The impact of acute air pollution fluctuations on bronchiectasis pulmonary exacerbation: a case-crossover analysis.

In bronchiectasis, exacerbations are believed to be triggered by infectious agents, but often no pathogen can be identified. We hypothesised that acute air pollution exposure may be associated with bronchiectasis exacerbations.We combined a case-crossover design with distributed lag models in an observational record linkage study. Patients were recruited from a specialist bronchiectasis clinic at Ninewells Hospital, Dundee, UK.We recruited 432 patients with clinically confirmed bronchiectasis, as diagnosed by high-resolution computed tomography. After excluding days with missing air pollution data, the final model for particles with a 50% cut-off aerodynamic diameter of 10 µm (PM10) was based on 6741 exacerbations from 430 patients and for nitrogen dioxide (NO2) it included 6248 exacerbations from 426 patients. For each 10 µg·m-³ increase in PM10 and NO2, the risk of having an exacerbation that same day increased significantly by 4.5% (95% CI 0.9-8.3) and 3.2% (95% CI 0.7-5.8) respectively. The overall (lag zero to four) increase in risk of exacerbation for a 10 µg·m-3 increase in air pollutant concentration was 11.2% (95% CI 6.0-16.8) for PM10 and 4.7% (95% CI 0.1-9.5) for NO2 Subanalysis showed higher relative risks during spring (PM10 1.198 (95% CI 1.102-1.303), NO2 1.146 (95% CI 1.035-1.268)) and summer (PM10 2.142 (95% CI 1.785-2.570), NO2 1.352 (95% CI 1.140-1.602)) when outdoor air pollution exposure would be expected to be highest.In conclusion, acute air pollution fluctuations are associated with increased exacerbation risk in bronchiectasis.

Proof of concept study to evaluate step-down therapy with inhaled corticosteroid alone or additive therapy on surrogate inflammatory markers in asthma.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Much of the focus of inflammatory surrogates and airway challenges in asthma has been directed towards success of therapy and diagnosis. Few have considered them in the context of guiding dose reduction once sufficient control has been achieved. WHAT THIS STUDY ADDS: Adenosine monophosphate (AMP) as an indirect bronchial airway challenge, together with non invasive inflammatory surrogate measures were not found to be clinically useful when guiding therapy in a group of asthmatic patients through step 3-4 in British Thoracic Society asthma guidelines. However, they may still play a role in predicting failure of individual step-down. AIM: The aim of the study was to evaluate the usefulness of inflammatory surrogates in determining step-down therapy in asthma. METHODS: AMP challenge, serum eosinophil cationic protein (ECP), exhaled nitric oxide (eNO) and pulmonary function tests were recorded. Subjects were divided into two groups following high dose inhaled corticosteroids (ICS): Group A fixed dose ICS vs. Group B ICS alone and in combination with add on therapies. RESULTS: No differences were seen in inflammatory measures between fixed dose ICS and reduced dose ICS alone or with combination therapies. CONCLUSIONS: AMP challenge conferred no additional benefit in guiding step-down therapy. The role of inflammatory surrogates may still play a role in predicting failed step-down on an individual basis.

Proposed changes to management of lower respiratory tract infections in response to the Clostridium difficile epidemic.

Clostridium difficile infection (CDI) remains a major healthcare problem associated with antibiotic use in hospitals. Recent years have seen a dramatic increase in the incidence of CDI in the UK and internationally. Lower respiratory tract infections (LRTIs) are the leading indication for antibiotic prescription in hospitals and are therefore a critical battleground in the fight against inappropriate antibiotic use and healthcare-associated infections. This article reviews the evidence for interventions to reduce CDI in hospitalized patients with LRTIs. Reducing prescriptions of cephalosporins and fluoroquinolones in favour of penicillin-based regimens and increased use of tetracyclines have been proposed. Expanding outpatient management of LRTIs and reducing length of hospital stay will limit patient exposure to the healthcare environment in which C. difficile is most easily acquired. Intravenous (iv) broad-spectrum antibiotics are often prescribed when narrower spectrum, oral antimicrobials would be equally effective and, in a proportion of patients, antibiotic therapy is used unnecessarily. Shorter antibiotic regimes may be as effective as prolonged therapy and reduce antibiotic-related complications. Early switch from iv to oral therapy allows simpler antibiotic regimens and facilitates early discharge from hospital. Simple improvements in the management of LRTIs have the potential to reduce the incidence of healthcare-associated infections.

