Use of the oral beta blocker bisoprolol to reduce the rate of exacerbation in people with chronic obstructive pulmonary disease (COPD): a randomised controlled trial (BICS).

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity, mortality and healthcare costs. Beta blockers are well-established drugs widely used to treat cardiovascular conditions. Observational studies consistently report that beta blocker use in people with COPD is associated with a reduced risk of COPD exacerbations. The bisoprolol in COPD study (BICS) investigates whether adding bisoprolol to routine COPD treatment has clinical and cost-effective benefits. A sub-study will risk stratify participants for heart failure to investigate whether any beneficial effect of bisoprolol is restricted to those with unrecognised heart disease. METHODS: BICS is a pragmatic randomised parallel group double-blind placebo-controlled trial conducted in UK primary and secondary care sites. The major inclusion criteria are an established predominant respiratory diagnosis of COPD (post-bronchodilator FEV1 < 80% predicted, FEV1/FVC < 0.7), a self-reported history of ≥ 2 exacerbations requiring treatment with antibiotics and/or oral corticosteroids in a 12-month period since March 2019, age ≥ 40 years and a smoking history ≥ 10 pack years. A computerised randomisation system will allocate 1574 participants with equal probability to intervention or control groups, stratified by centre and recruitment in primary/secondary care. The intervention is bisoprolol (1.25 mg tablets) or identical placebo. The dose of bisoprolol/placebo is titrated up to a maximum of 4 tablets a day (5 mg bisoprolol) over 4-7 weeks depending on tolerance to up-dosing of bisoprolol/placebo-these titration assessments are completed by telephone or video call. Participants complete the remainder of the 52-week treatment period on the final titrated dose (1, 2, 3, 4 tablets) and during that time are followed up at 26 and 52 weeks by telephone or video call. The primary outcome is the total number of participant reported COPD exacerbations requiring oral corticosteroids and/or antibiotics during the 52-week treatment period. A sub-study will risk stratify participants for heart failure by echocardiography and measurement of blood biomarkers. DISCUSSION: The demonstration that bisoprolol reduces the incidence of exacerbations would be relevant not only to patients and clinicians but also to healthcare providers, in the UK and globally. TRIAL REGISTRATION: Current controlled trials ISRCTN10497306 . Registered on 16 August 2018.

The Choice of Biologics in Patients with Severe Chronic Rhinosinusitis with Nasal Polyps.

Patients with severe chronic rhinosinusitis with nasal polyps represent an unmet clinical need in terms of recurrent disease despite current medical and surgical therapy. Targeting type 2 inflammatory cytokines (IL4/5/13) appears to be a promising therapeutic approach for such patients akin to what has already been seen in severe asthma. An indirect comparison from phase 3 placebo-controlled trials has shown relative improvements in the coprimary end point of nasal polyp score (NPS) ranging from a 15% reduction (-0.8 units) with mepolizumab, 18% with omalizumab (-1.14 units), and 35% (-2.06 units) with dupilumab. This trend was mirrored by relative improvements in health status with the 22-item Sinonasal Outcome Test score showing a 21% reduction (-13.7 units) with mepolizumab, 27% (-16.1 units) with omalizumab, and 43% (-21.1 units) with dupilumab, all exceeding the minimal clinically important difference of 8.9 units. All biologics improved the coprimary end point of nasal airway blockage and also reduced the need for rescue medical and/or surgical polypectomy. We advocate performing real-life studies looking at the response to biologics in patients who are at increased risk for disease recurrence, including initial optimal medical and surgical polyp clearance before commencing biologics.

Allopurinol in Patients with Pulmonary Hypertension Associated with Chronic Lung Disease.

Background: Oxidative stress (OS) has been implicated in the development of pulmonary hypertension (PH) and ventricular hypertrophy. Xanthine oxidase is a well-recognised source of reactive oxygen species, which lead to OS. The aim of this proof of concept study was to assess whether allopurinol (xanthine oxidase inhibitor) would reduce right ventricular mass (RVM) in patients with PH-associated chronic lung disease (PH-CLD). Methods: We conducted a randomised, double-blind, parallel-group, placebo-controlled trial in patients with PH-CLD (93% COPD, 7% IPF) who were randomly assigned to receive allopurinol or placebo for 12 months. The primary outcome was the mean change in RVM, as assessed by cardiac magnetic resonance imaging (CMRI). Secondary outcomes included quality of life (QOL), spirometry and six-minute walk test (6MWT). Results: Seventy-one patients were recruited: mean age 71 years, mean pulmonary arterial pressure 30 mm Hg, FEV1 60% and resting SpO2 96%. After 12 months, there was no significant difference in the change in RVM from baseline (allopurinol 1.85g vs placebo 0.97g with mean difference 0.88g, CI -4.77 to 3.01, p =0.7). There were also no significant changes in other cardiac parameters measured on MRI, in QOL, spirometry and 6MWT. Subgroup analysis showed that allopurinol significantly reduced RVM compared to placebo with -6.16g vs 0.75g and mean difference 6.92g (CI 1.14 to 12.69, p = 0.02) in COPD patients with more severe airflow limitation. Conclusion: Allopurinol had no overall impact on patients with PH-CLD but had potential benefit in COPD patients with more severe airflow limitation.

Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can manifest as a viral-induced hyperinflammation with multiorgan involvement. Such patients often experience rapid deterioration and need for mechanical ventilation. Currently, no prospectively validated biomarker of impending respiratory failure is available. OBJECTIVE: We aimed to identify and prospectively validate biomarkers that allow the identification of patients in need of impending mechanical ventilation. METHODS: Patients with COVID-19 who were hospitalized from February 29 to April 9, 2020, were analyzed for baseline clinical and laboratory findings at admission and during the disease. Data from 89 evaluable patients were available for the purpose of analysis comprising an initial evaluation cohort (n = 40) followed by a temporally separated validation cohort (n = 49). RESULTS: We identified markers of inflammation, lactate dehydrogenase, and creatinine as the variables most predictive of respiratory failure in the evaluation cohort. Maximal IL-6 level before intubation showed the strongest association with the need for mechanical ventilation, followed by maximal CRP level. The respective AUC values for IL-6 and CRP levels in the evaluation cohort were 0.97 and 0.86, and they were similar in the validation cohort (0.90 and 0.83, respectively). The calculated optimal cutoff values during the course of disease from the evaluation cohort (IL-6 level > 80 pg/mL and CRP level > 97 mg/L) both correctly classified 80% of patients in the validation cohort regarding their risk of respiratory failure. CONCLUSION: The maximal level of IL-6, followed by CRP level, was highly predictive of the need for mechanical ventilation. This suggests the possibility of using IL-6 or CRP level to guide escalation of treatment in patients with COVID-19-related hyperinflammatory syndrome.

Sensitivity of Lung Resistance and Compliance to Beta-Blocker Induced Bronchoconstriction and Long Acting Beta-Agonist Withdrawal in COPD.

Little is known about impulse oscillometry (IOS) in COPD. IOS is an effort independent measure of lung resistance and reactance (compliance). We assessed how frequency dependence of resistance (R) and reactance (X) changed in response to bronchoconstriction with carvedilol followed by long acting beta-agonist (LABA) withdrawal. N = 12 patients with moderate to severe COPD were analysed, who had ≥ 100 ml fall in FEV1 with carvedilol. Compared to baseline taking ICS/LABA there were 21, 59, and 135% significant changes in resistance at 5 Hz (R5), reactance at 5 Hz (X5), and reactance area (AX), respectively, with carvedilol, while after LABA withdrawal only AX showed a further significant increase to 210% (i.e. reduced compliance). Hence changes in lung compliance rather than resistance play a more important role in the beta-2 receptor-mediated responses in COPD.

Tolerability of Bisoprolol on Domiciliary Spirometry in COPD.

We investigated if serial domiciliary measures of spirometry were sensitive at detecting subtle effects of beta-2 blockade associated with bisoprolol in (n = 17) patients with COPD. After a two-week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA): beclometasone/formoterol 100/6 µg, patients' started additional a long acting muscarinic receptor antagonist: (LAMA) Tiotropium 18 µg, with concomitant weekly dose titration of bisoprolol: 1.25-2.5-5 mg. After a further week of bisoprolol 5 mg, they were stepped back down to (ICS/LABA) for one week. Mean age was 64 years, mean FEV1 52% predicted, and mean FEV1/FVC ratio of 0.46. Compared to baseline am FEV1 of 1.38 L (95% CI 1.14-1.61 L), both ICS/LABA/LAMA and ICS/LABA in conjunction with bisoprolol showed statistically significant mean falls of 100 ml (1.28 L, 95% CI 1.03-1.53 L), and 120 ml, respectively (1.26 L, 95% CI 1.01-1.51 L); equalling and exceeding the MCID of 100 ml, respectively. These changes were disconnected from symptoms, reliever use and oxygen saturation.

