Madelon Bracke

Severity of obstructive airway disease and risk of osteoporotic fracture

The use of inhaled corticosteroids has been associated with a dose-related increased risk of fracture. This may be related to systemic absorption. However, several studies have found that patients with more severe reductions in pulmonary function had reduced bone mineral density, independent of inhaled corticosteroids. The objective of this study was to evaluate the relationship between disease severity and fracture risk. A large case–control study (108,754 cases) was conducted using data from the UK General Practice Research Database. It was found that higher doses of inhaled corticosteroids were associated with greater risks of fracture. The crude odds ratio of fracture among patients exposed to >1,600 μg beclomethasone equivalents per day was 1.95 (95% confidence interval (CI) 1.68–2.27). When adjustments were made for disease severity and use of bronchodilators, the initial dose–response relationship between inhaled corticosteroids and fracture risk disappeared (adjusted odds ratio of 1.19 (95% CI 1.01–1.41)). In conclusion, patients with severe obstructive airway disease are at risk of fracture. However, adequate adjustment for disease severity is essential when the association between the use of inhaled corticosteroids and risk of osteoporotic fracture is studied in observational research.

Iron regulation of siderophore biosynthesis and transport in Pseudomonas putida WCS358: involvement of a transcriptional activator and of the Fur protein

Pseudobactin 358 is the yellow‐green fluorescent siderophore produced by Pseudomonas putida WCS358 in conditions of iron limitation. The genes encoding for siderophore biosynthesis are iron‐regulated at the transcriptional level. Previous work has shown that a positive regulator, PfrA, is absolutely required for the activation under iron‐limiting conditions of pseudobactin 358 biosynthesis. In this study we identified a set of Tn5 insertion mutants of strain WCS358 which lost the ability to activate an iron‐regulated siderophore promoter. These mutants no longer produced pseudobactin 358. Molecular analysis revealed that they carried a Tn5 insertion in a gene, designated pfrl (Pseudomonas ferric regulator), which codes for a protein (Pfrl) of 19.5kDa. Pfrl contains a putative helix‐turn‐helix motif typical of DNA‐binding proteins and has homology to two DNA‐binding transcriptional activators, Fecl from Escherichia coli and Pupl from P. putida. The proposed role of Pfrl in strain WCS358 is an activator protein regulating pseudobactin 358 biosynthesis under iron limitation. The pfrl promoter region contains a sequence which displays high identity to the Fur‐box consensus. This 19bp consensus sequence is recognized by Fur, an iron‐binding repressor protein found in many different bacteria. The E. coli Fur protein can bind to the pfrl promoter region, indicating that this activator gene is likely to be iron‐regulated by Fur. We also report the identification and characterization of the P. putida WCS358 fur gene. The Fur protein of strain WCS358 is structurally and functionally similar to all other cloned Fur proteins from other bacterial species.

Use of inhaled and oral glucocorticoids, severity of inflammatory disease and risk of hip/femur fracture: a population-based case-control study

Background.  Patients using higher dosages of inhaled or oral glucocorticoids (GCs) have an increased risk of hip/femur fractures. The role of the underlying disease in the aetiology of this increased risk has not been widely studied.

Prescription of respiratory medication without an asthma diagnosis in children: a population based study

BackgroundIn pre-school children a diagnosis of asthma is not easily made and only a minority of wheezing children will develop persistent atopic asthma. According to the general consensus a diagnosis of asthma becomes more certain with increasing age. Therefore the congruence between asthma medication use and doctor-diagnosed asthma is expected to increase with age. The aim of this study is to evaluate the relationship between prescribing of asthma medication and doctor-diagnosed asthma in children age 0–17.MethodsWe studied all 74,580 children below 18 years of age, belonging to 95 GP practices within the second Dutch national survey of general practice (DNSGP-2), in which GPs registered all physician-patient contacts during the year 2001. Status on prescribing of asthma medication (at least one prescription for beta2-agonists, inhaled corticosteroids, cromones or montelukast) and doctor-diagnosed asthma (coded according to the International Classification of Primary Care) was determined.ResultsIn total 7.5% of children received asthma medication and 4.1% had a diagnosis of asthma. Only 49% of all children receiving asthma medication was diagnosed as an asthmatic. Subgroup analyses on age, gender and therapy groups showed that the Positive Predictive Value (PPV) differs significantly between therapy groups only. The likelihood of having doctor-diagnosed asthma increased when a child received combination therapy of short acting beta2-agonists and inhaled corticosteroids (PPV = 0.64) and with the number of prescriptions (3 prescriptions or more, PPV = 0.66). Both prescribing of asthma medication and doctor-diagnosed asthma declined with age but the congruence between the two measures did not increase with age.ConclusionIn this study, less than half of all children receiving asthma medication had a registered diagnosis of asthma. Detailed subgroup analyses show that a diagnosis of asthma was present in at most 66%, even in groups of children treated intensively with asthma medication. Although age strongly influences the chance of being treated, remarkably, the congruence between prescribing of asthma medication and doctor-diagnosed asthma does not increase with age.

