Thrombocytosis is associated with increased short and long term mortality after exacerbation of chronic obstructive pulmonary disease: a role for antiplatelet therapy?

INTRODUCTION: Evidence suggests that platelets play a significant role in inflammation in addition to their role in thrombosis. Systemic inflammation is linked to poor short and long term outcomes in COPD. Increased platelet activation has been reported in acute exacerbations of COPD (AECOPD). We investigated whether thrombocytosis is independently associated with poor outcomes following AECOPD. METHODS: An observational cohort study of patients hospitalised with AECOPD was performed. Patients were >40 years with spirometry confirmed COPD admitted between 2009 and 2011. Platelet count was recorded on admission. The primary outcome was 1-year all-cause mortality. Secondary outcomes included inhospital mortality and cardiovascular events. Analyses were conducted using logistic regression after adjustment for confounding variables. RESULTS: 1343 patients (49% male) were included. Median age was 72 years (IQR 63-79 years). 157 (11.7%) had thrombocytosis. Thrombocytosis was associated with both 1-year mortality and inhospital mortality; OR 1.53 (95% CI 1.03 to 2.29, p=0.030) and OR 2.37 (95% CI 1.29 to 4.34, p=0.005), respectively. Cardiovascular hospitalisation was not significantly increased (OR 1.13 (95% CI 0.73 to 1.76, p=0.600)) in patients with thrombocytosis. Aspirin or clopidogrel treatment correlated with a reduction in 1-year mortality (OR 0.63 (95% CI 0.47 to 0.85, p=0.003)) but not inhospital mortality (OR 0.69 (95% CI 0.41 to 1.11, p=0.124)). CONCLUSIONS: After adjustment for confounders thrombocytosis was associated with increased 1-year mortality after exacerbation of COPD. Antiplatelet therapy was associated with significantly lower 1-year mortality and may have a protective role to play in patients with AECOPD.

The inverse agonist propranolol confers no corticosteroid-sparing activity in mild-to-moderate persistent asthma.

The murine asthma model shows that switching off airway ß2 receptors with an inverse agonist may confer anti-inflammatory effects as well as corticosteroid-sparing activity. We have assessed for any corticosteroid-sparing effects of propranolol, an inverse agonist, added to low-dose inhaled corticosteroid (ICS) compared with higher dose ICS. A randomized double-blind placebo-controlled cross-over trial in mild-to-moderate persistent asthmatic patients was performed. After a run-in (2 weeks) on hydrofluoroalkane-beclometasone dipropionate (HFA-BDP) at 100 µg/day (HFA-BDP100), patients received randomized treatments (4 weeks) with propranolol at 80 mg/day plus HFA-BDP at 100 µg/day compared with placebo plus HFA-BDP at 400 µg/day (HFA-BDP400). Propranolol was up-titrated to 80 mg/day over the initial 2 weeks. Tiotropium was co-administered until 5 days before each histamine challenge (the primary outcome). Sixteen patients completed the study [mean age, 38 years; forced expiratory volume in 1 s (FEV1), 86.4%; histamine provocative concentration causing a 20% fall in FEV1 (PC20), 1.39 mg/ml; ICS dose, 406 µg/day]. Histamine PC20 was unchanged by adding propranolol to HFA-BDP100 compared with baseline (HFA-BDP100) {0.17 doubling dilution (dd) difference [95% confidence interval (CI): -0.58 to 0.92]}, but there was a significant improvement with HFA-BDP400 compared with both baseline [1.05 dd (95% CI: 0.43-1.66); P=0.02], and propranolol+HFA-BDP100 [0.88 dd (95% CI: 0.45-1.30); P=0.006]. Significant improvements were also observed with HFA-BDP400 for exhaled nitric oxide, blood eosinophils, serum eosinophilic cationic protein and asthma quality-of-life questionnaire symptoms compared with propranolol+HFA-BDP100. Salbutamol recovery post-challenge was partially blunted by propranolol (median prolongation 5 min; P=0.002). Domiciliary evening FEV1 also fell with propranolol+HFA-BDP100 [mean reduction from baseline 0.22 litres (95% CI: 0.10-0.34); P=0.012], whereas Asthma Control Questionnaire remained unchanged. In conclusion, the inverse agonist propranolol produced no improvements when given with low-dose ICS, whereas further significant improvements in airway hyper-responsiveness and inflammation were demonstrated with higher dose ICS. Thus, propranolol does not confer corticosteroid-sparing activity in persistent asthma.

