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1.  Efficacy of Tiotropium + Olodaterol in Patients with Chronic Obstructive Pulmonary Disease by Initial Disease Severity and Treatment Intensity: A Post Hoc Analysis 
Advances in Therapy  2015;32(6):523-536.
Introduction
The once-daily long-acting muscarinic antagonist (LAMA) tiotropium and once-daily long-acting β2-agonist (LABA) olodaterol have been studied as a once-daily fixed-dose combination (FDC) in patients with chronic obstructive pulmonary disease (COPD). Two large, 52-week, double-blind, parallel-group studies in patients with moderate–very severe COPD demonstrated that tiotropium + olodaterol significantly improved lung function and symptoms versus the monocomponents. This post hoc analysis determined effects on lung function by prior LAMA or LABA maintenance treatment and initial disease severity.
Methods
5162 patients were randomized and treated with olodaterol 5 µg, tiotropium 2.5 µg, tiotropium 5 µg, tiotropium + olodaterol 2.5/5 µg, or tiotropium + olodaterol 5/5 µg (all once daily via Respimat® inhaler). Primary efficacy (lung-function) end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0–3) and trough FEV1 responses (i.e., change from baseline). Pooled data are presented for the following subgroups: prior maintenance treatment with LAMA or LABA, Global initiative for chronic Obstructive Lung Disease (GOLD) 2 (predicted FEV1 50% to <80%) and 3 (30% to <50%)/4 (<30%), sex, age, and prior use of inhaled corticosteroids.
Results
Tiotropium + olodaterol FDC improved lung function over the monocomponents in patients with GOLD 2 and 3–4 disease, irrespective of prior LAMA or LABA maintenance therapy; most comparisons between FDCs and their respective monocomponents were statistically significant (P < 0.05). FEV1 AUC0–3 and trough FEV1 responses for the individual treatments were generally greater in patients with less severe COPD at baseline.
Conclusions
Tiotropium + olodaterol 5/5 µg significantly improved FEV1 AUC0–3 and trough FEV1 in all GOLD severity groups compared to olodaterol 5 µg and tiotropium 5 µg alone, irrespective of whether patients had received prior LAMA or LABA maintenance treatment. Improvements from baseline in lung function were generally greater in patients with less severe disease.
Funding
Boehringer Ingelheim.
Trial registration: ClinicalTrials.gov numbers, NCT01431274 and NCT01431287.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-015-0218-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s12325-015-0218-0
PMCID: PMC4486785  PMID: 26112656
Bronchodilator; COPD; Disease severity; Lung function; Subgroup; Tiotropium + olodaterol
2.  Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases 
Allergo Journal International  2014;23(8):282-319.
Summary
The present guideline (S2k) on allergen-specific immunotherapy (AIT) was established by the German, Austrian and Swiss professional associations for allergy in consensus with the scientific specialist societies and professional associations in the fields of otolaryngology, dermatology and venereology, pediatric and adolescent medicine, pneumology as well as a German patient organization (German Allergy and Asthma Association; Deutscher Allergie- und Asthmabund, DAAB) according to the criteria of the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF).
AIT is a therapy with disease-modifying effects. By administering allergen extracts, specific blocking antibodies, toler-ance-inducing cells and mediators are activated. These prevent further exacerbation of the allergen-triggered immune response, block the specific immune response and attenuate the inflammatory response in tissue.
Products for SCIT or SLIT cannot be compared at present due to their heterogeneous composition, nor can allergen concentrations given by different manufacturers be compared meaningfully due to the varying methods used to measure their active ingredients. Non-modified allergens are used for SCIT in the form of aqueous or physically adsorbed (depot) extracts, as well as chemically modified allergens (allergoids) as depot extracts. Allergen extracts for SLIT are used in the form of aqueous solutions or tablets.
The clinical efficacy of AIT is measured using various scores as primary and secondary study endpoints. The EMA stipulates combined symptom and medication scores as primary endpoint. A harmonization of clinical endpoints, e. g., by using the combined symptom and medication scores (CSMS) recommended by the EAACI, is desirable in the future in order to permit the comparison of results from different studies. The current CONSORT recommendations from the ARIA/GA2LEN group specify standards for the evaluation, presentation and publication of study results.
