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Marc Miravitlles,1,2 Fernando González-Torralba,3 Cristina Represas-Represas,4 Xavier Pomares,2,5 Eduardo Márquez-Martín,2,6 Cruz González,7 Carlos Amado,8 Carles Forné,9,10 Soledad Alonso,11 Bernardino Alcázar,12 Miriam Barrecheguren,1 Juan María Jurado Mirete,13 Elsa Naval14 1Pneumology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 2CIBER de Enfermedades Respiratorias (CIBERES), ISCIII, Madrid, Spain; 3Pneumology Department, Hospital Universitario del Tajo, Aranjuez, Spain; 4Pneumology Department, Hospital Álvaro Cunqueiro, Vigo, Spain; 5Pneumology Department, Corporació Sanitària Parc Taulí, Sabadell, Spain; 6Medical-Surgical Unit for Respiratory Diseases, Hospital Universitario Virgen del Rocío, Sevilla, Spain; 7Pneumology Department, Hospital Clínico de Valencia, Valencia, Spain; 8Pneumology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain; 9Heorfy Consulting, Lleida, Spain; 10Basic Medical Sciences Department, University of Lleida, Lleida, Spain; 11Pneumology Department, Hospital Universitario de Torrejón, Torrejón de Ardoz, Spain; 12Pneumology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain; 13Scientific Department, GOC Health Consulting, Barcelona, Spain; 14Pneumology Department, Hospital Universitario de La Ribera, Alzira, SpainCorrespondence: Marc Miravitlles, Pneumology Department, Hospital Universitari Vall d’Hebron, P. Vall d’Hebron 119-129, Barcelona, 08035, Spain, Tel/Fax +34 932746083, Email marcm@separ.esIntroduction: Identifying the variables that guide decision-making in relation to the use of inhaled corticosteroids (ICS) can contribute to the appropriate use of these drugs. The objective of this study was to identify the clinical variables that physicians consider most relevant for prescribing or withdrawing ICS in COPD.Methods: A cross-sectional survey was conducted in Spain from November 2020 to May 2021. Therapeutic decisions on the use of ICS in 11 hypothetical COPD patient profiles were collected using an online survey answered by specialists with experience in the management of patients with COPD. Mixed-effects logistic regression was used to analyze the impact of patients’ characteristics in the therapeutic decision for prescribing ICS or proceeding to its withdrawal.Results: A total of 74 pulmonologists agreed to collaborate in the survey and answered the questionnaire. The results showed great variability, with only 2 profiles achieving consensus for starting or withdrawing the treatment. The frequency and severity of exacerbations influenced the decision to prescribe ICS in a dose-response fashion (1 exacerbation odds ratio (OR) = 1.86, 95% confidence interval (CI) 1.02 to 3.43, two exacerbations OR = 11.6, 95% CI: 4.47 to 30.2 and three OR = 123, 95% CI: 25 to 601). Similarly, increasing blood eosinophils and history of asthma were associated with ICS use. On the other hand, pneumonia reduced the probability of initiating treatment with ICS (OR = 0.54 [0.29 to 0.98]). Lung function and dyspnea degree did not influence the clinician’s therapeutic decision. The results for withdrawal of ICS were similar but in the opposite direction.Conclusion: In accordance with guidelines, exacerbations, blood eosinophils and history of asthma or pneumonia are the factors considered by pulmonologist for the indication or withdrawal of ICS. However, the agreement in prescription or withdrawal of ICS when confronted with hypothetical cases is very low, suggesting a great variability in clinical practice.Keywords: COPD, exacerbation, bronchodilators, inhaled corticosteroids, eosinophils, withdrawal