Proof-of-concept evaluation of trough airway hyper-responsiveness following regular racemic or levosalbutamol in genotype-stratified steroid-treated persistent asthmatic patients.

Asthmatic patients receiving ICSs (inhaled corticosteroids) may take frequent add-on therapy with salbutamol despite on-demand prescription. Frequent salbutamol use can be detrimental in asthma. The isomeric formulation of salbutamol and the B2ADR (ß2 adrenoceptor) 16 genotype may also influence this phenomenon. We performed a randomized, double-blind, placebo-controlled, triple crossover, proof of concept trial comparing 2 weeks of regular therapy with inhaled racemic salbutamol [200 µg q.i.d. (four times daily)], levosalbutamol (100 µg q.i.d.) or placebo on trough methacholine PC20 [provocative concentration causing 20% fall in FEV1 (forced expiratory volume in 1 s)] 6 h post-dose (the primary outcome) in 30 persistent asthmatic patients (15 who were Arg16 homozygous and 15 who were Gly16 homozygous) all receiving ICSs. There was no worsening of AHR (airway hyper-responsiveness) at trough to methacholine after 2 weeks regular exposure to either racemic (P=0.53) or levosalbutamol (P=0.84) compared with placebo, nor between genotypes-as dd (doubling dilution) difference in methacholine PC20 from placebo [salbutamol/Arg16=0.36 dd [95% CI (confidence interval), -0.43, 1.15]; salbutamol/Gly16=0.01 dd (95% CI, -0.47, 0.49); levosalbutamol/Arg16=-0.01 dd (95% CI, -0.89, 0.87); and levosalbutamol/Gly16=0.28 dd (95% CI, -0.22, 0.77)]. Both active treatments improved morning PEF (peak expiratory flow) in Gly16 (P=0.04 overall) but not Arg16 (P=0.50 overall) patients, whereas evening PEF improved in both Gly16 (P<0.001 overall) and Arg16 (P=0.006 overall) patients. In conclusion, the regular exposure to either racemic or levosalbutamol for 2 weeks added to ICSs did not cause worsening of AHR at trough compared with placebo; with no difference seen between B2ADR 16 genotypes.

Randomized placebo-controlled trial to evaluate chronic dosing effects of propranolol in asthma.

RATIONALE: Unblinded studies have shown improvements in airway hyperresponsiveness with chronic nadolol in steroid-naive patients with asthma. OBJECTIVES: To assess the effects of chronic nonselective ß-blockade as add-on to inhaled corticosteroids (ICS) in patients with asthma. METHODS: A double-blind randomized placebo-controlled crossover trial of propranolol in patients with mild-to-moderate asthma receiving ICS was performed. Participants underwent a 6- to 8-week dose titration of propranolol or placebo as tolerated to a maximum of 80 mg per day. Tiotropium was given for the first 4 to 6 weeks of each treatment period. MEASUREMENTS AND MAIN RESULTS: Primary outcome was methacholine challenge. Secondary outcomes included histamine challenge, pulmonary function, mini-asthma quality of life questionnaire (mini-AQLQ), and asthma control questionnaire (ACQ). Eighteen patients completed (mean [SEM]): age, 36 (4) yr; FEV1%, 93 (2); ICS, 440 (66) µg/d. No significant difference was observed in methacholine or histamine challenge after exposure to propranolol versus placebo. For methacholine challenge, the doubling dilution difference was 0.04 (95% confidence interval [CI], -0.56 to 0.63), P = 0.89. Albuterol recovery at 20 minutes after histamine challenge was partially attenuated by propranolol versus placebo: FEV1% mean difference, 5.28 (95% CI, 2.54-8.01), P = 0.001. After chronic ß-blockade there was a small worsening in FEV1 % predicted of 2.4% (95% CI, -0.1 to 4.8), P = 0.055. No difference was found for ACQ or mini-AQLQ. CONCLUSIONS: This is the first placebo-controlled study to assess the effects of chronic nonselective ß-blockade in asthma, showing no significant effect of propranolol compared with placebo on either methacholine or histamine airway hyperresponsiveness and no change in ACQ or AQLQ. Clinical trial registered with www.clinicaltrials.gov (NCT01074853).

