Huib Kerstjens

An Official American Thoracic Society/European Respiratory Society Statement: Asthma Control and Exacerbations Standardizing Endpoints for Clinical Asthma Trials and Clinical Practice

BACKGROUND The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways. PURPOSE The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older. METHODS A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures. RESULTS The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge about the multiple domains of asthma and asthma control, no single outcome measure can adequately assess asthma control. Its assessment in clinical trials and in clinical practice should include components relevant to both of the goals of asthma treatment, namely achievement of best possible clinical control and reduction of future risk of adverse outcomes. Recommendations are provided for the assessment of asthma control in clinical trials and clinical practice, both at baseline and in the assessment of treatment response. CONCLUSIONS The Task Force recommendations provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice.

A COMPARISON OF BRONCHODILATOR THERAPY WITH OR WITHOUT INHALED CORTICOSTEROID-THERAPY FOR OBSTRUCTIVE AIRWAYS DISEASE

BACKGROUND The morbidity from obstructive airways disease (asthma and chronic obstructive pulmonary disease) is considerable, and the mortality rate is rising in several countries. It has been hypothesized that long-term improvement in prognosis might result from vigorous bronchodilator or antiinflammatory therapy. METHODS In a multicenter trial we compared three inhalation regimens in which a beta 2-agonist (terbutaline, 2000 micrograms daily) was combined with a corticosteroid (beclomethasone, 800 micrograms daily), an anticholinergic bronchodilator (ipratropium bromide, 160 micrograms daily), or placebo. Patients with airways hyperresponsiveness and obstruction who were 18 to 60 years old were followed for 2 1/2 years. RESULTS Of the 274 patients enrolled, 56 percent had allergies. The mean forced expiratory volume in one second (FEV1) was 64 percent of the predicted value. The mean PC20 (the concentration of inhaled histamine causing a 20 percent decrease in FEV1, a measure of hyperresponsiveness) was 0.26 mg per milliliter. Withdrawal from the study, due mainly to pulmonary symptoms, was less frequent in the corticosteroid group (12 of 91 patients) than in the anticholinergic-drug group (45 of 92 patients) or the placebo group (44 of 91 patients; P < 0.001). The mean FEV1 (+/- SE) increased by 10.3 +/- 1.3 percent of the predicted value in the corticosteroid group within three months and remained stable thereafter, whereas it did not change in the other two groups (P < 0.001). The PC20 increased by 2.0 doubling concentrations in the corticosteroid group but did not change in the other groups (P < 0.001). In the corticosteroid group, patients who did not smoke, who had allergies, or who were less than 40 years old benefited more from their treatment than did those who smoked, did not have allergies, or were over 40, but all subgroups of the corticosteroid group had improvement as compared with the anticholinergic-drug or placebo group. CONCLUSIONS The addition of an inhaled corticosteroid--but not an inhaled anticholinergic agent--to maintenance treatment with a beta 2-agonist (terbutaline) substantially reduced morbidity, hyperresponsiveness, and airways obstruction in patients with a spectrum of obstructive airways disease.

A new perspective on concepts of asthma severity and control

Concepts of asthma severity and control are important in the evaluation of patients and their response to treatment but the terminology is not standardised and the terms are often used interchangeably. This review, arising from the work of an American Thoracic Society/European Respiratory Society Task Force, identifies the need for separate concepts of control and severity, describes their evolution in asthma guidelines and provides a framework for understanding the relationship between current concepts of asthma phenotype, severity and control. “Asthma control” refers to the extent to which the manifestations of asthma have been reduced or removed by treatment. Its assessment should incorporate the dual components of current clinical control (e.g. symptoms, reliever use and lung function) and future risk (e.g. exacerbations and lung function decline). The most clinically useful concept of asthma severity is based on the intensity of treatment required to achieve good asthma control, i.e. severity is assessed during treatment. Severe asthma is defined as the requirement for (not necessarily just prescription or use of) high-intensity treatment. Asthma severity may be influenced by the underlying disease activity and by the patients phenotype, both of which may be further described using pathological and physiological markers. These markers can also act as surrogate measures for future risk.

