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1.  Bronchodilator response of advanced lung function parameters depending on COPD severity 
COPD is defined as partly irreversible airflow obstruction. The response pattern of bronchodilators has not been followed in advanced lung function parameters.
The aim of this study was to investigate bronchodilator response pattern in advanced lung function parameters in a continuous fashion along forced expiratory volume in 1 second (FEV1) percent predicted (%p) in COPD patients and controls.
Patients and methods
Eighty-one smokers/ex-smokers (41 controls and 40 COPD) performed spirometry, body plethysmography, impulse oscillometry and single-breath helium dilution carbon monoxide diffusion at baseline, after salbutamol inhalation and then after an additional inhalation of ipratropium.
Most pulmonary function parameters showed a linear increase in response to decreased FEV1%p. The subjects were divided into groups of FEV1%p <65 and >65, and the findings from continuous analysis were verified. The exceptions to this linear response were inspiratory capacity (IC), forced vital capacity (FVC), FEV1/FVC and expiratory resistance (Rex), which showed a segmented response relationship to FEV1%p. IC and FVC, with break points (BP) of 57 and 58 FEV1%p respectively, showed no response above, but an incresed slope below the BP. In addition, in patients with FEV1%p <65 and >65, response of FEV1%p did not correlate to response of volume parameters.
Response of several advanced lung function parameters differs depending on patients’ baseline FEV1%p, and specifically response of volume parameters is most pronounced in COPD patients with FEV1%p <65. Volume and resistance responses do not follow the flow response measured with FEV1 and may thus be used as a complement to FEV1 reversibility to identify flow, volume and resistance responders.
PMCID: PMC5135072  PMID: 27932874
COPD; IOS; body plethysmography; bronchodilation; lung function; reversibility
2.  Two Phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma 
Chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cell (CRTh2) receptor antagonists is being investigated for asthma.
The aim of this study was to assess the effects of the CRTh2 receptor antagonist, AZD1981 (with/without inhaled corticosteroids [ICSs]), on lung function and asthma control.
Patients and methods
Adults aged 18–60 years were enrolled in two randomized, placebo-controlled, parallel-group trials (protocol number: D9830C00003 [study 1, n=209] and protocol number: D9830C00004 [study 2, n=510]). In study 1, patients with stable asthma (forced expiratory volume in 1 second [FEV1]: 65%−110%) were withdrawn from ICS (<400 µg/d) and randomized to AZD1981 1,000 mg twice daily (bid) or placebo. In study 2, patients with uncontrolled asthma (FEV1: 40%−85%) despite ICS therapy (≥500 µg/d) were randomized to 50 mg, 400 mg, or 1,000 mg bid AZD1981 or placebo. The primary efficacy variable for both trials was the change in morning peak expiratory flow after 4 weeks of treatment. Secondary variables included Asthma Control Questionnaire (ACQ-5) scores, FEV1 assessments, safety, and tolerability. In study 2, efficacy was also assessed according to atopic status.
Following 4 weeks of treatment, there was a nonsignificant increase in morning peak expiratory flow on AZD1981 1,000 mg bid (9.5 L/min vs placebo, P=0.086 [study 1] and 12 L/min vs placebo, P=0.16 [study 2]). In study 2, all doses of AZD1981 provided significant improvements in ACQ-5 scores (0.26–0.3 units vs placebo, P=0.010–0.022); however, there was no dose–response relationship. Improved ACQ-5 scores and FEV1 were observed in the majority of atopic patients treated with AZD1981. AZD1981 was well tolerated across treatment groups.
Further research may be warranted in atopic patients to fully evaluate the clinical efficacy of AZD1981.
PMCID: PMC5012601  PMID: 27621597
CRTh2 receptor; efficacy; Phase II; respiratory; Th2 cells; prostaglandin D2
3.  MSC from fetal and adult lungs possess lung-specific properties compared to bone marrow-derived MSC 
Scientific Reports  2016;6:29160.
Mesenchymal stromal cells (MSC) are multipotent cells with regenerative and immune-modulatory properties. Therefore, MSC have been proposed as a potential cell-therapy for bronchiolitis obliterans syndrome (BOS). On the other hand, there are publications demonstrating that MSC might be involved in the development of BOS. Despite limited knowledge regarding the functional role of tissue-resident lung-MSC, several clinical trials have been performed using MSC, particularly bone marrow (BM)-derived MSC, for various lung diseases. We aimed to compare lung-MSC with the well-characterized BM-MSC. Furthermore, MSC isolated from lung-transplanted patients with BOS were compared to patients without BOS. Our study show that lung-MSCs are smaller, possess a higher colony-forming capacity and have a different cytokine profile compared to BM-MSC. Utilizing gene expression profiling, 89 genes including lung-specific FOXF1 and HOXB5 were found to be significantly different between BM-MSC and lung-MSC. No significant differences in cytokine secretion or gene expression were found between MSC isolated from BOS patients compared recipients without BOS. These data demonstrate that lung-resident MSC possess lung-specific properties. Furthermore, these results show that MSC isolated from lung-transplanted patients with BOS do not have an altered phenotype compared to MSC isolated from good outcome recipients.