Inhaled and systemic corticosteroid response in severe asthma assessed by alveolar nitric oxide: a randomized crossover pilot study of add-on therapy.

AIMS: Alveolar nitric oxide (CA(NO)) is a potential biomarker of small airway inflammation. We investigated effects on CA(NO) of the addition of coarse and fine particle inhaled corticosteroids to standard therapy in severe asthma. METHODS: Severe asthmatics taking ≥1600 µg day(-1) budesonide or equivalent performed a randomized open-label crossover study. Subjects with FEV(1) < 80%, gas trapping and CA(NO) ≥2 ppb entered a 6 week dose-ramp run-in of fluticasone/salmeterol(FPSM) 250/50 µg twice daily for 3 weeks, then 500/50 µg twice daily for 3 weeks. Patients then received additional HFA-beclomethasone diproprionate (BDP) 200 µg twice daily or FP 250 µg twice daily for 3 weeks in a crossover. Participants then received prednisolone(PRED) 25 mg day(-1) for 1 week. Nitric oxide, lung function, mannitol challenge, systemic inflammatory markers and urinary cortisol were measured. RESULTS: Fifteen completed per protocol: mean (SD) age 51 (12) years, FEV(1) 58 (13)% predicted, residual volume 193 (100)% predicted and mannitol(PD10) 177 (2.8) µg. There was no significant difference between FPSM and add-on therapy for CA(NO). FPSM/BDP and FPSM/PRED suppressed broncial flux (Jaw(NO)) and FE(NO) compared with FPSM alone, but there was no significant difference between FPSM/BDP and FPSM/FP. ECP, e-selectin and ICAM-1 were suppressed by FPSM/PRED compared with FPSM and FPSM/FP but not FPSM/BDP. Plasma cortisol was significantly suppressed by FPSM/PRED. CONCLUSION: In severe asthma, CA(NO) is insensitive to changes in dose and delivery of inhaled corticosteroids and is not suppressed by systemic corticosteroids. Additional inhaled HFA-BDP reduced FE(NO) and Jaw(NO) without adrenal suppression. There was a trend to reduction in FE(NO) and Jaw(NO) with additional FP but this did not reach statistical significance. PRED reduced FE(NO) and Jaw(NO) with suppression of systemic inflammatory markers and urinary cortisol.

Effects of hydrocortisone on acute ß-adrenoceptor blocker and histamine induced bronchoconstriction.

AIMS: ß-adrenoceptor blockers are avoided in asthma due to concerns of bronchoconstriction. We investigated the safety of acute exposure to propranolol in asthmatics, sequentially challenged with histamine to mimic an asthma exacerbation and evaluated the role of intravenous hydrocortisone in potentiating salbutamol reversibility. METHODS: Persistent atopic asthmatics, requiring ≤ 1000 µg day(-1) budesonide, performed a randomized double-blind placebo-controlled crossover study. Following 10 mg or 20 mg of oral propranolol, patients received 400 mg intravenous hydrocortisone or placebo, followed by histamine challenge with nebulized salbutamol 5 mg and ipratropium 500 µg recovery. RESULTS: Thirteen patients completed per protocol. Hydrocortisone did not potentiate salbutamol recovery post propranolol and histamine challenge vs. placebo (mean difference in FEV(1) 0.04 ml, 95% CI -0.07, 0.15, P= 0.417). ß-adrenoceptor blocker induced bronchoconstriction was demonstrated by spirometry and impulse oscillometry. For the placebo visit, FEV(1) fell 4.7% 2 hours post propranolol (95% CI 1.8, 7.5, P= 0.008) whilst total airway resistance (R5%) increased 31.3% (95% CI 15.6, 47.0, P= 0.04). On both visits FEV(1) % and R5% returned to baseline after salbutamol post histamine. CONCLUSION: Nebulized salbutamol and ipratropium produced a full recovery after propranolol and histamine induced bronchoconstriction, independent of hydrocortisone use. Since the greatest risk of ß-adrenoceptor blockade is after first dose, our findings offer reassurance to those undertaking further evaluation of chronic ß-adrenoceptor blockade as a potential treatment for mild-to-moderate asthma.