According to the Therapy allergen ordinance (TAV), preparations containing common allergen sources (pollen from grasses, birch, alder, hazel, house dust mites, as well as bee and wasp venom) need a marketing authorization in Germany. During the marketing authorization process, these preparations are examined regarding quality, safety and efficacy. In the opinion of the authors, authorized allergen preparations with documented efficacy and safety, or preparations tradeable under the TAV for which efficacy and safety have already been documented in clinical trials meeting WAO or EMA standards, should be preferentially used. Individual formulations (NPP) enable the prescription of rare allergen sources (e.g., pollen from ash, mugwort or ambrosia, mold Alternaria, animal allergens) for specific immunotherapy. Mixing these allergens with TAV allergens is not permitted.
Allergic rhinitis and its associated co-morbidities (e. g., bronchial asthma) generate substantial direct and indirect costs. Treatment options, in particular AIT, are therefore evaluated using cost-benefit and cost-effectiveness analyses. From a long-term perspective, AIT is considered to be significantly more cost effective in allergic rhinitis and allergic asthma than pharmacotherapy, but is heavily dependent on patient compliance.
Meta-analyses provide unequivocal evidence of the efficacy of SCIT and SLIT for certain allergen sources and age groups. Data from controlled studies differ in terms of scope, quality and dosing regimens and require product-specific evaluation. Therefore, evaluating individual preparations according to clearly defined criteria is recommended. A broad transfer of the efficacy of certain preparations to all preparations administered in the same way is not endorsed. The website of the German Society for Allergology and Clinical Immunology (www.dgaki.de/leitlinien/s2k-leitlinie-sit; DGAKI: Deutsche Gesellschaft für Allergologie und klinische Immunologie) provides tables with specific information on available products for AIT in Germany, Switzerland and Austria. The tables contain the number of clinical studies per product in adults and children, the year of market authorization, underlying scoring systems, number of randomized and analyzed subjects and the method of evaluation (ITT, FAS, PP), separately given for grass pollen, birch pollen and house dust mite allergens, and the status of approval for the conduct of clinical studies with these products.
Strong evidence of the efficacy of SCIT in pollen allergy-induced allergic rhinoconjunctivitis in adulthood is well-documented in numerous trials and, in childhood and adolescence, in a few trials. Efficacy in house dust mite allergy is documented by a number of controlled trials in adults and few controlled trials in children. Only a few controlled trials, independent of age, are available for mold allergy (in particular Alternaria). With regard to animal dander allergies (primarily to cat allergens), only small studies, some with methodological deficiencies are available. Only a moderate and inconsistent therapeutic effect in atopic dermatitis has been observed in the quite heterogeneous studies conducted to date. SCIT has been well investigated for individual preparations in controlled bronchial asthma as defined by the Global Initiative for Asthma (GINA) 2007 and intermittent and mild persistent asthma (GINA 2005) and it is recommended as a treatment option, in addition to allergen avoidance and pharmacotherapy, provided there is a clear causal link between respiratory symptoms and the relevant allergen.
The efficacy of SLIT in grass pollen-induced allergic rhinoconjunctivitis is extensively documented in adults and children, whilst its efficacy in tree pollen allergy has only been shown in adults. New controlled trials (some with high patient numbers) on house dust mite allergy provide evidence of efficacy of SLIT in adults.
Compared with allergic rhinoconjunctivitis, there are only few studies on the efficacy of SLIT in allergic asthma. In this context, newer studies show an efficacy for SLIT on asthma symptoms in the subgroup of grass pollen allergic children, adolescents and adults with asthma and efficacy in primary house dust mite allergy-induced asthma in adolescents aged from 14 years and in adults.
Aspects of secondary prevention, in particular the reduction of new sensitizations and reduced asthma risk, are important rationales for choosing to initiate treatment early in childhood and adolescence. In this context, those products for which the appropriate effects have been demonstrated should be considered.
