A Trial of Atorvastatin as an Anti-Inflammatory Agent in Non-Cystic Fibrosis Bronchiectasis

BACKGROUND AND RATIONAL FOR STUDY Bronchiectasis is a chronic debilitating respiratory condition. Patients suffer daily cough, excess sputum production and recurrent chest infections because of inflamed and permanently damaged airways. It is a common with a Scottish incidence of 1 in 1,000 to 1 in 10,000. Over 600 patients in Edinburgh are monitored in secondary care. They frequently utilise primary and secondary care resources through consultations, A&E attendances and inpatient admissions. The economic burden is huge- hospital admissions alone for bronchiectasis cost NHS Lothian just over 1 million pounds alone last year.

LIMITATIONS OF TREATMENT There are few evidence based long term treatments currently available. Long term antibiotics are a feasible option, but with the increasing problems of antimicrobial resistance and side effects, in particular Clostridium difficile and methicillin resistant Staphylococcus aureus (MRSA), there is an international drive to reduce antibiotic usage. There is an urgent need for novel non antibiotic treatments.

Statins as a potential new non antibiotic treatment in bronchiectasis Excessive neutrophilic airways inflammation is the central feature of bronchiectasis. This paradoxically both promotes bacterial colonisation and perpetuates damage to the airways creating a vicious cycle of bacterial colonisation and inflammation.1-3

Statins have been shown to have powerful anti-inflammatory effects.4-6 In animal models, statins can reduce neutrophil recruitment to the inflamed lung and reduce protease activity.7 Statin treatment has been shown to reduce epithelial cell adherence and invasion by Streptococcus pneumoniae in-vitro suggesting a role for statins in preventing bacterial colonisation.8 In healthy controls exposed to lipopolysaccharide to induce acute lung inflammation, pre-treatment with simvastatin reduced neutrophil accumulation in the lung and inhibited production of myeloperoxidase, tumour necrosis factor-alpha, matrix metalloproteinases and C-reactive protein.9 There was also an increase in neutrophil apoptosis, suggesting that statins may aid the resolution of inflammation in the airway.10

STUDY HYPOTHESIS The investigators hypothesise that long term statin treatment will improve patients' symptoms through its anti-inflammatory effect. The beneficial effects on patient symptoms (cough, sputum volume, bacterial load, airway function, exercise tolerance, exacerbation frequency and health related quality of life) will be consequent on reduced neutrophilic airways inflammation.

Planned study

• This is a randomised double blind placebo controlled trial to assess the efficacy of atorvastatin therapy in patients with clinically significant bronchiectasis.
• No such study has previously been undertaken (PUBMED Search "statins" and "bronchiectasis" 18 March 2010- no relevant articles).
• This is a unique proof of principle study assessing a new non antibiotic treatment that could benefit all patients with clinically significant bronchiectasis, without the side effect profile of long term antibiotics.
• Following this proof of principle study, the investigators aim to design a large multi-centred study assessing long term statins as a new treatment.

References

• Stockley RA et al. Elastolytic activity of sputum and its relation to purulence and to lung function in patients with bronchiectasis. Thorax 1984;39(6):408-413.
• Hill AT et al. Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis. Am J Med 2000;109(4):288-95.
• Inflammation: a two-edged sword-the model of bronchiectasis. Cole PJ. Eur J Respir Dis Suppl. 1986;147:6-15.
• Ridker PM et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20-8.
• Terblanche M et al. Statins and Sepsis: multiple modifications at multiple levels. Lancet Infect Dis. 2007; 7(5):358-368.
• Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet 1996;348:1079-82.
• Fessler MB et al. A role for HMG coenzyme A reductase in pulmonary inflammation and host defense. Am J Respir Crit Care Med 2005;171:606-15.
• Rosch JW et al. Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease. J Clin Invest 2010; 120(2);627-35.
• Shyamsundar M et al. Simvastatin decreases lipopolysacchraide-induced pulmonary inflammation in healthy volunteers. Am J Respir Crit Care Med. 2009 179:1107-1114.
• Watt AP et al. Neutrophil apoptosis, proinflammatory mediators and cell counts in bronchiectasis. Thorax 2004;59(3):231-6.

Inclusion criteria

• Patients aged 18-75 will be recruited. All will have an established radiological diagnosis of bronchiectasis (CT of the chest). Patients will have clinically significant bronchiectasis expectorating mucopurulent or purulent sputum when clinically stable with at least 2 chest infections per year.

Exclusion criteria

• current smokers or ex-smokers of less than 1 year; >15 pack year history
• cystic fibrosis
• active allergic bronchopulmonary aspergillosis
• active tuberculosis
• poorly controlled asthma
• pregnancy or breast feeding
• known allergy to statins
• active malignancy
• chronic liver disease
• established cardiovascular or cerebrovascular disease
• statin use in the last year
• patients on long term oral macrolides due to the interaction with statin therapy patients chronically colonised with Pseudomonas aeruginosa (defined as two or more isolates of Pseudomonas aeruginosa whilst clinically stable in 6 months prior to the study).