Sensitivity of impulse oscillometry and spirometry in beta-blocker induced bronchoconstriction and beta-agonist bronchodilatation in asthma.

BACKGROUND: Impulse oscillometry (IOS) provides an alternative method of assessing pulmonary function to conventional spirometry. OBJECTIVE: To compare the sensitivities of IOS and spirometry in assessing bronchoconstriction to propranolol and bronchodilation with salbutamol. METHODS: A post-hoc analysis of a randomized placebo-controlled crossover study was performed. Patients with mild-to-moderate persistent stable asthma taking 1,000 µg/day or less beclomethasone dipropionate equivalent received 10 or 20 mg of oral propranolol followed by histamine challenge, with recovery to nebulized salbutamol (5 mg). Spirometry and IOS were measured before and 2 hours after beta-blocker, post histamine, and 20 minutes post-salbutamol. Pre versus post percent change (95%CI) values were compared, and standardized response means (SRM) were calculated to assess the "signal to noise" of each test. RESULTS: Thirteen participants (mean age, 34 years) completed the protocol. Eleven participants received 20 mg of propranolol; 2 received 10 mg, because this dose caused more than 10% decrease in forced expiratory volume in 1 second (FEV(1)) on the test-dose algorithm. All IOS indices (R5, R5-R20, AX, RF) showed significant worsening of airways resistance or reactance to propranolol. FEV(1) but not FEF25-75 showed significant deterioration after beta-blocker (mean percent change, 4.6% and 6.2%). The magnitude of change was consistently higher for parameters of IOS, with the largest change being observed with R5 and RF (mean percent change, 30.8% and 39.4%). The SRMs for IOS outcomes were better than for spirometry. All measures of lung function showed significant bronchodilator response, with the best SRMs seen in R5 and RF. CONCLUSION: IOS is a more sensitive response outcome than spirometry with respect to bronchoconstriction to oral propranolol and bronchodilatation after salbutamol in patients with mild to moderate asthma.

Effects of extra-fine inhaled and oral corticosteroids on alveolar nitric oxide in COPD.

PURPOSE: Alveolar nitric oxide (CA(NO)) has been suggested as a surrogate marker of distal airway inflammation in COPD. Coarse particle-inhaled corticosteroids (ICS) have been shown not to suppress CA(NO). We evaluated whether extra-fine particle size ICS (HFA-BDP) or systemic oral corticosteroids could suppress CA(NO) in COPD. METHODS: Chronic obstructive pulmonary disease (COPD) patients with a FEV1/FVC ratio <0.7, FEV1 <80% predicted with CA(NO) > 2 ppb underwent a double-blind randomized, controlled, crossover trial with an open-label systemic steroid comparator. After a 2 week steroid washout period, participants were randomized to 3 weeks of 100 mcg of HFA-BDP twice daily and then 3 weeks of 400 mcg of HFA-BDP twice daily, or matched placebos with subsequent crossover. All patients then received 1 week open-label, 25 mg/day of prednisolone. Exhaled nitric oxide, plasma cortisol, and lung function were recorded. CA(NO) was corrected for axial diffusion. RESULTS: In 16 participants, there were no significant differences seen with either dose of HFA-BDP compared with placebo. Oral prednisolone significantly reduced FE(NO) and J'aw(NO) but not CA(NO). Plasma cortisol was significantly suppressed by oral prednisolone only. CONCLUSIONS: Whilst CA(NO) remains a biomarker of interest in COPD, it is not suppressed by systemic or extra-fine particle ICS. CA(NO) is not a useful marker for monitoring response of small airway disease to therapies in COPD. The study was approved by the local Committee on Medical Research Ethics and registered on ClinicalTrials.Gov (NCT 00921921).

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.

Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide.

AIMS: A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations. METHODS: Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC(24h) [area under the concentration-time curve (0-24 h)], budesonide AUC(0-12h) and C(max) . Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC(20) (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated. RESULTS: In the pharmacokinetic study, there were no differences in cortisol, AUC(0-12h) [area under the concentration-time curve (0-12 h)], T(max) (time to maximum concentration) or C(max) (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC(24h) was 1.02 (95% confidence interval 0.93-1.11) and budesonide AUC(0-12h) was 1.03 (90% confidence interval 0.9-1.18). In the asthma pharmacodynamic study, there was a significant dose response (P < 0.0001) for methacholine PC(20) (provocative concentration of methacholine needed to produce a 20% fall in FEV(1) ) with a relative potency ratio of 1.10 (95% confidence interval 0.49-2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables. CONCLUSIONS: Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects.

Assessment of small-airways disease using alveolar nitric oxide and impulse oscillometry in asthma and COPD.

The contribution of the alveolar compartment to exhaled nitric oxide (alveolar nitric oxide or CA(NO)) can be calculated as a surrogate of distal inflammation. This value should be corrected for nitric oxide produced in the conducting airways which "back-diffuses" into the alveolar compartment (Corrected CA(NO)). Impulse oscillometry (IOS) (Nava et al., Am J Respir Crit Care Med 168:1432-1437, 2003) is used to derive values for peripheral airways resistance. Twenty-four healthy volunteers, 21 severe asthmatics, 15 mild-to-moderate asthmatics, and 24 COPD patients were assessed with spirometry, impulse oscillometry, and fractionated exhaled nitric oxide. Compared to healthy volunteers, FE(NO) was higher in mild-to-moderate and severe asthmatics: geometric mean fold ratios of 1.91 (P = 0.02) and 2.74 (P < 0.001), respectively. However, there was no difference for mild-to-moderate versus severe asthma. Ratios for CA(NO) were not different for severe asthma versus COPD, but both were elevated compared to that of healthy volunteers [2.64 (P < 0.001) and 3.07 (P < 0.001), respectively] and mild-to-moderate asthma [1.95 (P = 0.04) and 2.28 (P < 0.01)]. However, after correction for axial diffusion, Corrected CA(NO) was increased in COPD compared to severe asthma (geometric mean fold ratio 1.28, P = 0.04), mild-to-moderate asthma (1.34, P < 0.01), and healthy volunteers (1.28, P = 0.02), and there was no difference between other groups. R5 and RF were reduced in healthy volunteers versus mild-to-moderate asthma (P = 0.011 and P < 0.001 respectively), severe asthma (P = 0.002 and P < 0.001), and COPD (P < 0.001 and P < 0.001). Peripheral resistance (R5-R20) was not different for healthy versus mild-to-moderate asthma but was higher in severe asthma (P < 0.001) and COPD (P < 0.001). Correlations were observed between R5-R20 versus FEF(25-75) (r = 0.71, P < 0.01), CA(NO) (r = 0.44, P < 0.01), and Corrected CA(NO) (r = 0.24, P < 0.01). CA(NO) and IOS provide additional information to traditional measures of spirometry and tidal nitric oxide. Previous data reporting elevated alveolar nitric oxide in severe asthma may reflect back-diffusion of nitric oxide from the conducting airways into the alveolar compartment. Corrected CA(NO) and IOS may prove to be useful noninvasive measurements of small-airways disease.