PMCID: PMC4933903  PMID: 27381039
4.  Symptoms and quality of life in patients with chronic obstructive pulmonary disease treated with aclidinium in a real-life setting 
European Clinical Respiratory Journal  2016;3:10.3402/ecrj.v3.31232.
Chronic obstructive pulmonary disease (COPD) is a progressive disease with symptoms that can have a major impact on patients’ physical health. The aim of this study was to evaluate quality of life (QoL), symptom severity and dyspnoea in COPD patients treated with aclidinium up to 24 weeks.
In this prospective non-interventional multicentre study (198 centres in Sweden, Denmark, and Norway), COPD patients (age ≥40 years) who started treatment with aclidinium (initial therapy, change of treatment, or add-on therapy) could be included. Health-related QoL was obtained by COPD assessment test (CAT). Symptoms were evaluated on a 6-point Likert scale. The modified Medical Research Council (mMRC) Dyspnoea Scale was used as a simple grading system to assess the level of dyspnoea/shortness of breath from0 to 4. Patients on treatment with aclidinium who completed baseline and at least one follow-up visit (week 12 or 24) were included in the study population.
Overall, 1,093 patients were enrolled (mean 69 years, 54% females), one-third had ≥1 exacerbation the year prior to baseline. At enrolment, 48% were LAMA naïve. Mean (standard deviation, SD) CAT score decreased from 16.9 (7.7) at baseline to 14.3 (7.3) at week 24 (p<0.01) with a decrease in all individual CAT items (p<0.05). Mean difference in morning and night-time symptoms from baseline to week 24 was −0.60 (SD 2.51) and −0.44 (SD 2.48), respectively (both p<0.001). Mean (SD) mMRC Dyspnoea Scale changed from 1.6 (1.0) at baseline to 1.5 (1.0) at week 24 (p<0.001).
In this observational study of a Nordic real-life COPD population, treatment with aclidinium was associated with a clinically important improvement in QoL and morning and night-time symptoms, most pronounced in the LAMA naïve group. However, there is still room for improvement in the management of symptomatic COPD patients.
PMCID: PMC4937723  PMID: 27387608
patient-reported outcomes; patient satisfaction; dyspnoea; COPD; LAMA; observational study
5.  Azithromycin induces anti-viral effects in cultured bronchial epithelial cells from COPD patients 
Scientific Reports  2016;6:28698.
Rhinovirus infection is a major cause of chronic obstructive pulmonary disease (COPD) exacerbations and may contribute to the development into severe stages of COPD. The macrolide antibiotic azithromycin may exert anti-viral actions and has been reported to reduce exacerbations in COPD. However, little is known about its anti-viral actions on bronchial epithelial cells at clinically relevant concentrations. Primary bronchial epithelial cells from COPD donors and healthy individuals were treated continuously with azithromycin starting 24 h before infection with rhinovirus RV16. Expression of interferons, RIG-I like helicases, pro-inflammatory cytokines and viral load were analysed. Azithromycin transiently increased expression of IFNβ and IFNλ1 and RIG-I like helicases in un-infected COPD cells. Further, azithromycin augmented RV16-induced expression of interferons and RIG-I like helicases in COPD cells but not in healthy epithelial cells. Azithromycin also decreased viral load. However, it only modestly altered RV16-induced pro-inflammatory cytokine expression. Adding budesonide did not reduce interferon-inducing effects of azithromycin. Possibly by inducing expression of RIG-I like helicases, azithromycin increased rhinovirus-induced expression of interferons in COPD but not in healthy bronchial epithelium. These effects would reduce bronchial viral load, supporting azithromycin’s emerging role in prevention of exacerbations of COPD.
PMCID: PMC4923851  PMID: 27350308
6.  Effects of tiotropium + olodaterol versus tiotropium or placebo by COPD disease severity and previous treatment history in the OTEMTO® studies 
Respiratory Research  2016;17:73.
As lung function declines rapidly in the early stages of chronic obstructive pulmonary disease (COPD), the effects of bronchodilators in patients with moderate disease and those who have not previously received maintenance therapy are of interest. OTEMTO® 1 and 2 were two replicate, 12-week, Phase III studies investigating the benefit of tiotropium + olodaterol on lung function and quality of life in patients with moderate to severe disease. Post hoc analyses were performed to assess the benefits for patients according to disease severity and treatment history.
