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Biomedical subjects

H A Kerstjens

Publications and source records attributed to H A Kerstjens.

At least 19 recordsLinked to original sources
PubMed2004

Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma.

BACKGROUND: Patients with severe asthma are often inadequately controlled on existing anti-asthma therapy, constituting an unmet clinical need. OBJECTIVE: This randomized, double-blind, placebo-controlled trial evaluated the ability of omalizumab, a humanized monoclonal anti-IgE antibody, to improve disease control sufficiently to enable inhaled corticosteroid reduction in patients with severe allergic asthma. METHODS: After a run-in period when an optimized fluticasone dose (> or =1000 microg/day) was received for 4 weeks, patients were randomized to receive subcutaneous omalizumab [minimum 0.016 mg/kg/IgE (IU/mL) per 4 weeks; n=126] or matching placebo (n=120) at intervals of 2 or 4 weeks. The study comprised a 16-week add-on phase of treatment followed by a 16-week fluticasone-reduction phase. Short-/long-acting beta(2)-agonists were allowed as needed. RESULTS: Median reductions in fluticasone dose were significantly greater with omalizumab than placebo: 60% vs. 50% (P=0.003). Some 73.8% and 50.8% of patients, respectively, achieved a > or =50% dose reduction (P=0.001). Fluticasone dose reduction to < or =500 microg/day occurred in 60.3% of omalizumab recipients vs. 45.8% of placebo-treated patients (P=0.026). Through both phases, omalizumab reduced rescue medication requirements, improved asthma symptoms and asthma-related quality of life compared to placebo. CONCLUSION: Omalizumab treatment improves asthma control in severely allergic asthmatics, reducing inhaled corticosteroid requirements without worsening of symptom control or increase in rescue medication use.

Adolescent↗
PubMed2001

Corticosteroid-induced improvement in the PC20 of adenosine monophosphate is more closely associated with reduction in airway inflammation than improvement in the PC20 of methacholine.

It has been suggested in cross-sectional studies that provocation with adenosine 5'-monophosphate (AMP) more closely reflects the inflammatory process in asthma than does provocation with methacholine or histamine. We investigated whether the steroid-induced improvement in the provocative concentration of AMP producing a 20% decline in FEV1 (PC20 AMP) is more closely associated with the concomitant reduction in airway inflammation than is the improvement in PC20 methacholine. In 120 asthmatic patients, we measured PC20 methacholine and PC20 AMP as well as sputum induction and nitric oxide (NO) in exhaled air before and after 2 weeks of treatment with corticosteroids. Improvement in PC20 AMP was solely related to reduction in airway inflammation (i.e., change in the number of sputum eosinophils, lymphocytes, epithelial cells, and concentration of NO in exhaled air). In contrast, improvement in PC20 methacholine was related to both reduction in airway inflammation (i.e., change in the number of sputum eosinophils and lymphocytes) and increase in FEV1 %predicted. The total explained variance of the improvement in bronchial hyperresponsiveness was greater for AMP than for methacholine (36% versus 22%, respectively). We conclude that PC20 AMP is more sensitive to changes in acute airway inflammation than is PC20 methacholine, further reinforcing the notion that PC20 AMP can be a useful tool for monitoring the effects of antiinflammatory therapy.

Adenosine Monophosphate↗
PubMed2001

PC(20) adenosine 5'-monophosphate is more closely associated with airway inflammation in asthma than PC(20) methacholine.

Inhalation of a direct stimulus such as histamine or methacholine is generally used to measure bronchial hyperresponsiveness (BHR). Provocation with adenosine 5'-monophosphate (AMP), an indirect airway challenge, has been suggested to be a better marker of airway inflammation than direct challenges. However, so far little information on this subject is available. The aim of our study was to assess whether the concentration of AMP causing the FEV(1) to drop by 20% (PC(20)) is more closely associated with inflammatory parameters in asthma than PC(20) methacholine. In 120 patients with atopic asthma (median FEV(1) 81% predicted [pred], median age 27 yr), PC(20) methacholine and PC(20) AMP as well as sputum induction, blood sampling, and measurement of nitric oxide in exhaled air were performed. PC(20) methacholine was predominantly predicted by FEV(1) %pred (explained variance [ev] = 18%) with the percentage of peripheral blood monocytes being a weak additional independent predictor (total ev = 23%). By contrast, PC(20) AMP was predominantly predicted by the percentage of eosinophils in sputum (ev = 25%), while FEV(1) %pred was only an additional independent predictor (total ev = 36%). PC(20) AMP reflects more closely the extent of airway inflammation due to asthma than PC(20) methacholine.