Pharmacokinetic/pharmacodynamic evaluation of urinary cortisol suppression after inhalation of fluticasone propionate and mometasone furoate.

AIM: Fluticasone propionate (FP) and mometasone furoate (MF) are inhaled corticosteroids that possess a high ratio of topical to systemic activity. The systemic bioavailability of MF has been claimed to be minimal (1%). FP has been shown to exhibit the same degree of systemic effects, but its systemic availability is between 13 and 17%. We hypothesize that FP and MF have comparable systemic availabilities that can explain their potential to cause systemic effects. METHODS: Steady-state FP and MF trough plasma samples were determined from a clinical study by Fardon et al. in patients with persistent asthma (forced expiratory volume in 1 s = 91%). The percent plasma protein binding of FP and MF was measured using ultracentrifugation. Free FP plasma concentrations were normalized for their differences in receptor binding affinity compared with MF and linked to overnight urinary cortisol/creatinine with an inhibitory E(max). RESULTS: A plot of steady-state FP and MF total trough plasma concentrations vs. dose showed that both drugs exhibit dose linearity. MF has comparable bioavailability to FP based on the steady-state concentrations observed for the different doses. The free plasma concentration producing 50% of urinary cortisol suppression (IC(50)) for MF was not statistically different from the free, normalized IC(50) for FP. CONCLUSION: FP and MF have similar pulmonary deposition and the same potential to cause systemic side-effects due to their similar IC(50) values. The observed urinary cortisol suppression of FP and MF is in agreement with their systemic availability, their differences in plasma protein binding and receptor binding affinity.

Respiratory symptoms, pulmonary function, and markers of inflammation among bar workers before and after a legislative ban on smoking in public places.

CONTEXT: Scotland prohibited smoking in confined public places on March 26, 2006. OBJECTIVE: To investigate the association of smoke-free legislation with symptoms, pulmonary function, and markers of inflammation of bar workers. DESIGN, SETTING, AND PARTICIPANTS: This prospective observational study was conducted in Tayside, Scotland from February-June 2006. One hundred five nonasthmatic and asthmatic nonsmoking bar workers were initially enrolled, of whom 77 completed the study per protocol. MAIN OUTCOME MEASURES: Respiratory and sensory symptoms, spirometry measurements, serum cotinine levels, peripheral inflammatory cell count, asthma quality-of-life scores, and exhaled nitric oxide levels were evaluated before and after introduction of the smoking ban. RESULTS: For the per-protocol analysis, the percentage of bar workers with respiratory and sensory symptoms decreased from 79.2% (n = 61) before the smoke-free policy to 53.2% (n = 41) (total change, -26%; 95% confidence interval [CI], -13.8% to -38.1%; P<.001) and 46.8% (n = 38) (-32.5%; 95% CI, -19.8% to -45.2%; P<.001) 1 and 2 months afterward. Forced expiratory volume in the first second increased from 96.6% predicted to 104.8% (change, 8.2%; 95% CI, 3.9% to 12.4%; P<.001) and then 101.7% (change, 5.1%; 95% CI, 2.1% to 8.0%; P = .002), and serum cotinine levels decreased from 5.15 ng/mL to 3.22 ng/mL (change, -1.93 ng/mL; 95% CI, -2.83 to -1.03 ng/mL; P<.001) and then 2.93 ng/mL (-2.22 ng/mL; 95% CI, -3.10 to -1.34 ng/mL; P<.001). The total white blood cell and neutrophil count was reduced from 7610 to 6980 cells/microL at 2 months (-630 cells/muL; 95% CI, -1010 to -260 cells/microL; P = .002) and from 4440 to 4030 cells/microL (-410 cells/microL; 95% CI, -740 to -90 cells/microL; P = .03), respectively. Asthmatic bar workers also had less airway inflammation, with a reduction in exhaled nitric oxide from 34.3 parts per billion (ppb) to 27.4 ppb 1 month after the ban (0.8-fold change; 95% CI, 0.67 to 0.96 ppb; P = .04), and Juniper quality-of-life scores increased from 80.2 to 87.5 points (7.3 points; 95% CI, 0.1 to 14.6 points; P = .049). CONCLUSIONS: Smoke-free legislation was associated with significant early improvements in symptoms, spirometry measurements, and systemic inflammation of bar workers. Asthmatic bar workers also had reduced airway inflammation and improved quality of life.