Fernando González-Torralba,1 Adolfo Baloira,2 Araceli Abad,3 Antonia Fuster,4 Juan Luis García-Rivero,5 Patricia García-Sidro,6 Eduardo Márquez-Martín,7 Marta Palop,8 Néstor Soler,9 José Luis Velasco10 1Respiratory Department, University Hospital of Aranjuez, Madrid, Spain; 2Respiratory Department, University Hospital of Pontevedra, Pontevedra, Spain; 3Respiratory Department, University Hospital of Getafe, Madrid, Spain; 4Respiratory Department, University Hospital Son Llatzer, Palma de Mallorca, Spain; 5Respiratory Department, University Hospital Marqués de Valdecilla, Santander, Spain; 6Respiratory Department, University Hospital of La Plana, Castellón, Spain; 7Respiratory Department, University Hospital Virgen del Rocío, Sevilla, Spain; 8Respiratory Department, Hospital of Sagunto, Valencia, Spain; 9Respiratory Department, Hospital Clinic, Barcelona, Spain; 10Respiratory Department, University Hospital Virgen de la Victoria, Málaga, SpainCorrespondence: Adolfo Baloira, Email adolfo.baloira.villar@sergas.esPurpose: The pharmacological treatment of chronic obstructive pulmonary disease (COPD) is largely based on inhaled bronchodilators. Inspiratory flow and lung deposition are key parameters to be considered in inhaled therapy; however, the relationship between these two parameters, the patient specificities, and the suitability of the inhaler type for COPD management has not been fully addressed. The present study follows a Delphi Panel methodology to find expert consensus on the role of inspiratory flow and lung deposition as key decision factors in COPD inhaled therapy.Methods: A two-round Delphi Panel, consisting of 38 statements (items) and completed by 57 Spanish pulmonologists, was carried out to measure the experts’ consensus degree with each item.Results: A high degree of consensus was reached on most of the items consulted, among these inspiratory flow or inspiratory capacity should be periodically considered when choosing an inhalation device and to ensure the suitability of the inhaler used; the outflow velocity and particle size of the different devices should be considered to ensure adequate lung deposition; an active device (pressurized metered-dose inhalers (pMDI) or soft mist inhalers (SMI)) should be used in patients with low inspiratory flow to achieve adequate lung deposition; and, the use of dry powder inhalers (DPI) should be re-evaluated in patients with severe obstruction and severe exacerbations.Conclusion: This study shows the relevance of inspiratory flow and the degree of particle deposition in the lung in the choice of an inhalation device for COPD management, as well as the convenience of an SMI type device in cases of low inspiratory flow. Moreover, it highlights the scarcity of information on the specific features of inhalation devices in COPD guidelines.Keywords: dry powder inhalers, pressurized metered-dose inhalers, soft mist inhaler, inhaled therapy device, exacerbations

Objective: The objective of this study was to investigate which of two short questionnaires, the Asthma Control Test (ACT) or the COPD Assessment Test (CAT), correlates better with severity variables and whether they share similar determinants in patients with asthma–COPD overlap. Method: This observational, cross-sectional, multicentric study included smokers and former smokers of more than 10 pack-years, with non-fully reversible airflow obstruction and either a concomitant diagnosis of asthma or signs of type 2 inflammation, from 15 centres in Spain. Results: A total of 157 patients were included, 109 (69.4%) were men, the mean age was 63.3 (SD: 9) years and the mean FEV1 (%) was 59.7% (SD: 20.5%). The mean CAT score was 14.5 (SD: 8.7), and the mean ACT score was 17.9 (SD: 5.2). Both scores showed good correlations (r = 0.717; p < 0.001). In the multivariate analysis, the Hospital Anxiety and Depression Scale and mMRC dyspnoea scores were independently and significantly associated with both the CAT and ACT scores; however, age was only significantly associated with the CAT, and the EQ-5D scores and the number of exacerbations in the previous year were only significantly associated with the ACT scores. The ACT had a slightly better predictive value for exacerbations than the CAT (AUC = 0.70 (95% CI: 0.62 to 0.79 vs. 0.65 (95% CI: 0.56 to 0.74))). Conclusions: There is a good correlation between ACT and CAT scores in patients with ACO. However, severe patients scored worse on the CAT than the ACT. Anxiety, depression and dyspnoea were significantly associated with both the CAT and ACT scores. The ACT was a slightly better predictor of exacerbations than the CAT in this population. [ABSTRACT FROM AUTHOR]

