M. van den Berge

The role of female sex hormones in the development and severity of allergic and non‐allergic asthma

Allergic asthma is usually diagnosed by the presence of variable airway obstruction, bronchial hyperresponsiveness, and allergy. However, a significant proportion of adult asthma patients (up to 40%) are non‐allergic. Patients with non‐allergic asthma often have a later disease onset and greater disease severity, as reflected by more severe airway obstruction and bronchial hyperresponsiveness. Furthermore, females have a higher risk of developing non‐allergic asthma. The latter suggests that hormone‐related events play an important role in the development and severity of adult‐onset non‐allergic asthma. This paper describes the associations between asthma and hormonal changes throughout the female life‐span, such as those associated with the monthly cycle of menstruation and menopausal hormonal changes.

Effects of small airway dysfunction on the clinical expression of asthma: a focus on asthma symptoms and bronchial hyper-responsiveness.

The small airways are an important site of inflammation in asthma. However, the relation between small airway dysfunction and clinical expression of asthma has hardly been studied.

Altered beta2-adrenergic regulation of T cell activity after allergen challenge in asthma

Background Airway inflammation in asthma is orchestrated by recruitment of T helper (Th)2 lymphocytes to the lung and subsequent production of Th2‐like cytokines upon allergen challenge.

Less small airway dysfunction in asymptomatic bronchial hyperresponsiveness than in asthma

Bronchial hyperresponsiveness (BHR) can be present in subjects without any respiratory symptoms. Little is known about the role of the small airways in asymptomatic subjects with BHR.

Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma

Genomewide association studies (GWASs) of asthma have identified single‐nucleotide polymorphisms (SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness (BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis‐eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctors diagnosed) asthma to our GWAS of asthma with BHR.

Management of Asthma with ICS and LABAs: different treatment strategies

In recent years considerable insight has been gained in the optimal management of adult asthma. In asthma patients who have persistent symptoms despite the daily use of (a low dose) inhaled corticosteroids (ICS), adding a long- acting β 2 -agonist to ICS improves asthma control and decreases the number of exacerbations. Currently two different LABAs are available, ie formoterol and salmeterol. The most important difference between both LABAs is a more rapid onset of action of formoterol (2-5 minutes) when compared to salmeterol (15-30 minutes). Partly based on these pharmacological differences, two major different approaches have been put forward to asthma management. The fi rst approach (Gaining Optimal Asthma Control) is promoted by the producers of fl uticasone/salmeterol and recommends to step up ICS to the dose needed to achieve optimal asthma control in order to keep the patient symptom free and to prevent exacerbations. The second approach is promoted by the producers of budesonide/formoterol and recommends a low maintenance dose which can be adjusted up or down according to the clinical control of asthma. Initially, a treatment strategy with Adjustable Main- tenance Dosing with budesonide/formoterol was introduced. At a later time, this concept was changed to the Symbicort Maintenance And Reliever Therapy (SMART) approach. The aim of this manuscript is to review the current literature on the management of asthma with ICS and LABAs and to discuss the different treatment strategies.

Latrophilin receptors: novel bronchodilator targets in asthma

Background Asthma affects 300 million people worldwide. In asthma, the major cause of morbidity and mortality is acute airway narrowing, due to airway smooth muscle (ASM) hypercontraction, associated with airway remodelling. However, little is known about the transcriptional differences between healthy and asthmatic ASM cells. Objectives To investigate the transcriptional differences between asthmatic and healthy airway smooth muscle cells (ASMC) in culture and investigate the identified targets using in vitro and ex vivo techniques. Methods Human asthmatic and healthy ASMC grown in culture were run on Affymetrix_Hugene_1.0_ST microarrays. Identified candidates were confirmed by PCR, and immunohistochemistry. Functional analysis was conducted using in vitro ASMC proliferation, attachment and contraction assays and ex vivo contraction of mouse airways. Results We suggest a novel role for latrophilin (LPHN) receptors, finding increased expression on ASMC from asthmatics, compared with non-asthmatics in vivo and in vitro, suggesting a role in mediating airway function. A single nucleotide polymorphism in LPHN1 was associated with asthma and with increased LPHN1 expression in lung tissue. When activated, LPHNs regulated ASMC adhesion and proliferation in vitro, and promoted contraction of mouse airways and ASMC. Conclusions Given the need for novel inhibitors of airway remodelling and bronchodilators in asthma, the LPHN family may represent promising novel targets for future dual therapeutic intervention.