Pharmacogenetics of anti-inflammatory treatment in children with asthma: rationale and design of the PACMAN cohort

AIMS To investigate the effects of genetic variation on treatment response to asthma medication in children and to identify (profiles of) SNPs that characterize response phenotypes. MATERIAL & METHODS The Pharmacogenetics of Asthma medication in Children: Medication with Anti-inflammatory effects (PACMAN) study was initiated in April 2009 as an observational retrospective pharmacy-based study, including at least 1000 children with asthma medication (aged 4-12 years). Data on respiratory symptoms and medication use behavior will be collected using a questionnaire; complete medication histories will be extracted from the pharmacy information system; additional health information will be requested from the general practitioner; quality of inhalation technique and lung function measurements will be performed and saliva samples for DNA extraction and genotyping will be collected. Two groups of patients will be defined based on questionnaire data and lung function measurements: responders and nonresponders to anti-inflammatory asthma treatment. These two groups will be compared with respect to genetic variation. Corrections will be made for potential confounding factors. RESULTS The main study end point is treatment response, including asthma control, medication use and exhaled nitric oxide as a measure of airway inflammation. Whilst our focus is on genetic factors, this study allows us to also investigate other treatment response determinants, such as inhalation technique and therapy adherence. CONCLUSION Results from the PACMAN study could eventually lead to a more individualized therapy approach. PACMAN will focus on pharmacogenetics of asthma medication in children, while knowledge will be gained of relevant interest to the treatment of the asthma population at large.

Use of β2 agonists and risk of acute myocardial infarction in patients with hypertension

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Use of beta(2) agonists has been associated with tachycardia, an abnormal ECG and atrial fibrillation. * Previous observational studies of the association between use of beta(2) agonists and the risk of acute myocardial infarction (MI) have demonstrated conflicting results. * Instead of a causal effect, the positive association between beta(2) agonist use and MI may be explained by latent ischaemic heart disease, which has symptoms that appear similar to respiratory complaints in chronic obstructive pulmonary disease. WHAT THIS STUDY ADDS * The majority of beta(2) agonist users in our study population did not have an increased risk of nonfatal acute MI. * Only patients with ischaemic heart disease and who had recently started beta(2) agonists had an increased risk of acute MI. * It is likely that this increased risk was related to latent cardiovascular disease rather than direct effects of beta(2) agonists. AIM Observational retrospective studies of the association between use of beta(2) agonists and the risk of acute myocardial infarction (MI) have demonstrated conflicting results, particularly among first-time users. The aim of this study was to examine the association between beta(2) agonist use and first nonfatal acute MI. METHODS We conducted a case-control study (2476 cases) nested in a cohort of antihypertensive drug users in the Dutch PHARMO RLS database. PHARMO RLS consists of drug dispensing linked to the national hospitalizations register. Each case of nonfatal acute MI was matched with up to 12 control patients by gender, age and region. Drug and disease history and the severity of the underlying respiratory disease were adjusted for. RESULTS Risk of acute MI was increased in current beta(2) agonist users [crude odds ratio (OR) 1.36, 95% confidence interval (CI) 1.15, 1.61]. However, this excess risk was reduced after adjustment for severity of asthma and chronic obstructive pulmonary disease (adjusted OR 1.18, 95% CI 0.93, 1.49). The risk was highest in patients with ischaemic heart disease and low cumulative dose of beta(2) agonists (adjusted OR 2.47, 95% CI 1.60, 3.82). CONCLUSION Most users of beta(2) agonists did not have an increased risk of acute MI. Only patients with ischaemic heart disease with low cumulative exposure to beta(2) agonists had an increased risk of acute MI. It is likely that this increased risk was related to latent cardiovascular disease rather than to the direct effects of beta(2) agonists.

What drives prescribing of asthma medication to children? A multilevel population-based study.

PURPOSE Diagnosing asthma in children with asthmatic symptoms remains a challenge, particularly in preschool children. This challenge creates an opportunity for variability in prescribing. The aim of our study was to investigate how and to what degree patient, family, and physician characteristics influence prescribing of asthma medication in children. METHODS We undertook a multilevel population-based study using the second Dutch national survey of general practice (DNSGP-2), 2001. Participants were 46,371 children aged 1 to 17 years belonging to 25,537 families registered with 109 general practitioners. Using a multilevel multivariate logistic regression analysis with 3 levels, our main outcome measure was the prescribing of asthma medication, defined as at least 1 prescription for β2-adrenergic agonists, inhaled corticosteroids, cromones, or montelukast during the 1-year study period. RESULTS We identified characteristics significantly associated with prescribing asthma medication on all 3 levels (child, family, and physician). The variance in prescribing among physicians was significantly higher with children who were younger than 6 years than with children aged 6 years and older (95% CI, 3.5%–25.2% vs 2.4%–13.4%). Several diagnoses other than asthma and asthmatic complaints were strongly associated with prescribing asthma medication, including bronchitis/bronchiolitis (OR = 9.04; 95% CI, 7.57–10.8) and cough (OR = 6.51; 95% CI, 5.68–7.47). CONCLUSIONS Our study shows a much higher variance in prescribing patterns among general practitioners for children younger than 6 years compared with older children, which could be a direct result of the diagnostic complexities found in young children with asthmatic symptoms. Thus diagnostic gaps may lead to more physician-driven prescribing irrespective of the clinical context.

