Inhaled corticosteroid dose response in asthma: Should we measure inflammation?

BACKGROUND: Inhaled corticosteroid (ICS) titration in asthma is primarily based on symptoms and pulmonary function. ICSs may not be increased on this basis despite residual airway inflammation. OBJECTIVE: To compare the dose-response relationships of ICSs on measures of pulmonary function, symptoms, and inflammation in patients with persistent asthma. METHODS: We performed a pooled post hoc analysis of 121 patients with mild to moderate asthma from 4 randomized clinical trials that incorporated an ICS dose ramp. Dose ramps were 0 to 200, 0 to 800, and 200 to 800 µg/d (beclomethasone equivalents). Outcome measures included spirometry, fractional exhaled nitric oxide, airway hyperresponsiveness (AHR), symptoms, serum eosinophilic cationic protein, and blood eosinophils. RESULTS: We found a plateau beyond a small improvement at 0 to 200 µg for forced expiratory volume in 1 second: 3.3% (95% confidence interval [CI], 2.0%-4.7%) at 0 to 200 µg vs 0.3% (95% CI, -0.8% to 1.4%) 200 to 800 µg (P = .001). A similar plateau was seen for symptom improvement beyond 0 to 200 µg. Inflammatory and AHR outcomes revealed further room for improvement beyond low-dose ICSs. There was dose-related suppression (P < .001) for fractional exhaled nitric oxide: 40.4 ppb (95% CI, 34.7-46.9 ppb) for ICS free, 26.8 ppb (95% CI, 23.4-30.2 ppb) for 200 µg, and 20.8 ppb (95% CI, 18.8-23.1 ppb) for 800 µg. Eosinophilic cationic protein concentration was significantly reduced with both higher dose ramps. Eosinophil counts also improved across all 3 dose ramps, with dose separation of 370/µL (95% CI, 280-450/µL) for ICS free vs 250/µL (95% CI, 200-300/µL) 800 µg (P = .03). AHR improved with all 3 dose ramps, with greater improvement at lower doses for indirect vs direct challenges. CONCLUSION: ICS dose response may extend beyond low dose for inflammation and AHR but not symptoms or spirometry. Further study is required to identify whether this correlates with suboptimal longitudinal asthma control. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT00667992, NCT00995657, NCT01216579, NCT01544634.

Usefulness of impulse oscillometry for the assessment of airway hyperresponsiveness in mild-to-moderate adult asthma.

BACKGROUND: Impulse oscillometry (IOS) is a novel method of assessing airway resistance. IOS is rarely used in assessing airway resistance after bronchoprovocation in adult asthma. OBJECTIVE: To ascertain the degree of change in IOS measurements seen in patients with asthma undergoing bronchial challenge testing. METHODS: Patients 18 to 65 years old with mild to moderate asthma, forced expiratory volume in 1 second (FEV1) greater than 80% predicted, and diurnal FEV1 variation less than 30% and taking inhaled corticosteroid (≤1,000 µg/day of beclomethasone dipropionate equivalent dose) were recruited. Sequential spirometry and IOS results were measured during bronchial challenge testing to inhaled methacholine and histamine. RESULTS: The magnitude of percentage of change demonstrated in total airway resistance at 5 Hz was greater than that observed for FEV1 in the 2 bronchial challenge tests. For example, at a methacholine provocation concentration that caused a decrease in FEV1 of 20%, a 43.5% change (95% confidence interval 29.4-57.5) was seen in total airway resistance at 5 Hz as measured by IOS compared with a 23.3% change (95% confidence interval 18.7-27.9) in FEV1. The magnitude of change seen with other IOS outcomes, including peripheral airway resistance, area under the curve, and resonant frequency, also was greater compared with spirometry. CONCLUSION: The potential application of IOS in the assessment of airway hyperresponsiveness in adult asthma has been demonstrated. Further population studies are required. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01074853).

Impact of Left Ventricular Hypertrophy on Survival in Chronic Obstructive Pulmonary Disease.