A comparison of 2 extrafine hydrofluoroalkane-134a-beclomethasone formulations on methacholine hyperresponsiveness.

BACKGROUND: Small airways inflammation is a recognized pathologic component of asthma, and it is postulated that the observed airway-wall remodeling in small airways could be due to uncontrolled inflammation in airways that are not penetrated by conventional inhaled corticosteroids. Thus, extrafine particle formulations of inhaled corticosteroids are of clinical interest. OBJECTIVE: To compare 2 extrafine solution hydrofluoroalkane-134a formulations of beclomethasone dipropionate (Beclate and Qvar). METHODS: Fifteen asthmatic patients (mean +/- SEM forced expiratory volume in 1 second [FEV1], 2.62 +/- 0.21 L; provocative concentration of methacholine causing a 20% decrease in FEV1 [PC20], 1.06 +/- 0.58) were randomized to completion in a placebo-controlled, double-blind, crossover manner to receive Beclate or Qvar at doses of 100 or 400 microg/d for 2 weeks, with a 1-week washout period before each randomized treatment. Methacholine hyperresponsiveness was the primary outcome measure. RESULTS: The 2 formulations were equivalent in terms of predefined equivalence limits of +/- 1 doubling dilution for PC20 at both doses: -0.25 (95% confidence interval [CI], -0.77 to 0.27) doubling dilution difference between the 100-microg doses and a 0.26 (95% CI, -0.29 to 0.82) doubling dilution difference between the 400-microg doses for the difference between Beclate and Qvar, respectively. Both formulations, at either dose, produced a statistically significant (P < .05) reduction in mean exhaled nitric oxide levels: 400 microg/d of Beclate, 14.1 ppb (95% CI, 5.6 to 22.6 ppb); and 400 microg/d of Qvar, 14.2 ppb (95% CI, 6.0 to 22.4 ppb). The higher doses produced a statistically significant (P < .05) reduction in early morning urinary cortisol-creatinine ratio (geometric mean fold suppression: Beclate, 1.48 [95% CI, 1.16 to 1.89]; and Qvar, 1.42 [95% CI, 1.12 to 1.79]). Both formulations significantly improved peak expiratory flow, FEV1, and forced expiratory flow between 25% and 75% of forced vital capacity at the higher doses (P < .05). CONCLUSIONS: Beclate and Qvar were equivalent for all primary and secondary outcome measures.

Addition of fexofenadine to inhaled corticosteroid therapy to reduce inflammatory biomarkers in atopic asthma.