Four subgroup analyses were performed: Global initiative for chronic Obstructive Lung Disease (GOLD) 2/3, GOLD A/B/C/D, treatment naive/not treatment naive and receiving inhaled corticosteroids (ICS) at baseline/not receiving ICS at baseline. Primary end points were change in forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h response, change in trough FEV1 and St George’s Respiratory Questionnaire (SGRQ) total score. Transition Dyspnoea Index (TDI) focal score was a secondary end point, and SGRQ and TDI responder analyses were further end points; all were assessed at 12 weeks.
In all subgroups, patients receiving tiotropium + olodaterol responded better overall than those receiving tiotropium monotherapy. Improvements with tiotropium + olodaterol over placebo or tiotropium monotherapy were noted across GOLD 2/3 and GOLD A/B/C/D; however, improvements in SGRQ total score were most evident in the GOLD B subgroup. Moreover, lung-function outcomes were generally greater in those patients who had been receiving previous long-acting bronchodilator and/or ICS maintenance treatment.
These data suggest that tiotropium + olodaterol should be considered as a treatment option in patients with moderate COPD who are initiating maintenance therapy, as well as those with more severe disease.
Trial registration NCT01964352 and NCT02006732.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-016-0387-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4912717  PMID: 27316465
COPD; Long-acting bronchodilator; Tiotropium; Olodaterol; Severity; Treatment history
7.  The lung function profile of once-daily tiotropium and olodaterol via Respimat® is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler® (ENERGITO® study) 
Tiotropium + olodaterol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD. Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation, there is substantial use in individuals at lower risk. This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens.
The study aimed to assess the effect on lung function of once-daily tiotropium + olodaterol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 (moderate to severe) COPD.
This was a randomized, double-blind, double-dummy, four-treatment, complete crossover study in which participants received once-daily tiotropium + olodaterol (5/5 µg and 2.5/5 µg) via Respimat® and twice-daily salmeterol + fluticasone propionate (50/500 µg and 50/250 µg) via Accuhaler® for 6 weeks. The primary end point was change in forced expiratory volume in 1 second (FEV1) area under the curve from 0 hour to 12 hours (AUC0–12) relative to the baseline after 6 weeks.
Tiotropium + olodaterol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0–12 compared to salmeterol + fluticasone propionate (improvements from baseline were 317 mL and 295 mL with tiotropium + olodaterol 5/5 µg and 2.5/5 µg, and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg, respectively). Tiotropium + olodaterol was superior to salmeterol + fluticasone propionate in lung function secondary end points, including FEV1 area under the curve from 0 hour to 24 hours (AUC0–24).
Once-daily tiotropium + olodaterol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate. Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD.
PMCID: PMC4745834  PMID: 26893551
COPD; maintenance treatment; lung function; tiotropium; FEV1; inhaled corticosteroid
8.  Expert Nordic perspectives on the potential of novel inhalers to overcome unmet needs in the management of obstructive lung disease 
European Clinical Respiratory Journal  2015;2:10.3402/ecrj.v2.29445.
The effective self-management of obstructive lung disease is dependent upon the patient achieving good inhaler technique. However, many current inhalers are complicated to use, which may lead to handling difficulties. These difficulties can cause clinically relevant errors, whereby pharmacotherapy fails to achieve adequate lung deposition and therapeutic effect. In this report, the potential of novel inhaler devices to overcome unmet needs in the management of obstructive lung disease is considered by a panel of Nordic experts. The panel concludes that innovative inhalers can contribute to good disease management and better use of healthcare resources.
PMCID: PMC4684578  PMID: 26689215
asthma*; COPD*; obstructive lung disease*; innovation; patient preference*; patient compliance*; metered dose inhaler*; dry powder inhaler*; medication errors*; economic; outcome; choice; price; cost; reimbursement; access; substitution
9.  Exercise and asthma: an overview 
European Clinical Respiratory Journal  2015;2:10.3402/ecrj.v2.27984.
The terms ‘exercise-induced asthma’ (EIA) and ‘exercise-induced bronchoconstriction’ (EIB) are often used interchangeably to describe symptoms of asthma such as cough, wheeze, or dyspnoea provoked by vigorous physical activity. In this review, we refer to EIB as the bronchoconstrictive response and to EIA when bronchoconstriction is associated with asthma symptoms. EIB is a common occurrence for most of the asthmatic patients, but it also affects more than 10% of otherwise healthy individuals as shown by epidemiological studies. EIA and EIB have a high prevalence also in elite athletes, especially within endurance type of sports, and an athlete's asthma phenotype has been described. However, the occurrence in elite athletes shows that EIA/EIB, if correctly managed, may not impair physical activity and top sports performance. The pathogenic mechanisms of EIA/EIB classically involve both osmolar and vascular changes in the airways in addition to cooling of the airways with parasympathetic stimulation. Airways inflammation plays a fundamental role in EIA/EIB. Diagnosis and pharmacological management must be carefully performed, with particular consideration of current anti-doping regulations, when caring for athletes. Based on the demonstration that the inhaled asthma drugs do not improve performance in healthy athletes, the doping regulations are presently much less strict than previously. Some sports are at a higher asthma risk than others, probably due to a high environmental exposure while performing the sport, with swimming and chlorine exposure during swimming as one example. It is considered very important for the asthmatic child and adolescent to master EIA/EIB to be able to participate in physical activity on an equal level with their peers, and a precise early diagnosis with optimal treatment follow-up is vital in this aspect. In addition, surprising recent preliminary evidences offer new perspectives for moderate exercise as a potential therapeutic tool for asthmatics.