PURPOSE: Left ventricular hypertrophy (LVH) is a significant cardiac risk factor, associated with increased mortality. The impact of LVH on mortality in chronic obstructive pulmonary disease (COPD) is unknown. We evaluated the impact of LVH on mortality in COPD patients by measurement of left ventricular dimensions by echocardiography. METHODS: Retrospective cohort study utilizing a NHS database of COPD patients (TARDIS), in Tayside, Scotland (2001-2010), linked with databases regarding echocardiograms, pharmacy prescription, and the General Register Office for Scotland death registry. Cox proportional hazard regression was used to determine hazard ratios for mortality and hospital admissions based upon left ventricular mass index (LVMI) and left ventricular internal diastolic diameter after correction for all available influential covariates. Increased LVIDd was defined as >5.3 cm (female) and >5.9 cm (male). LVH was defined as an LVMI of >95 g/m(2) (female) and >115 g/m(2) (male). RESULTS: 617 patients were included for analysis. Mean (SD) age at diagnosis, 70 (9); mean FEV1 % (SD), 60.6 (19.3); mean resting SaO2 % (SD), 92.7 (10). Mean follow-up 4.5 years. Increased LVIDd was not associated with increased mortality, χ (2)= 0.767, p = 0.381. Increased LVMI was associated with a significant increased risk of mortality, χ (2) = 5.447, p = 0.02 with an adjusted HR (95 % CI) of 1.542 (1.068-2.228), p = 0.021. CONCLUSIONS: The presence of LVH, demonstrated by elevated left ventricular mass index is associated with a significantly increased risk of mortality in COPD patients. Therapeutic interventions are required to address this important modifiable risk factor in COPD patients.

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.

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.

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).

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.

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.

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).

A randomized primary care trial of steroid titration against mannitol in persistent asthma: STAMINA trial.

BACKGROUND: We compared titrating inhaled corticosteroid (ICS) against mannitol airway hyperresponsiveness (AHR) or a reference strategy (control) based on symptoms, reliever use, and lung function in primary care. METHODS: One hundred sixty-four patients with persistent asthma were randomized in parallel group fashion following an initial ICS tapering. Subsequent ICS doses (as ciclesonide) were titrated against either the provocative dose of mannitol causing a 10% fall in FEV(1) (PD(10)) (AHR strategy) or a control group (reference strategy) over a 1-year period. RESULTS: One hundred nineteen participants (n = 61 AHR, n = 58 control) completed the study. Time to first mild exacerbation was not significantly different: hazard ratio, 1.29; 95% CI, 0.716-2.31; P = .40. Although there were 27% fewer total number of mild exacerbations over 12 months in AHR vs control groups (n = 84 vs n = 115, P = .03), there was no difference in severe exacerbations (n = 12 vs n = 13). No other significant differences were seen between groups with the exception of mannitol PD(10) and ICS dose. There was a 1.52 (95% CI, 0.61-2.42; P = .001) doubling dose difference in mannitol PD(10) between AHR vs control groups. The final mean daily ciclesonide dose was higher (P < .0001) in AHR vs control groups (514 µg vs 208 µg), with no associated significant suppression of overnight urinary cortisol/creatinine. Significant improvements were seen within the AHR group but not the control group for the provocative concentration of methacholine causing a 20% fall in FEV(1) (P < .05), salivary eosinophilic cationic protein (P < .05), exhaled nitric oxide (P < .05), symptoms (P < .005), and reliever use (P < .001). CONCLUSIONS: Mannitol challenge was well tolerated in a primary care setting. Using mannitol resulted in exposure to a higher dose of ciclesonide, which was associated with equivocal effects on exacerbations without associated adrenal suppression. Large-scale trials using mannitol in patients with more severe disease may now be warranted to further define its role. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01216579; URL: www.clinicaltrials.gov.

Inhaled corticosteroid dose response using domiciliary exhaled nitric oxide in persistent asthma: the FENOtype trial.

