study looking at the potential therapeutic role of a specific LTB4 receptor antagonist showed no beneficial effect on respiratory function and a higher exacerbation rate in treated patients so that the study was terminated prematurely (Schmitt-Grohe et al, 2005).
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 (alpha-1AT) and secretory leukoprotease inhibitor (SLPI). These anti-proteases can be administered by aerosol to supplement the inadequate amount of anti-proteases present in the CF airway. A phase II trial to assess the clinical efficacy of transgenic alpha-1AT as an effective treatment of CF showed a trend towards improvement in 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 the alpha-1AT was well tolerated. In this small study of nebulised transgenic alpha-1AT in CF there were indications of clinical benefit warranting further investigation (Bilton et al, 1999). Subsequent studies have confirmed the safety of alpha-1AT administration but with no evidence for a positive effect on airway inflammation (Martin et al, 2006). A decrease in sputum elastase activity, neutrophils, pro-inflammatory cytokines and P. aeruginosa numbers has been documented, but with no effect of alpha-1AT on lung function (Griese et al, 2007). This latter study was limited by lack of a placebo control.
Although no study has yet found a significant effect on lung function, all studies have involved adults with established disease which may have reached an irreversible point, and in whom large amounts of sputum may have prevented effective alpha-1AT penetration into the airways. A reduction in neutrophil elastase may only slow disease progression and longer study periods than the maximum four weeks to date may be necessary to show drug efficacy. The potential anti-inflammatory effect of alpha-1AT may be best realised following drug delivery to young children with early lung disease (Brennan, 2007).
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 species. Their value in CF depends on their anti-inflammatory properties and their ability to interfere with pseudomonas adherence to epithelial cells and biofilm mode of growth. Macrolide use in CF was stimulated by the success of long-term erythromycin in the treatment of diffuse pan-bronchiolitis (DPB), a condition that shows some similarities to CF in that it is associated with chronic sinusitis, mucoid P. aeruginosa colonisation and bronchiectasis (Hoiby, 1994; Koyama et al, 1997; Jaffe & Bush, 2001). The introduction of erythromycin as a treatment for DPB had a dramatic impact on mortality increasing 10-year survival from between 12% to 22% to over 90% in those colonised with P. aeruginosa (Hoiby, 1994; Black, 1997). The effectiveness of these drugs appears to be limited to the 14-membered and 15-membered macrolides, such as erythromycin, clarithromycin and azithromycin.
Macrolide modulation of airway inflammation
There are several theoretical reasons why macrolides modulate the disease process in CF. Important anti-inflammatory activity is mediated by an inhibition of neutrophil chemotaxis, 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; Khan et al, 1995; Armstrong et al, 1995; Black, 1997; Koyama et al, 1997; Bell et al, 2000; Jaffe & Bush, 2001; Bell et al, 2002; Hodge et al, 2006). Secondly, macrolides may reduce sputum viscoelasticity, airway adhesion of P. aeruginosa, and increase the killing of mucoid P. aeruginosa, 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; Carfartan et al, 2004; Wozniak & Keyser, 2004). Finally, low dose azithromycin has been shown to improve macrophage function, reduce neutrophil counts in the bronchial lavage fluid and reduce pulmonary tissue damage by impairing superoxide generation by activated neutrophils (Tamaoki, 2004; Hodge et al, 2006).
Evidence for the use of macrolides in CF
Hansen et al reported a retrospective analysis of the effect of long-term azithromycin treatment in 50 adult patients (Hansen et al, 2005). The median follow up time was eight months (range 4-12 months). Azithromycin was associated with a small increase in lung function and weight and a fall in the percentage of sputum samples containing mucoid P. aeruginosa colonies. Similar results have been reported in children (Jaffe et al, 1998; Pirzada & Taylor, 1999).
