Annelies M. Slats

Expression of smooth muscle and extracellular matrix proteins in relation to airway function in asthma

BACKGROUND Smooth muscle content is increased within the airway wall in patients with asthma and is likely to play a role in airway hyperresponsiveness. However, smooth muscle cells express several contractile and structural proteins, and each of these proteins may influence airway function distinctly. OBJECTIVE We examined the expression of contractile and structural proteins of smooth muscle cells, as well as extracellular matrix proteins, in bronchial biopsies of patients with asthma, and related these to lung function, airway hyperresponsiveness, and responses to deep inspiration. METHODS Thirteen patients with asthma (mild persistent, atopic, nonsmoking) participated in this cross-sectional study. FEV(1)% predicted, PC(20) methacholine, and resistance of the respiratory system by the forced oscillation technique during tidal breathing and deep breath were measured. Within 1 week, a bronchoscopy was performed to obtain 6 bronchial biopsies that were immunohistochemically stained for alpha-SM-actin, desmin, myosin light chain kinase (MLCK), myosin, calponin, vimentin, elastin, type III collagen, and fibronectin. The level of expression was determined by automated densitometry. RESULTS PC(20) methacholine was inversely related to the expression of alpha-smooth muscle actin (r = -0.62), desmin (r = -0.56), and elastin (r = -0.78). In addition, FEV(1)% predicted was positively related and deep inspiration-induced bronchodilation inversely related to desmin (r = -0.60), MLCK (r = -0.60), and calponin (r = -0.54) expression. CONCLUSION Airway hyperresponsiveness, FEV(1)% predicted, and airway responses to deep inspiration are associated with selective expression of airway smooth muscle proteins and components of the extracellular matrix.

Fluctuations and determinism of respiratory impedance in asthma and chronic obstructive pulmonary disease

Asthma and COPD are chronic respiratory diseases that fluctuate widely with regard to clinical symptoms and airway obstruction, complicating treatment and prediction of exacerbations. Time series of respiratory impedance obtained by the forced oscillation technique are a convenient tool to study the respiratory system with high temporal resolution. In previous studies it was suggested that power-law-like fluctuations exist also in the healthy lung and that respiratory system impedance variability differs in asthma. In this study we elucidate such differences in a population of well-characterized subjects with asthma (n = 13, GINA 1+2), COPD (n = 12, GOLD I+II), and controls (n = 10) from time series at single frequency (12 min, f = 8 Hz). Maximum likelihood estimation did not rule out power-law behavior, accepting the null hypothesis in 17/35 cases (P > 0.05) and with significant differences in exponents for COPD (P < 0.03). Detrended fluctuation analysis exhibited scaling exponents close to 0.5, indicating few correlations, with no differences between groups (P > 0.14). In a second approach, we considered asthma and COPD as dynamic diseases, corresponding to changes of unknown parameters in a deterministic system. The similarity in shape between the combined probability distributions of normalized resistance and reactance was quantified by Wasserstein distances and reliably distinguished the two diseases (cross-validated predictive accuracy 0.80; sensitivity 0.83, specificity 0.77 for COPD). Wasserstein distances between 3+3 dimensional phase space reconstructions resulted in marginally better classification (accuracy 0.84, sensitivity 0.83, specificity 0.85). These latter findings suggest that the dynamics of respiratory impedance contain valuable information for the diagnosis and monitoring of patients with asthma and COPD, whereas the value of the stochastic approach is not clear presently.

Asthma and chronic obstructive pulmonary disease overlap: asthmatic chronic obstructive pulmonary disease or chronic obstructive asthma?:

Asthma and chronic obstructive pulmonary disease (COPD) are different disease entities. They are both clinical diagnoses, with diagnostic tools to discriminate between one another. However, especially in older patients (>55 years) it seems more difficult to differentiate between asthma and COPD. This has led to the definition of a new phenotype called asthma COPD overlap syndrome (ACOS). However, our understanding of ACOS is at a very preliminary stage, as most research has involved subjects with existing diagnoses of asthma or COPD from studies with different definitions for ACOS. This has led to different and sometimes opposing results between studies on several features of ACOS, also depending on the comparison with COPD alone, asthma alone or both, which are summarized in this review. We suggest not using the term ACOS for a patient with features of both asthma and COPD, but to describe a patient with chronic obstructive airway disease as completely as possible, with regard to characteristics that determine treatment response (e.g. eosinophilic inflammation) and prognosis (such as smoking status, exacerbation rate, fixed airflow limitation, hyperresponsiveness, comorbidities). This will provide a far more clinically relevant diagnosis, and would aid in research on treatment in more homogenous groups of patients with chronic airways obstruction. More research is certainly needed to develop more evidence-based definitions for this patient group and to evaluate biomarkers, which will help to further classify these patients, treat them more adequately and unravel the underlying pathophysiological mechanism.

Enhanced airway dilation by positive-pressure inflation of the lungs compared with active deep inspiration in patients with asthma

Deep inspiration temporarily reduces induced airways obstruction in healthy subjects. This bronchodilatory effect of deep inspiration is impaired in asthma. Passive machine-assisted lung inflation may augment bronchodilation compared with an active deep inspiration in patients with asthma by either opening closed airways or by reducing fluid flux across the airway wall during deep inspiration, and thereby increasing the tethering forces on the airway wall. We recruited 24 patients with asthma [18-46 yr old, forced expiratory volume in 1 s (FEV(1)) > 70% predicted; provocative concentration of methacholine inducing a 20% fall in FEV(1) (PC(20)) < 8 mg/ml], with either an impaired (n = 12) or an intact (n = 12) bronchodilatory response to deep inspiration. Two methacholine challenges were performed on separate days. At a 50% increase in respiratory resistance (forced oscillation technique at 8 Hz), the change in resistance by a positive-pressure inflation (computer-driven syringe) or an active deep inspiration was measured in randomized order. The reduction in resistance by positive-pressure inflation was significantly greater than by active deep inspiration in the impaired deep inspiration response group (mean change +/- SE: -0.6 +/- 0.1 vs. -0.03 +/- 0.2 cmH(2)O.l(-1).s, P = 0.002). No significant difference was found between positive-pressure inflation and active deep inspiration in the intact deep inspiration response group (-0.6 +/- 0.2 vs. -1.0 +/- 0.3 cmH(2)O.l(-1).s, P = 0.18). Positive-pressure inflation of the lungs can significantly enhance deep inspiration-induced bronchodilation in patients with asthma.

A systematic diagnostic evaluation combined with an internet-based self-management support system for patients with asthma or COPD

Introduction An (inter)national systematic approach for patients with asthma COPD referred to secondary care is lacking. Therefore, a novel systematic approach was designed and tested in clinical practice. Methods This was a retrospective observational study of data from the electronic record system of the Leiden University Medical Center. Asthma and COPD patients were included if they were evaluated with a novel systematic approach or if they had a new record for asthma or COPD and received usual care. The novel systematic approach consisted of a predefined diagnostic evaluation combined with an optional internet-based self-management support system. Diagnostic tests, final diagnosis, lifestyle advices, symptoms and individual care plans in the electronic records, number of patients referred back to primary care, and time to referral back to primary care were compared between the systematic approach and usual care groups using t-tests and chi-squared tests. Results A total of 125 patients were included, of which 22 (21.4%) were evaluated with the systematic approach. Mean (±SD) age was 48.8 (±18.4) years and 59.2% were women. Mean (±SD) number of diagnostic tests was higher in the systematic approach group compared with the usual care group (7.6±1.0 vs 5.5±1.8, P<0.001). Similarly, in the systematic approach group, more lifestyle advices (81.8% vs 29.1%), symptom scores (95.5% vs 21.4%), and individual care plans (50.0% vs 7.8%) were electronically recorded (P<0.001), and more patients were referred back to primary care (81.8% vs 56.3%, P=0.03). There were no differences in the final diagnoses and time to referral back. Conclusion Our study suggested that not all tests that were included in the systematic approach are regularly needed in the diagnostic work-up. In addition, a designated systematic approach stimulates physicians to record lifestyle advices, symptoms, and individual care plans. Thus, this approach could increase the number of patients referred back to primary care.