BACKGROUND: International guidelines advocate a standard approach to asthma management for all, despite its heterogeneity. "Personalized" treatment of inflammatory asthma phenotypes confers superior benefits. We wished to evaluate dose response to inhaled corticosteroids (ICSs) in patients with asthma with an elevated fractional exhaled nitric oxide (Feno) phenotype using domiciliary measurements. METHODS: We performed a randomized, crossover trial in 21 patients with mild to moderate persistent asthma receiving ICSs with elevated Feno (>30 parts per billion [ppb]) that increased further (>10 ppb) after ICS washout. Patients were randomized to 2 weeks of either fluticasone propionate 50 µg bid (FP100) or 250 µg bid (FP500). The primary outcome was response in diurnal domiciliary Feno levels. Secondary outcomes included mannitol challenge, serum eosinophilic cationic protein (ECP), blood eosinophil count, and asthma control questionnaire. RESULTS: We found significant dose-related reductions of diurnal Feno compared with baseline - morning Feno: baseline = 71 ppb (95% CI, 61-83 ppb); FP100 = 34 ppb (95% CI, 29-40 ppb), P < .001; FP500 = 27 ppb (95% CI, 22-33 ppb), P < .001; and significant dose separation for morning, P < .05, and evening, P < .001. Time-series Feno displayed exponential decay: FP100 R² = 0.913, half-life = 69 h (95% CI, 50-114 h); FP500 R² = 0.966, half-life = 55 h (95% CI, 45-69 h), as well as diurnal variation. The Asthma Control Questionnaire showed significant improvements exceeding the minimal important difference (>0.5) with values in keeping with controlled asthma (<0.75) after each dose: FP100 = 0.48 (95% CI, 0.24-0.71), P = .004; FP500 = 0.37 (95% CI, 0.18-0.57), P = .001. All other secondary inflammatory related outcomes (mannitol, ECP, and eosinophils) showed significant improvements from baseline but no dose separation. CONCLUSIONS: There is a significant dose response of diurnal Feno to ICS in patients with asthma with an elevated Feno phenotype, which translates into well-controlled asthma. Further interventional studies are warranted using domiciliary Feno in this specific phenotype. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00995657; URL: clinicaltrials.gov.

The impact of tiotropium on mortality and exacerbations when added to inhaled corticosteroids and long-acting ß-agonist therapy in COPD.

BACKGROUND: Tiotropium has been shown to improve lung function, quality of life, and exacerbations and reduce mortality when compared with placebo in COPD. It remains unclear whether benefits are seen when tiotropium is used in conjunction with inhaled corticosteroids (ICSs) plus long-acting ß-agonists (LABAs). METHODS: We performed a retrospective cohort study using a National Health Service database of patients with COPD in Tayside, Scotland, between 2001 and 2010 that is linked with databases regarding hospital admissions, pharmacy prescriptions, and death registries. The impact of the addition of tiotropium (Tio) to ICS + LABA therapy on all-cause mortality, hospital admissions for respiratory disease, and emergency oral corticosteroid bursts was evaluated. Adjusted hazard ratios (HRs) were calculated by Cox regression after inclusion of the following covariates: cardiovascular and respiratory disease, diabetes, smoking, age, sex, and deprivation index. RESULTS: A total of 1,857 patients were given ICS + LABA + Tio, and 996 were given ICS + LABA. Mean follow-up was 4.65 years. The adjusted HR for all-cause mortality for ICS + LABA + Tio vs ICS + LABA was 0.65 (95% CI, 0.57-0.75; P < .001). Adjusted HRs for hospital admissions and oral corticosteroid bursts were 0.85 (95% CI, 0.73-0.99; P = .04) and 0.71 (95% CI, 0.63-0.80; P < .001), respectively. CONCLUSIONS: The study suggests that the addition of tiotropium to ICSs and LABA therapy may confer benefits in reducing all-cause mortality, hospital admissions, and oral corticosteroid bursts in patients with COPD. Triple therapy is widely used in the real-life management of COPD, with only limited scientific support. The study supports the use of triple therapy in COPD and provides a platform for randomized controlled trials specifically addressing this topic.

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.

Relationships between airway hyperresponsiveness, inflammation, and calibre in asthma.

BACKGROUND: Previous studies have focused upon the relationship between airway inflammation and hyperresponsiveness with different conclusions. We re-examined the relationship between airway inflammation (FE(NO)), hyperresponsiveness to methacholine (AHR), and calibre (FEV(1) % predicted) in mild-to-moderate asthmatics. METHODS: We searched our database for asthmatics who had attended our research department. FEV(1) % predicted, FE(NO), and methacholine PC(20) were collected. Patients were divided into groups based upon AHR as follows: severe (<0.5 mg/ml, group A), moderate (>0.5-2 mg/ml, group B), and mild (>2-8 mg/ml, group C), and upon FE(NO): low (<25 ppb, group D), medium (25-50 ppb, group E), and high (>50 ppb, group F). RESULTS: In 208 asthmatics, when stratified by AHR, there was an 8.5% difference in FEV(1) % predicted (95% CI 2.6-14.4%; P = 0.002) and a 29% difference in FE(NO) between groups A and C (95% CI 2-48%; P = 0.034). When stratified by FE(NO,) there was a 1.29 doubling dilution difference in methacholine PC(20) (95% CI 0.26-2.33; P = 0.009) between groups D and F. There was no difference between FEV(1) % predicted when grouped by FE(NO). Multivariate regression analysis with covariates, including inhaled corticosteroids, supported our findings from categorical analysis. CONCLUSIONS: We found no relationship between airway inflammation and calibre, whilst showing significant relationships between AHR and airway calibre and AHR and airway inflammation. Whilst relationships exist, the lack of complete concordance highlights the important role each contributes to the assessment of the asthmatic individual.

