Remote consultations in primary care across low-, middle- and high-income countries: Implications for policy and care delivery.

The COVID-19 pandemic mandated a substantial switch in primary health care delivery from an in-person to a mainly remote telephone or video service. As the COVID-19 pandemic approaches its third year, limited progress appears to have been made in terms of policy development around consultation methods for the post-acute phase of the pandemic. In September 2020, the International Primary Care Respiratory Group convened a global panel of primary care clinicians - including family physicians, paediatricians, pharmacists, academics and patients - to consider the policy and health management implications of the move to remote consultations in the primary care setting. The group gave special consideration to how and how far remote consultations should be integrated into routine primary health care delivery. Remote consultations can be a useful alternative to in-person consultations in primary care not only in situations where there is a need for viral infection control but also for the routine delivery of chronic disease management. However, they may not be more time efficient for the clinician, and they can add to the workload and work-related stress for primary care practitioners if they remain the dominant consultation mode. Remote consultations are also less appropriate than in-person consultations for new disease diagnosis, dealing with multiple issues and providing complex care. Ensuring health care professionals have the appropriate skill set to effectively deliver remote consultations, administrative and/or IT support and appropriate reimbursement will be key to achieving optimal integration of remote consultations into routine clinical practice. Addressing digital access and digital literacy issues at a societal level will also be essential to ensure individuals have fair and equitable access to the internet and sufficient security for exchange of personal and health-related data.

Pharmacokinetics of mometasone furoate delivered via two dry powder inhalers.

BACKGROUND: QMF149 is an inhaled fixed-dose combination of indacaterol acetate and mometasone furoate (MF) delivered via Breezhaler®, under development for once-daily treatment of asthma. MF delivered via Twisthaler® is approved as Asmanex® Twisthaler® for the treatment of asthma. Bridging of MF delivered via Twisthaler® to MF delivered via Breezhaler® was undertaken as part of QMF149 development to enable dose comparisons between the devices. Pharmacokinetics (PK) of MF were characterized in two studies; a single dose PK study in healthy volunteers and a pharmacokinetic/pharmacodynamic (PK/PD) study in asthma patients. OBJECTIVES: The PK study in healthy volunteers evaluated the PK of single doses of MF via Breezhaler® (50-400 µg) and compared systemic exposure of MF following administration via Breezhaler® and Twisthaler® 400 µg (2 inhalations of 200 µg). The study in patients with asthma characterized the MF PK profile following once-daily inhalation of MF via Breezhaler® and Twisthaler® devices for 4 weeks. METHODS: In the open-label, single-dose, crossover study, healthy subjects sequentially received MF via Twisthaler® (400 µg, medium-dose inhaled corticosteroid [ICS]) and escalating doses via Breezhaler® (50, 100, 200, 400 µg). PK data were obtained up to 72 h post-dose. In the double-blind, double-dummy, parallel-group study, asthma patients were randomised to receive either MF 80 µg (low-dose ICS) or 320 µg (high-dose ICS) via Breezhaler®, or 200 µg (low-dose ICS) or 800 µg (2 inhalations of 400 µg; high-dose ICS) via Twisthaler® once daily for 4 weeks. PK sampling was performed on Days 1 and 28 at pre-dose and up to 24 h post-dose. RESULTS: In the healthy volunteer PK study, 20 healthy subjects completed all treatments. Dose-normalised AUClast of MF was 1.8-1.9-fold higher when delivered via Breezhaler® versus Twisthaler®. AUC and Cmax of MF increased in a dose-proportional manner over the range of 50-400 µg via Breezhaler®. Results from this study guided dose selection of MF via Breezhaler® for the asthma study. In the asthma study, in a subset of 96 patients, mean systemic exposure (AUClast and Cmax) for MF 80 and 320 µg via Breezhaler® was comparable with MF 200 and 800 µg via Twisthaler®, respectively, on Day 28. CONCLUSION: PK characterization in a healthy volunteer PK study and subsequently an asthma study enabled selection of 80 µg (low), 160 µg (medium), and 320 µg (high) delivered via Breezhaler® as MF doses comparable to the 200 µg, 400 µg and 800 µg doses delivered by Twisthaler®, respectively, as part of QMF149 formulation development.