SCIT or SLIT with pollen or mite allergens can be performed in patients with allergic rhinoconjunctivitis using allergen extracts that have been proven to be effective in at least one double-blind placebo-controlled (DBPC) study. At present, clinical trials are underway for the indication in asthma due to house dust mite allergy, some of the results of which have already been published, whilst others are still awaited (see the DGAKI table “Approved/potentially completed studies” via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit (according to www.clinicaltrialsregister.eu)). When establishing the indication for AIT, factors that favour clinical efficacy should be taken into consideration. Differences between SCIT and SLIT are to be considered primarily in terms of contraindications. In individual cases, AIT may be justifiably indicated despite the presence of contraindications.
SCIT injections and the initiation of SLIT are performed by a physician experienced in this type of treatment and who is able to administer emergency treatment in the case of an allergic reaction. Patients must be fully informed about the procedure and risks of possible adverse events, and the details of this process must be documented (see “Treatment information sheet”; available as a handout via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit). Treatment should be performed according to the manufacturer‘s product information leaflet. In cases where AIT is to be performed or continued by a different physician to the one who established the indication, close cooperation is required in order to ensure that treatment is implemented consistently and at low risk. In general, it is recommended that SCIT and SLIT should only be performed using preparations for which adequate proof of efficacy is available from clinical trials.
Treatment adherence among AIT patients is lower than assumed by physicians, irrespective of the form of administration. Clearly, adherence is of vital importance for treatment success. Improving AIT adherence is one of the most important future goals, in order to ensure efficacy of the therapy.
Severe, potentially life-threatening systemic reactions during SCIT are possible, but – providing all safety measures are adhered to – these events are very rare. Most adverse events are mild to moderate and can be treated well.
Dose-dependent adverse local reactions occur frequently in the mouth and throat in SLIT. Systemic reactions have been described in SLIT, but are seen far less often than with SCIT. In terms of anaphylaxis and other severe systemic reactions, SLIT has a better safety profile than SCIT.
The risk and effects of adverse systemic reactions in the setting of AIT can be effectively reduced by training of personnel, adhering to safety standards and prompt use of emergency measures, including early administration of i. m. epinephrine. Details on the acute management of anaphylactic reactions can be found in the current S2 guideline on anaphylaxis issued by the AWMF (S2-AWMF-LL Registry Number 061-025).
AIT is undergoing some innovative developments in many areas (e. g., allergen characterization, new administration routes, adjuvants, faster and safer dose escalation protocols), some of which are already being investigated in clinical trials.
Cite this as Pfaar O, Bachert C, Bufe A, Buhl R, Ebner C, Eng P, Friedrichs F, Fuchs T, Hamelmann E, Hartwig-Bade D, Hering T, Huttegger I, Jung K, Klimek L, Kopp MV, Merk H, Rabe U, Saloga J, Schmid-Grendelmeier P, Schuster A, Schwerk N, Sitter H, Umpfenbach U, Wedi B, Wöhrl S, Worm M, Kleine-Tebbe J. Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases – S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the Austrian Society for Allergy and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Pneumology (GPP), the German Respiratory Society (DGP), the German Association of ENT Surgeons (BV-HNO), the Professional Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of Pulmonologists (BDP) and the German Dermatologists Association (BVDD). Allergo J Int 2014;23:282–319
doi:10.1007/s40629-014-0032-2
PMCID: PMC4479478  PMID: 26120539
allergen-specific immunotherapy; AIT; Hyposensitization; guideline; allergen; allergen extract; allergic disease; allergic rhinitis; allergic asthma
3.  Efficacy and safety of once-daily QVA149 compared with the free combination of once-daily tiotropium plus twice-daily formoterol in patients with moderate-to-severe COPD (QUANTIFY): a randomised, non-inferiority study 
Thorax  2015;70(4):311-319.
Background
QVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD. The QUANTIFY study compared QVA149 with a free-dose bronchodilator combination of tiotropium plus formoterol (TIO+FOR) in improving health-related quality of life (HRQoL) of patients with COPD.