Severity assessment tools to guide ICU admission in community-acquired pneumonia: systematic review and meta-analysis.

BACKGROUND: The aim of this meta-analysis was to determine if severity assessment tools can be used to guide decisions regarding intensive care unit (ICU) admission of patients with community-acquired pneumonia. METHODS: A search of PUBMED and EMBASE (1980-2009) was conducted to identify studies reporting pneumonia severity scores and prediction of ICU admission. Two reviewers independently collected data and assessed study quality. Performance characteristics were pooled using a random-effects model. RESULTS: Sufficient data were collected to perform a meta-analysis on five current scoring systems: the Pneumonia Severity Index (PSI), the CURB65 score, the CRB65 score, the American Thoracic Society (ATS) 2001 criteria and the Infectious Disease Society of America/ATS (IDSA/ATS) 2007 criteria. The analysis was limited due to large variations in the ICU admission criteria, ICU admission rates and patient characteristics between different studies and different healthcare systems. In the pooled analysis, PSI, CURB65 and CRB65 performed similarly in terms of sensitivity and specificity across a range of cut-offs. Patients in CURB65 group 0 were at lowest risk of ICU admission (negative likelihood ratio 0.14; 95% confidence interval 0.06-0.34) while the ATS 2001 criteria had the highest positive likelihood ratio (7.05; 95% confidence interval 4.39-11.3). CONCLUSION: Large variations exist in the use of ICU resources between different studies and different healthcare systems. Scoring systems designed to predict 30-day mortality perform less well when ICU admission is taken into account. Further studies of dedicated ICU admission scores are required.

Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study.

OBJECTIVE: To examine the effect of ß blockers in the management of chronic obstructive pulmonary disease (COPD), assessing their effect on mortality, hospital admissions, and exacerbations of COPD when added to established treatment for COPD. DESIGN: Retrospective cohort study using a disease specific database of COPD patients (TARDIS) linked to the Scottish morbidity records of acute hospital admissions, the Tayside community pharmacy prescription records, and the General Register Office for Scotland death registry. SETTING: Tayside, Scotland (2001-2010) Population 5977 patients aged >50 years with a diagnosis of COPD. MAIN OUTCOME MEASURES: Hazard ratios for all cause mortality, emergency oral corticosteroid use, and respiratory related hospital admissions calculated through Cox proportional hazard regression after correction for influential covariates. RESULTS: Mean follow-up was 4.35 years, mean age at diagnosis was 69.1 years, and 88% of ß blockers used were cardioselective. There was a 22% overall reduction in all cause mortality with ß blocker use. Furthermore, there were additive benefits of ß blockers on all cause mortality at all treatment steps for COPD. Compared with controls (given only inhaled therapy with either short acting ß agonists or short acting antimuscarinics), the adjusted hazard ratio for all cause mortality was 0.28 (95% CI 0.21 to 0.39) for treatment with inhaled corticosteroid, long acting ß agonist, and long acting antimuscarinic plus ß blocker versus 0.43 (0.38 to 0.48) without ß blocker. There were similar trends showing additive benefits of ß blockers in reducing oral corticosteroid use and hospital admissions due to respiratory disease. ß blockers had no deleterious impact on lung function at all treatment steps when given in conjunction with either a long acting ß agonist or antimuscarinic agent CONCLUSIONS: ß blockers may reduce mortality and COPD exacerbations when added to established inhaled stepwise therapy for COPD, independently of overt cardiovascular disease and cardiac drugs, and without adverse effects on pulmonary function. NCT Number: NCT01221480