PTTG1IP and MAML3, novel genomewide association study genes for severity of hyperresponsiveness in adult asthma

The severity of bronchial hyperresponsiveness (BHR) is a fundamental feature of asthma. The severity of BHR varies between asthmatics and is associated with lack of asthma control. The mechanisms underlying this trait are still unclear. This study aimed to identify genes associated with BHR severity, using a genomewide association study (GWAS) on the slope of BHR in adult asthmatics.

Novel genes and insights in complete asthma remission: A genome-wide association study on clinical and complete asthma remission

Asthma is a chronic respiratory disease without a cure, although there exists spontaneous remission. Genome‐wide association (GWA) studies have pinpointed genes associated with asthma development, but did not investigate asthma remission.

Small airway dysfunction in asymptomatic bronchial hyperresponsiveness and asthma

We read with great interest the article by Boudewijn et al. (1), who compared the small airway dysfunction in healthy controls, subjects with asymptomatic airway hyperresponsiveness, and patients with asthma. We are grateful to the authors for their insights into advancing our understandings of the changes in small airway indices prior to and following methacholine bronchial inhalation challenge as well as their relationship with sensation of dyspnea. We respectfully disagree with the way in which the data were presented. First, the small airway dysfunction seemed to be defined as the presence of either of the aberrant small airway indices in the present study. Although the ‘gold criteria’ for defining small airway dysfunction are lacking, a combination of miscellaneous techniques (i.e., interrupter technique, helium–oxygen mixed gas ventilation, biopsy) may be preferred (2), or alternatively, this should be stated as a major limitation of the study. Second, we found that the changes in small airways caliber following methacholine inhalation challenge were better reflected by resonant frequency (Fres) and the area of reactance integrated from 5Hz to Fres (AX), but not R5–R20, in patients with different levels of asthma control (W.-J. Guan and J.-P. Zheng, unpublished data). This suggested that the frequency dependence should be preferentially employed to determine the degree of small airway dysfunction, particularly in those with asymptomatic airway hyperresponsiveness. Third, the changes in forced vital capacity (FVC) should be explicitly stated, for it represented the degree of air trapping or ventilation heterogeneity as a consequence of small airway dysfunction. The readers might be perplexed by the issue as to whether FVC remained normal following inhalation challenge, and if so, the conclusion that a greater change in small airway indices indicated a more pronounced small airway dysfunction could then be safely made. A surrogate approach could be the measurement of residual volume (RV) and the ratio of RV to total lung capacity (TLC) following inhalation challenge, as the authors did at the baseline measurement only. Furthermore, patients with asthma had a mean FEV1 of 101% predicted, suggesting that they had a very limited magnitude of small airway dysfunction. The bronchial inhalation challenge test might have been precluded because those with moderate to severe asthma, who had more pronounced small airway dysfunction, did not meet the eligibility for enrollment. Apart from the aforementioned pitfalls, some other remarks are made. Airway hyperresponsiveness could be, to our knowledge, significantly influenced by the stimuli insults, for instance cigarette smoking. In this cohort, 53% of subjects with asymptomatic airway hyperresponsiveness were current smokers, and this figure was significantly higher than that in patients with asthma (13%) and healthy controls (33%). This was likely to generate a bias toward the small airway dysfunction detected by impulse oscillometry. Moreover, although it would be reasonable to link the changes in small airway indices to the Borg’s score of dyspnea at PC20, the correlation analysis has been, as determined by its inherited demerits, difficult to fully elucidate the causative effects. And the hypothesis that the dyspnea sensation was influenced by small airways was, at least partly, dampened by the observations in patients with asthma who did not yield statistically significant correlations, although several potential confounders have been mentioned in the authors’ discussion. Once these issues have been appropriately addressed, we could explore deeper into the roles that small airways play in the development of asymptomatic airway hyperresponsiveness and the sensation of dyspnea. This is expected to call for further research on the early intervention of mildest form of asthma. A study that compares the utility of different small airway indices on identifying subjects with asymptomatic airway hyperresponsiveness and reflecting the level of asthma control is also necessary.