Adenosine Monophosphate↗
PubMed2000

Changes in peak expiratory flow indices as a proxy for changes in bronchial hyperresponsiveness. Dutch Chronic Non-Specific Lung Disease study group.

Guidelines for asthma management advocate home peak expiratory flow (PEF) monitoring. It is commonly stated that PEF variability is a good proxy of bronchial hyperresponsiveness (BHR), a hallmark of asthma. However, this has hardly been tested longitudinally, as required to monitor asthma. This study assesses which PEF index correlates best with BHR longitudinally and whether the correlation improves when correcting PEF values for the known nonlinearity of mini-Wright PEF meters. Every 6 months, for a period of 2 yrs, PEF diary cards were filled in and BHR to histamine was tested in 104 patients with BHR and reversible airways obstruction, who started treatment with bronchodilators with (n=33) or without (n=71) inhaled corticosteroids. Within each subject, PEF indices and BHR were correlated longitudinally. The highest median correlation coefficients were obtained in the group of patients using inhaled corticosteroids. The PEF indices providing the best correlation with BHR were: mean PEF bronchodilator response (rho=-0.50) and within-day variation (% mean or % maximum) (with postbronchodilator values, rho=-0.50; without postbronchodilator values, rho=-0.40). Using PEF data corrected for the nonlinearity of the PEF meters did not result in higher correlation coefficients. Since current guidelines on asthma management recommend only bronchodilators on demand, the most useful peak expiratory flow index for reflecting bronchial hyperresponsiveness longitudinally is mean within-day peak expiratory flow variation (% mean or % maximum) (without postbronchodilator values). Since the correlation coefficients are not very strong, the authors suggest that peak expiratory flow measurements are not used as a proxy for bronchial hyperresponsiveness longitudinally but as a measurement in its own right. The use of corrections of peak expiratory flows for the nonlinearity of mini-Wright peak expiratory flow meters does not improve the correlation between peak expiratory flow and bronchial hyperresponsiveness.

Administration, Inhalation↗
PubMed1999

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 micrograms beclomethasone daily, six with 1600 micrograms budesonide daily, and eight with 800 micrograms 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 FEV1 45% 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.

Administration, Inhalation↗
PubMed1999

Effects of inhaled fluticasone and oral prednisolone on clinical and inflammatory parameters in patients with asthma.

BACKGROUND: Guidelines state that oral and inhaled corticosteroids are the cornerstone of asthma treatment. The effect of both types of treatment can be assessed by measuring lung and systemic parameters. Treatment for two weeks with either oral prednisolone (30 mg/day), high dose fluticasone propionate (2000 microg/day, FP2000), or lower dose FP (500 microg/day, FP500), both given by a dry powder inhaler, were compared. METHODS: One hundred and twenty patients with asthma were treated for two weeks in a double blind parallel group design. Lung function, asthma symptoms, airway hyperresponsiveness (PC(20) methacholine and adenosine-5'-monophosphate), sputum eosinophil and eosinophilic cationic protein (ECP) levels were measured as lung parameters. In addition, morning serum blood cortisol, blood eosinophil, and serum ECP levels were measured as systemic parameters. RESULTS: PC(20) methacholine and adenosine-5'-monophosphate showed significantly greater improvement with FP2000 (1.99 and 4.04 doubling concentrations (DC), respectively) than prednisolone (0.90 DC, p = 0.02; 2.15 DC, p = 0. 05) and marginally more than with FP500 (1.69 and 3.54 DC). Changes in sputum eosinophil and ECP concentrations showed similar trends; the decrease in ECP was significantly greater with FP2000 than with FP500. In contrast, the systemic parameters of steroid activity (cortisol, peripheral blood eosinophils, and serum ECP) decreased to a similar extent with FP2000 and prednisolone but significantly less with FP500. CONCLUSIONS: Oral prednisolone (30 mg/day) was inferior to FP2000 in improving airway hyperresponsiveness to both methacholine and AMP, with similar trends in forced expiratory volume in one second (FEV(1)), sputum eosinophil and ECP concentrations. Systemic effects were similar with prednisolone and FP2000 and less with FP500.

Administration, Inhalation↗
PubMed1999

Are inhaled glucocorticosteroids effective in chronic obstructive pulmonary disease?

Chronic obstructive pulmonary disease (COPD) constitutes an enormous, and growing, health problem, the treatment of which has been less than satisfactory so far. COPD is a chronic inflammatory process in the airway wall of the large and peripheral airways as well as in the parenchyma. Because of this inflammation, glucocorticosteroids (steroids) have been investigated in more than 100 studies. By tradition, the forced expiratory volume in 1 s (FEV(1)) has been utilized as the main outcome parameter. More recently, exacerbation frequency and health status (quality of life) have been added as end points. Oral steroids have been demonstrated to be useful during exacerbations, although the effects are smaller than in exacerbations of asthma. In stable COPD, 10% more patients respond favorably to a 2-wk course of steroids than to placebo. The long-term effects of oral steroids have not been evaluated in randomized controlled trials. There have now been 10 studies of inhaled steroids of short duration, defined as up to 3 mo. In general, there was no effect on FEV(1). No other parameters of lung function were consistently measured. Several studies showed a small effect on some inflammatory parameters, but none of these were comparable between studies and therefore await further confirmation and elaboration. In total, eight studies evaluated inhaled steroids over a long period, i.e., at least 6 mo. Five of these have been published, and three major large-scale studies have been presented as abstracts at major meetings but not yet published in full. On the basis of these studies, there seems to be an effect of inhaled steroids during the first 3-6 mo of use, but thereafter no effect on the subsequent decline of lung function has been found. Two studies have documented a reduction in exacerbation frequency and an improvement in health status. In summary, as far as FEV(1) is concerned, there is only a short-term benefit of inhaled steroids at best. The improvements in exacerbations and health status need to be confirmed and valued, but could well be important to patients. There is an urgent need to identify those patients within the large heterogeneous group of patients with COPD who benefit from steroids. For this, it would be useful to pool data from the long-term studies. Postma DS, Kerstjens HAM. Are inhaled glucocorticosteroids effective in chronic obstructive pulmonary disease?

Administration, Inhalation↗
PubMed1998

The utility of methacholine airway responsiveness measurements in evaluating anti-asthma drugs.

BACKGROUND: Measurements of airway responsiveness are frequently used to evaluate anti-asthma drugs. OBJECTIVE: This study investigated the utility of methacholine airway responsiveness measurements in evaluating anti-asthma medications, both in terms of a bronchoprotective effect and the ability to attenuate allergen-induced methacholine airway hyperresponsiveness. METHODS: Methacholine airway responsiveness was measured as PC20 on two occasions (separated by 35+/-17 days, mean +/- SD) in 40 subjects with mild, stable asthma. Additional subjects had PC20 measurements made before and after administration of either inhaled salbutamol (200 microg) (n = 20) or allergen inhalation challenge (n = 31). RESULTS: The reproducibility of the methacholine PC20 with this method was high (intraclass correlation coefficient = 0.94). The average shift in PC20 after salbutamol was 4.11 doubling concentrations (SD = 1.08). On the basis of these results, a sample size of 12 subjects would be required to demonstrate a 1 doubling concentration difference in the bronchoprotective effect of two drugs with a 90% power. The average shift in PC20 after allergen was 1.29 doubling concentrations. On the basis of these results and an estimated SD of 0.96, a sample size of 24 subjects would be required to demonstrate that a drug is effective in attenuating 50% of allergen-induced airway hyperresponsiveness with a 90% power. CONCLUSION: These results confirm the high reproducibility of methacholine PC20 measurements in subjects with mild, stable asthma and demonstrate its utility in evaluating the effects of anti-asthma drugs.

Administration, Inhalation↗
PubMed1998

The importance of serum IgE for level and longitudinal change in airways hyperresponsiveness in COPD.

BACKGROUND: Airways hyperresponsiveness (AHR) is an important feature of patients with chronic obstructive pulmonary disease (COPD). Little is known about factors that modulate AHR in COPD. OBJECTIVE: To study these factors, we performed a long-term, double-blind, parallel intervention study in 58 male, non-allergic patients with COPD. METHODS: During a period of 2 years, patients were treated with inhaled budesonide (1600 microg/day), inhaled budesonide (1600 microg/day) plus oral prednisolone (5 mg/day), or placebo. PC20 histamine was measured at 4-monthly intervals. The influence of treatment, smoking, age, level of lung function, initial serum IgE level and peripheral blood eosinophils on level and longitudinal change of PC20 histamine was analysed. RESULTS: During follow-up, PC20 decreased in our group, and this decrease was not influenced by treatment. PC20 tended to decrease faster in current smokers than in ex-smokers. PC20 was significantly associated with pre-challenge FEV1 at each time point. Level nor decline of PC20 were significantly related to age. A higher initial serum IgE level was independently associated with a lower PC20. Moreover, a higher initial serum IgE level was associated with a slower annual decline of PC20, regardless of treatment, pre-challenge FEV1, and other modulating factors. No significant associations were found between initial blood eosinophils and level or decline of PC20. CONCLUSION: We conclude that AHR increases over time in non-allergic patients with COPD. Treatment with an inhaled corticosteroid alone or in combination with oral prednisolone does not change this increase. Our study suggests an important role for IgE in the course of the disease, since a higher initial serum IgE level predicts a more favourable course with regard to annual decline of PC20 histamine.

Aged↗
PubMed1998

Characteristics of airway hyperresponsiveness in asthma and chronic obstructive pulmonary disease.

Airway obstruction and airway hyperresponsiveness are important features of asthma and chronic obstructive pulmonary disease (COPD). Both diseases are characterized by airway wall and lung tissue inflammation, and in asthma there exists a relationship between the inflammatory state of the airways and the severity of hyperresponsiveness. However, the type and cause of this inflammation, as well as the extent and consequences of the inflammatory process, are different in asthma and COPD. Inflammatory processes affecting the airway wall both in peripheral and central areas of the lung appear to be important, the former one dominating in COPD and the latter in asthma. However, it is not clear which structural changes are open for therapy and which are not. Therefore, a better understanding of the consequence of inflammation for lung tissue and airway wall changes in asthma and COPD has to evolve before a full understanding of airway hyperresponsiveness will emanate.

Asthma↗
PubMed1998

Nitric oxide measured with single-breath and tidal-breathing methods in asthma and COPD.

Nitric oxide (NO) can be measured in exhaled air with the single-breath (SB) and tidal-breathing (TB) methods. To allow comparison between different laboratories, a European Respiratory Society task force recently reported guidelines for standardization of both methods. To facilitate comparison between laboratories further, this study investigated whether there is a difference between NO values measured with SB and TB methods in subjects with asthma or chronic obstructive pulmonary disease (COPD), and in healthy subjects. Moreover, the differences between groups were studied and the influence of smoking in asthma was assessed. Sixteen atopic nonsmoking asthmatics, 16 atopic currently smoking asthmatics, 16 nonatopic nonsmoking healthy controls, 16 nonatopic exsmokers with COPD and 16 nonatopic exsmoking healthy controls were studied. NO concentrations differed substantially between both methods. Mean NO concentrations were higher with the SB than with the TB method in nonsmoking and in smoking asthmatics and especially so with the higher NO values. Furthermore, NO values with both methods were higher in nonsmoking asthmatics than in nonsmoking healthy subjects. NO was not significantly different between exsmokers with COPD and healthy exsmokers. In conclusion nitric oxide values of the single-breath and tidal-breathing methods are not interchangeable. Both methods can be used to measure differences between groups.

Adolescent↗
PubMed1998

Risk of overtreatment with current peak flow criteria in self-management plans. Dutch CNSLD Study Group. Chronic Non-Specific Lung Disease.

Home peak expiratory flow (PEF) measurements have become the cornerstone of asthma self-management plans. However, the cut-off values for changing treatment have not been formally tested. This study focusses on the possible overtreatment brought about by the different cut-off values and denominators currently employed. Data from 133 clinically stable asthmatic patients from a 2.5 yr follow-up study were analysed. The results showed that strict adherence to current criteria would lead to severe overtreatment, with up to 30% of clinically stable patients crossing into the lowest (red) zone at least once a year when personal best is the denominator and when it has not been limited to a defined time of day or to defined prior bronchodilator use. As expected, the passage of clinically stable patients into the lower zones became less frequent when cut-off values were sharpened and when time- and treatment-specific PEFs were used as the denominators. Strict adherence to commonly used peak expiratory flow cut-off values would lead to considerable overtreatment. In order to avoid overtreatment, the morning peak expiratory flow before any (bronchodilator) treatment should be related to the personal best peak expiratory flow measured under the same conditions. The choice of the right cut-off value will also depend on studies being performed to test the amount of undertreatment with a given value.

Administration, Inhalation↗