Effects of contrast administration on cardiac MRI volumetric, flow and pulse wave velocity quantification using manual and software-based analysis.

OBJECTIVE: The aim of the current study was to determine the effects of gadolinium contrast agent on right (RV) and left ventricular (LV) volumetric, aortic flow and pulse wave velocity (PWV) quantification using manual, semi-automatic and fully automatic analysis techniques. METHODS: 61 participants free from known cardiovascular disease were recruited. Cardiac MR was performed on a 3 T scanner. A balanced steady-state free precession stack was acquired of the ventricles with phase contrast imaging of the aorta performed pre- and post-administration of 10 ml 0.5 mmol ml-1 gadoterate meglumine. The images were analysed manually, and using a semi-automated and a fully automated technique. RESULTS: 54 completed the study. Gadolinium-based contrast administration significantly increase the signal-to-noise ratio (pre: 830 ± 398 vs post: 1028 ± 540, p = 0.003) with no significant change in contrast-to-noise ratio (pre: 583 ± 302 vs post: 559 ± 346, p = 0.54). On LV analysis, post-contrast analysis yielded significantly higher end systolic volume (54 ± 20 vs 57 ± 18 ml, p = 0.04), and lower ejection fraction (59 ± 9 vs 57 ± 8%, p = 0.023). On RV analysis, gadolinium contrast resulted in no significant differences. Similar results were seen using the semi-automated and fully-automated techniques but with a larger magnitude of difference. Conversely, using both manual and software analysis aortic flow and PWV quantification proved robust to the effects of contrast agent producing only small non-significant differences. CONCLUSION: Gadolinium contrast administration significantly alters LV endocardial contour detection with this effect amplified when using semi-automated analysis techniques. In comparison, RV and PWV analysis is robust to these effects. Advances in knowledge: Contrast administration alters LV quantification but not flow analysis. However, these differences are small.

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.

Fluticasone/Salmeterol combination confers benefits in people with asthma who smoke.

BACKGROUND: Smoking induces airway inflammation and relative resistance to inhaled steroids. The objective of this study was to evaluate the effects on airway hyperresponsiveness of adding salmeterol to fluticasone vs doubling the dose of fluticasone in patients with asthma who smoked and patients with asthma who did not smoke. METHODS: Sixteen patients with mild to moderate persistent asthma who did not smoke and 15 such patients who smoked completed a double-blind, randomized, placebo-controlled crossover study. They received either a fluticasone/salmeterol combination (FP/SM) (125/25 µg) two puffs bid (plus fluticasone placebo), or active fluticasone (250 µg) two puffs bid (plus FP/SM placebo), for 2 weeks each, with baselines after 1-week to 2-week run-in and washout periods. The primary outcome was the change from baseline in the provocative concentration of methacholine required to produce a 20% fall in FEV(1) (PC(20)). RESULTS: In the patients who did not smoke, there were similar improvements in the methacholine PC(20) with the use of fluticasone and FP/SM. The patients who smoked gained a benefit from FP/SM but not fluticasone, amounting to a PC(20) difference of 1.6 doubling dilutions (95% CI, 1.0-2.2), P < .01. The provocative dose of mannitol required to produce a 15% fall in FEV(1) (PD(15)) showed greater improvements with FP/SM than fluticasone in both patients who smoked and did not smoke. Similar differences in airway caliber between those who smoked and did not smoke were observed in FEV(1) and airway resistance. CONCLUSIONS: FP/SM confers greater improvements in airway hyperresponsiveness and airway caliber in patients with asthma who smoke compared with double the dose of fluticasone. We hypothesize that in the presence of relative steroid resistance, the smooth muscle stabilization conferred by salmeterol is of greater clinical importance in patients who smoke than in those who do not smoke. TRIAL REGISTRY: ClinicalTrials.gov: No.: NCT00830505; URL: www.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 intranasal salmeterol and fluticasone given alone and in combination in persistent allergic rhinitis.

