Background: AHR and inflammation are main characteristics of human and equine asthma. Challenging equine airways with LPS elicits AHR, representing also a suitable model for human airways dysfunction (Pulm Pharmacol Ther. 2018;49:88-94). Aim To match the inflammatory and contractile profile in LPS-challenged equine isolated bronchi to identify molecular targets potentially effective to counteract AHR. Methods Equine isolated bronchi were incubated overnight with LPS (0.1-100 ng/ml). The contractile response to electrical field stimulation (EFS) and levels of cytokines, chemokines, and NKA were quantified. The role of capsaicin sensitive-sensory nerves, NK2 receptor, TRPV1, and epithelium were also investigated. Results LPS 1 ng/ml elicited AHR to EFS (+238.17±25.20% P<0.001). LPS significantly (P<0.05) increased the levels of IL-4 (+36.08±1.62%), IL-5 (+38.60±3.58%), IL-6 (+33.79±2.59%), IL-13 (+40.91±1.93%), IL-1β (+1650.16±71.16%), IL-33 (+88.14±8.93%), TGF-β (22.29±1.03%), TNF-α (+56.13±4.61%), CXCL-8 (+98.49±17.70%), EOTAXIN (+32.26±2.27%), MCP-1 (+49.63±4.59%), (RANTES +36.38±2.24%), and NKA (+112.81±6.42%). Capsaicin sensitive-sensory nerves, NK2 receptor, and TRPV1 were generally involved in the LPS-mediated inflammation. Epithelium modulated the release of IL-1β, IL-33, and TGF-β. Only the levels of IL-6 fitted with EFS-induced AHR, an effect inhibited by anti-IL-6 antibody (P<0.05); exogenous IL-6 induced AHR to EFS similar to that elicited by LPS. Conclusions: Targeting IL-6 may represent an effective strategy to prevent equine AHR, supporting recent evidence on the pivotal role of IL-6 in human severe asthma (Am J Respir Crit Care Med. 2020;1324-1325).

SummaryBackgroundAirway obstruction is the main trait of severe equine asthma that affects respiratory function and elicits detrimental effects on clinical presentation. Only few and underpowered clinical studies have investigated the impact of improvement in lung function induced by bronchodilators on the clinical signs of asthma‐affected horses.ObjectivesTo identify the minimal important difference (MID) in lung function elicited by bronchodilator leading to a meaningful improvement in clinical signs.Study designPairwise meta‐analysis and meta‐regression analysis.MethodsLiterature searches were performed for studies that investigated the effect of bronchodilator therapy on lung function and clinical condition of asthmatic horses. The relationship between the change in lung function variables and clinical score was analysed via random‐effect meta‐regression. One‐point change of the Improved clinically Detectable Equine Asthma Scoring System (IDEASS) score was used to identify the MID.ResultsA significant (P<0.05) relationship was found between the changes in IDEASS score and maximum change in transpulmonary pressure (ΔPplmax) or pulmonary resistance (RL). Since only the model resulting for RLpassed through the origin (Y‐intercept when X = 0: −0.31, 95% CI −0.75 to 0.14), this variable was used to identify the MID correlated with a meaningful improvement in clinical signs. The resulting MID value was a change in RLof 0.63 cm H2O/L/s (95% CI 0.33–0.94), representing the slope of meta‐regression model (high quality of evidence).Main limitationsNo long‐term studies investigated the effect of bronchodilator agents on both lung function and clinical signs in asthmatic horses.ConclusionsIn conclusion, bronchodilator pharmacotherapy in equine asthma elicits clinically meaningful effect when RLincreases ≥1 cm H2O/L/s, a value indicating the MID. Assessing the MID based on change in RLmay improve the quality of evidence and the scientific impact of future clinical trials as it extends beyond the simple, and limiting, evaluation of statistical significance.

BACKGROUND:There are limited findings from low-powered studies based on few number of subjects with equine asthma. Furthermore, no studies have been performed to assess a meaningful clinically detectable impact of corticosteroids in equine asthma. OBJECTIVES:To assess and compare the clinical effect of inhaled and systemic corticosteroids in equine asthma and identify a quantitative clinical score suitable to assess the Minimal Important Difference (MID), expressed as the Minimally Clinically Detectable Difference (MCDD). STUDY DESIGN:Pair-wise and network meta-analysis. METHODS:Literature searches for studies on corticosteroid therapy in equine asthma were performed. The risk of publication bias was assessed by Funnel plots and Egger's test. The effect on changes in clinical scores vs. control was analysed via random-effects models and Bayesian networks. RESULTS:Corticosteroids significantly improved the clinical condition (Standardised Mean Difference: -1.52, 95% CrI -2.07 to -0.98; P<0.001 vs. control). No difference was detected between inhaled and systemic corticosteroids with regard to the changes in clinical scores (Relative Effect: 0.08, 95% CrI -1.45 to 1.32; P = 0.8). An Improved clinically Detectable Equine Asthma Scoring System (IDEASS) indicated that corticosteroids improved the clinical condition of asthmatic horses by 30% compared with controls (IDEASS value: -2.36, 95% CI -3.39 to -1.33; P<0.001). A one-point change in IDEASS represented the MCDD in equine asthma. MAIN LIMITATIONS:Moderate quality of evidence for systemic corticosteroids. CONCLUSIONS:Inhaled corticosteroids are effective in improving the clinical condition of horses with equine asthma and prevent exacerbations. Systemic corticosteroids should be used only in selected cases with symptomatic airway hyperresponsiveness during exacerbation. IDEASS requires further validation but may represent a suitable approach to rank the level of asthma severity and assess the clinical effect of pharmacotherapy in horses with equine asthma.

