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Biomedical subjects

Huib A M Kerstjens

Publications and source records attributed to Huib A M Kerstjens.

12 recordsLinked to original sources
PubMed2006

Cigarette smoke-induced emphysema: A role for the B cell?

RATIONALE: Little is known about what drives the inflammatory reaction in the development of chronic obstructive lung disease. B cells have been found. OBJECTIVE: To study the involvement of B cells in the development of emphysema. METHODS: The presence of B-cell follicles and their interaction with other cells were investigated in lungs of patients with chronic obstructive pulmonary disease and of smoking mice. B cells were isolated from lymphoid follicles by laser microdissection and analyzed for the presence of immunoglobulin rearrangements and somatic mutations. MAIN RESULTS: Lymphoid follicles consisting of B cells and follicular dendritic cells with adjacent T cells were demonstrated both in the parenchyma and in bronchial walls of patients with emphysema. A clonal process was observed in all follicles and the presence of ongoing somatic mutations was observed in 75% of the follicles, indicating oligoclonal, antigen-specific proliferation. Similar lymphoid follicles were detected in mice that had developed pulmonary inflammation and progressive alveolar airspace enlargement after smoking. The increase in the number of B-cell follicles was progressive with time and correlated with the increase in mean linear intercept. Specific bacterial or viral nucleic acids could not be detected. CONCLUSIONS: B-cell follicles with an oligoclonal, antigen-specific reaction were found in men and mice with emphysema. In mice, the development was progressive with time and correlated with the increase in airspace enlargement. We hypothesize that these B cells contribute to the inflammatory process and/or the development and perpetuation of emphysema by producing antibodies against either tobacco smoke residues or extracellular matrix components.

Animals↗
PubMed2005

Discriminating asthma and COPD based on bronchodilator data: an improvement of the methods.

The degree of bronchodilation is usually expressed as a percentage of the predicted or baseline value. It has been shown that the relation between pre- and post-dilation lung function values is not adequately described by this approach: the sensitivity/specificity in separating asthmatics from cases of chronic obstructive pulmonary disease (COPD) could be improved. The alternative method we investigate is based on a logistic regression approach incorporating pre- and post-dilation lung function, age, sex and height. The discriminatory power of forced expiratory volume in one second (FEV1) increase as a percentage of the predicted or baseline FEV1 is compared to our approach using two databases containing bronchodilator data and diagnoses (asthma, chronic bronchitis or emphysema, the latter two grouped as (OPD). The increase as a percentage of the predicted or baseline approach and our alternative method show areas under the receiver operator curve (ROC) (males/females) of 0.552/0.629, 0.523/0.550 and 0.867/0.879 in one database. In the other database the same trend is present although less obvious: 0.628/0.730, 0.592/0.737 and 0.709/0.749. This increase in discriminatory power is obtained in the optimal use of all available information, especially age, which is not used in the increase of the predicted/baseline FEV1 rule.

Adult↗
PubMed2005

Obtaining optimal control in mild asthma: theory and practice.

BACKGROUND: Studies have shown that asthma severity is easily under-estimated and as a result, patients may be under-treated with reduced asthma control. OBJECTIVE: This study, performed in the General Practice Research Database (GPRD), investigates asthma control in patients treated as intermittent asthmatics (short-acting beta agonist (SABA) alone), or persistent asthmatics (additional inhaled cortico-steroid (ICS), no other medication). METHODS: Patients (0-45 years) diagnosed with asthma between 1 January 1995 and 31 December 2001 taking > or =2 scripts for SABA (SABA only group) or > or =3 scripts for ICS (ICS group) in the first six months following diagnosis were selected. Factors associated with drug prescriptions were assessed. RESULTS: SABA script rates were 3.6 and 5.1 per year in the SABA and ICS group respectively, i.e. >1 dose/day. 10.5% of SABA group and 13.4% of ICS group used oral steroids. Within the SABA group, 37% were stepped up to ICS, the time to first ICS script being significantly associated with prior hospitalization (RR 2.26, CI 1.65-3.10) and atopy (RR 1.47, CI 1.33-1.63). A higher rate of oral steroid use was significantly associated with using ICS, being female, adult and smoking. Smokers and atopic individuals had increased risk of obtaining an earlier script for oral steroid (RR 1.32, CI 1.10-1.59 and RR 1.28, CI 1.10-1.49, respectively). CONCLUSIONS: Asthma control was sub-optimal in a substantial proportion of patients using relatively high doses of SABA, or SABA and ICS from the outset of asthma treatment in general practice. Being female, atopic, a smoker and prior hospitalization were all associated with lack of asthma control and could guide physicians in treatment prescribing.