Methods
This multicentre, blinded, triple-dummy, parallel-group, non-inferiority study randomised patients aged ≥40 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥30% to <80% predicted) to QVA149 110/50 µg o.d. or TIO 18 µg o.d.+ FOR 12 µg twice daily (1:1) for 26 weeks. The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George's Respiratory Questionnaire-COPD (SGRQ-C). The prespecified non-inferiority margin was 4 units. Secondary endpoints included Transition Dyspnoea Index (TDI) score, pre-dose FEV1, forced vital capacity (FVC) and safety.
Results
Of the 934 patients randomised (QVA149=476 and TIO+FOR=458), 87.9% completed the study. At week 26, non-inferiority was met for SGRQ-C (QVA149 vs TIO+FOR; difference: –0.69 units; 95% CI −2.31 to 0.92; p=0.399). A significantly higher percentage of patients achieved a clinically relevant ≥1 point improvement in TDI total score with QVA149 (49.6%) versus TIO+FOR (42.4%; p=0.033). QVA149 significantly increased pre-dose FEV1 (+68 mL, 95% CI 37 mL to 100 mL; p<0.001) and FVC (+74 mL, 95% CI 24 mL to 125 mL; p=0.004) compared with TIO+FOR at week 26. The incidence of adverse events was comparable between both treatments (QVA149=43.7% and TIO+FOR=42.6%).
Conclusions
QVA149 is non-inferior to TIO+FOR in improving HRQoL, with clinically meaningful and significant improvements in breathlessness and lung function in patients with COPD.
Trial registration number
NCT01120717.
doi:10.1136/thoraxjnl-2014-206345
PMCID: PMC4392202  PMID: 25677679
COPD Pharmacology
4.  Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4) 
The European Respiratory Journal  2015;45(4):969-979.
Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials.
Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0–3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks.
In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0–3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg. Incidence of adverse events was comparable between the FDCs and the mono-components.
These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.
Lung function and symptomatic benefits of daily tiotropium+olodaterol fixed-dose combination in moderate to very severe COPD http://ow.ly/DIKiY
doi:10.1183/09031936.00136014
PMCID: PMC4391658  PMID: 25573406
5.  The Prospective Non-Interventional DACCORD Study in the National COPD Registry in Germany: design and methods 
Background
A variety of large randomized controlled trials (RCT’s) evaluating pharmacotherapy in chronic obstructive pulmonary disease (COPD) patients does exist. One of the drugs that has been tested is the new long-acting anticholinergic glycopyrronium bromide.
Methods
As the generalizability of results from RCT’s is questionable we designed a longitudinal, prospective non-interventional study (DACCORD) of two years duration plus two years extension with at least 6000 participants in approximately 500 primary and secondary care practices in Germany (within the new established COPD National Prospective Registry), to assess patient reported outcomes (PRO’s), lung function, adherence and drug safety. To circumvent the hurdle of inappropriate COPD diagnosis in a non-interventional trial, patients have to fulfill the inclusion criteria of the COPD disease management program (DMP) of the German statutory health insurances. Patient management should follow the German national COPD guidelines, which are based on Global Initiative for Chronic Obstructive Lung Disease 2007 (GOLD) report. Labels of prescribed drugs should also be taken into account. Patients received treatment as part of their standard care: at the discretion of the investigator patients were included in one of two arms. A: standard care with glycopyrronium containing regimen, and arm B: standard care without glycopyrronium.
Discussion
For 2016 we expect important results regarding longitudinal development of PRO’s including exacerbations, lung function, adherence and side effects. We also investigate applicability of the new GOLD staging system in usual care. Data on diagnostic and treatment modalities in current German primary and secondary care, as well as pharmaco-economic data will be generated.
Trial registration
1. German Register for non-interventional studies: http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb.
2. EMA EnCePP http://www.encepp.eu/.
doi:10.1186/1471-2466-15-2
PMCID: PMC4417326  PMID: 25578330
COPD; Non-interventional study; Out-patient; Pharmacological therapy; Register
6.  Severe and uncontrolled adult asthma is associated with vitamin D insufficiency and deficiency 
Respiratory Research  2013;14(1):25.
