Potential benefits of statins on morbidity and mortality in chronic obstructive pulmonary disease: a review of the evidence.

Studies show reduced forced expiratory volume in 1 s (FEV(1)) in patients with chronic obstructive pulmonary disease (COPD) is an important independent predictor of cardiovascular death and is characterised by both pulmonary and systemic inflammation. Evidence shows statins have important anti-inflammatory effects in both the lungs and arteries. Although randomised control trials are yet to be reported, non-randomised studies have consistently shown benefit in COPD patients taking statins compared with those not. These include reductions in both cardiovascular and respiratory morbidity/mortality. Other potential benefits include a reduced decline in FEV(1) and reduced risk of lung cancer. It is argued that confounding by a "healthy user effect" is unlikely to explain the observed benefit. Given the undisputed benefit of statins in high risk populations and the growing body of data suggesting statins may benefit patients with COPD, the question arises "Should statins be considered more often in patients with COPD?".

Pharmacological actions of statins: potential utility in COPD.

Chronic obstructive pulmonary disease (COPD) is characterised by minimally reversible airflow limitation and features of systemic inflammation. Current therapies for COPD have been shown to reduce symptoms and infective exacerbations and to improve quality of life. However, these drugs have little effect on the natural history of the disease (progressive decline in lung function and exercise tolerance) and do not improve mortality. The anti-inflammatory effects of statins on both pulmonary and systemic inflammation through inhibition of guanosine triphosphatase and nuclear factor-κB mediated activation of inflammatory and matrix remodelling pathways could have substantial benefits in patients with COPD due to the following. 1) Inhibition of cytokine production (tumour necrosis factor-α, interleukin (IL)-6 and IL-8) and neutrophil infiltration into the lung; 2) inhibition of the fibrotic activity in the lung leading to small airways fibrosis and irreversible airflow limitation; 3) antioxidant and anti-inflammatory (IL-6 mediated) effects on skeletal muscle; 4) reduced inflammatory response to pulmonary infection; and 5) inhibition of the development (or reversal) of epithelial-mesenchymal transition, a precursor event to lung cancer. This review examines the pleiotropic pharmacological action of statins which inhibit key inflammatory and remodelling pathways in COPD and concludes that statins have considerable potential as adjunct therapy in COPD.

Forced expiratory volume in one second: not just a lung function test but a marker of premature death from all causes.

The clinical utility of spirometric screening of asymptomatic smokers for early signs of air flow limitation has recently come under review. The current authors propose that reduced forced expiratory volume in one second (FEV(1)) is more than a measure of airflow limitation, but a marker of premature death with broad utility in assessing baseline risk of chronic obstructive pulmonary disease (COPD), lung cancer, coronary artery disease and stroke, collectively accounting for 70-80% of premature death in smokers. Reduced FEV(1) identifies undiagnosed COPD, has comparable utility to that of serum cholesterol in assessing cardiovascular risk and defines those smokers at greatest risk of lung cancer. As such, reduced FEV(1) should be considered a marker that identifies smokers at greatest need of medical intervention. Smoking cessation has been shown to attenuate FEV(1) decline and, if achieved before the age of 45-50 yrs, may not only preserve FEV(1) within normal values but substantially reduce cardiorespiratory complications of smoking. Recent findings suggest inhaled drugs (bronchodilators and corticosteroids), and possibly statins, may be effective in reducing morbidity and mortality in patients with chronic obstructive pulmonary disease. The current authors propose that spirometry has broad utility in identifying smokers who are at greatest risk of cardiorespiratory complications and greatest benefit from targeted preventive strategies, such as smoking cessation, prioritised screening and effective pharmacotherapy.

Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is predominantly the consequence of chronic smoking exposure, but its development may be influenced by genetic variants that affect lung remodelling, inflammation, and defence from oxidant stress. A study was undertaken to determine whether genetic variants within genes encoding the antioxidant enzymes superoxide dismutase (SOD) and catalase may be associated with the development of impaired lung function. METHODS: In a case-control study, the allele and genotype frequencies of functional polymorphisms from SOD1 (CuZnSOD), SOD2 (MnSOD), SOD3 (extracellular SOD), and catalase (CAT) were compared in chronic smokers with normal lung function (resistant smokers) and in those with COPD. RESULTS: Significantly higher frequencies of the G allele and CG/GG genotype of the 213 SOD3 polymorphism were found in resistant smokers (odds ratios (ORs) 4.3 (95% CI 1.5 to 13.3) and 4.2, 95% CI 1.4 to 13.3), Bonferroni corrected p = 0.02 and p = 0.02, respectively) than in those with COPD. There were no differences between the COPD and resistant smokers for the SOD1, SOD2, or CAT polymorphisms tested. CONCLUSIONS: The 213Gly variant of the SOD3 gene may, through antioxidant or anti-inflammatory effects, confer a degree of resistance in some smokers to the development of COPD.

Short-burst oxygen immediately before and after exercise is ineffective in nonhypoxic COPD patients.