PMCID: PMC4653278  PMID: 26672959
exercise-induced asthma; exercise-induced bronchoconstriction; EIA; EIB; sports; allergy
10.  Small airway epithelial-C/EBPβ is increased in patients with advanced COPD 
Respiratory Research  2015;16:133.
The expression of CCAAT/enhancer-binding protein (C/EBP)β in the small airway epithelium of COPD is unknown. C/EBPβ was assessed in peripheral lung tissue of non-smoking/smoking controls and patients with GOLD I-IV COPD by quantitative immunohistochemistry. The expression of C/EBPβ was decreased in smokers compared to never smokers. Furthermore, C/EBPβ was significantly elevated in advanced COPD vs. asymptomatic smokers, and the expression correlated to lung function decline. As C/EBPβ exerts pro-inflammatory effects in the context of cigarette smoke, the elevated C/EBPβ in advanced COPD may be an indication of a breakdown of regulatory mechanisms and excessive inflammation.
PMCID: PMC4625456  PMID: 26511475
COPD; C/EBPβ; Airway epithelium
11.  A new approach to assess COPD by identifying lung function break-points 
COPD is a progressive disease, which can take different routes, leading to great heterogeneity. The aim of the post-hoc analysis reported here was to perform continuous analyses of advanced lung function measurements, using linear and nonlinear regressions.
Patients and methods
Fifty-one COPD patients with mild to very severe disease (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stages I–IV) and 41 healthy smokers were investigated post-bronchodilation by flow-volume spirometry, body plethysmography, diffusion capacity testing, and impulse oscillometry. The relationship between COPD severity, based on forced expiratory volume in 1 second (FEV1), and different lung function parameters was analyzed by flexible nonparametric method, linear regression, and segmented linear regression with break-points.
Most lung function parameters were nonlinear in relation to spirometric severity. Parameters related to volume (residual volume, functional residual capacity, total lung capacity, diffusion capacity [diffusion capacity of the lung for carbon monoxide], diffusion capacity of the lung for carbon monoxide/alveolar volume) and reactance (reactance area and reactance at 5Hz) were segmented with break-points at 60%–70% of FEV1. FEV1/forced vital capacity (FVC) and resonance frequency had break-points around 80% of FEV1, while many resistance parameters had break-points below 40%. The slopes in percent predicted differed; resistance at 5 Hz minus resistance at 20 Hz had a linear slope change of −5.3 per unit FEV1, while residual volume had no slope change above and −3.3 change per unit FEV1 below its break-point of 61%.
Continuous analyses of different lung function parameters over the spirometric COPD severity range gave valuable information additional to categorical analyses. Parameters related to volume, diffusion capacity, and reactance showed break-points around 65% of FEV1, indicating that air trapping starts to dominate in moderate COPD (FEV1 =50%–80%). This may have an impact on the patient’s management plan and selection of patients and/or outcomes in clinical research.
PMCID: PMC4610777  PMID: 26508849
spirometry; severity; body plethysmography; single-breath carbon-monoxide diffusion test; impulse oscillometry; break-point
12.  Randomized, Double-Blind, Dose-Finding Study for Tiotropium when Added to Olodaterol, Administered via the Respimat® Inhaler in Patients with Chronic Obstructive Pulmonary Disease 
Advances in Therapy  2015;32(9):809-822.
Combining long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) is beneficial in chronic obstructive pulmonary disease (COPD), as the two classes of bronchodilator have complementary modes of action. The optimal dose for the fixed-dose combination of the LAMA tiotropium and the LABA olodaterol needed to be determined. In this phase II trial, the dose response of tiotropium on top of olodaterol was investigated in a free-dose combination, while other phase II studies have explored different doses of olodaterol on top of tiotropium, with both drugs delivered using the Respimat® inhaler.
This was a double-blind incomplete crossover trial in which 233 patients with moderate or severe COPD were randomized to receive four out of eight free-dose combinations of olodaterol (5 or 10 µg) and tiotropium (1.25, 2.5, or 5 µg) or placebo for 4 weeks each. Primary end point was trough forced expiratory volume in 1 s (FEV1) change from baseline (response) after 4 weeks.
Addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 5 µg increased mean trough FEV1 response by 0.054, 0.065, and 0.084 L, respectively; addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 10 µg increased mean trough FEV1 response by 0.051, 0.083, and 0.080 L, respectively. All treatments were well tolerated and incidence of adverse events was similar with all treatments.
Overall, a dose response for tiotropium on top of both doses of olodaterol was observed, with increasing improvements in trough FEV1 compared to olodaterol alone as the tiotropium dose was increased.
Boehringer Ingelheim.
Trial registration: number, NCT01040403.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-015-0239-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4604503  PMID: 26404912
Bronchodilator; Chronic obstructive pulmonary disease; Dose finding; Long-acting β2-agonists; Long-acting muscarinic antagonists; Olodaterol; Tiotropium
13.  Rhinoviral stimuli, epithelial factors and ATP signalling contribute to bronchial smooth muscle production of IL-33 
Bronchial smooth muscle cells (BSMCs) from severe asthmatics have been shown to overexpress the Th2-driving and asthma-associated cytokine IL-33. However, little is known regarding factors involved in BSMC production of IL-33. Rhinovirus (RV) infections cause asthma exacerbations, which exhibit features of Th2-type inflammation. Here, we investigated the effects of epithelial-derived media and viral stimuli on IL-33 expression in human BSMCs.
Primary human BSMCs from healthy (n = 3) and asthmatic (n = 3) subjects were stimulated with conditioned media from primary human bronchial epithelial cells (BECs), double-stranded (ds)RNA, dsRNA/LyoVec, or infected with RV. BSMCs were also pretreated with the purinergic receptor antagonist suramin. IL-33 expression was analysed by RT-qPCR and western blot and ATP levels were determined in cell supernatants.
RV infection and activation of TLR3 by dsRNA increased IL-33 mRNA and protein in healthy and asthmatic BSMCs. These effects were inhibited by dexamethasone. BSMC expression of IL-33 was also increased by stimulation of RIG-I-like receptors using dsRNA/LyoVec. Conditioned media from BECs induced BSMC expression of IL-33, which was further enhanced by dsRNA. BEC-derived medium and viral-stimulated BSMC supernatants exhibited elevated ATP levels. Blocking of purinergic signalling with suramin inhibited BSMC expression of IL-33 induced by dsRNA and BEC-derived medium.
RV infection of BSMCs and activation of TLR3 and RIG-I-like receptors cause expression and production of IL-33. Epithelial-released factor(s) increase BSMC expression of IL-33 and exhibit positive interaction with dsRNA. Increased BSMC IL-33 associates with ATP release and is antagonised by suramin. We suggest that epithelial-derived factors contribute to baseline BSMC IL-33 production, which is further augmented by RV infection of BSMCs and stimulation of their pathogen-recognising receptors.
PMCID: PMC4552418  PMID: 26318341
IL-33; dsRNA; Rhinovirus; Asthma; Bronchial smooth muscle cells; Bronchial epithelial cells; ATP
14.  Application of nitric oxide measurements in clinical conditions beyond asthma 
European Clinical Respiratory Journal  2015;2:10.3402/ecrj.v2.28517.
Fractional exhaled nitric oxide (FeNO) is a convenient, non-invasive method for the assessment of active, mainly Th2-driven, airway inflammation, which is sensitive to treatment with standard anti-inflammatory therapy. Consequently, FeNO serves as a valued tool to aid diagnosis and monitoring in several asthma phenotypes. More recently, FeNO has been evaluated in several other respiratory, infectious, and/or immunological conditions. In this short review, we provide an overview of several clinical studies and discuss the status of potential applications of NO measurements in clinical conditions beyond asthma.
PMCID: PMC4653314  PMID: 26672962
exhaled nitric oxide; allergic rhinitis; COPD; cystic fibrosis; bronchopulmonary dysplasia; respiratory infections; pulmonary hypertension; hepatopulmonary syndrome; scleroderma; allograft rejections
15.  Patients with chronic obstructive pulmonary disease and chronically colonized with Haemophilus influenzae during stable disease phase have increased airway inflammation 
Some patients with chronic obstructive pulmonary disease (COPD) show increased airway inflammation and bacterial colonization during stable phase. The aim of this study was to follow COPD patients and investigate chronic colonization with pathogenic bacteria during stable disease phase, and relate these findings to clinical parameters, inflammatory pattern, lung function, and exacerbations.
Forty-three patients with COPD were included while in a stable state and followed up monthly until exacerbation or for a maximum of 6 months. The patients completed the Clinical COPD Questionnaire and Medical Research Council dyspnea scale questionnaires, and exhaled breath condensate was collected, followed by spirometry, impulse oscillometry, and sputum induction.