The first published placebo-controlled study investigated the effect of three months of 250mg daily azithromycin versus placebo in 49 adults with CF (Wolter et al, 2002). Treatment with azithromycin was associated with significantly fewer courses of intravenous antibiotics, maintenance of lung function, reduction in median CRP levels and improvement in quality of life scores. These results were supported by the findings from a study by Equi et al who investigated the effect of 250mg (<40 kg) or 500mg (>40 kg) azithromycin versus placebo in 41 children with CF (age 8-18 years), (Equi et al, 2002). The study had a randomised, double-blind, placebo controlled, crossover design and included a six month treatment period. Importantly, 17 out of the 41 patients who completed the study did not culture P. aeruginosa from sputum. The use of azithromycin was associated with a significant but modest (5.4%) group response in FEV1 and less use of oral antibiotics. Five of 41 patients had a clinically important deterioration. The full benefit of treatment was seen two to four months after the commencement of therapy.
A multicentre, randomised, placebo-controlled trial which investigated the effect of azithromycin (500mg or 250mg three times a week if weight was greater or less than 40 kg respectively) in patients chronically infected with P. aeruginosa included individuals with an age greater than six years old and an FEV1 greater than 30% predicted (Saiman et al, 2003). Routine therapies such as Pulmozyme®, TOBI® and high dose ibuprofen were continued. Eighty-seven patients received azithromycin and 98 placebo. Treatment with azithromycin resulted in a relative change in % predicted FEV1 and body weight of 6.2% and 0.8 kg respectively. The improvement in FEV1 was seen in the first 28 days and was sustained with treatment but declined to baseline levels after discontinuation of azithromycin. Patients on active treatment had less risk of developing a pulmonary exacerbation when compared to placebo (p=0.03). Azithromycin reduced the number of participants hospitalised and the mean number of days of non quinolone oral antibiotics use. Although not statistically significant, there was a 40% reduction in the number of intravenous antibiotic courses, a 47% reduction in the number of days in hospital and a trend to improvement in quality of life. There was a mean reduction in P. aeruginosa density from baseline to the end of treatment period. There was no difference in acquisition of resistant organisms during the treatment period. Azithromycin was well tolerated but symptoms were reported more frequently in the active study arm (nausea, diarrhoea and wheeze).
Clement et al have recently published their results of a multicentre, randomised, double-blind, placebo controlled trial in young patients with CF (Clement et al, 2006). The criteria for enrolment were age older than six years and FEV1 40% predicted or more. The active group received either 250 mg or 500 mg (body weight < or > 40 kg) oral azithromycin three times a week for 12 months. The primary end point was change in FEV1. A total of 82 patients (mean age 11.0 years, mean FEV1 85% predicted) were randomised; 40 in the azithromycin group and 42 in the placebo group. Nineteen patients were infected with P. aeruginosa. The relative change in FEV1 at month 12 did not differ significantly between the two groups. The number of pulmonary exacerbations (p<0.005), and the number of additional courses of oral antibiotics were significantly reduced, and the time to the first pulmonary exacerbation significantly increased in the azithromycin group, regardless of the patient’s infectious status (p<0.0001). No severe adverse events were reported. Low dose azithromycin appears to have beneficial effects in both patients with milder disease and those free from chronic P. aeruginosa colonisation (Kastelik et al, 2005; Clement et al, 2006) .
Patients receiving long term azithromycin show an increased prevalence of macrolide resistant strains of S. aureus and H. influenzae (Prunier et al, 2003; Phaff et al, 2006). In the Leeds CF Unit, staphylococcal macrolide resistance has increased since the greater use of azithromycin therapy (unpublished data). There is also a theoretical risk of inducing resistance in atypical mycobacteria and encouraging the emergence of bacteria intrinsically resistant to macrolides. Units prescribing macrolides should monitor the emergence of resistance very carefully.
There have been no reports of any serious adverse outcomes in any studies of azithromycin use in CF. Nausea and diarrhoea were significantly more common but did not lead to an increased withdrawal rate in any of the clinical trials. Although a rise in liver enzymes was seen in three patients these returned to normal levels. Hearing loss and tinnitus are potential side effects in patients receiving concurrent ototoxic medication but Saiman et al found no ototoxicity in a subpopulation of 94 patients (Saiman et al, 2003).
Precautions before starting treatment
Patients attending the Leeds CF Unit have an ECG prior to starting long term, low dose macrolide therapy. This is because macrolides have been associated with prolongation of cardiac repolarisation. The overall risk of ventricular arrhythmias is very small but treatment should be avoided in patients with an abnormal ECG and a prolonged QT interval (Owens, 2004).
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