Short-burst oxygen therapy (SBOT) remains an unproven treatment for reduction of exertional dyspnoea in chronic obstructive pulmonary disease (COPD). This study aimed to assess whether SBOT before exercise reduces dyspnoea or improves performance, and whether SBOT after exercise reduces dyspnoea during recovery. Twenty-two clinically stable COPD patients (mean forced expiratory volume in one second 34% predicted, mean resting saturation 94%) attended a respiratory gymnasium and undertook four 6-min walk (6MW) tests at each of two sessions, 1 week apart. Cylinder air or oxygen was administered single-blind in random order for 5 min prior to the first two 6MW and during recovery following the final two 6MW. Dyspnoea was self-rated by subjects using the modified Borg scale. There was no significant difference in mean 6MW distance or final Borg score for air and oxygen given before exercise. There was also no significant difference in mean time-to-resting Borg score for air and oxygen given after exercise. Only two subjects demonstrated a clinically significant and consistent reduction in dyspnoea for oxygen compared with air either before or after exercise. Overall, short-burst oxygen therapy neither reduced dyspnoea nor improved performance. This study does not support the use of short-burst oxygen therapy either immediately before or after exercise.

Cystic fibrosis transmembrane conductance regulator gene mutations: do they play a role in the aetiology of allergic bronchopulmonary aspergillosis?

BACKGROUND: Previous work suggests that cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations may be implicated in the aetiology of allergic bronchopulmonary aspergilosis (ABPA). OBJECTIVE: To compare the frequency of CF gene mutations in asthmatics with ABPA of varying severity with asthmatics who were skin prick test (SPT)-positive to Aspergillus fumigatus (Af) without evidence of ABPA and asthmatics SPT-negative to Af. METHODS: Thirty-one Caucasian patients with ABPA were identified, together with asthmatics SPT positive to Af without evidence of ABPA (n = 23) and SPT negative to Af (n = 28). Genomic DNA was tested for 16 CF mutations accounting for approximately 85% of CF alleles in Caucasian New Zealanders. RESULTS: Four (12.9%) ABPA patients were found to be carriers of a CF mutation (DeltaF508 n = 3, R117H n = 1), one (4.3%) asthmatic SPT positive to Af without ABPA (DeltaF508), and one (3.6%) asthmatic SPT negative to Af (R117H). All patients with a CF mutation had normal sweat chloride (< 40 mM). There was no significant difference between the frequency of CF mutations in the ABPA patients and asthmatics without ABPA. However, the frequency of CF mutations in the ABPA patients was significantly different (P = 0.0125) to the expected carrier rate in the general population. CONCLUSION: These results lend further support to a possible link between CF mutations and ABPA.

An evaluation of short-term oxygen therapy: the prescription of oxygen to patients with chronic lung disease hypoxic at discharge from hospital.

The provision of domiciliary oxygen to patients hypoxic at hospital discharge has been termed short-term oxygen therapy (STOT). This practice appears widespread, although there is a paucity of literature and no evidence-based guidelines. We undertook this audit to examine the prescription of STOT and determine the proportion fulfilling for long-term oxygen therapy (LTOT) 2 months post-discharge. STOT was defined prospectively: resting PaO2 < or = 7.3 kPa (55 mmHg) or PaO2 between 7.3 and 8.0 kPa (60 mmHg) with any of the following: clinical evidence of cor pulmonale (pedal oedema or jugular venous distension), ECG evidence of pulmonale, echocardiogram evidence of pulmonary hypertension, haematocrit > 0.55 (adapted directly from LTOT criteria). Patients were evaluated for LTOT 2 months post-discharge when clinically stable on optimal medical management. All referrals to the Auckland Regional Oxygen Service between July 1998 and 1999 were systematically reviewed. The majority 289/405 (71%) of new referrals were for the prescription of STOT/LTOT in patients with chronic lung disease: 160/289 (55%) derived from hospitalized patients with the majority 130 (81%) fulfilling criteria for STOT, median age 73, range 24-96 years. Mean hospital stay was 10.2 days. Two months after discharge 22/127 (17%) of STOT patients had died, comparable with 4/22 (18%) not fulfilling criteria for STOT. A total of 123 patients were assessed for LTOT at 2 months; 76 (62%) fulfilled criteria for LTOT. The prescription of oxygen at hospital discharge represented a considerable proportion of our referral load. There was a high mortality in the 2-month follow-up period. A significant proportion of STOT patients did not subsequently fulfill criteria for LTOT. Further prospective studies are required in order to develop evidence-based guidelines.

Bronchiectasis following colectomy for Crohn's disease.

Bronchiectasis developing following colectomy for ulcerative colitis has been reported in a few cases. This may be the first report of bronchiectasis developing after colectomy for Crohn's disease. The close temporal relationship to colectomy, lack of bacterial pathogens in the sputum, and an impressive response to oral steroids suggest a difference in pathogenesis from idiopathic bronchiectasis.

Selection of Streptomyces ambofaciens mutants that produce large quantities of spiramycin and determination of optimal conditions for spiramycin production.

The aim of this work was to develop a strategy to isolate a morphologically stable mutant of Streptomyces ambofaciens ATCC 15154 which produced high titers of spiramycin. The rationale was to grow a nitrosoguanidine-mutated population for many generations under nonselective conditions followed by two cycles of protoplast formation and regeneration. A total of 2,400 surviving colonies were then screened for spiramycin production and subsequently checked for stability. From this experiment, strain 6-37 was isolated that produced 181 mg of spiramycin per liter and only one morphological type. The parent strain (ATCC 15154) produced 107 mg of spiramycin per liter and four morphological types. Strain 6-37 was then mutated with nitrosoguanidine, and 14,000 colonies were screened for spiramycin production. From this experiment, five strains were isolated that produced titers ranging from 187 to 373 mg of spiramycin per liter. Subsequent media and time studies with these strains resulted in a fermentation that produced 1,728 mg of spiramycin per liter.