BACKGROUND: ß(2)-Agonists have previously been shown to be effective inhibitors of mediator release from airway mucosal mast cells. OBJECTIVE: To evaluate the effects of intranasal salmeterol and fluticasone propionate alone and in combination on the response to nasal adenosine monophosphate (AMP) challenge to assess mast cell activation. METHODS: Twenty-three patients with persistent allergic rhinitis completed a randomized, double-blind, placebo-controlled, 4-way crossover trial. They received once daily treatment with placebo, salmeterol, 50 µg, fluticasone propionate, 500 µg, or fluticasone propionate and salmeterol combination, 500/50 µg, delivered via an antistatic spacer with nasal adapter for 1 week each, with trough measurements being made 12 hours after the first and last dose. The primary outcome was the maximum percentage decrease in peak nasal inspiratory flow after nasal AMP challenge. RESULTS: For the primary outcome there was significant protection after single and long-term dosing with fluticasone alone and fluticasone-salmeterol combination, whereas salmeterol alone only afforded protection after the first dose. Fluticasone-salmeterol combination and fluticasone but not salmeterol conferred significant chronic dosing effects on secondary outcomes of nasal symptoms and disease-specific quality of life. There was no potentiation of the response to fluticasone by salmeterol on any outcomes when given in combination. CONCLUSION: Chronic dosing with fluticasone but not salmeterol confers anti-inflammatory activity against nasal AMP challenge, but there was no potentiation of fluticasone when given in combination with salmeterol. Thus, salmeterol may not be an effective treatment for use in allergic rhinitis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01388595.

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.

Relationship between fractional exhaled nitric oxide and nasal nitric oxide in airways disease.

BACKGROUND: Invasive techniques show evidence of a unified allergic airway. Nitric oxide is measured noninvasively from the lungs (fractional exhaled nitric oxide [FeNO]) and nose (nasal nitric oxide [nNO]). OBJECTIVE: To investigate the relationship between FeNO and nNO in different airway conditions. METHODS: A total of 227 participants were assessed: 41 healthy volunteers (HVs), 33 patients with asthma, 52 patients with allergic rhinitis (AR), 63 with unified airway disease (UAD), and 38 with nasal polyposis (NP). Correlation and multiple linear regression analyses were performed. RESULTS: Geometric means (95% confidence intervals) for FeNO were as follows: 14.7 (12.4-17.5) ppb for HVs, 29.0 (22.5-37.4) ppb for asthma patients, 23.1 (19.0-28.1) for AR patients, 27.2 (23.0-32.4) for UAD patients, and 28.5 (21.5-37.8) for NP patients. For nNO, the values were as follows: 878.1 (807.0-955.6) ppb for HVs, 674.1 (557.4-815.1) for asthma patients, 853.3 (778.8-934.8) ppb for AR patients, 763.4 (694.1-839.5) for UAD patients, and 388.6 (317.9-474.9) for NP patients. The nNO was lower in the NP group than the other groups (P < .001). The nNO and FeNO were correlated in the AR patients (r = 0.56; P < .0001) and HVs (r = 0.44; P = .004) but not significantly in the other groups. Multiple linear regression of the whole cohort demonstrated that after diagnosis, age, sex, and inhaled corticosteroids were taken into account nNO had a significant association with FeNO (P = .02). CONCLUSION: Reduced nNO in NP patients is due to ostiomeatal complex obstruction. FeNO is sensitive to suppression by inhaled corticosteroids. The AR and HV groups have no such confounders; hence, correlation is most evident. Exclusion of confounders reveals a correlation between upper and lower airway inflammation with noninvasive techniques.

A proof of concept study to evaluate stepping down the dose of fluticasone in combination with salmeterol and tiotropium in severe persistent asthma.

We conducted a double blind, randomised, placebo-controlled, crossover study evaluating the effects of halving inhaled steroid dosage plus salmeterol, or salmeterol and tiotropium. Eighteen life-long non-smoking severe asthmatics [mean FEV(1) 1.49 l (51%)] were run-in for 4 weeks on HFA-fluticasone propionate 1000 microg daily, and were subsequently randomised to 4 weeks of either (a) HFA-fluticasone propionate 500 microg BD/salmeterol 100 microg BD/HFA-tiotropium bromide18 microg od; or (b) fluticasone propionate 500 microg BD/salmeterol 100 microg BD matched placebo. Measurements of spirometry and body plethysmography were made. Adding salmeterol to half the dose of fluticasone led to a mean improvement (95% CI) vs. baseline in morning PEF of 41.5 (14.0-69.0)l/min [p<0.05]; and RAW of 0.98 (0.14-1.8)cm H(2)O/l/s [p<0.05]. Adding salmeterol/tiotropium produced similar improvements in PEF and RAW, but also improved FEV(1) by 0.17 (0.01-0.32)l [p<0.05]; FVC 0.24 (0.05-0.43)l [p<0.05] and reduced exhaled NO by 2.86 (0.12-5.6)ppb [p<0.05]. RV and TLC were not altered by either treatment; there were no significant changes in symptoms or quality of life compared with baseline. Addition of salmeterol/tiotropium to half the dose of fluticasone afforded small, but significant improvements in pulmonary function. These effects were not associated with commensurate changes in subjective symptoms or quality of life.

