Susanne J. H. Vijverberg

FCER2 T2206C variant associated with chronic symptoms and exacerbations in steroid‐treated asthmatic children

To cite this article: Koster ES, Maitland‐van der Zee A‐H, Tavendale R, Mukhopadhyay S, Vijverberg SJH, Raaijmakers JAM, Palmer CNA. FCER2 T2206C variant associated with chronic symptoms and exacerbations in steroid‐treated asthmatic children. Allergy 2011; 66: 1546–1552.

Clinical utility of asthma biomarkers: from bench to bedside

Asthma is a chronic disease characterized by airway inflammation, bronchial hyperresponsiveness, and recurrent episodes of reversible airway obstruction. The disease is very heterogeneous in onset, course, and response to treatment, and seems to encompass a broad collection of heterogeneous disease subtypes with different underlying pathophysiological mechanisms. There is a strong need for easily interpreted clinical biomarkers to assess the nature and severity of the disease. Currently available biomarkers for clinical practice – for example markers in bronchial lavage, bronchial biopsies, sputum, or fraction of exhaled nitric oxide (FeNO) – are limited due to invasiveness or lack of specificity. The assessment of markers in peripheral blood might be a good alternative to study airway inflammation more specifically, compared to FeNO, and in a less invasive manner, compared to bronchoalveolar lavage, biopsies, or sputum induction. In addition, promising novel biomarkers are discovered in the field of breath metabolomics (eg, volatile organic compounds) and (pharmaco)genomics. Biomarker research in asthma is increasingly shifting from the assessment of the value of single biomarkers to multidimensional approaches in which the clinical value of a combination of various markers is studied. This could eventually lead to the development of a clinically applicable algorithm composed of various markers and clinical features to phenotype asthma and improve diagnosis and asthma management.

Inhaled corticosteroid adherence in paediatric patients: the PACMAN cohort study

Poor adherence with inhaled corticosteroids (ICSs) has been reported frequently and may be associated with uncontrolled asthma. A better understanding of factors influencing adherence may help to achieve higher adherence rates for a larger part of the population, which will eventually lead to better asthma control. The aim of this study was to investigate factors associated with adherence in paediatric ICS users.

Biomarkers of therapy responsiveness in asthma: pitfalls and promises

Asthma is one of the most common chronic diseases worldwide. There is a large inter‐individual variability in response to asthma treatment. Most patients respond well to standard therapy; however, a small proportion of the patients remain symptomatic despite treatment with high dosages of corticosteroids. Uncontrolled asthma leads to a decreased quality of life. Therefore, it is important to identify individuals who will respond poorly to standard asthma medication, especially to standard maintenance therapy with inhaled corticosteroids, at an early stage. Response to anti‐inflammatory therapy is generally monitored by the assessment of clinical symptoms, which only partially correlates with underlying airway inflammation. The identification of specific inflammatory biomarkers might help to guide treatment or predict a corticosteroid response more accurately. Some inflammatory biomarkers are already finding their way into clinical practice (e.g. fraction of nitric oxide in exhaled breath), whereas others are predominantly used as a research tool (e.g. profiles of volatile organic compounds). Currently, there is no inflammatory biomarker used in routine clinical practice to predict a corticosteroid response. More knowledge on the underlying biological mechanism(s) of heterogeneous therapeutic responses could help to identify novel biomarkers. This review will focus on inflammatory patterns and genetic variations that may underlie differences in treatment response in patients with asthma, and will provide an overview of inflammatory biomarkers that could potentially serve as response predictors.

Arg16 ADRB2 genotype increases the risk of asthma exacerbation in children with a reported use of long-acting β2-agonists: results of the pacman cohort

BACKGROUND Current evidence suggests that asthma patients with the ADRB2 Arg16 genotype have a poorer response to long-acting β2-agonists (LABA), but the results remain inconsistent. AIM This study assessed the association between Arg16 variants and treatment outcome in children treated with inhaled corticosteroids (ICS) and LABA. MATERIALS & METHODS ADRB2 Arg16 was genotyped in 597 children (4-12 years of age) participating in the PACMAN cohort study. A questionnaire was used to assess asthma control, frequency of asthma-related emergency department visits and use of oral corticosteroids in the past year. RESULTS Arg/Arg carriers with a reported use of ICS and LABA had an increased risk of oral corticosteroid use (odds ratio: 14.9; 95% CI: 1.59-140.1) and emergency department visits in the past year (odds ratio: 11.9; 95% CI: 1.22-115.8) compared to Gly/Gly carriers. This effect was not observed in Arg/Arg genotype carriers reporting ICS use only. CONCLUSION Children who are homozygous for ADRB2 Arg16 have an increased risk of exacerbations when treated with combined LABA and ICS.