Ten patients were chronically colonized (ie, colonized at all visits) with Haemophilus influenzae during stable phase. These patients had higher sputum levels of leukotriene B4 (P<0.001), 8-isoprostane (P=0.002), myeloperoxidase activity (P=0.028), and interleukin-8 (P=0.02) during stable phase when compared with other patients. In addition, they had lower forced vital capacity (P=0.035) and reactance at 5 Hz (P=0.034), but there was no difference in forced expiratory volume in 1 second (FEV1), FEV1 % predicted, forced vital capacity % predicted, exhaled breath condensate biomarkers, C-reactive protein, or Clinical COPD Questionnaire and Medical Research Council dyspnea scale results. Three patients had intermittent colonization (colonized at only some visits) of H. influenzae during stable phase, and had lower levels of inflammatory biomarkers in sputum when compared with the chronically colonized patients. The difference in airway inflammation seen during stable phase in patients chronically colonized with H. influenzae was not observed during exacerbations.
Some COPD patients who were chronically colonized with H. influenzae during stable phase showed increased airway inflammation and reduced lung volumes when compared with non-chronically colonized patients.
PMCID: PMC4427610  PMID: 26005341
chronic obstructive pulmonary disease; inflammation; biomarker; colonization; sputum; spirometry
16.  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
PMCID: PMC4391658  PMID: 25573406
18.  Clinical pharmacokinetics of AZD3199, an inhaled ultra-long-acting β2-adrenoreceptor agonist (uLABA) 
The clinical pharmacokinetics of AZD3199, an ultra-long-acting β2-agonist, were investigated in healthy volunteers and patients with asthma or chronic obstructive pulmonary disease (COPD).
Materials and methods
Five studies are presented: one single ascending dose study in healthy Caucasian males; two multiple ascending dose studies in healthy males, one in Caucasians and one in Japanese; a Phase IIA asthma study; and a Phase IIB COPD study. Subjects received AZD3199 via a Spira nebulizer (Turbuhaler; equivalent delivered doses 5–3200 μg) or Turbuhaler (single delivered doses of 120–1920 μg or repeated delivered once-daily doses 240–1,680 μg). AZD3199 pharmacokinetics were assessed using total plasma concentration and urinary excretion, and tolerability using adverse events, clinical laboratory tests, and physical examinations.
AZD3199 appeared rapidly in the systemic circulation following single and multiple dosing in healthy volunteers and patients (maximum plasma concentration within 30 minutes), with dose-proportional time-independent pharmacokinetics. Plasma exposure to unmetabolized drug was similar in healthy volunteers and patients with asthma, but relatively lower in patients with COPD. Estimated terminal half-life was up to 142 hours in healthy Caucasian males. AZD3199 was well tolerated and showed no or at most mild systemic effects.
AZD3199 plasma exposure in healthy volunteers and patients suggested linear pharmacokinetics and a long half-life. Systemic availability was similar in healthy subjects and patients with asthma, but was lower in patients with COPD. These clinical trials suggest that AZD3199 is well-tolerated in healthy male volunteers and patients, with no safety concerns identified to preclude further evaluation.
PMCID: PMC4330041  PMID: 25709399
AZD3199; uLABA; COPD; asthma; pharmacokinetics; tolerability
19.  The added value of hybrid ventilation/perfusion SPECT/CT in patients with stable COPD or apparently healthy smokers. Cancer-suspected CT findings in the lungs are common when hybrid imaging is used 
Ventilation/perfusion (V/P) single-photon emission computed tomography (SPECT) is recognized as a diagnostic method with potential beyond the diagnosis of pulmonary embolism. V/P SPECT identifies functional impairment in diseases such as heart failure (HF), pneumonia, and chronic obstructive pulmonary disease (COPD). The development of hybrid SPECT/computed tomography (CT) systems, combining functional with morphological imaging through the addition of low-dose CT (LDCT), may be useful in COPD, as these patients are prone to lung cancer and other comorbidities. The aim of this study was to investigate the added value of LDCT among healthy smokers and patients with stable COPD, when examined with V/P SPECT/CT hybrid imaging. Sixty-nine subjects, 55 with COPD (GOLD I–IV) and 14 apparently healthy smokers, were examined with V/P SPECT and LDCT hybrid imaging. Spirometry was used to verify COPD grade. Only one apparently healthy smoker and three COPD patients had a normal or nearly normal V/P SPECT. All other patients showed various degrees of airway obstruction, even when spirometry was normal. The same interpretation was reached on both modalities in 39% of the patients. LDCT made V/P SPECT interpretation more certain in 9% of the patients and, in 52%, LDCT provided additional diagnoses. LDCT better characterized the type of emphysema in 12 patients. In 19 cases, tumor-suspected changes were reported. Three of these 19 patients (ie, 4.3% of all subjects) were in the end confirmed to have lung cancer. The majority of LDCT findings were not regarded as clinically significant. V/P SPECT identified perfusion patterns consistent with decompensated left ventricular HF in 14 COPD patients. In 16 patients (23%), perfusion defects were observed. HF and perfusion defects were not recognized with LDCT. In COPD patients and long-time smokers, hybrid imaging had added value compared to V/P SPECT alone, by identifying patients with lung malignancy and more clearly identifying emphysema. V/P SPECT visualizes comorbidities to COPD not seen with LDCT, such as pulmonary embolism and left ventricular HF.