Administration, Inhalation↗
PubMed2004

Dissociation of lung function and airway inflammation in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is defined by progressive, irreversible airflow limitation and an inflammatory response of the lungs, usually to cigarette smoke. However, COPD is a heterogeneous disease in terms of clinical, physiologic, and pathologic presentation. We aimed to evaluate whether airflow limitation, airway responsiveness, and airway inflammation are separate entities underlying the pathophysiology of COPD by using factor analysis. A total of 114 patients (99 males/15 females, age 62 +/- 8 years, 42 pack-years smoking, no inhaled or oral steroids > 6 months) with irreversible airflow limitation (postbronchodilator FEV(1) 63 +/- 9% predicted, FEV(1)/inspiratory vital capacity [IVC] 48 +/- 9%) and symptoms of chronic bronchitis or dyspnea were studied in a cross-sectional design. Postbronchodilator FEV(1) and FEV(1)/IVC, reversibility to inhaled beta(2)-agonists, diffusing capacity, provocative concentration of methacholine required to produce a 20% drop in FEV(1), total serum IgE, exhaled nitric oxide, and induced sputum cell counts (% eosinophils, % neutrophils) were collected. Factor analysis yielded 4 separate factors that accounted for 63.6% of the total variance. Factor 1 was comprised of FEV(1), FEV(1)/IVC, and residual volume/total lung capacity. Factor 2 included reversibility, IgE, provocative concentration of methacholine required to produce a 20% drop in FEV(1,) and diffusing capacity. Factor 3 contained exhaled nitric oxide and factor 4 included sputum % neutrophils and % eosinophils. We conclude that airflow limitation, airway inflammation, and features commonly associated with asthma are separate and largely independent factors in the pathophysiology of COPD.

Aged↗
PubMed2004

Short-term smoke exposure attenuates ovalbumin-induced airway inflammation in allergic mice.

Little is known about effects of smoking on airway inflammation in asthma. We tested the hypothesis that smoking enhances established airway inflammation in a mouse model of allergic asthma. C57Bl/6j mice were sensitized to ovalbumin (OVA) and challenged with OVA (OVA-mice) or sham-sensitized to phosphate-buffered saline (PBS) and challenged with PBS aerosols (PBS-mice) for 7 wk. At 4 wk, mice were additionally exposed to air (nonsmoking controls) or mainstream smoke for 3 wk. Using whole body plethysmography, we found OVA-induced bronchoconstriction to be significantly inhibited in smoking OVA-mice as compared with nonsmoking OVA-mice (1 +/- 2% increase versus 22 +/- 6% increase in enhanced pause, respectively). Smoking did not change airway hyperresponsiveness (AHR) to methacholine in PBS-mice, yet significantly attenuated AHR in OVA-mice 24 h after OVA challenge as compared with nonsmoking mice. This was accompanied by reduced eosinophil numbers in lung lavage fluid and tissue of smoking OVA-mice compared with nonsmoking OVA-mice. In contrast to our hypothesis, short-term smoking reduced responsiveness to OVA and methacholine in OVA-mice and decreased airway inflammation when compared with nonsmoking mice. This effect of smoking may be different for long-term smoking, in which remodeling effects of smoking can be expected to interrelate with remodeling changes caused by asthmatic disease.