Limited agreement between current and long-term asthma control in children: the PACMAN cohort study

To cite this article: Koster ES, Raaijmakers JAM, Vijverberg SJH, Koenderman L, Postma DS, Koppelman GH, van der Ent CK, Maitland‐van der Zee A‐H. Limited agreement between current and long‐term asthma control in children: the PACMAN cohort study. Pediatr Allergy Immunol 2011: 22: 776–783

Pharmacogenomics in Pediatric Patients: Towards Personalized Medicine

It is well known that drug responses differ among patients with regard to dose requirements, efficacy, and adverse drug reactions (ADRs). The differences in drug responses are partially explained by genetic variation. This paper highlights some examples of areas in which the different responses (dose, efficacy, and ADRs) are studied in children, including cancer (cisplatin), thrombosis (vitamin K antagonists), and asthma (long-acting β2 agonists). For childhood cancer, the replication of data is challenging due to a high heterogeneity in study populations, which is mostly due to all the different treatment protocols. For example, the replication cohorts of the association of variants in TPMT and COMT with cisplatin-induced ototoxicity gave conflicting results, possibly as a result of this heterogeneity. For the vitamin K antagonists, the evidence of the association between variants in VKORC1 and CYP2C9 and the dose is clear. Genetic dosing models have been developed, but the implementation is held back by the impossibility of conducting a randomized controlled trial with such a small and diverse population. For the long-acting β2 agonists, there is enough evidence for the association between variant ADRB2 Arg16 and treatment response to start clinical trials to assess clinical value and cost effectiveness of genotyping. However, further research is still needed to define the different asthma phenotypes to study associations in comparable cohorts. These examples show the challenges which are encountered in pediatric pharmacogenomic studies. They also display the importance of collaborations to obtain good quality evidence for the implementation of genetic testing in clinical practice to optimize and personalize treatment.

Exhaled NO is a poor marker of asthma control in children with a reported use of asthma medication: a pharmacy-based study.

To cite this article: Vijverberg SJH, Koster ES, Koenderman L, Arets HGM, van der Ent CK, Postma DS, Koppelman GH, Raaijmakers JAM, Maitland‐van der Zee A‐H. Exhaled NO is a poor marker of asthma control in children with a reported use of asthma medication: a pharmacy‐based study. Pediatr Allergy Immunol 2012: 23: 529–536.

Pharmacogenetic analysis of GLCCI1 in three north European pediatric asthma populations with a reported use of inhaled corticosteroids

BACKGROUND GLCCI1 rs37972 has previously been associated with decreased lung function improvement upon treatment with inhaled corticosteroids (ICS) in asthmatics. AIM To assess whether variation in rs37972 is associated with altered ICS efficacy in north European asthmatic children and young adults with a reported use of ICS. PATIENTS & METHODS rs37972 was genotyped in three cohort studies of asthmatic children with a reported use of ICS. As an indicator for asthma exacerbations, asthma-related hospital visits and oral corticosteroid use were studied. Asthma control was assessed using a questionnaire. RESULTS rs37972 T allele was not significantly associated with an increased risk of oral corticosteroid use (summary odds ratio: 1.20; 95% CI: 0.99-1.45), an increased risk of asthma-related hospital visits (summary odds ratio: 1.07; 95% CI: 0.89-1.29), uncontrolled symptoms (summary odds ratio: 1.01; 95% CI: 0.75-1.36) or higher ICS dosages (summary β: 0.01, 95% CI: -0.06-0.08). CONCLUSION Variation in GLCCI1 rs37972 genotype does not seem to affect ICS efficacy in north European asthmatic children. Original submitted 26 November 2013; Revision submitted 13 February 2014.

ST13 polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults

The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS.