The COPD assessment test and the modified Medical Research Council scale are not equivalent when related to the maximal exercise capacity in COPD patients.

INTRODUCTION: The management and treatment of Chronic Obstructive Pulmonary Disease (COPD) are based on a cutoff point either of ≥ 10 on the COPD Assessment Test (CAT) or of ≥ 2 of the Medical Research Council (mMRC). Up to now, no study has assessed the equivalence between CAT and mMRC, as related to exercise tolerance in COPD. The aim of this study was to investigate as primary outcome the relationship between CAT and mMRC and maximal exercise capacity in COPD patients. We also evaluated as secondary outcome the agreement between CAT (≥ 10) and mMRC (≥ 2) to categorize patients according to their exercise tolerance. MATERIAL AND METHODS: 118 consecutive COPD patients (39 females), aged between 47 and 85 years with a wide range of airflow obstruction and lung hyperinflation were studied. Maximal exercise capacity was assessed by cardiopulmonary exercise test. RESULTS: CAT and mMRC scores were significantly related to VO2 peak (p<0.01). CAT (≥ 10) and mMRC (≥ 2) have a high likelihood to be associated to a value of VO2 peak less than 15.7 and 15.6 mL/kg/min, respectively. The interrater agreement between CAT (≥ 10) and mMRC (≥ 2) was found to be fair (κ = 0.20) in all patients but slight when they were subdivided in those with VO2 peak < 15 mL/kg/min and in those with VO2 peak ≥ 15 mL/kg/min (κ = 0.10 and κ = 0.20 respectively). CONCLUSION: This study shows that CAT and mMRC are useful tools to predict exercise tolerance in COPD, but they cannot be considered as supplementary measures.

Clinical efficacy of bronchodilators in equine asthma: Looking for minimal important difference.

BACKGROUND: Airway 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. OBJECTIVES: To identify the minimal important difference (MID) in lung function elicited by bronchodilator leading to a meaningful improvement in clinical signs. STUDY DESIGN: Pairwise meta-analysis and meta-regression analysis. METHODS: Literature 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. RESULTS: A 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 RL passed 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 RL of 0.63 cm H2 O/L/s (95% CI 0.33-0.94), representing the slope of meta-regression model (high quality of evidence). MAIN LIMITATIONS: No long-term studies investigated the effect of bronchodilator agents on both lung function and clinical signs in asthmatic horses. CONCLUSIONS: In conclusion, bronchodilator pharmacotherapy in equine asthma elicits clinically meaningful effect when RL increases ≥1 cm H2 O/L/s, a value indicating the MID. Assessing the MID based on change in RL may 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.

Pharmacology and Therapeutics of Bronchodilators Revisited.

Bronchodilators remain the cornerstone of the treatment of airway disorders such as asthma and chronic obstructive pulmonary disease (COPD). There is therefore considerable interest in understanding how to optimize the use of our existing classes of bronchodilator and in identifying novel classes of bronchodilator drugs. However, new classes of bronchodilator have proved challenging to develop because many of these have no better efficacy than existing classes of bronchodilator and often have unacceptable safety profiles. Recent research has shown that optimization of bronchodilation occurs when both arms of the autonomic nervous system are affected through antagonism of muscarinic receptors to reduce the influence of parasympathetic innervation of the lung and through stimulation of ß 2-adrenoceptors (ß 2-ARs) on airway smooth muscle with ß 2-AR-selective agonists to mimic the sympathetic influence on the lung. This is currently achieved by use of fixed-dose combinations of inhaled long-acting ß 2-adrenoceptor agonists (LABAs) and long-acting muscarinic acetylcholine receptor antagonists (LAMAs). Due to the distinct mechanisms of action of LAMAs and LABAs, the additive/synergistic effects of using these drug classes together has been extensively investigated. More recently, so-called "triple inhalers" containing fixed-dose combinations of both classes of bronchodilator (dual bronchodilation) and an inhaled corticosteroid in the same inhaler have been developed. Furthermore, a number of so-called "bifunctional drugs" having two different primary pharmacological actions in the same molecule are under development. This review discusses recent advancements in knowledge on bronchodilators and bifunctional drugs for the treatment of asthma and COPD. SIGNIFICANCE STATEMENT: Since our last review in 2012, there has been considerable research to identify novel classes of bronchodilator drugs, to further understand how to optimize the use of the existing classes of bronchodilator, and to better understand the role of bifunctional drugs in the treatment of asthma and chronic obstructive pulmonary disease.

Frequency of allergic sensitization to Can f 5 in North East Italy. An analysis of 1403 ISACs 112 (Component Resolved Diagnosis) collected retrospectively.

Summary: Recent studies have shown the increasing relevance of allergic sensitization to Can f 5, a prostatic kallicrein expressed in the prostate and detectable only in male dogs. The aim of the present study was to establish the frequency, level of sensitization and association with other dog allergens of Can f 5, as assessed by Component Resolved Diagnosis (CRD- ISAC 112, ThermoFisher Scientific, Uppsala, Sweden), in North East Italy. A total of 1403 CRD ISAC 112 were examined retrospectively. Five-hundred twenty subjects (37 %) had a positive IgE response to at least one of the available animal allergens. Among these 520 subjects, 268 (51.5 %) showed at least one sensitization to dog allergens. Among dog-sensitized individuals, 183 (69.02%) showed IgE against Can f 5, and 106 (57.92%) were sensitized exclusively against Can f 5. The average Can f 5 specific IgE was 8.810 ISU-E, with 77.6 % of individuals showing medium or high values of specific IgE according to manufacturer's specifications. In conclusions, our data confirmed that there is a high number of sensitized patients to Can f 5, which have a high degree of allergic sensitization. These results should be taken into account by allergists managing dog allergic patients. In fact, clinical consequences of this sensitization regard respiratory allergy (burden of rhinitis/asthma), systemic reactions (anaphylaxis during sexual intercourse from cross-reaction with human prostatic antigen), allergen immunotherapy-AIT (likely ineffective in patients with exclusive sensitization), and preventive measures (possibility to own a female dog and a likely reduction of allergen passive transport). Further studies are needed to better explore these aspects in "real life".

Allergy in adolescent population (14-18 years) living in Campania region (Southern Italy). A multicenter study.

Summary: Adolescents (Ad) constitute a difficult to manage population among individuals suffering from asthma. The aim of our study was to assess the prevalence, clinical characteristics and age of onset of allergic sensitization and clinical symptoms in a sample of atopic Ad living in the Campania region (Southern Italy). Sixteen Allergy units or Centers belonging to the Italian Association of Hospital and Territorial Allergologists (AAIITO, Campania region) participated in this cross-sectional study. A case report form (CRF) was specifically designed for this study and commercial allergen extracts used for screening SPTs were provided by ALK-Abelló Group (Milan, Italy). A total of 443 patients were examined (females, f 220, 49.6 %; males, m 223, 50.3%). Dust mites represent the most common sensitizing agents in allergic Ad living in Campania region (Dermatoph. pteronyssinus 67.4% and Dermatoph. farinae 66.5%), followed by Parietaria (58.9%), grasses (45.8%), Artemisia vulgaris (16.7%), Olea Europaea (32.2%), dog dander (17.1%), cat dander (20.0%), Alternaria alternata (8.1%), Cupressus sempervirens (4.9%), Betula pendula (4.7%), other allergens (19.4%). An interesting comparison has been made between clinical data of our Ad with data of elderly patients (E). The role of allergic sensitization is significantly higher in Ad compared to E. Dermatophagoides pteronyssinus is the first sensitizing allergen in Ad and the last in E. Parietaria constitutes the first sensitizing pollen both in Ad and E, the percentage of sensitization is higher in Ad. Another important difference is the higher prevalence of As, as only symptom, in E compared to Ad (19.7% versus 7.6%). In conclusion, our findings confirm the high prevalence and clinical significance of airway allergic sensitization in the adolescents living in Campania region.

Geographical characteristics influencing the risk of poisoning in pet dogs: Results of a large population-based epidemiological study in Italy.

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.

Combining long-acting bronchodilators with different mechanisms of action: A pharmacological approach to optimize bronchodilation of equine airways.

The ultra long-acting ß2 -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.

Allergic sensitization to common pets (cats/dogs) according to different possible modalities of exposure: an Italian Multicenter Study.