Administration, Inhalation↗
PubMed2004

The role of endogenous and exogenous AMP in asthma and chronic obstructive pulmonary disease.

Bronchial hyperresponsiveness is present in virtually all patients with asthma and in more than two thirds of patients with chronic obstructive pulmonary disease. Thus far, methacholine and histamine are usually used to measure bronchial hyperresponsiveness. Both are direct stimuli, because they act directly on airway smooth muscle. Another possible stimulus to measure bronchial hyperresponsiveness is AMP. AMP is an indirect stimulus, because it acts via the release of histamine and other mediators from immunologically primed mast cells. There is increasing interest in the role of AMP as a bronchoconstrictor stimulus because it has been suggested that the concentration of AMP causing the FEV 1 to decrease by 20% (PC 20 AMP) may be used as a noninvasive marker of airway inflammation. The aim of this article was to review the literature assessing AMP's value in asthma and chronic obstructive pulmonary disease.

Adenosine Monophosphate↗
PubMed2004

Cognitive performance in patients with COPD.

BACKGROUND: Hypoxemic patients with Chronic Obstructive Pulmonary Disease (COPD) have impaired cognitive performance. These neuropsychological impairments are related to the degree of hypoxemia. So far, cognitive performance has not been tested in non-hypoxemic patients with COPD. METHODS: We recruited patients with stable COPD and PaO2 > 8.0 kPa (60 mmHg), as well as healthy subjects, who were matched for age, intelligence quotient (IQ), and level of education. Cognitive performance was studied by Stroop Colour Word Test, Trailmaking, digit-symbol of the Wechsler Adult Intelligence Scale, addition subtest of the Groningen Intelligence Test, and Story Recall. RESULTS: Thirty patients with COPD (FEV1 49.8% pred, mean age 64.8 yr) and 20 healthy volunteers (65.6 yr) were enrolled. COPD patients performed significantly worse on trailmaking B, the digit-symbol test, and on the addition subtest. There was no significant correlation between the tests of cognitive performance and disease specific health status (Chronic Respiratory Questionnaire). CONCLUSIONS: We conclude that even non-hypoxemic patients with COPD show significant impairments in cognitive performance. These impairments are not associated with deteriorations in health related quality of life. Prospective evaluation of the impact of treatment on cognitive performance in non-hypoxemic patients with COPD would be a logical subsequent study.

Aged↗
PubMed2003

Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study.

Antagonizing the effect of interleukin (IL)-5 is a potential new treatment strategy in allergic disorders. We evaluated the safety, biological activity, and pharmacokinetics of SCH55700, a humanized anti-human IL-5 antibody, in subjects with severe persistent asthma treated with oral or high doses of inhaled steroids. In a double-blind, randomized, multicenter trial, a rising single dose of SCH55700 (0.03 mg/kg [n = 2], 0.1 mg/kg [n = 4], 0.3 mg/kg [n = 6], or 1.0 mg/kg [n = 12]) or placebo (n = 8) was administered intravenously. SCH55700 dose dependently reduced circulating eosinophil counts. At a dose of 1.0 mg/kg, the decrease remained significant up to Day 30 [(0.07 +/- 0.01) x 10(9)/L versus (0.23 +/- 0.04) x 10(9)/L at baseline] (mean +/- SEM) (p = 0.05). After administration of SCH55700 at 0.3 and 1.0 mg/kg, a trend toward improvement in baseline FEV1 was observed, which reached significance 24 hours after the 0.3-mg/kg dose (p = 0.019 versus placebo). No significant changes occurred in other clinical indices of disease activity. Adverse events were not different between active treatment and placebo. We conclude that SCH55700 is a biologically active anti-human IL-5 antibody that can be safely used in severe steroid-treated asthma. Its therapeutic potential needs to be addressed in specifically designed efficacy trials.