A randomized, double-blind study to compare the efficacy and safety of two doses of mometasone furoate delivered via Breezhaler® or Twisthaler® in patients with asthma.

INTRODUCTION: Mometasone furoate (MF) is the inhaled corticosteroid (ICS) component in the long-acting ß2-agonist (LABA)/ICS fixed-dose combination of indacaterol/MF, delivered via Breezhaler®, in development for asthma. MF at low (80 µg) and high (320 µg) doses delivered via Breezhaler® is expected to be comparable to MF at low (200 µg) and high (800 µg) doses respectively, delivered via Twisthaler®. METHODS: This was a randomized, double-blind, double-dummy, four-week, parallel-group study of 739 adolescents and adults with persistent asthma. Eligible patients were receiving ICS treatment up to the maximum dose per day on a stable regimen for at least four weeks before screening. The study population was enriched for patients who were responsive to ICS therapy. The primary objective of the present study was to show non-inferiority of these doses, i.e. the low (80 µg) and high (320 µg) doses of MF delivered via Breezhaler® once daily, compared with the corresponding low (200 µg) and high (800 µg) doses of MF delivered via Twisthaler® once daily. The primary endpoint was 24 h post-dose trough forced expiratory volume in 1 s (FEV1), after four weeks of treatment in patients with asthma. A secondary objective was to evaluate the efficacy of MF 80 µg and 320 µg delivered via Breezhaler®, and MF 200 µg and 800 µg delivered via Twisthaler® in terms of Asthma Control Questionnaire-5 (ACQ-5) after one, two, three and four weeks of treatment. RESULTS: The LS mean difference in trough FEV1 after four weeks of treatment between MF low dose 80 µg (Breezhaler®) and MF low dose 200 µg (Twisthaler®) was 27 mL (95% CI -34, 89); for MF high dose 320 µg (Breezhaler®) and MF high dose 800 µg (Twisthaler®) the difference was 0 mL (95% CI -60, 61). These differences were neither clinically nor statistically significant. All treatment arms provided similar clinically relevant improvements in ACQ-5 after four weeks of treatment compared with baseline. Both treatments showed a similar safety profile with a low incidence of adverse events. CONCLUSION: The similarities in effects on lung function and ACQ after four weeks of treatment demonstrate the comparability of MF at low (80 µg) and high (320 µg) doses delivered with Breezhaler® with MF at low (200 µg) and high (800 µg) doses delivered with Twisthaler®, respectively. The study formally demonstrated that MF, delivered via Breezhaler®, is non-inferior to MF, delivered via Twisthaler® at corresponding ICS doses.

ERS/EAACI statement on severe exacerbations in asthma in adults: facts, priorities and key research questions.

Despite the use of effective medications to control asthma, severe exacerbations in asthma are still a major health risk and require urgent action on the part of the patient and physician to prevent serious outcomes such as hospitalisation or death. Moreover, severe exacerbations are associated with substantial healthcare costs and psychological burden, including anxiety and fear for patients and their families. The European Academy of Allergy and Clinical Immunology (EAACI) and the European Respiratory Society (ERS) set up a task force to search for a clear definition of severe exacerbations, and to also define research questions and priorities. The statement includes comments from patients who were members of the task force.

Patient Satisfaction and Clinical Outcomes with Budesonide plus Formoterol Spiromax for Asthma and Chronic Obstructive Pulmonary Disease: A Real-World, Observational Trial.

BACKGROUND: The fixed-dose combination of budesonide/formoterol (B/F) has been available in the Spiromax® dry powder inhaler since 2014. OBJECTIVES: To assess patient satisfaction, inhaler use errors, and disease control in patients with asthma or chronic obstructive pulmonary disease (COPD) treated with B/F Spiromax. METHODS: This non-interventional, prospective, 12-week study enrolled consecutive asthma or COPD patients who had recently begun treatment with B/F Spiromax or were switched from another inhaled corticosteroid/long-acting ß2-agonist combination to B/F Spiromax in routine clinical practice. Patients recruited from 243 specialist respiratory clinics or general practices in Germany were assessed for patient satisfaction (Satisfaction with Inhalers and Preference questionnaire), inhaler application errors (modified Easy Low Instruction over Time checklist), disease control, and safety. RESULTS: The population included 3,943 patients: asthma n = 2,707 (68.7%); COPD n = 1,236 (31.3%). At baseline, 60.1% of patients were "satisfied" or "very satisfied" with their previous inhaler, and this increased to 88.8% at week 12 of B/F Spiromax use. Overall, 62.1% of pre-treated patients preferred B/F Spiromax to their old inhaler. The frequency of any handling error observed with B/F Spiromax at week 12 was lower than at baseline (11.9 vs. 25.5% of patients, respectively). After 12 weeks, 77.4% were assessed as having improved (minimally, much, or very much) overall health status versus baseline. Guideline-defined disease severity (as rated by physicians) and patient-reported symptom severity improved during the study in both asthma and COPD patients. B/F Spiromax was well tolerated. CONCLUSION: B/F Spiromax was associated with high patient satisfaction, low device handling error rate, and improvements in clinical outcomes in real-world clinical practice.