BACKGROUND: We previously showed that H1-antihistamines may shift the PC20 (provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20%) threshold to adenosine monophosphate (AMP) challenge but may paradoxically prolong recovery. OBJECTIVES: To measure AMP recovery using a constant predetermined AMP PC20 and to evaluate whether fexofenadine use confers add-on effects to treatment with either fluticasone propionate alone or combined fluticasone propionate-salmeterol. METHODS: Fourteen atopic patients with mild-to-moderate asthma (forced expiratory volume in 1 second of 76%) completed a double-blind, randomized, crossover study consisting of 3-week treatment blocks of either fluticasone propionate-salmeterol, 250 microg twice daily, or fluticasone propionate alone, 250 microg twice daily, in conjunction with either fexofenadine, 180 mg once daily, or matched placebo. Recovery after a predetermined AMP PC20 challenge was measured (primary outcome), along with exhaled nitric oxide levels, plasma eosinophil cationic protein levels, peripheral eosinophil counts, pulmonary function, diary card outcomes, and quality of life (all secondary outcomes). RESULTS: There were no differences in any of the primary or secondary outcomes when fexofenadine was added to treatment with either fluticasone propionate-salmeterol or fluticasone propionate alone. The mean AMP recovery time was 25.0 vs 23.4 minutes for fexofenadine and placebo, respectively, as add-on to fluticasone-salmeterol and 22.5 vs 23.9 minutes, respectively, as add-on to fluticasone alone. CONCLUSION: Fexofenadine did not affect recovery to a fixed dose of AMP challenge or any other surrogate inflammatory markers when given as add-on therapy to corticosteroid-treatedatopic asthmatic patients.

Evaluation of an abbreviated adenosine monophosphate bronchial challenge.

RATIONALE: Airway hyperresponsiveness to adenosine monophosphate (AMP) has been validated as a surrogate marker for airway inflammation. We wished to know whether an abbreviated challenge at the final threshold dose would produce the same fall in FEV1 as a full, conventional dose-response challenge. METHODS: Seventeen patients with mild-to-moderate asthma (mean FEV1, 75.5% predicted) attended for a full dose-response protocol, where the highest concentration of AMP to produce > 20% fall in FEV1 was noted, along with the maximum percentage fall and recovery time. Patients returned within 2 days for a further challenge, when they received only the highest concentration (as a single bolus) reached on the previous visit. RESULTS: The mean (+/- SEM) percentage fall in FEV1 after the full challenge was 25.5 +/- 1.3%, and after the abbreviated challenge was 9.4 +/- 2.4%. The mean recovery after the full challenge was 28.13 +/- 4.65 min, and after the abbreviated test was 10.81 +/- 4.27 min. CONCLUSION: An abbreviated challenge using a single bolus dose of AMP grossly underestimates bronchial hyperresponsiveness. Although the pharmacologic half-life of AMP is short (90 s), the lesser response and shortened recovery with the abbreviated challenge suggest a more prolonged physiologic half-life, which in turn may have implications for abbreviated challenge protocols.

The role of measuring airway hyperresponsiveness and inflammatory biomarkers in asthma.

Asthma is characterized by inflammation and airway hyperresponsiveness, which results in episodic airflow obstruction. It is diagnosed once a compatible clinical history plus objective evidence of diurnal variability in peak expiratory flow or significant reversibility to inhaled bronchodilator is documented. In accordance with current guidelines, measures of airway calibre and symptoms allow patients and clinicians to assess the degree of asthma control and titrate pharmacotherapy. However, these parameters fail to reflect the extent of underlying endobronchial inflammation and airway hyperresponsiveness, which in turn suggests that additional measures of asthma control may be of benefit. This evidence-based review highlights ways by which inflammation and airway hyperresponsiveness can be assessed and how they may provide additional useful information in the diagnosis and management of asthmatic patients.

Decongestant effects of nasal xylometazoline and mometasone furoate in persistent allergic rhinitis.

