Rhinoviruses are the most common cause of virally-induced asthma exacerbations which continue to account for the greatest burden in terms of morbidity, mortality and cost associated with this disease. IL-25 activates type-2-driven inflammation and is potentially important in virally-induced asthma exacerbations. Rhinovirus-infected cultured asthmatic bronchial epithelial cells exhibited a heightened intrinsic capacity for IL-25 expression which correlated with donor atopic status. In vivo human IL-25 expression was greater in asthmatics at baseline and during experimental rhinovirus infection. In mice rhinovirus infection induced IL-25 expression and augmented allergen-induced IL-25. Blockade of the IL-25 receptor reduced many RV-induced exacerbationspecific responses including type-2 cytokine expression, mucus production and recruitment of eosinophils, neutrophils, basophils, T and non-T type-2 cells. We have identified that asthmatic epithelial cells possess increased intrinsic capacity for expression of a pro-type-2 cytokine in

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AimTo determine the potential for drug interactions involving cy tochrome P450 (CYP) in patients receiving palliative day care. MethodsDrugs used by patients attending four specialist palliative day care centres were reviewed to identify combinations that could result in a pharmacokinetic interaction via any of the five main human forms of CYP. ResultsOf 160 patients, 145 (91%) were prescribed at least one drug that was a substrate, inhibitor or inducer of one of the five main CYP isoforms. Twenty-four drug combinations, involving 34 patients, could have given rise to a clinically important interaction. ConclusionsPrescribers should be aware that in this group of patients, one in five are at risk of a clinically important CYP-mediated drug interaction.

The interplay of type-2 inflammation and antiviral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma; however, mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells in vitro and mice in vivo, we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild to moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. In vitro airway epithelial cell-and mouse-RV infection models were then used to define STAT6-and NF-kBmediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface-differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression, increasing CCL17 and suppressing CCL22, whereas NF-kB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6, which was required for CCL17 but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-kB-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-kB activation, whereas expression was differentially regulated by STAT6. Together, these findings suggest that therapeutic targeting of type-2 STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.

Background: This retrospective cohort study aimed to characterize epidemiology, medication use and healthcare resource utilization (HCRU) of patients diagnosed with severe eosinophilic asthma (SEA) compared to other patients with asthma in New Zealand.Methods: Adult patients with asthma with no concurrent diagnosis of Chronic Obstructive Lung Disease (COPD) were identified from the HealthStat primary care database and the National Minimum Dataset using asthma diagnosis, hospital codes and prescriptions. Patients with SEA were identified using a 1-year baseline period (2011) and were those with: inhaled corticosteroid prescription above medium dose (including high dose) plus controller medication, ≥2 exacerbations, and eosinophils ≥300 cells/µl (or ≥150 in 6 weeks prior to index date); patients were followed for 1 year (2012).Results: 160/3276 (4.9%) asthmatics with available eosinophil counts met SEA criteria. Patients with SEA were more likely to be Māori, former smokers, have more comorbidities, higher mean BMI and higher neutrophil counts compared with other patients with asthma. In the follow-up period, SEA patients had over 4 times as many exacerbations; incidence of exacerbations of the same frequency were highest in Māori patients.Conclusions: Compared with other patients with asthma, SEA patients had over 1.5 times as many respiratory treatment prescriptions and higher all-cause HCRU and total healthcare costs; asthma-related healthcare costs were 3.6 times greater.

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