Adult↗
PubMed2002

Initial improvements in lung function and bronchial hyperresponsiveness are maintained during 5 years of treatment with inhaled beclomethasone dipropionate and terbutaline.

OBJECTIVES: Treatment with inhaled corticosteroids reduces bronchial hyperresponsiveness and relieves airways obstruction in patients with asthma. Up to now, it is unknown whether initial improvements are maintained over a long period of time. Therefore, we assessed whether initial improvements in FEV(1), provocative concentration of histamine causing a 20% fall in FEV(1) (PC(20)), and peak expiratory flow (PEF) persist with a constant dose of inhaled corticosteroids. Furthermore, we investigated whether FEV(1), PC(20), PEF indexes, and symptom scores improve after increasing the dose of inhaled corticosteroids in patients who did not respond sufficiently to treatment with beclomethasone dipropionate (BDP), 800 microg/d. METHODS: Sixty-eight patients with bronchial hyperresponsiveness and airways obstruction completed a previous study on 3 years of treatment with terbutaline, 500 microg qid, and BDP, 200 microg qid. Fifty-eight of these patients participated in the current extension of another 2.5 years of follow-up. Every 6 months, FEV(1) and PC(20) were measured. Five patients dropped out of the study, one for pulmonary reasons. Forty-four patients continued treatment with BDP, 800 microg/d (BDP-800 group), and 9 patients received a higher dose of BDP (500 microg tid; BDP-1,500 group) after the first 3 years because of a rapid decline in FEV(1) (> 50 mL/yr) despite BDP treatment during the previous study period. RESULTS: After the initial improvement, the mean slope of individual regression lines for FEV(1), PC(20), and morning PEF were - 28 mL/yr, - 0.01 doubling concentrations per year, and 0.6 L/min/yr, respectively, in the BDP-800 group. In the BDP-1,500 group, there were no statistically significant improvements in FEV(1), PC(20), PEF indexes, and symptom scores after increasing the dose of BDP. CONCLUSIONS: We conclude that initial improvements in FEV(1), PC(20), and PEF are well preserved over 5 years in patients with obstructive airways diseases who are treated with terbutaline and BDP. In the patients who responded sufficiently to 800 microg/d of BDP, there was no accelerated decline in FEV(1) compared with the general population. Increasing the dose of BDP in a small group of patients with an accelerated fall in FEV(1) (initially treated with a moderate dose of BDP) resulted in no significant improvement in FEV(1), PC(20), PEF indexes, and symptom scores.

Administration, Inhalation↗
PubMed2002

A systematic review of the effects of bronchodilators on exercise capacity in patients with COPD.

One of the major goals of bronchodilator therapy in patients with COPD is to decrease airflow limitation in the airways and, as a consequence, improve dyspnea and exercise tolerance. The focus of this systematic review is to assess the effects of treatment with beta-agonists, anticholinergics, and theophyllines on dyspnea, and steady-state and incremental exercise capacity. Thirty-three, double-blind, randomized, placebo-controlled studies written in English were selected. This review shows that approximately half of the studies showed a significant effect of bronchodilator therapy on exercise capacity. Anticholinergic agents have significant beneficial effects in the majority of studies, especially when measured by steady-state exercise protocols. There is a trend toward a better effect of high-dose compared to low-dose anticholinergics. Short-acting beta(2)-mimetics have favorable effects on exercise capacity in more than two thirds of the studies; surprisingly, the situation is less clear for long-acting beta(2)-agents. The majority of the results of the published reports on theophyllines and their effects on exercise are negative. Direct comparisons of different classes of bronchodilators have not been made in a sufficient number of studies for a rational preference. The addition of a second bronchodilator has no proven advantage for improving exercise test results, but this has not been studied extensively and not in sufficiently large studies. The majority of studies reporting a measure of dyspnea found improvements, even in the absence of improvement in exercise capacity.

Adrenergic beta-Agonists↗