Thirty-six persistent allergic rhinitis (PAR) sufferers were studied, to both compare and correlate 15 minute response to nasal xylometazoline (XYLO) with 28 day response to nasal mometasone furoate (MF). 0.1% XYLO (1 spray each nostril) response was measured on two occasions, then a randomised double blind cross-over comparison of MF (200 mcg daily) to placebo conducted. Outcomes were peak nasal inspiratoly flow (PNIF), nasal forced inspiratory volume in one second (nFIV1) and nasal blockage score (NBS) improvements. Thirty-one participants completed per protocol. Within subject standard deviation for percentage improvement to XYLO was 26.0 for PNIF and 25.2 for nFIV1. Median % improvement (95%CI) in PNIF for XYLO vs. MF was 20.0 (11.4 to 31.0) vs. 9.6 (3.2 to 15.8) and in nFIV1 was 17.8 (10.0 to 28.1) vs. 3.3 (-4.3 to 19.1). XYLO effects were greater than MF (p<0.05) for PNIF, nFIV1 and NBS. There was no significant correlation of MF to XYLO improvements in PNIF, nFIV1 or NBS. In conclusion, acute reversibility to XYLO showed poor repeatability and XYLO reversibility is not predictive of decongestant response to nasal corticosteroid. XYLO was a stronger decongestant than MF but rhinitis medicamentosa still precludes any preference for long term XYLO therapy at this time.

Comparative cutoff points for adenosine monophosphate and methacholine challenge testing.

BACKGROUND: Current use of the PC20 (provocation concentration that causes a decrease in forced expiratory volume in 1 second of 20%) cutoff point for bronchial challenge precludes its use in patients with more severe airflow obstruction. OBJECTIVE: To evaluate the efficacy and safety of lower cutoff points for adenosine monophosphate (AMP) and methacholine (MCH) bronchial challenge tools to monitor response to treatment in chronic asthma. METHODS: We retrospectively examined data from 5 previously published studies (2 using AMP, 2 using MCH, and 1 with MCH and AMP arms) and recalculated 10% and 15% cutoff points for AMP and MCH. Data were analyzed for correlation of single results and doubling dose shifts after anti-inflammatory treatment intervention. RESULTS: A total of 175 individual MCH challenges and 152 AMP challenges were evaluated. Evaluating the doubling dose shift produced by the addition of anti-inflammatory treatment (inhaled corticosteroids or montelukast) produced the following Pearson correlation coefficients: MCH PD20 (provocation dose that causes a decrease in forced expiratory volume in 1 second of 20%) vs PD15, 0.80; MCH PD20 vs PD10, 0.65; AMP PC20 vs PC15, 0.96; and AMP PC20 vs PC10, 0.84 (P < .001 for all). Subgroup analysis of AMP for before and after inhaled corticosteroids only (n = 41) shows AMP PC20 vs PC15 of 0.92 and AMP PC20 vs PC10 of 0.84 (P < .001 for both). CONCLUSIONS: The 10% and 15% cutoff points strongly predict the 20% cutoff value for AMP and MCH, as do the doubling dose shifts after anti-inflammatory treatment. The lower thresholds are suitable for monitoring response to therapy, and they expose patients to significantly less provocation agent.

Adrenal suppression with dry powder formulations of fluticasone propionate and mometasone furoate.

Mometasone furoate (MF) and fluticasone propionate (FP) are high potency inhaled corticosteroids. The systemic bioavailability of MF is claimed to be negligible, leading to a minimal potential for systemic adverse effects. We assessed the overnight urinary cortisol/creatinine as the primary outcome of adrenal suppression in 21 patients with persistent asthma (mean FEV1 = 91%). Patients were randomized in a crossover fashion to receive 2 weekly consecutive doubling incremental doses of either FP Accuhaler (500, 1,000, and 2,000 microg/day) or MF Twisthaler (400, 800, and 1,600 microg/day). For the 21 per protocol completed patients, there was significant suppression of overnight urinary cortisol/creatinine with high and medium doses of both drugs-as geometric mean fold suppression (95% confidence interval) from baseline: FP 2,000 microg, 1.85 (1.21-2.82, p = 0.002); FP 1,000 microg, 1.45 (1.07-1.96, p = 0.02); MF 1,600 microg, 1.92 (1.26-2.93, p = 0.001); and MF 800 microg, 1.39 (1.04-1.88, p = 0.02). For secondary outcomes of 8:00 A.M. plasma cortisol, serum osteocalcin, and early morning urinary cortisol/creatinine, there was significant suppression with MF and FP at the highest dose. Our data refute the assertion that MF has negligible systemic bioavailability and a lower potential for systemic adverse effects compared with FP.