Systemic bioavailability of hydrofluoroalkane (HFA) formulations of fluticasone/salmeterol in healthy volunteers via pMDI alone and spacer.

AIM: To compare a test version of HFA fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) with the reference product Seretide (GlaxoSmithKline, UK). METHODS: An in vitro Anderson cascade impactor was used to compare the fine particle dose (<4.7 microm). Two separate randomized cross-over studies were performed to compare the systemic bioavailability of test vs. reference (T vs. R) formulations of FP/SM 250/25 microg pMDI in healthy volunteers. In study 1 blood pharmacokinetic analysis using oral charcoal block was performed over 24 h following a single dose of four puffs via pMDI alone. In study 2 systemic bioactivity was measured following single doses of four and eight puffs via a spacer device: serum potassium (K(+)) to reflect SM, and overnight urinary cortisol : creatinine (OUCC) for FP. An early pharmacokinetic profile was also assessed over 120 min. RESULTS: The in vitro fine particle dose was similar for test vs. reference pMDI alone and via spacer. The results of both studies were consistent: No significant differences between formulations were seen in terms of FP kinetics. Analysis of SM kinetics revealed superiority of the test product. No significant dose-response or difference in T : R ratio was noted for OUCC. Fall in K(+) revealed a significant dose-response with a non-significant T : R ratio. CONCLUSIONS: The in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. Single dosing studies with fluticasone/salmeterol 250/25 microg via pMDI or with spacer showed pharmacokinetic equivalence with FP, but not SM. No significant difference between formulations was seen with either adrenal suppression or hypokalaemia.

Think the impossible: beta-blockers for treating asthma.

Asthma was originally thought to be associated with an intrinsic defect in beta2ADR (beta2-adrenoceptor) function, tipping the balance towards parasympathetic bronchoconstriction. Hence beta-blocking drugs (such as beta2ADR antagonists and inverse agonists) may cause acute bronchoconstriction which, in turn, may be attenuated by anti-cholinergic agents. Although beta2-agonists are highly effective for the acute relief of bronchoconstriction, their chronic use is accompanied by an adaptive reduction in beta2ADR numbers and associated desensitization of response, resulting in increased exacerbations and rare cases of death. The hypothesis examined in the present article is that, while single dosing with a beta-blocker may cause acute bronchoconstriction, chronic dosing may afford putative beneficial effects including attenuated airway hyperresponsiveness.

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.

Effects of intravenous and oral ß-blockade in persistent asthmatics controlled on inhaled corticosteroids.

OBJECTIVE: Despite their benefits in the treatment of cardiovascular disease, ß-blockers are seldom used to treat asthmatics. We assessed the safety and tolerability of acute dosing with esmolol and propranolol in patients with asthma. DESIGN: Post-hoc analysis of a double blind, randomised, placebo controlled trial of ß-blocker use in asthma. PATIENTS: Mild-to-moderate asthmatics on inhaled corticosteroids. INTERVENTIONS: Each participant underwent a 6-8 week dose titration of oral propranolol. A subgroup received an intravenous bolus dose of esmolol (0.5 mg/kg). Measurements were recorded pre- and post-esmolol and first dose exposure to 10 mg, 20 mg, and 80 mg of propranolol. Tiotropium was given concurrently with propranolol. Bronchoconstriction was reflected as a fall in forced expiratory volume in 1 s (FEV1) or increase in total airway resistance at 5 Hz (R5). RESULTS: 12 patients completed the trial. There were no adverse effects on FEV1% or R5% following intravenous esmolol. There were significant reductions at 2 min post-esmolol in heart rate (-4.7 beats/min (bpm), 95% CI -7.9 to -1.3 bpm; p=0.002) and systolic blood pressure (-5.9 mm Hg, 95% CI -11.4 to -0.4 mm Hg; p=0.03). No bronchoconstriction was seen during up titration following the first dose of 10 mg, 20 mg or 80 mg of propranolol in the presence of tiotropium. No difference in the asthma control questionnaire at 80 mg propranolol was seen versus placebo in the presence of tiotropium. CONCLUSIONS: Intravenous esmolol was administered without any adverse effects on pulmonary function in selected, stable, mild-to-moderate asthmatics controlled on inhaled corticosteroids. Tiotropium prevented propranolol induced bronchoconstriction after acute dosing during up-titration to 80 mg with no adverse impact on asthma control.