Patients' understanding of the reasons for starting and discontinuing inhaled corticosteroids

AIM Although early discontinuation of treatment in new users of inhaled corticosteroids (ICS) has been widely discussed, the reasons for stopping have not been investigated in depth. We aimed to describe reasons for discontinuation from a patients perspective in relation to their experience of symptoms at the time of the investigation. METHODS A cross-sectional study among new users that discontinued ICS use in the Netherlands was performed. Patients were interviewed by telephone, aiming to identify the symptoms for which they were prescribed ICS, the reasons for discontinuing treatment and the respiratory symptoms patients still experienced at the time of the survey. In addition, automated dispensing records of all patients were retrieved. RESULTS From 287 eligible patients, 230 (80.1%) were interviewed. Only 22 patients (9.6%) mentioned asthma as the reason for a first ICS prescription. A decrease in symptoms was the main reason for discontinuation (45%). Thirty patients (13%) reported clinically significant residual symptoms. These patients reported more seasonal variation of symptoms and were more often prescribed short-acting beta(2)-agonists. CONCLUSIONS The majority of patients mentioned a wide range of symptoms and conditions, other than asthma or chronic obstructive pulmonary disease, as the reason for the start of ICS therapy. Most of these conditions may be expected to be of short duration. Not surprisingly a decrease in symptoms was the main, and justifiable, reason for discontinuing ICS. However, a non-negligible proportion of patients reported residual symptoms that suggest the need of continued ICS use. Physicians and pharmacists could cooperate in identifying those patients for which ICS are really indicated and motivate them to continue the use of ICS.

Persistence of asthma medication use in preschool children

OBJECTIVE In young children with asthmatic symptoms diagnostic difficulties lead to use of trials of asthma medication as a diagnostic tool. Our aim is to quantify the persistent use of asthma medication, initiated in the first year of life and identify determinants of this persistent use. PATIENTS AND METHODS We identified 165 children within the PIAMA (Prevention and Incidence of Asthma and Mite Allergy) birth cohort who used asthma medication before the age of one. Persistent use was investigated during three years after the first prescription. A Cox regression analysis was performed to identify factors associated with persistent use. RESULTS A total of 58.8% of children continued using asthma medication after the first prescription and 10.3% continued during three years. Children with doctor-diagnosed asthma (Hazard ratio of discontinuation (HR)=0.64, 95% CI: 0.45-0.91) or prescribed inhaled corticosteroids in the first year of life (HR of discontinuation=0.59, 95% CI: 0.40-0.86) were 1.6-1.7 times more likely to continue using asthma medication. CONCLUSIONS Persistence of asthma medication, prescribed in the first year of life is very low and is positively associated with doctor-diagnosed asthma and use of inhaled corticosteroids. Characterizing persistent users of asthma medication is important to understand prescribing of asthma medication in this age group.

Distinguishing patterns in the dynamics of long-term medication use by Markov analysis: beyond persistence

BackgroundIn order to accurately distinguish gaps of varying length in drug treatment for chronic conditions from discontinuation without resuming therapy, short-term observation does not suffice. Thus, the use of inhalation corticosteroids (ICS) in the long-term, during a ten-year period is investigated. To describe medication use as a continuum, taking into account the timeliness and consistency of refilling, a Markov model is proposed.MethodsPatients, that filled at least one prescription in 1993, were selected from the PHARMO medical record linkage system (RLS) containing >95% prescription dispensings per patient originating from community pharmacy records of 6 medium-sized cities in the Netherlands.The probabilities of continuous use, the refilling of at least one ICS prescription in each year of follow-up, and medication free periods were assessed by Markov analysis. Stratified analysis according to new use was performed.ResultsThe transition probabilities of the refilling of at least one ICS prescription in the subsequent year of follow-up, were assessed for each year of follow-up and for the total study period.The change of transition probabilities in time was evaluated, e.g. the probability of continuing ICS use of starters in the first two years (51%) of follow-up increased to more than 70% in the following years. The probabilities of different patterns of medication use were assessed: continuous use (7.7%), cumulative medication gaps (1–8 years 69.1%) and discontinuing (23.2%) during ten-year follow-up for new users. New users had lower probability of continuous use (7.7%) and more variability in ICS refill patterns than previous users (56%).ConclusionIn addition to well-established methods in epidemiology to ascertain compliance and persistence, a Markov model could be useful to further specify the variety of possible patterns of medication use within the continuum of adherence. This Markov model describes variation in behaviour and patterns of ICS use and could also be useful to investigate continuous use of other drugs applied in chronic diseases.