Background
Vitamin D has effects on the innate and adaptive immune system. In asthmatic children low vitamin D levels are associated with poor asthma control, reduced lung function, increased medication intake, and exacerbations. Little is known about vitamin D in adult asthma patients or its association with asthma severity and control.
Methods
Clinical parameters of asthma control and 25-hydroxyvitamin D (25(OH)D) serum concentrations were evaluated in 280 adult asthma patients (mean ± SD: 45.0 ± 13.8 yrs., 40% male, FEV1 74.9 ± 23.4%, 55% severe, 51% uncontrolled).
Results
25(OH)D concentrations in adult asthmatics were low (25.6 ±11.8 ng/ml) and vitamin D insufficiency or deficiency (vitamin D <30 ng/ml) was common (67%). 25(OH)D levels were related to asthma severity (intermittent: 31.1 ± 13.0 ng/ml, mild: 27.3 ± 11.9 ng/ml, moderate: 26.5 ± 12.0 ng/ml, severe: 24.0 ± 11.8 ng/ml, p = 0.046) and control (controlled: 29.5 ± 12.5 ng/ml, partly controlled 25.9 ± 10.8 ng/ml, uncontrolled: 24.2 ± 11.8 ng/ml, p = 0.030). The frequency of vitamin D insufficiency or deficiency was significantly higher in patients with severe or uncontrolled asthma and was associated with a lower FEV1 (vitamin D <30 vs. ≥30 ng/ml 2.3 ± 0.9 L vs. 2.7 ± 1.0 L, p = 0.006), higher levels of exhaled NO (45 ± 46 ppb vs. 31 ± 37 ppb, p = 0.023), a higher BMI (28.3 ± 6.2 vs. 25.1 ± 3.9, p < 0.001), and sputum eosinophilia (5.1 ± 11.8% vs. 0.5 ± 1.0%, p = 0.005). The use of oral corticosteroids or sputum eosinophilia was associated with a 20% or 40% higher risk of vitamin D insufficiency or deficiency.
Conclusions
25(OH)D levels below 30 ng/ml are common in adult asthma and most pronounced in patients with severe and/or uncontrolled asthma, supporting the hypothesis that improving suboptimal vitamin D status might be effective in prevention and treatment of asthma.
doi:10.1186/1465-9921-14-25
PMCID: PMC3648461  PMID: 23432854
Asthma; BMI; Corticosteroids; Eosinophils; Vitamin D
7.  Profile of glycopyrronium for once-daily treatment of moderate-to-severe COPD 
Bronchodilators are central in the symptomatic management of chronic obstructive pulmonary disease (COPD). Long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) are the main classes of long-acting bronchodilators. To date, tiotropium is the only once-daily LAMA available for the treatment of COPD. Glycopyrronium is a novel LAMA, currently in development for COPD. Phase II studies have shown that glycopyrronium 50 μg once daily provides clinically significant 24-hour bronchodilation with a rapid onset of action, which is faster than that of tiotropium, and a favorable safety and tolerability profile. The Phase III GLycopyrronium bromide in COPD airWays (GLOW) program has now confirmed the long-term efficacy and tolerability of glycopyrronium 50 μg once daily. The three studies included in this program have further shown that the effect of glycopyrronium versus placebo is similar to that of tiotropium in reducing dyspnea and the risk of exacerbations, as well as improving lung function, exercise tolerance, and health status in patients with COPD. The safety profile of glycopyrronium is also similar to that of tiotropium in terms of overall incidence of adverse events and muscarinic side effects. Glycopyrronium could be an alternative choice to tiotropium, and like tiotropium, has the potential to be used as a monotherapy or combination therapy. Phase II studies have shown that a fixed-dose combination of glycopyrronium and the 24-hour LABA indacaterol, produces rapid and sustained bronchodilation compared with indacaterol monotherapy in patients with COPD. Phase III studies are currently ongoing to assess the long-term efficacy and safety of this combination.
doi:10.2147/COPD.S36001
PMCID: PMC3484531  PMID: 23118536
NVA237; glycopyrronium; chronic obstructive pulmonary disease; once daily; muscarinic antagonist
8.  The effect of budesonide/formoterol maintenance and reliever therapy on the risk of severe asthma exacerbations following episodes of high reliever use: an exploratory analysis of two randomised, controlled studies with comparisons to standard therapy 
Respiratory Research  2012;13(1):59.
Background
Divergent strategies have emerged for the management of severe asthma. One strategy utilises high and fixed doses of maintenance treatment, usually inhaled corticosteroid/long-acting β2-agonist (ICS/LABA), supplemented by a short-acting β2-agonist (SABA) as needed. Alternatively, budesonide/formoterol is used as both maintenance and reliever therapy. The latter is superior to fixed-dose treatment in reducing severe exacerbations while achieving similar or better asthma control in other regards. Exacerbations may be reduced by the use of budesonide/formoterol as reliever medication during periods of unstable asthma. We examined the risk of a severe exacerbation in the period after a single day with high reliever use.
Methods
Episodes of high reliever use were quantified and exacerbations occurring post-index day with these episodes were examined post hoc in two double-blind studies comparing the efficacy and safety of budesonide/formoterol maintenance and reliever therapy (Symbicort SMART™, Turbuhaler®) 160/4.5 μg twice daily plus as needed with similar or higher maintenance doses of ICS/LABA plus SABA or formoterol.
Results
Budesonide/formoterol maintenance and reliever therapy significantly reduced the risk of episodes of high reliever use (>6 inhalations/day) vs. all alternative ICS/LABA regimens. With conventional fixed-dose treatment the need for exacerbation treatment within 21 days ranged from 6.0–10.1% of days post-index for all regimens compared with 2.5–3.4% of days with budesonide/formoterol maintenance and reliever therapy.
Conclusions
Budesonide/formoterol maintenance and reliever therapy reduces the incidence of high reliever episodes and the exacerbation burden immediately following these episodes vs. alternative ICS/LABA plus SABA regimens at up to double the maintenance dose of ICS.
Trial registration
These studies do not have registration numbers as they were conducted before clinical trial registration was required
doi:10.1186/1465-9921-13-59
PMCID: PMC3561645  PMID: 22816878
Asthma; Asthma in primary care
9.  Guideline-based survey of outpatient COPD management by pulmonary specialists in Germany 
Background
Little is known about the role of guidelines for the practical management of chronic obstructive pulmonary disease (COPD) by office-based pulmonary specialists. The aim of this study was to assess their outpatient management in relation to current guideline recommendations for COPD.
Methods
A nationwide prospective cross-sectional COPD questionnaire survey in the form of a multiple-choice questionnaire was sent to 1000 office-based respiratory specialists in Germany. The product-neutral questions focused on routine COPD management and were based on current national and international COPD guideline recommendations being consistent in severity classification and treatment recommendations.
Results
A total of 590 pulmonary specialists (59%) participated in the survey. Body plethysmography was considered the standard for diagnosis (65.9%), followed by spirometry (32%). Most respondents were able to cite the correct spirometric criteria for classifying moderate (87%) to very severe COPD (77%). A quarter of the respondents equated the World Health Organization (WHO) definition of chronic bronchitis with COPD. Notably, most participants preferred the updated national COPD guidelines (51.4%) to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (40.2%). Improvement of functional exercise capacity and quality of life were considered the two most relevant treatment goals; whereas impact on mortality was secondary. Treatment of COPD largely complied with the guidelines. However, a significant percentage of the pulmonary specialists differed in their assessment of the benefits of various therapeutic measures from evidence-based results. Referral for pulmonary rehabilitation was uncommon, regardless of the severity of COPD.
Conclusion
The findings of this large national survey suggest that most pulmonary specialists adhere to the current COPD guideline recommendations in daily practice. However, physicians’ knowledge of guidelines is not sufficient as the sole benchmark when assessing their implementation in day-to-day practice. Necessary changes in the health care system must include more effective ways to transfer knowledge to clinical practice and to give access to interventions of proven clinical benefit.
doi:10.2147/COPD.S27887
PMCID: PMC3282602  PMID: 22371651
pulmonary rehabilitation; survey; GOLD; clinical outcomes; therapy; diagnosis
10.  IL-22 Is Produced by Innate Lymphoid Cells and Limits Inflammation in Allergic Airway Disease 
PLoS ONE  2011;6(7):e21799.
Interleukin (IL)-22 is an effector cytokine, which acts primarily on epithelial cells in the skin, gut, liver and lung. Both pro- and anti-inflammatory properties have been reported for IL-22 depending on the tissue and disease model. In a murine model of allergic airway inflammation, we found that IL-22 is predominantly produced by innate lymphoid cells in the inflamed lungs, rather than TH cells. To determine the impact of IL-22 on airway inflammation, we used allergen-sensitized IL-22-deficient mice and found that they suffer from significantly higher airway hyperreactivity upon airway challenge. IL-22-deficiency led to increased eosinophil infiltration lymphocyte invasion and production of CCL17 (TARC), IL-5 and IL-13 in the lung. Mice treated with IL-22 before antigen challenge displayed reduced expression of CCL17 and IL-13 and significant amelioration of airway constriction and inflammation. We conclude that innate IL-22 limits airway inflammation, tissue damage and clinical decline in allergic lung disease.
doi:10.1371/journal.pone.0021799
PMCID: PMC3138740  PMID: 21789181
11.  Overall asthma control achieved with budesonide/formoterol maintenance and reliever therapy for patients on different treatment steps 
Respiratory Research  2011;12(1):38.
Background
Adjusting medication for uncontrolled asthma involves selecting one of several options from the same or a higher treatment step outlined in asthma guidelines. We examined the relative benefit of introducing budesonide/formoterol (BUD/FORM) maintenance and reliever therapy (Symbicort SMART® Turbuhaler®) in patients previously prescribed treatments from Global Initiative for Asthma (GINA) Steps 2, 3 or 4.
Methods
This is a post hoc analysis of the results of five large clinical trials (>12000 patients) comparing BUD/FORM maintenance and reliever therapy with other treatments categorised by treatment step at study entry. Both current clinical asthma control during the last week of treatment and exacerbations during the study were examined.
Results
At each GINA treatment step, the proportion of patients achieving target levels of current clinical control were similar or higher with BUD/FORM maintenance and reliever therapy compared with the same or a higher fixed maintenance dose of inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) (plus short-acting β2-agonist [SABA] as reliever), and rates of exacerbations were lower at all treatment steps in BUD/FORM maintenance and reliever therapy versus same maintenance dose ICS/LABA (P < 0.01) and at treatment Step 4 versus higher maintenance dose ICS/LABA (P < 0.001). BUD/FORM maintenance and reliever therapy also achieved significantly higher rates of current clinical control and significantly lower exacerbation rates at most treatment steps compared with a higher maintenance dose ICS + SABA (Steps 2-4 for control and Steps 3 and 4 for exacerbations). With all treatments, the proportion of patients achieving current clinical control was lower with increasing treatment steps.
Conclusions
BUD/FORM maintenance and reliever therapy may be a preferable option for patients on Steps 2 to 4 of asthma guidelines requiring a more effective treatment and, compared with other fixed dose alternatives, is most effective in the higher treatment steps.
doi:10.1186/1465-9921-12-38
PMCID: PMC3082240  PMID: 21463522
12.  Outcome measures in chronic obstructive pulmonary disease (COPD): strengths and limitations 
Respiratory Research  2010;11(1):79.
Current methods for assessing clinical outcomes in COPD mainly rely on physiological tests combined with the use of questionnaires. The present review considers commonly used outcome measures such as lung function, health status, exercise capacity and physical activity, dyspnoea, exacerbations, the multi-dimensional BODE score, and mortality. Based on current published data, we provide a concise overview of the principles, strengths and weaknesses, and discuss open questions related to each methodology. Reviewed is the current set of markers for measuring clinically relevant outcomes with particular emphasis on their limitations and opportunities that should be recognized when assessing and interpreting their use in clinical trials of COPD.
doi:10.1186/1465-9921-11-79
PMCID: PMC2902430  PMID: 20565728
13.  Lung function in idiopathic pulmonary fibrosis - extended analyses of the IFIGENIA trial 
Respiratory Research  2009;10(1):101.
Background
The randomized placebo-controlled IFIGENIA-trial demonstrated that therapy with high-dose N-acetylcysteine (NAC) given for one year, added to prednisone and azathioprine, significantly ameliorates (i.e. slows down) disease progression in terms of vital capacity (VC) (+9%) and diffusing capacity (DLco) (+24%) in idiopathic pulmonary fibrosis (IPF). To better understand the clinical implications of these findings we performed additional, explorative analyses of the IFGENIA data set.
Methods
We analysed effects of NAC on VC, DLco, a composite physiologic index (CPI), and mortality in the 155 study-patients.
Results
In trial completers the functional indices did not change significantly with NAC, whereas most indices deteriorated with placebo; in non-completers the majority of indices worsened but decline was generally less pronounced in most indices with NAC than with placebo. Most categorical analyses of VC, DLco and CPI also showed favourable changes with NAC. The effects of NAC on VC, DLco and CPI were significantly better if the baseline CPI was 50 points or lower.
Conclusion
This descriptive analysis confirms and extends the favourable effects of NAC on lung function in IPF and emphasizes the usefulness of VC, DLco, and the CPI for the evaluation of a therapeutic effect. Most importantly, less progressed disease as indicated by a CPI of 50 points or lower at baseline was more responsive to therapy in this study.
Trial Registration
Registered at http://www.ClinicalTrials.gov; number NCT00639496.
doi:10.1186/1465-9921-10-101
PMCID: PMC2774307  PMID: 19860915
14.  Soluble Triggering Receptor Expressed on Myeloid Cells 1 Is Released in Patients with Stable Chronic Obstructive Pulmonary Disease 
Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a systemic disease that is associated with increased serum levels of markers of systemic inflammation. The triggering receptor expressed on myeloid cells 1 (TREM-1) is a recently identified activating receptor on neutrophils, monocytes, and macrophage subsets. TREM-1 expression is upregulated by microbial products such as the toll-like receptor ligand lipoteichoic acid of Gram-positive or lipopolysaccharides of Gram-negative bacteria. In the present study, sera from 12 COPD patients (GOLD stages I–IV, FEV1 51 ± 6%) and 10 healthy individuals were retrospectively analyzed for soluble TREM-1 (sTREM-1) using a newly developed ELISA. In healthy subjects, sTREM-1 levels were low (median 0.25 ng/mL, range 0–5.9 ng/mL). In contrast, levels of sTREM-1 in sera of COPD patients were significantly increased (median 11.68 ng/mL, range 6.2–41.9 ng/mL, P<.05). Furthermore, serum levels of sTREM-1 showed a significant negative correlation with lung function impairment. In summary, serum concentrations of sTREM-1 are increased in patients with COPD. Prospective studies are warranted to evaluate the relevance of sTREM-1 as a potential marker of the disease in patients with COPD.
doi:10.1155/2007/52040
PMCID: PMC2246041  PMID: 18317529
15.  Against all odds: anti-IgE for intrinsic asthma? 
Thorax  2013;69(1):94-96.
For many years, pathogenetic concepts and the results of clinical trials supported the view that anti-IgE treatment is specifically effective in allergic asthma. However, there is now growing clinical and mechanistic evidence suggesting that treatment with the anti-IgE antibody omalizumab can be effective in patients with intrinsic asthma. Therefore, large and well-controlled clinical trials with anti-IgE are urgently warranted in patients with intrinsic asthma. In addition, there is a need to find new biomarkers which can identify patients with asthma who respond to anti-IgE treatment.
doi:10.1136/thoraxjnl-2013-203738
PMCID: PMC3888607  PMID: 23709757
Asthma; Asthma Mechanisms; Asthma Pharmacology

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