Protein Tyrosine Nitration: Selectivity, Physicochemical and Biological Consequences, Denitration, and Proteomics Methods for the Identification of Tyrosine-Nitrated Proteins

Protein tyrosine nitration (PTN) is a post-translational modification occurring under the action of a nitrating agent. Tyrosine is modified in the 3-position of the phenolic ring through the addition of a nitro group (NO2). In the present article, we review the main nitration reactions and elucidate why nitration is not a random chemical process. The particular physical and chemical properties of 3-nitrotyrosine (e.g., pKa, spectrophotometric properties, reduction to aminotyrosine) will be discussed, and the biological consequences of PTN (e.g., modification of enzymatic activity, sensitivity to proteolytic degradation, impact on protein phosphorylation, immunogenicity and implication in disease) will be reviewed. Recent data indicate the possibility of an in vivo denitration process, which will be discussed with respect to the different reaction mechanisms that have been proposed. The second part of this review article focuses on analytical methods to determine this post-translational modification in complex proteomes, which remains a major challenge.

Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial.

BACKGROUND Some patients with severe asthma remain symptomatic and obstructed despite maximal recommended treatment. Tiotropium, a long-acting inhaled anticholinergic agent, might be an effective bronchodilator in such patients. OBJECTIVE We sought to compare the efficacy and safety of 2 doses of tiotropium (5 and 10 μg daily) administered through the Respimat inhaler with placebo as add-on therapy in patients with uncontrolled severe asthma (Asthma Control Questionnaire score, ≥ 1.5; postbronchodilator FEV₁, ≤ 80% of predicted value) despite maintenance treatment with at least a high-dose inhaled corticosteroid plus a long-acting β₂-agonist. METHODS This was a randomized, double-blind, crossover study with three 8-week treatment periods. The primary end point was peak FEV₁ at the end of each treatment period. RESULTS Of 107 randomized patients (54% female patients; mean, 55 years of age; postbronchodilator FEV₁, 65% of predicted value), 100 completed all periods. Peak FEV₁ was significantly higher with 5 μg (difference, 139 mL; 95% CI, 96-181 mL) and 10 μg (difference, 170 mL; 95% CI, 128-213 mL) of tiotropium than with placebo (both P < .0001). There was no significant difference between the active doses. Trough FEV₁ at the end of the dosing interval was higher with tiotropium (5 μg: 86 mL [95% CI, 41-132 mL]; 10 μg: 113 mL [95% CI, 67-159 mL]; both P < .0004). Daily home peak expiratory flow measurements were higher with both tiotropium doses. There were no significant differences in asthma-related health status or symptoms. Adverse events were balanced across groups except for dry mouth, which was more common on 10 μg of tiotropium. CONCLUSION The addition of once-daily tiotropium to asthma treatment, including a high-dose inhaled corticosteroid plus a long-acting β₂-agonist, significantly improves lung function over 24 hours in patients with inadequately controlled, severe, persistent asthma.

Decline of FEV1 by age and smoking status: facts, figures, and fallacies.

Assessment of pulmonary function testing plays as well as in patient based research and in epidemiological studies of healthy subjects, and a central role in everyday practice of the pultherefore the items discussed will be mainly monary physician. New patients are diagnosed centred around the FEV1. and graded in severity on the basis of results from these tests, and the course of the disease in previously diagnosed patients is judged with General course of FEV1 over time the help of lung function measurements. The There is still considerable debate over the shape use of pulmonary function tests for these purof lung function increase and decline during poses requires a concept of what constitutes life. During childhood and adolescence there both a normal level and a normal decline and, is naturally a rise in lung function, the exact consequently, an unusually low level and acshape of which is beyond the scope of this celerated decline. The concept of a normal paper. For the period early in adult life, differlevel is perceived to be fairly straightforward ent shapes have been suggested. Although some and is routinely deducted from some set of authors have taken the decline in lung function reference values. The population selection of to start at 15–20 years of age, 3 others have the reference equations used is taken to be found that the FEV1 continues to rise to the sufficiently representative of the patient under age of 25 years, or even into the fourth Department of study. In this review the problems associated Pulmonology decade. 7 It is probably fair to say that in with this assumption will be discussed and the and Department of healthy individuals there is a plateau phase in Epidemiology, cut off values between normal and abnormal early adulthood in which there is little or no University of examined. The same reference equations are change in FEV1. 6 8 The European Community Groningen, often employed for the judgement of normal Groningen, for Coal and Steel stipulates that no change The Netherlands decline, assuming that the coefficient for age occurs between the ages of 18 to 25 and an H A M Kerstjens adequately represents decline in individuals. age of 25 years should be entered into the B Rijcken This approach, however, can be rather inregression equation for this whole age range. J P Schouten D S Postma adequate and this will be reviewed. AdAfter this plateau FEV1 starts to decrease, with ditionally, special reference will be given to the newer studies that exclude smokers more Correspondence to: Dr H A M Kerstjens, estimating decline in smokers. Because of its carefully suggesting a later start in nonDepartment of Pulmonology, ease of measurement and its very good resmokers. It has long been thought that this University Hospital Groningen, producibility, the forced expiratory volume in ensuing decrease is linear — that is, that FEV1 PO Box 30001, one second (FEV1) is the most widely used and decreases by the same number of ml each year. 9700 RB Groningen, The Netherlands. quoted lung function test in clinical practice However, many authors have now shown that the decline accelerates with ageing. 7 10–12 As a result of these models of change in FEV1, at any given time in adulthood FEV1 is determined by three factors: (1) the maximally attained level of lung function during early adulthood; (2) the onset of decline of lung function or, alternatively, the duration of the plateau phase; and (3) the rate of decline of lung function (fig 1). In other words, from one low measurement of FEV1 in an adult it is impossible to determine whether the reduced lung function is due to not having achieved a high maximum during early adulthood, to having had a shortened plateau phase, to having an accelerated rate of decline, or to any combination of these. c

Long term effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a meta-analysis.

BACKGROUND The role of inhaled corticosteroids in the long term management of chronic obstructive pulmonary disease (COPD) is still unclear. A meta-analysis of the original data sets of the randomised controlled trials published thus far was therefore performed. The main question was: “Are inhaled corticosteroids able to slow down the decline in lung function (FEV1) in COPD?” METHODS A Medline search of papers published between 1983 and 1996 was performed and three studies were selected, two of which were published in full and one in abstract form. Patients with “asthmatic features” were excluded from the original data. Ninety five of the original 140 patients treated with inhaled corticosteroids (81 with 1500 μg beclomethasone daily, six with 1600 μg budesonide daily, and eight with 800 μg beclomethasone daily) and 88 patients treated with placebo (of the initial 144 patients) were included in the analysis. The effect on FEV1 was assessed by a multiple repeated measurement technique in which points of time in the study and treatment effects (inhaled corticosteroids compared with placebo) were investigated. RESULTS No baseline differences were observed (mean age 61 years, mean FEV145% predicted). The estimated two year difference in prebronchodilator FEV1 was +0.034 l/year (95% confidence interval (CI) 0.005 to 0.063) in the inhaled corticosteroid group compared with placebo. The postbronchodilator FEV1 showed a difference of +0.039 l/year (95% CI –0.006 to 0.084). No beneficial effect was observed on the exacerbation rate. Worsening of the disease was the reason for drop out in four patients in the treatment group compared with nine in the placebo group. In the treatment group six of the 95 subjects dropped out because of an adverse effect which may have been related to the treatment compared with two of the 88 patients in the placebo group. CONCLUSIONS This meta-analysis in patients with clearly defined moderately severe COPD showed a beneficial course of FEV1 during two years of treatment with relatively high daily dosages of inhaled corticosteroids.

Effect of Fluticasone With and Without Salmeterol on Pulmonary Outcomes in Chronic Obstructive Pulmonary Disease: A Randomized Trial

BACKGROUND Inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD). OBJECTIVE To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD. DESIGN Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847) SETTING 2 university medical centers in The Netherlands. PATIENTS 114 steroid-naive current or former smokers with moderate to severe COPD. MEASUREMENTS Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months. INTERVENTION Random assignment by minimization method to receive fluticasone propionate, 500 microg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 microg twice daily, and salmeterol, 50 microg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29). RESULTS 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3(+) cells (-55% [95% CI, -74% to -22%]; P = 0.004), CD4(+) cells (-78% [CI, -88% to 60%]; P < 0.001), CD8(+) cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV(1) decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3(+) cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV(1) level. LIMITATIONS The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months. CONCLUSION ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. .