[Efficacy of Disease Management Programs Asthma and COPD? Results of a Cross-Sectional Study]. / Wirksamkeit von Disease-Management-Programmen für Asthma und COPD? Ergebnisse einer Querschnittstudie.

BACKGROUND: The efficacy of the German disease management programs (DMP) asthma and chronic obstructive pulmonary disease (COPD) cannot be shown with the legally bound documentations. Studies with control groups are rare. Aim of this work was to investigate in a cross-sectional study whether the disease control differs in participants (DMP+) and non-participants (DMP-) of the DMPs asthma and COPD. METHODS: The study was a prospective multicenter cross-sectional study. Primary endpoints were the Asthma Control Test™ (ACT) in the asthma part of the study and the COPD Assessment Test™ (CAT) for the COPD part. RESULTS: A total of 1038 asthma patients and 846 COPD patients were included, of whom about 70 % participated in the corresponding DMP. The ACT total score was higher in asthma DMP+ patients than in DMP- patients (mean difference 0.86; 95 %CI:0.29 - 1.43;p = 0.003), but not clinically relevant. For COPD there was no clinically relevant difference in COPD disease impact (0.52; 95 %CI:-0.71 - 1.75;p = 0.405). Although DMP patients had to be enrolled in the respective DMP for at least one year, only 60 % of these patients had participated in a structured education. We did not observe a difference in disease control in DMP patients who respectively participated and did not participate in a structured education. DISCUSSION: There was no clinically relevant difference in disease control between DMP+ and DMP- patients. The efficacy of DMPs has been demonstrated internationally in randomized controlled trials. Randomized controlled trials should be conducted in Germany for demonstrating efficacy of DMPs asthma and COPD. REGISTRATION: drks.de, DRKS00007664, Registration date: Jan 15, 2015.

Effects of low- versus high-dose fluticasone propionate/formoterol fumarate combination therapy on AMP challenge in asthmatic patients: A double-blind, randomised clinical trial.

BACKGROUND: The dose-response relationship between two dose levels of fluticasone/formoterol (flutiform(®), 100/10 µg and 500/20 µg) was evaluated in asthmatic patients. Non-invasive inflammatory markers were used including adenosine monophosphate (AMP) challenge (primary endpoint), and sputum eosinophils and fractional exhaled nitric oxide (FeNO) (secondary endpoints). METHODS: Patients aged ≥18 years with forced expiratory volume in 1 s (FEV1) ≥60% predicted and who required a dose of <60 mg AMP to elicit a 20% drop in FEV1 (AMP PD20) were randomised in this incomplete block, crossover study to receive 2 of 3 treatments b.i.d.: fluticasone/formoterol 500/20 µg (high dose), 100/10 µg (low dose) or placebo, during 2 periods of 28 ± 3 days each, separated by 2-3 weeks. AMP challenges were performed pre-dose and 12 h after last dose at the end of each treatment period. A series of post hoc analyses were performed only in patients allocated to both fluticasone/formoterol doses, who completed the study and had evaluable AMP PD20 data for both treatments ("fluticasone/formoterol subgroup"). Changes in AMP PD20 FEV1, percentage sputum eosinophils and FeNO levels (Day 1 vs Day 28) between treatments were compared by an analysis of covariance (ANCOVA). RESULTS: Sixty-two patients were randomised and 46 completed the study. Fifteen patients received both high- and low-dose fluticasone/formoterol (post hoc subgroup). The difference in AMP PD20 for the overall population was not statistically significant between high- and low-dose fluticasone/formoterol (LS mean fold difference: 1.3; p = 0.489), although both dose levels were superior to placebo: high-dose vs placebo LS mean fold difference: 4.4, p < 0.001; low-dose vs placebo LS mean fold difference: 3.5, p < 0.001. In the post hoc subgroup, the difference in AMP PD20 between the doses was statistically significant in favour of the high-dose (LS mean fold difference: 2.4, p = 0.012). Other inflammatory parameters (sputum eosinophil counts and FeNO) showed small differences and statistically non-significant changes between high- and low-dose fluticasone/formoterol. CONCLUSIONS: A significant dose-response was found between low- and high-dose fluticasone/formoterol in the post hoc subgroup (patients who received both doses), but not in the overall population, with the higher dose demonstrating a greater reduction in airway responsiveness to AMP.