BACKGROUND: The query "are there animals at home?" is usually administered for collecting information on anamnesis. This modality to consider exposure to pet allergens constitutes a potential bias in epidemiological studies and in clinical practice. The aim of our study was to evaluate/quantify different modalities of exposure to cat/dog in inducing allergic sensitization. METHODS: Thirty Italian Allergy units participated in this study. Each centre was required to collect the data of at least 20 consecutive outpatients sensitized to cat/dog allergens. A standardized form reported all demographic data and a particular attention was paid in relieving possible modalities of exposure to cat/dog. RESULTS: A total 723 patients sensitized to cat/dog were recorded, 359 (49.65%) reported direct pet contact, 213 patients (29.46%) were pet owners, and 146 subjects (20.19%) were exposed to pets in other settings. Other patients were sensitized by previous pet ownership (150-20.75%) or indirect contact (103-14.25%), in 111 subjects (15.35%) any contact was reported. CONCLUSIONS: Only 213 patients (29.46%) would be classified as "exposed to animals" and 510 (70.54%) as "not exposed" according to usual query. Our classification has shown that many "not-exposed" subjects (399-55.19%) were "really exposed". The magnitude of exposure to pet allergens at home is not related exclusively to pet ownership. These considerations should be taken into account during the planning of epidemiological studies and in clinical practice for the management of pet allergic individuals.

Dog allergy: can a prevalent or exclusive sensitization to Can f 5 be considered a lucky or negative event in real life?

Summary: Recent studies have shown the increasing relevance of allergic sensitization to Can f 5 (a prostatic kallikrein), which is an androgen-regulated protein expressed in the prostate and detectable only in male dogs. Can f 5 can be a prevalent or exclusive sensitizing agent in a considerable percentage of dog-allergic patients. Its specific allergenic characteristics are able to induce possible negative as well as positive clinical effects in individuals sensitized to dogs. In the present article we pointed out the possible pros or cons of sensitization to this allergen in real life. Further studies should be carried out to correctly assess some peculiar characteristics of Can f 5, in order to support the most of positive aspects and remedy at best the negative effects.

Clinical effect of corticosteroids in asthma-affected horses: A quantitative synthesis.

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.

Letter to the Editor: Can dog allergen immunotherapy reduce concomitant allergic sensitization to other furry animals? A preliminary experience.

Summary: It has been shown that allergen immunotherapy (AIT) is effective in reducing symptoms of allergic asthma and rhinitis. Data on the efficacy are less convincing with regard to AIT for allergens of common pets (cats/dogs). We describe a case of dog allergy in which we explored if dog AIT (DAI) could reduce a concomitant allergic sensitization to other allergens of furry animals. Our case demonstrates the efficacy of sublingual DAI on SPTs, symptom score, and spirometric responses despite persistent exposure to dog allergens at home in a patient sensitized, but not exposed, to several other furry animals. Moreover, this is the first report suggesting that DAI is able to reduce SPTs responses not only to dog, but also to other furry animals such as rabbit, horse, mouse, rat, hamster, cow. We recommend an accurate anamnesis and diagnosis of dog allergy before prescribing DAI. In particular, the use of ImmunoCAP ISAC is essential to verify the presence of IgE to lipocalins / albumins belonging to other furry animals. Obviously further studies carried out by using different DAI schedules, allergen amount and time of re-evaluation, laboratory procedure should be performed to confirm our findings.

Pharmacological treatments in asthma-affected horses: A pair-wise and network meta-analysis.

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 ß2 -adrenoreceptor (ß2 -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 ß2 -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.

Benralizumab for the treatment of asthma.

Benralizumab is a humanized monoclonal antibody directed at the a subunit of the interleukin-5 receptor (IL-5R) that is under clinical development. The binding of benralizumab with the alpha chain of IL-5R results in inhibition of hetero-oligomerization of alpha and beta subunits and thus no signal transduction occurs. Consequently, this inhibition prevents proliferation of eosinophils and basophils and the cascade of events following it. Several pivotal trials have documented that benralizumab reduces asthma exacerbation rates with a significant increase in time to the next exacerbation, statistically improves prebronchodilator forced expiratory volume in 1 second (FEV1) and disease-specific health-related quality of life, and is well tolerated in patients with severe asthma and blood eosinophil counts greater than or equal to 150 cells/mcL.