Reconstruction of an extensive peri-orbital defect secondary to mucormycosis in a patient with myelodysplasia.

We present the case of a 68-year old gentleman with previously diagnosed myelodysplastic syndrome with pancytopenia who presented with exophthalmia, rhinorrhea, and ophthalmoplegia. Nasal endoscopy revealed black necrotic lesions. He was diagnosed with rhino-orbital mucormycosis and commenced on intravenous antifungals. Despite this therapy he progressed to have total unilateral loss of visual acuity and cutaneous necrosis. He underwent emergency orbital exenteration and extensive cheek and sinus debridement. Necrotic lesions were found in the orbit, the maxillary and ethmoidal sinuses. He underwent reconstruction of this defect using a free myocutaneous ALT flap with a segment of vastus lateralis. Prior to surgery his anemia and thrombocytopenia were addressed with packed red cell and platelet transfusions as well as preoperative thromboelastography (TEG) to measure functional fibrinogen to platelet ratio. Intraoperative platelet administration was guided by repeated TEG analysis. There were no significant intraoperative or postoperative bleeding complications and both flap and donor site healed unremarkably. Few reports exist in the literature related to free tissue transfer in patients with hematological disorders but low platelet count has been implicated in an increased complication rate.

Cardiovascular events after clarithromycin use in lower respiratory tract infections: analysis of two prospective cohort studies.

OBJECTIVE: To study the association of clarithromycin with cardiovascular events in the setting of acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia. DESIGN: Analysis of two prospectively collected datasets. SETTING: Chronic obstructive pulmonary disease dataset including patients admitted to one of 12 hospitals around the United Kingdom between 2009 and 2011; Edinburgh pneumonia study cohort including patients admitted to NHS Lothian Hospitals between 2005 and 2009. POPULATION: 1343 patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease and 1631 patients admitted with community acquired pneumonia. MAIN OUTCOME MEASURES: Hazard ratios for cardiovascular events at one year (defined as hospital admissions with acute coronary syndrome, decompensated cardiac failure, serious arrhythmia, or sudden cardiac death) and admissions for acute coronary syndrome (acute ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina). Secondary outcomes were all cause and cardiovascular mortality at one year. RESULTS: 268 cardiovascular events occurred in the acute exacerbations of chronic obstructive pulmonary disease cohort and 171 in the community acquired pneumonia cohort over one year. After multivariable adjustment, clarithromycin use in acute exacerbations of chronic obstructive pulmonary disease was associated with an increased risk of cardiovascular events and acute coronary syndrome-hazard ratios 1.50 (95% confidence interval 1.13 to 1.97) and 1.67 (1.04 to 2.68). After multivariable adjustment, clarithromycin use in community acquired pneumonia was associated with increased risk of cardiovascular events (hazard ratio 1.68, 1.18 to 2.38) but not acute coronary syndrome (1.65, 0.97 to 2.80). The association between clarithromycin use and cardiovascular events persisted after matching for the propensity to receive clarithromycin. A significant association was found between clarithromycin use and cardiovascular mortality (adjusted hazard ratio 1.52, 1.02 to 2.26) but not all cause mortality (1.16, 0.90 to 1.51) in acute exacerbations of chronic obstructive pulmonary disease. No association was found between clarithromycin use in community acquired pneumonia and all cause mortality or cardiovascular mortality. Longer durations of clarithromycin use were associated with more cardiovascular events. Use of ß lactam antibiotics or doxycycline was not associated with increased cardiovascular events in patients with acute exacerbations of chronic obstructive pulmonary disease, suggesting an effect specific to clarithromycin. CONCLUSIONS: The use of clarithromycin in the setting of acute exacerbations of chronic obstructive pulmonary disease or community acquired pneumonia may be associated with increased cardiovascular events. These findings require confirmation in other datasets.