The ultra long-acting β2 -adrenoceptor agonist olodaterol plus the ultra long-acting muscarinic antagonist tiotropium bromide are known to relax equine airways. In human bronchi combining these drugs elicits a positive interaction, thus we aimed to characterize this information further in equine isolated airways stimulated by electrical field stimulation (EFS) and using the Concentration-Reduction Index (CRI) and Combination Index (CI) equations. The drugs were administered alone and together by reproducing ex vivo the concentration-ratio delivered by the currently available fixed-dose combination (1:1). The single agents elicited a significant (p < .05) concentration-dependent reduction in the EFS-induced contractility, that was synergistically improved (CI 0.18) when administered in combination (0.9 logarithms more potent, 24% more effective than the monocomponents). The drugs mixture allowed a reduction in the concentration of olodaterol from ≃1 to ≃2.3 logarithms. A favorable CRI was detected also for tiotropium bromide, whose concentration can be reduced ≃1 logarithm at medium effect levels, remaining positive up to submaximal relaxant effect in the presence of olodaterol. The combination of tiotropium bromide/olodaterol allows the reduction in the concentration of the monocomponents to achieve airway smooth muscle relaxation, thus potentially decreases the risk of adverse events when these drugs are used to treat severe asthmatic horses.

Pets can act as sentinels for human health and thus surveillance of pet dogs has the potential to improve awareness of emerging risks for animal and public health. The aim of this study was to investigate factors associated with the risk of canine poisoning. In a large population-based epidemiological investigation in Italy performed from January 2015 to January 2016 and April 2016 to April 2017, descriptive statistics were acquired and analysed to determine variables associated with poisoning events in pet dogs. Results were validated in a test population and forecast analysis of risk was performed. The cumulative incidence of poisoning events was low (10.2/1000 dogs/year). Anticoagulant rodenticides, organophosphate pesticides, metaldehyde and strychnine were the most frequent causes of intoxications. Territory characteristics significantly modulated both the frequency and the nature of the involved substances. The seashore area was associated with poisoning by rodenticides (odds ratio, OR, 1.81, 95% confidence interval, CI, 1.54-2.13) and metaldehyde (OR 1.61, 95% CI 1.16-2.28). The hill country area was associated with poisoning by organophosphate pesticides (OR 1.73, 95% CI 1.38-2.15), metaldehyde (OR 2.26, 95% CI 1.53-3.25) and strychnine (OR 1.86, 95% CI, 1.34-2.57). The mountain area was associated with strychnine poisoning (OR 3.79, 95% CI 2.84-5.06). The prospective cumulative incidence of poisoning over 10 years was 9.74% (95% CI 9.57-9.91). These results may be useful for predicting the risk of poisoning and for estimating the risk index related to specific toxic compounds in specific territories. This study suggests that poisoning events in dogs may represent a problem of public health with the potential to affect wildlife and human beings. (C) 2018 Elsevier Ltd. All rights reserved.

BACKGROUND Equine asthma is a disease characterised by reversible airflow obstruction, bronchial hyper-responsiveness and airway inflammation following exposure of susceptible horses to specific airborne agents. Although clinical remission can be achieved in a low-airborne dust environment, repeated exacerbations may lead to irreversible airway remodelling. The available data on the pharmacotherapy of equine asthma result from several small studies, and no head-to-head clinical trials have been conducted among the available medications. OBJECTIVES To assess the impact of the pharmacological interventions in equine asthma and compare the effect of different classes of drugs on lung function. STUDY DESIGN Pair-wise and network meta-analysis. METHODS Literature searches for clinical trials on the pharmacotherapy of equine asthma were performed. The risk of publication bias was assessed by funnel plots and Egger's test. Changes in maximum transpulmonary or pleural pressure, pulmonary resistance and dynamic lung compliance vs. control were analysed via random-effects models and Bayesian networks. RESULTS The results obtained from 319 equine asthma-affected horses were extracted from 32 studies. Bronchodilators, corticosteroids and chromones improved maximum transpulmonary or pleural pressure (range: -8.0 to -21.4 cmH2 O; P<0.001). Bronchodilators, corticosteroids and furosemide reduced pulmonary resistance (range: -1.2 to -1.9 cmH2 O/L/s; P<0.001), and weakly increased dynamic lung compliance. Inhaled β2 -adrenoreceptor (β2 -AR) agonists and inhaled corticosteroids had the highest probability of being the best therapies. Long-term treatments were more effective than short-term treatments. MAIN LIMITATIONS Weak publication bias was detected. CONCLUSIONS This study demonstrates that long-term treatments with inhaled corticosteroids and long-acting β2 -AR agonists may represent the first choice for treating equine asthma. Further high quality clinical trials are needed to clarify whether inhaled bronchodilators should be preferred to inhaled corticosteroids or vice versa, and to investigate the potential superiority of combination therapy in equine asthma.