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.

Non-invasive measurement of airway inflammation in asthma.

Assessing the severity and control of a patient's asthma is of great importance to ensure that pharmacotherapy is optimized. Measures such as lung function, symptoms, and reliever use have traditionally been used as objective means of undertaking this assessment, but until now the level of airway inflammation has not been quantified. As asthma is primarily an inflammatory disorder, it would be desirable to include a measure of this process when evaluating disease control. The following article outlines methods of non-invasively measuring asthmatic airway inflammation and highlights their potential role in clinical practice.

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.

Dose-response comparison of budesonide dry powder inhalers using adenosine monophosphate bronchial challenge.

BACKGROUND: Bronchial hyperresponsiveness to adenosine monophosphate, an indirect measure of airway inflammation, is a sensitive marker of inhaled corticosteroid efficacy. OBJECTIVE: To evaluate the relative therapeutic efficacy of budesonide delivered via Clickhaler and Turbuhaler dry powder inhalers in patients with mild-to-moderate persistent asthma. METHODS: In a double-masked, dose-response crossover study, 27 patients received inhaled budesonide in cumulative sequential doubling dose increments, 2 weeks per dose, of 200, 400, and 800 microg/d. Each treatment block was preceded by 1- to 3-week placebo run-in and washout periods. End points were measured after each placebo (ie, baseline) and treatment period. Adenosine monophosphate bronchial challenge was the primary outcome, and exhaled nitric oxide, serum eosinophilic cationic protein, spirometry, domiciliary peak expiratory flow, symptoms, and rescue medication use were the secondary outcomes. RESULTS: For the adenosine monophosphate provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% (PC20), a significant overall dose-response effect (P = .006) was found, and there was no significant difference between the devices (P = .8). The relative microgram dose potency ratio between Clickhaler and Turbuhaler was 1.11 (95% confidence interval [CI], 0.50-2.46). After administration of the highest dose of budesonide, the mean doubling dilution shift in adenosine monophosphate PC20 from placebo baseline was 3.46 (95% CI, 2.66-4.27) with the Clickhaler vs 3.41 (95% CI, 2.47-4.35) with the Turbuhaler. A significant overall dose-response effect was demonstrated for exhaled nitric oxide (P = .03) but not for any of the other secondary outcome measures. There were no significant differences between the devices for any of the outcome measures. CONCLUSION: Inhaled budesonide exhibited overall dose-response effects on adenosine monophosphate PC20 delivered via Turbuhaler and Clickhaler, with no significant difference between the devices.

Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease.

Inhibitors of phosphodiesterase type 4 (PDE4) act by increasing intracellular concentrations of cyclic AMP, which has a broad range of anti-inflammatory effects on various key effector cells involved in asthma and chronic obstructive pulmonary disease (COPD). The therapeutic ratio for PDE4 inhibitors is thought to be determined by selectivity on receptor subtypes for relative effects on PDE4B (anti-inflammatory) and PDE4D (emesis). The two main orally active PDE4 inhibitors in the late phase III of clinical development are cilomilast and roflumilast; the latter (and its active metabolite N-oxide) is more selective and potent with a superior therapeutic ratio. Studies on cilomilast in COPD based on bronchial biopsy material have shown a broad range of anti-inflammatory activity, and the available evidence on clinical outcomes for up to 6 months with cilomilast 15 mg twice daily and roflumilast 500 mug once daily have shown variable but significant effects on exacerbations and quality of life, with small improvements in measures of pulmonary function. Roflumilast has a better safety and tolerability profile than cilomilast, with the main adverse effects being nausea, diarrhoea, and abdominal pain. Roflumilast also has activity in asthma as assessed by its attenuation of allergen and exercise challenges, and it shows clinical efficacy equivalent to that of beclomethasone dipropionate 400 mug daily. The emerging results of clinical trials on PDE4 inhibitors in asthma and COPD should be interpreted with cautious optimism since much of the evidence has been published only in abstract form to date. The next few years should resolve important issues about the potential role of these drugs as oral non-steroidal anti-inflammatory therapy for asthma and COPD and their place in management guidelines. Ultimately, clinicians will want to know whether PDE4 inhibitors are anything more than expensive "designer" theophylline, the archetypal non-selective phosphodiesterase inhibitor.