PMCID: PMC4279608  PMID: 25565797
lung; lung cancer; V/P SPECT; ventilation/perfusion; single-photon emission computed tomography; computed tomography
20.  Versican in inflammation and tissue remodeling: The impact on lung disorders 
Glycobiology  2014;25(3):243-251.
Versican is a proteoglycan that has many different roles in tissue homeostasis and inflammation. The biochemical structure comprises four different types of the core protein with attached glycosaminoglycans (GAGs) that can be sulfated to various extents and has the capacity to regulate differentiation of different cell types, migration, cell adhesion, proliferation, tissue stabilization and inflammation. Versican's regulatory properties are of importance during both homeostasis and changes that lead to disease progression. The GAGs that are attached to the core protein are of the chondroitin sulfate/dermatan sulfate type and are known to be important in inflammation through interactions with cytokines and growth factors. For a more complex understanding of versican, it is of importance to study the tissue niche, where the wound healing process in both healthy and diseased conditions take place. In previous studies, our group has identified changes in the amount of the multifaceted versican in chronic lung disorders such as asthma, chronic obstructive pulmonary disease, and bronchiolitis obliterans syndrome, which could be a result of pathologic, transforming growth factor β driven, on-going remodeling processes. Reversely, the context of versican in its niche is of great importance since versican has been reported to have a beneficial role in other contexts, e.g. emphysema. Here we explore the vast mechanisms of versican in healthy lung and in lung disorders.
PMCID: PMC4310351  PMID: 25371494
extracellular matrix; lung disorders; remodeling; versican
21.  Grading obstructive lung disease using tomographic pulmonary scintigraphy in patients with chronic obstructive pulmonary disease (COPD) and long-term smokers 
Annals of Nuclear Medicine  2014;29:91-99.
The severity of chronic obstructive lung disease (COPD) is defined by the degree of flow limitation measured as forced expiratory volume in 1 s, which mainly reflects impairment of large and intermediate airways. However, COPD is primarily a small airways disease. Therefore, better diagnostic tools are needed. Ventilation-Perfusion (V/P) SPECT is a sensitive method to detect obstructive lung changes but criteria for staging airway obstruction are missing.
To define and validate criteria to stage COPD using V/P SPECT.
74 subjects (healthy non-smokers, healthy smokers or with stable COPD) were included. All were examined with V/P SPECT in a hybrid SPECT/CT system. Spirometry was performed and patients were evaluated with the clinical COPD questionnaire (CCQ). V/P SPECT was interpreted independently. Preserved lung function (%) was evaluated. The degree of airway obstruction on V/P SPECT was graded according to newly-developed grading criteria. The degree of airway obstruction was graded from normal (0) to severe (3). The airway obstructivity-grade and degree of preserved lung function were compared to GOLD, CCQ and LDCT emphysema extent.
Obstructivity-grade (r = 0.66, P < 0.001) and the degree of preserved lung function (r = −0.70, P < 0.001) both correlated to GOLD. Total preserved lung function decreased in relation to higher GOLD stage. There was a significant difference between healthy controls and apparently healthy long time smokers both regarding obstructivity-grade (P = 0.001) and preserved lung function (P < 0.001). Long-time smokers did not differ significantly from GOLD 1 COPD patients (P = 0.14 and P = 0.55 for obstructivity-grade and preserved lung function, respectively). However, patients in GOLD 1 differed in obstructivity-grade from non-smoking controls (P = 0.02).
Functional imaging with V/P SPECT enables standardized grading of airway obstruction as well as reduced lung function, both of which correlate with GOLD stage. V/P SPECT shows that long-term smokers in most cases have signs of ventilatory impairment and airway obstruction not shown by spirometry.
PMCID: PMC4284371  PMID: 25315109
Ventilation/Perfusion SPECT; Pulmonary scintigraphy; Chronic obstructive pulmonary disease (COPD); Imaging interpretation criteria; Technegas
22.  Controlled and uncontrolled asthma display distinct alveolar tissue matrix compositions 
Respiratory Research  2014;15(1):67.
Whether distal inflammation in asthmatics also leads to structural changes in the alveolar parenchyma remains poorly examined, especially in patients with uncontrolled asthma. We hypothesized that patients who do not respond to conventional inhaled corticosteroid therapy have a distinct tissue composition, not only in central, but also in distal lung.
Bronchial and transbronchial biopsies from healthy controls, patients with controlled atopic and patients with uncontrolled atopic asthma were processed for immunohistochemical analysis of fibroblasts and extracellular matrix molecules: collagen, versican, biglycan, decorin, fibronectin, EDA-fibronectin, matrix metalloproteinase (MMP)-9 and tissue-inhibitor of matrix metalloproteinase (TIMP)-3.
In central airways we found increased percentage areas of versican and decorin in patients with uncontrolled asthma compared to both healthy controls and patients with controlled asthma. Percentage area of biglycan was significantly higher in both central airways and alveolar parenchyma of patients with uncontrolled compared to controlled asthma. Ratios of MMP-9/TIMP-3 were decreased in both uncontrolled and controlled asthma compared to healthy controls. In the alveolar parenchyma, patients with uncontrolled asthma had increased percentage areas of collagen, versican and decorin compared to patients with controlled asthma. Patients with uncontrolled asthma had significantly higher numbers of myofibroblasts in both central airways and alveolar parenchyma compared to patients with controlled asthma.
Tissue composition differs, in both central and distal airways, between patients with uncontrolled and controlled asthma on equivalent doses of ICS. This altered structure and possible change in tissue elasticity may lead to abnormal mechanical properties, which could be a factor in the persistent symptoms for patients with uncontrolled asthma.
PMCID: PMC4089934  PMID: 24950767
Asthma; Controlled; Uncontrolled; ICS; Remodeling; Alveolar parenchyma; Extracellular matrix; Myofibroblasts
24.  Primary mesenchymal stem cells in human transplanted lungs are CD90/CD105 perivascularly located tissue-resident cells 
BMJ Open Respiratory Research  2014;1(1):e000027.
Mesenchymal stem cells (MSC) have not only been implicated in the development of lung diseases, but they have also been proposed as a future cell-based therapy for lung diseases. However, the cellular identity of the primary MSC in human lung tissues has not yet been reported. This study therefore aimed to identify and characterise the ‘bona fide’ MSC in human lungs and to investigate if the MSC numbers correlate with the development of bronchiolitis obliterans syndrome in lung-transplanted patients.
Primary lung MSC were directly isolated or culture-derived from central and peripheral transbronchial biopsies of lung-transplanted patients and evaluated using a comprehensive panel of in vitro and in vivo assays.
Primary MSC were enriched in the CD90/CD105 mononuclear cell fraction with mesenchymal progenitor frequencies of up to four colony-forming units, fibroblast/100 cells. In situ staining of lung tissues revealed that CD90/CD105 MSCs were located perivascularly. MSC were tissue-resident and exclusively donor lung-derived even in biopsies obtained from patients as long as 16 years after transplantation. Culture-derived mesenchymal stromal cells showed typical in vitro MSC properties; however, xenotransplantation into non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice showed that lung MSC readily differentiated into adipocytes and stromal tissues, but lacked significant in vivo bone formation.
These data clearly demonstrate that primary MSC in human lung tissues are not only tissue resident but also tissue-specific. The identification and phenotypic characterisation of primary lung MSC is an important first step in identifying the role of MSC in normal lung physiology and pulmonary diseases.
PMCID: PMC4212711  PMID: 25478178
Lung Transplantation
25.  Integrating Evidence for Managing Asthma in Patients Who Smoke 
Cigarette smoking among asthma patients is associated with worsening symptoms and accelerated decline in lung function. Smoking asthma is also characterized by increased levels of neutrophils and macrophages, and greater small airway remodeling, resulting in increased airflow obstruction and impaired response to corticosteroid therapy. As a result, smokers are typically excluded from asthma randomized controlled trials (RCTs). The strict inclusion/exclusion criteria used by asthma RCTs limits the extent to which their findings can be extrapolated to the routine care asthma population and to reflect the likely effectiveness of therapies in subgroups of particular clinical interest, such as smoking asthmatics. The inclusion of smokers in observational asthma studies and pragmatic trials in asthma provides a way of assessing the relative effectiveness of different treatment options for the management of this interesting clinical subgroup. Exploratory studies of possible treatment options for smoking asthma suggest potential utility in: prescribing higher-dose ICS; targeting the small airways of the lungs with extra-fine particle ICS formulations; targeting leukotreines, and possibly also combinations of these options. However, further studies are required. With the paucity of RCT data available, complementary streams of evidence (those from RCTs, pragmatic trials and observational studies) need to be combined to help guide judicious prescribing decisions in smokers with asthma.
PMCID: PMC3936038  PMID: 24587946
Smoking; asthma; leukotriene receptor antagonists (LTRAs); small airways; inhaled glucocorticosteroids (ICS); extra-fine particle

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