Endobronchial Valves for Emphysema without Interlobar Collateral Ventilation

BACKGROUND Bronchoscopic lung-volume reduction with the use of one-way endobronchial valves is a potential treatment for patients with severe emphysema. To date, the benefits have been modest but have been hypothesized to be much larger in patients without interlobar collateral ventilation than in those with collateral ventilation. METHODS We randomly assigned patients with severe emphysema and a confirmed absence of collateral ventilation to bronchoscopic endobronchial-valve treatment (EBV group) or to continued standard medical care (control group). Primary outcomes were changes from baseline to 6 months in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and 6-minute walk distance. RESULTS Eighty-four patients were recruited, of whom 16 were excluded because they had collateral ventilation (13 patients) or because lobar segments were inaccessible to the endobronchial valves (3 patients). The remaining 68 patients (mean [±SD] age, 59±9 years; 46 were women) were randomly assigned to the EBV group (34 patients) or the control group (34). At baseline, the FEV1 and FVC were 29±7% and 77±18% of the predicted values, respectively, and the 6-minute walk distance was 374±86 m. Intention-to-treat analyses showed significantly greater improvements in the EBV group than in the control group from baseline to 6 months: the increase in FEV1 was greater in the EBV group than in the control group by 140 ml (95% confidence interval [CI], 55 to 225), the increase in FVC was greater by 347 ml (95% CI, 107 to 588), and the increase in the 6-minute walk distance was greater by 74 m (95% CI, 47 to 100) (P<0.01 for all comparisons). By 6 months, 23 serious adverse events had been reported in the EBV group, as compared with 5 in the control group (P<0.001). One patient in the EBV group died. Serious treatment-related adverse events in this group included pneumothorax (18% of patients) and events requiring valve replacement (12%) or removal (15%). CONCLUSIONS Endobronchial-valve treatment significantly improved pulmonary function and exercise capacity in patients with severe emphysema characterized by an absence of interlobar collateral ventilation. (Funded by the Netherlands Organization for Health Research and Development and the University Medical Center Groningen; Netherlands Trial Register number, NTR2876.).

Bronchoscopic Lung Volume Reduction Coil Treatment of Patients With Severe Heterogeneous Emphysema

BACKGROUND The lung volume reduction coil (LVR-coil), a new experimental device to achieve lung volume reduction by bronchoscopy in patients with severe emphysema, works in a manner unaffected by collateral airflow. We investigated the safety and efficacy of LVR-coil treatment in patients with heterogeneous emphysema. METHODS In this prospective cohort pilot study, patients were treated bronchoscopically with Nitinol LVR-coils under fluoroscopic guidance in either one procedure or two sequential procedures. Follow-up tests included the St. George Respiratory Questionnaire (SGRQ), pulmonary function testing, and the 6-min walk test (6MWT). RESULTS Twenty-eight LVR-coil procedures were performed in 16 patients (baseline FEV₁, 28% [± 7.6%] predicted). Four patients were treated in one lung, and 12 patients were treated in both lungs. A median of 10 (5-12) coils was placed per lung in 36.5 (20-60) min. Adverse events (AEs) rated as possibly related to either the device or the procedure < 30 days after treatment were pneumothorax (n ± 1), pneumonia (n ± 2), COPD exacerbation (n ± 6), chest pain (n ± 4), and mild (< 5 mL) hemoptysis (n ± 21). From 30 days to 6 months, the AEs that occurred were pneumonia (n ± 3) and COPD exacerbation (n ± 14). All events resolved with standard care. Six months after LVR-coil treatment, there were significant improvements in SGRQ (-14.9 points [± 12.1 points, with 11 patients improving by > 4 points]), FEV₁ (+14.9% ± 17.0%), FVC (+13.4% ± 12.9%), residual volume (-11.4% ± 9.0%), and 6MWT (+84.4 ± 73.4 m), all P < .005. CONCLUSIONS LVR-coil treatment is a promising technique for the treatment of patients with severe heterogeneous emphysema. The treatment is technically feasible and results in significant improvements in pulmonary function, exercise capacity, and quality of life, with an acceptable safety profile. TRIAL REGISTRY ClinicalTrials.gov; No.:NCT01220908; URL: www.clinicaltrials.gov