Clinical asthma phenotypes in the real world: opportunities and challenges.

Asthma is a common, chronic and heterogeneous syndrome, affecting people of all ages, all races and both sexes. It may range from mild disease with barely noticeable symptoms, to very severe disease with constant symptoms that greatly hinder the life of the patient. Guidelines issued by various medical societies provide guidance on how to diagnose and manage asthmatic patients. It is now increasingly recognised that asthma management must be individualised, tailored not only to the severity of the disease but to the phenotypic characteristics of each patient. The aim of asthma treatment is control of asthma and the prevention of risk of exacerbations and fixed airflow limitation. Asthma control can be easily assessed clinically through simple screening tools such as the use of validated questionnaires and spirometry. The use of inflammatory biomarkers can be an alternative approach that, however, requires more time and resources. Asthma treatment involves the use of controllers, mainly inhaled corticosteroids and long-acting ß2-agonists, and relievers, mainly rapid-acting ß2-agonists. Controller medications reduce airway inflammation, lead to better symptom control and reduce the risk of future exacerbations. Reliever (rescue) medications alleviate symptoms and prevent exercise-induced bronchoconstriction. Treatment must be based on a "stepwise approach" in order to achieve good control of symptoms and to minimise future risks of exacerbations. That is, less treatment for mild disease, more treatment for severe, uncontrolled disease. Once good asthma control has been achieved and maintained, treatment should be stepped down. In severe asthmatics, phenotypic characterisation becomes more clinically useful and add-on treatment such as anti-immunoglobulin E monoclonal antibodies may be required. Despite our better understanding of asthma, there are still patients who will not respond to treatment and remain symptomatic. Dissemination of guidelines and national plans allowing early diagnosis of asthma as well as access to specialised primary and secondary care for asthmatic patients, personalised treatment and continuity of care may lead to excellence in care and controlled asthma for the majority of patients. Education of the patient in asthma is also very important, as in every chronic disease, as the patients live with the disease every day while they visit a healthcare professional a few times a year. Future planning for new treatments should focus on the needs of such severe asthma patients.

CXCR2 Antagonist MK-7123. A Phase 2 Proof-of-Concept Trial for Chronic Obstructive Pulmonary Disease.

RATIONALE: An antagonist (MK-7123) of the cytokine receptor CXCR2 reduces neutrophil chemotaxis and thus may alleviate airway inflammation in chronic obstructive pulmonary disease (COPD). OBJECTIVES: To assess the efficacy, safety, and tolerability of three dose levels of MK-7123, compared with placebo, in patients with moderate to severe COPD. METHODS: This 6-month, double-blind study randomized patients with moderate to severe COPD (already on standard therapy) to daily MK-7123 at 10, 30, or 50 mg or placebo. The primary endpoint was change from baseline in post-bronchodilator FEV1. MEASUREMENTS AND MAIN RESULTS: A total of 616 patients (71% male; mean age, 63 yr; 45% current smokers; baseline FEV1 [SD], 1.43 L [0.45]; mean FEV1 percent predicted, 43.9%) were randomized. Only MK-7123 50 mg led to significant improvement in FEV1 over placebo (mean difference [SE], 67 ml [32]). Reduced sputum neutrophil count was observed among the 122 patients examined; P = 0.003 (3 mo) and P = 0.092 (6 mo) (MK-7123 50 mg vs. placebo). The stratum of current smokers, but not that of nonsmokers, showed significant improvement versus placebo in FEV1 (168 ml) and time-to-first exacerbation, and showed numerical improvement in St. George's Respiratory Questionnaire for COPD score. MK-7123 caused a dose-dependent decrease in absolute neutrophil count (ANC) and reduced inflammatory biomarkers matrix metallopeptidase-9 and myeloperoxidase in plasma and sputum; ANC lower than 1.5 × 10(9)/L led to discontinuations with higher doses of MK-7123 (18% in the MK-7123 50-mg group vs. 1% in placebo). Plasma C-reactive protein and fibrinogen increased with MK-7123 treatment. Rates of infections at 6 months were similar in all groups. CONCLUSIONS: Treatment with MK-7123 50 mg versus placebo led to significant improvement in FEV1 in patients with COPD, suggesting clinically important antiinflammatory effects with CXCR2 antagonism, although dose-related discontinuations were observed because of ANC decreases with MK-7123. Greater response was observed in smokers versus ex-smokers. Clinical trial registered with www.clinicaltrials.gov (NCT 01006616).

Extrafine beclomethasone/formoterol combination via a dry powder inhaler (NEXThaler(®)) or pMDI and beclomethasone monotherapy for maintenance of asthma control in adult patients: A randomised, double-blind trial.

BACKGROUND: The fixed combination of extrafine beclomethasone dipropionate and formoterol fumarate (BDP/FF) pMDI (Foster(®)) is approved for treatment of adult asthmatic patients. In order to provide an alternative drug delivery system for BDP/FF to physicians and patients, a dry powder inhaler (NEXThaler(®)) has been developed, capable to deliver extrafine particles to the lungs and therefore improve the dosing of the drugs, especially in patients with poor hand-breath coordination. OBJECTIVE: This trial was performed to compare efficacy and safety of extrafine BDP/FF NEXThaler(®) with extrafine BDP/FF pMDI or non-extrafine BDP DPI alone in adult patients with controlled asthma. METHODS: In this 8-week randomised, double-blind, parallel-group trial, patients were randomized to receive either extrafine BDP/FF NEXThaler(®) 100/6 µg bid, extrafine BDP/FF 100/6 µg pMDI bid or non-extrafine BDP DPI 100 µg bid. The primary efficacy variable was change from baseline to the entire 8-week randomised treatment period in average pre-dose morning PEF. RESULTS: The ITT population comprised 754 patients. Extrafine BDP/FF NEXThaler(®) was non-inferior (pre-defined margin: -15 L/min) relative to extrafine BDP/FF pMDI (mean difference: -1.84; 95% CI: -6.73, 3.05) in terms of the primary efficacy variable, change from baseline in average pre-dose morning PEF. Statistical superiority of both extrafine BDP/FF formulations over non-extrafine BDP DPI was demonstrated for the primary efficacy variable (providing evidence of assays sensitivity of the trial), ACQ score and percentage of rescue medication use-free days. No significant safety signals were observed. CONCLUSION: NEXThaler(®) is an effective and well-tolerated delivery device for treatment of patients with asthma who need a regular treatment.

Longitudinal measurement of airway inflammation over one year in children and adults with intermittent asthma.

BACKGROUND: Asthma is an inflammatory disease of the airways, but in clinical practice inflammation is rarely monitored. The aim of this study was to assess the level of airway inflammation in steroid naïve adult and pediatric patients with intermittent asthma over one year. METHODS: 54 children and 50 adults with intermittent asthma (GINA step 1) were included. On up to 6 visits lung function, airway hyperresponsiveness to methacholine (PC20FEV1), sputum eosinophils and exhaled nitric oxide (FeNO) were assessed. RESULTS: 36 pediatric and 34 adult patients were able to produce at least three adequate sputum samples over the study period and were included into the analysis.In 8 children (22%) the percentage of sputum eosinophils was always below 2.5%. A higher level of eosinophils (>2.5%) was found on at least one visit in 16 (44%) and always >2.5% in 12 children (33%). In the adult group the respective numbers were 14 patients (41%) with always low (<2.5%), 17 (50%) with at least once over 2.5% and three patients (9%) were always above the threshold of 2.5% sputum eosinophils. CONCLUSION: These results demonstrate that a substantial number of children and adults with intermittent asthma under ß-agonist treatment only, have variable or persistently high levels of eosinophilic airway inflammation. Long-term studies are needed to observe the progression of asthma severity in such patient populations.

Detection of exacerbations in asthma based on electronic diary data: results from the 1-year prospective BIOAIR study.

BACKGROUND: Objective measures are required that may be used as a proxy for exacerbations in asthma. The aim was to determine the sensitivity and specificity of electronic diary data to detect severe exacerbations (SEs) of asthma. A secondary aim was to identify phenotypic variables associated with a higher risk of exacerbation. METHODS: In the BIOAIR study, 169 patients with asthma (93 severe (SA); 76 mild to moderate (MA)) recorded lung function, symptoms and medication use in electronic diaries for 1 year. Data were analysed using receiver-operator characteristics curves and related to physician-diagnosed exacerbations. Medical history and baseline clinical data were used to assess risk of exacerbation. RESULTS: Of 122 physician-diagnosed exacerbations, 104 occurred in the SA group (1.1 per patient/year), 18 in the MA group (0.2 per patient/year) and 63 were severe using American Thoracic Society/European Respiratory Society criteria. During exacerbations, peak expiratory flow (PEF) and forced expiratory volume in 1 s significantly decreased, whereas day and night symptoms significantly increased. An algorithm combining a 20% decrease in PEF or a 20% increase in day symptoms on 2 consecutive days was able to detect SEs with 65% sensitivity and 95% specificity. The strongest risk factors for SEs were low Asthma Control Questionnaire score, sputum eosinophils ≥ 3%, body mass index >25 and low quality of life (St George's Respiratory Questionnaire), with ORs between 3.61 and 2.22 (p<0.05). CONCLUSIONS: Regular electronic monitoring of PEF and asthma symptoms provides an acceptable sensitivity and specificity for the detection of SEs and may be suitable for personal internet-based monitoring of asthma control.

The novel TLR-9 agonist QbG10 shows clinical efficacy in persistent allergic asthma.

BACKGROUND: Allergen-specific TH2 responses contribute to the development of allergic asthma. Their increase may be due to a reduced early exposure to environmental pathogens, which induces a TH1 response, and thereby suppresses the allergic TH2 response. QbG10 (bacteriophage Qbeta-derived virus-like particle with CpG-motif G10 inside), a novel Toll-like receptor 9 agonist packaged into virus-like particles, was designed to stimulate the immune system toward a TH1-mediated protective response. OBJECTIVE: We examined clinical efficacy, safety, and tolerability of QbG10 with patient-reported and objective clinical outcome parameters in patients with mild-to-moderate persistent allergic asthma. METHODS: In this proof-of-concept parallel-group, double-blind, randomized trial, 63 asthmatic patients followed conversion to a standardized inhaled steroid and were treated with 7 injections of either QbG10 or placebo. Incorporating a controlled steroid withdrawal, the effects on patient-reported (day- and nighttime asthma symptoms, salbutamol usage, and 7-item-Asthma Control Questionnaire scores) and objective clinical outcome measures (FEV1, fraction of exhaled nitric oxide, and blood eosinophils) were assessed over 12 weeks (ClinicalTrials.gov number, NCT00890734). RESULTS: All patient-reported parameters improved overall between week 0 and 12 in QbG10-treated patients (n = 33) despite steroid withdrawal, compared with deteriorations observed under placebo (n = 30, P < .05). At week 12, two thirds of the QbG10-treated patients had their asthma "well controlled" (Asthma Control Questionnaire score ≤0.75) compared with one third under placebo. FEV1 had worsened to a clinically significant extent in patients on placebo, while it remained stable in QbG10 patients. Adverse events were mostly injection site reactions occurring after QbG10 administration. CONCLUSION: Treatment with QbG10 may contribute to continued asthma control during steroid reduction in patients on moderate or high-dose inhaled steroids.

Airway response to emotional stimuli in asthma: the role of the cholinergic pathway.

In asthma, airways constrict in response to emotion and stress, but underlying mechanisms, potential extrathoracic contributions, and associations with airway pathophysiology have not been elucidated. We therefore investigated the role of the cholinergic pathway in emotion-induced airway responses in patients with asthma and the association of these responses with airway pathophysiology. Patients with asthma (n=54) and healthy participants (n=25) received either 40 microg ipratropium bromide or a placebo in a double-blind double-dummy cross-over design in two laboratory sessions with experimental emotion induction. Stimuli were preevaluated films and pictures of pleasant, unpleasant, and neutral quality. Respiratory resistance and reactance at 5 and 20 Hz were measured continuously before and during presentations, together with respiration by impedance plethysmography and end-tidal PCO2 by capnometry. In addition, measures of airway inflammation (fraction of exhaled nitric oxide), airway hyperreactivity (methacholine challenge), and reversibility of obstruction were obtained. Respiratory resistance at 5 and 20 Hz increased during unpleasant stimuli in asthma patients. This response was blocked by ipratropium bromide and was not substantially associated with asthma severity, airway inflammation, hyperreactivity and reversibility, or pattern of ventilation and PCO2. Under the placebo condition, changes in resistance during unpleasant films were positively correlated with patients' reports of psychological asthma triggers. In conclusion, airway constriction to unpleasant stimuli in asthma depends on an intact cholinergic pathway, is largely due to the central airways, and is not substantially associated with other indicators of airway pathology. Its link to the perceived psychological triggers in patients' daily lives suggests a physiological basis for emotion-induced asthma.

Emotional reactivity of the airways in asthma: consistency across emotion-induction techniques and emotional qualities.

Considerable individual differences exist in asthma patients' airway responses to emotional stimuli, but little is known about the generalization of such responses across situations or states of airways constriction. Fifty-four asthma patients and 25 healthy controls viewed in two separate sessions, films and blocks of pictures from each of three emotional qualities, pleasant, unpleasant, and neutral. At the beginning of each session, patients received a placebo or anti-cholinergic bronchodilator (ipratropium bromide), respectively, in a randomized double-blind design. Respiratory resistance, reactance and impedance were recorded throughout stimulus presentations with impulse oscillometry. Resistance increases showed a moderate degree of generalization across unpleasant films and pictures, unpleasant and pleasant pictures, as well as cholinergic blockade and placebo. Thus, the intensity of airway responses to unpleasant emotional stimuli is a moderately stable characteristic of asthma patients. In addition to the central airway, peripheral and extrathoracic airways may also contribute the consistency of such responses.

Efficacy and safety of indacaterol, a new 24-hour beta2-agonist, in patients with asthma: a dose-ranging study.

BACKGROUND: Indacaterol is a new once-daily inhaled beta(2)-agonist in clinical development for asthma as a component of a fixed-dose combination with an inhaled corticosteroid. OBJECTIVES: To investigate the efficacy and safety of indacaterol in patients with chronic persistent asthma. METHODS: A total of 115 patients were randomized in a double-blind, incomplete-block cross-over design to sequences of four 7-day treatment periods (separated by 7-day washouts) with indacaterol 100, 200, 300, 400, or 600 micro g or placebo, once daily, via single-dose dry-powder inhaler. After the fourth washout, patients received 1 day of open-label formoterol 12 mu g twice daily. Forced expiratory volume in 1 second (FEV(1)) was measured for 24 hours post-dose on days 1 and 7. RESULTS: For standardized (with respect to time) FEV(1) area under the curve at 22 to 24 hours (AUC(22-24h)) on day 1, indacaterol doses >or=200 micro g were superior to placebo (p < 0.05) and similar or greater than formoterol 12 micro g twice daily. By day 7, mean differences from placebo in FEV(1) standardized AUC(22-24h) were 0.08, 0.16, 0.15, 0.11, and 0.16 L for indacaterol 100, 200, 300, 400, and 600 micro g, respectively (all p < 0.05 vs. placebo). Mean FEV(1) for indacaterol doses >or= 200 micro g on day 7 was higher than placebo (p < 0.05) pre-dose and at all post-dose time points. AEs were generally mild in severity; no serious AEs occurred. No clinically meaningful differences were observed between treatments in any safety assessments. CONCLUSIONS: Once-daily indacaterol demonstrated sustained 24-hour bronchodilator efficacy, with similar efficacy on days 1 and 7, and was generally well tolerated.

Psychological triggers and hyperventilation symptoms in asthma.

BACKGROUND: Anecdotal accounts have identified hyperventilation as one route through which psychological factors can trigger bronchoconstriction. However, little is known about the empirical association between psychological and other trigger factors and hyperventilation in asthma exacerbations. OBJECTIVE: To study the cross-sectional association between perceived triggers and hyperventilation symptoms in 1 British and 1 German sample of patients with asthma who were recruited from the community and from primary care clinics. METHOD: Patients completed relevant language versions of the Asthma Trigger Inventory and the Asthma Symptom Checklist. RESULTS: After controlling for demographics and asthma severity, perceived asthma triggers measured by subscales of the Asthma Trigger Inventory explained 12.5% to 37.3% of the variance in Asthma Symptom Checklist hyperventilation-hypocapnia symptoms. Psychological triggers accounted for 10.6% to 26.7% of the variance alone and 4.3% to 11.0% of the variance over and above other trigger factors. In contrast, perceived animal and pollen allergen triggers did not contribute unique variance to the hyperventilation symptom report. Psychological triggers did not explain variance in classic airway obstruction symptoms, thus arguing against a general bias toward inflated symptom reports in patients with psychologically induced asthma. CONCLUSION: Differences in perceived asthma triggers are substantially associated with hyperventilation symptoms, and patients with more frequent psychological triggers also tend to report that they experience more hyperventilation symptoms during their asthma symptom episodes.

Stress effects on lung function in asthma are mediated by changes in airway inflammation.

OBJECTIVE: To examine the association of changes in current negative mood and long-term daily hassles with changes in lung function and airway inflammation in patients suffering from asthma and in healthy controls. Associations between psychological factors and asthma symptoms have been documented, but the relationship between airway inflammation and psychological factors has been largely unexplored. METHOD: Data were analyzed from 46 asthma patients and 25 controls who completed questionnaires on current mood and daily hassles at two assessments 3 months apart. Lung function was measured by spirometry (forced expiratory volume in the first second (FEV(1))) and airway inflammation by the fraction of nitric oxide in exhaled air (FeNO). Regression analyses controlling for allergen load and air pollution (ozone) were calculated to study the association between changes in psychological factors and changes in lung function and airway inflammation, and to examine the mediational role of airway inflammation in the stress-lung function association. RESULTS: In patients with asthma, increases in negative affect were associated with decreases in FEV(1) and increases in FeNO. For daily hassles, a reverse pattern of associations was found, with decreases in daily hassles linked to decreases in FEV(1) and increases in FeNO. Mediation analyses showed that FeNO was a significant mediator of the association of both negative affect and daily hassles with lung function changes. No significant associations were found for healthy controls. CONCLUSION: Psychological variables are consistently associated with spirometric lung function and airway inflammation in asthma patients. For asthma patients, effects of acute negative affect must be distinguished from more chronic distress due to daily hassles.

Perceived triggers of asthma: evaluation of a German version of the Asthma Trigger Inventory.

BACKGROUND AND OBJECTIVE: Patients' perception of asthma triggers has been explored in a largely unstructured fashion in the past. Therefore, we developed the Asthma Trigger Inventory (ATI), a questionnaire that allows for a psychometrically valid measurement of patients' perceived asthma triggers. Here we evaluate a German language version of the ATI and studied the relationship of subscales with self-reported health status, health care use, psychopathology, and results of allergy skin testing. METHOD: Data were obtained from 370 asthma patients recruited from the community, primary care, and in-patient asthma treatment and education. RESULTS: Analysis revealed a five-factor structure that largely confirmed results with the English original. Reliability was good to satisfactory (Cronbach's alpha=0.77-0.89) for allergy, exercise, air pollution/irritants, infection, and psychological trigger subscales. In hierarchical regression analysis adjusting for demographics and asthma severity, asthma patients with stronger non-allergic triggers showed less physical and mental well-being and more asthma-related health care use. Psychological triggers showed unique associations with anxious and depressed mood. Pollen and animal allergen scores of the ATI were significantly related to skin test results for relevant allergens. Non-allergic but not allergic triggers showed substantial associations with asthma control. CONCLUSION: The German version of the ATI reliably measures asthma patients' trigger perceptions. Non-specific asthma triggers exert a greater burden on patients' well-being and primary health care use.