Methacholine Chloride

The methacholine challenge requires a 20% fall in forced expiratory volume in one second (FEV1). The fall is measured as litre (L) change from the pre-challenge (baseline) value. A higher baseline FEV1 requires a greater volume change to reach a 20% fall. The aim of this study was to evaluate change using percent predicted, which may remove dependence on the baseline value.

Challenge data from a cohort of 114 asthma patients was re-analysed. The dose causing an 20% fall from baseline (PD20) was compared to a 15% fall in predicted value (PD15%) for the classification of bronchial hyperresponsiveness.

There was significant agreement between PD20 and PD15% (r = 0.95, p < 0.0001), with an ICC of 0.97. PD20 was significantly higher than PD15% (0.0055 mg, p < 0.0001). Greater decreases in FEV1 were observed with PD20 versus PD15% (21.4% pred vs 19.1% pred respectively, p = 0.0004), with 29% of patients requiring at least one additional dose of methacholine to achieve PD20 compared to PD15%. A higher baseline FEV1 resulted in higher PD20 values, whereas no relationship was found for PD15%. Variability in FEV1 between repeated visits (n = 15) was associated with the change in PD20, but not the change in PD15%.

We suggest a PD criteria based on 15% predicted change should be used for bronchial challenge testing. This method is less influenced by baseline airflow obstruction, and is a more efficient and safer way of measuring airway hyperresponsiveness.

Airway remodelling (AR) is a disabling phenomenon in patients with severe asthma, yet suitable models are lacking. We previously developed a dog allergen-induced murine asthma model characterized by T2low Th17-driven neutrophilic airway inflammation and AR. To assess its relevance to human AR associated with T2low severe asthma, a condition characterised by poor response to inhaled steroids, we tested the steroid sensitivity of the key features of this model.

Asthma was induced in C57BL/6 J mice by intranasal sensitization, followed by a three-week challenge with dog allergen. Treatment: Daily intraperitoneal 1 mg kg−1 dexamethasone was administrated during the last week of challenge. Methods: We measured airway resistances in response to methacholine, cellular inflammation in bronchoalveolar lavage, lung cytokines, and quantified AR features, in response to dexamethasone.

Dexamethasone-treated mice showed persistent airway hyperresponsiveness, neutrophilic inflammation, and Il17a overexpression, whereas Il22 expression was abrogated. Pathological AR features, including mucus hyperproduction, subepithelial fibrosis and smooth muscle hypertrophy were not eliminated by dexamethasone.

Our dog allergen-induced murine model of asthma mirrors the steroid-insensitive traits of human severe T2low asthma with AR, making it a relevant tool for identifying novel therapeutic targets in this orphan asthma subset.