Bisphosphonate-anchored PEGylation and radiolabeling of superparamagnetic iron oxide: long-circulating nanoparticles for in vivo multimodal (T1 MRI-SPECT) imaging.

The efficient delivery of nanomaterials to specific targets for in vivo biomedical imaging is hindered by rapid sequestration by the reticuloendothelial system (RES) and consequent short circulation times. To overcome these two problems, we have prepared a new stealth PEG polymer conjugate containing a terminal 1,1-bisphosphonate (BP) group for strong and stable binding to the surface of ultrasmall-superparamagnetic oxide nanomaterials (USPIOs). This polymer, PEG(5)-BP, can be used to exchange the hydrophobic surfactants commonly used in the synthesis of USPIOs very efficiently and at room temperature using a simple method in 1 h. The resulting nanoparticles, PEG(5)-BP-USPIOs are stable in water or saline for at least 7 months and display a near-zero ζ-potential at neutral pH. The longitudinal (r(1)) and transverse (r(2)) relaxivities were measured at a clinically relevant magnetic field (3 T), revealing a high r(1) of 9.5 mM(-1) s(-1) and low r(2)/r(1) ratio of 2.97, making these USPIOs attractive as T1-weighted MRI contrast agents at high magnetic fields. The strong T1-effect was demonstrated in vivo, revealing that PEG(5)-BP-USPIOs remain in the bloodstream and enhance its signal 6-fold, allowing the visualization of blood vessels and vascular organs with high spatial definition. Furthermore, the optimal relaxivity properties allow us to inject a dose 4 times lower than with other USPIOs. PEG(5)-BP-USPIOs can also be labeled using a radiolabeled-BP for visualization with single photon emission computed tomography (SPECT), and thus affording dual-modality contrast. The SPECT studies confirmed low RES uptake and long blood circulation times (t(1/2) = 2.97 h). These results demonstrate the potential of PEG(5)-BP-USPIOs for the development of targeted multimodal imaging agents for molecular imaging.

Is a positive nasal lysine-aspirin challenge test associated with a more severe phenotype of chronic rhinosinusitis and asthma?

BACKGROUND: Current guidelines recommend a greater use of aspirin challenge testing in the diagnosis of aspirin-intolerant rhinosinusitis and asthma, a disorder with high burden of illness and resistance to treatment. The indications for these tests and their clinical significance remain unclear. This study was designed to characterize the phenotype of patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) with or without asthma undergoing a nasal lysine-aspirin (L-ASA) challenge to evaluate which factors strongly predict a positive test. METHODS: Seventy-five patients with CRSwNP underwent nasal challenge with 16 mg (total) of L-ASA after 30 minutes of acclimatization and diluent challenge. A positive challenge was defined as a 25% drop in total nasal volume measured by acoustic rhinometry. RESULTS: Twenty-three (31%) participants gave a history of aspirin intolerance and 38 (51%) had a positive nasal L-ASA challenge. Upper airway measures (CT scan score, olfaction, polyp grading, peak nasal inspiratory flow, nasal symptoms, etc.) and lower airway measures (methacholine provocative concentration required to produce a 20% drop in forced expiratory volume in 1 second, effective special airway resistance, and spirometry) were not significantly worse in patients with a positive aspirin challenge. Test sensitivity was 48%, specificity was 52%, positive predictive value was 29%, and negative predictive value was 68%. A regression analysis identified forced expiratory flow at 25-75% (FEF(25-75)), history of aspirin intolerance, and duration of rhinosinusitis as significant predictors of a positive aspirin challenge. CONCLUSION: A positive response to nasal L-ASA challenge is not associated with a more severe phenotype of CRSwNP with or without asthma. A history of aspirin intolerance, duration of rhinosinusitis, and FEF(25-75) predict a greater response to aspirin.