Adolfo Baloira,1 Araceli Abad,2 Antonia Fuster,3 Juan Luis García Rivero,4 Patricia García-Sidro,5 Eduardo Márquez-Martín,6,7 Marta Palop,8 Néstor Soler,9 JL Velasco,10 Fernando González-Torralba11 1Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain; 2Hospital Universitario de Getafe, Madrid, Spain; 3Hospital Unvidersitario Son Llàtzer, Palma de Mallorca, Spain; 4Hospital Comarcal de Laredo, Cantabria, Spain; 5Hospital Universitario de la Plana, Castellón, Spain; 6Hospital Virgen del Rocío, Sevilla, Spain; 7CIBERES, Instituto de Salud Carlos III, Madrid, Spain; 8Hospital de Sagunto, Valencia, Spain; 9Hospital Universitario Clínic, Barcelona, Spain; 10Hospital Universitario Virgen de la Victoria, Málaga, Spain; 11Pulmonology Section, Hospital Universitario del Tajo, Aranjuez, SpainCorrespondence: Fernando González-TorralbaPulmonology Section, Hospital Universitario del Tajo, Av. Amazonas Central, s/n, Aranjuez, 28300, Madrid, SpainTel +0034 918 01 41 00Email docbectorralba@hotmail.comBackground: Our aim was to describe: 1) lung deposition and inspiratory flow rate; 2) main characteristics of inhaler devices in chronic obstructive pulmonary disease (COPD).Methods: A systematic literature review (SLR) was conducted to analyze the features and results of inhaler devices in COPD patients. These devices included pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), and a soft mist inhaler (SMI). Inclusion and exclusion criteria were established, as well as search strategies (Medline, Embase, and the Cochrane Library up to April 2019). In vitro and in vivo studies were included. Two reviewers selected articles, collected and analyzed data independently. Narrative searches complemented the SLR. We discussed the results of the reviews in a nominal group meeting and agreed on various general principles and recommendations.Results: The SLR included 71 articles, some were of low–moderate quality, and there was great variability regarding populations and outcomes. Lung deposition rates varied across devices: 8%– 53% for pMDIs, 7%-69% for DPIs, and 39%– 67% for the SMI. The aerosol exit velocity was high with pMDIs (more than 3 m/s), while it is much slower (0.84– 0.72 m/s) with the SMI. In general, pMDIs produce large-sized particles (1.22– 8 μm), DPIs produce medium-sized particles (1.8– 4.8 μm), and 60% of the particles reach an aerodynamic diameter < 5 μm with the SMI. All inhalation devices reach central and peripheral lung regions, but the SMI distribution pattern might be better compared with pMDIs. DPIs’ intrinsic resistance is higher than that of pMDIs and SMI, which are relatively similar and low. Depending on the DPI, the minimum flow inspiratory rate required was 30 L/min. pMDIs and SMI did not require a high inspiratory flow rate.Conclusion: Lung deposition and inspiratory flow rate are key factors when selecting an inhalation device in COPD patients.Keywords: COPD, lung deposition, inspiratory flow, inhalation devices, systematic literature review

Objective: Describing the occurrence of infections in patients with relapsing-remitting multiple sclerosis (RRMS) treated with fingolimod and with different degrees of lymphopenia in our unit. Patients and Methods: Observational, descriptive, longitudinal, and retrospective study in the Hospital Centro Médico Nacional Siglo XXI. Patients with RRMS and treatment with fingolimod were grouped based on lymphocyte count and infections. Quantitative variables were expressed as mean, standard deviation, and interquartile range; qualitative variables were expressed as frequencies and percentages. Results: 110 patients, 76 (69.1%) female, 34 (30.9%) male, mean age 38.3 years (17-63, SD 9.85). Mean of initial expanded disability status scale 1.59 (0-5.5, SD 1.15) with a mean diagnosis time of 63.6 months (3-252, SD 50.96). Prior to starting fingolimod, 90.09% of patients had lymphocyte count >1,000. At six months of treatment, 35.64% had lymphocyte >1,000. At twelve months 32.95% had lymphocyte from 501 to 700. At 24 months, 34.21% had lymphocyte from 701 to 1,000. Of the 110 patients, 31.8% had mild infections, of which pharyngitis was reported in 10%, gastroenteritis 2.7%, urinary tract infection 10.9%, HPV infection 0.9%, SARS-CoV-2 infection 3.6%, ophthalmic herpes 0.9%, molluscum contagiosum 0.9%, oral candidiasis 0.9%. 68.18% did not present infections of any kind, no serious infections were reported even with lymphocyte levels below 200. Conclusions: Selective lymphopenia caused by fingolimod was not associated with infections of any kind in this population even at levels of 200-500 cells/mm3.

The use of phytogenic extracts is considered a sustainable strategy for the prevention of fish diseases, including Alliaceae as a potential option due to their variety of bioactive compounds. In this study, we analyzed the antibacterial and antiparasitic potential of propyl-propane-thiosulfinate (PTS) and propyl-propane-thiosulfonate (PTSO) from onions. The in vitro activity against Pseudomonas anguilliseptica, Tenacibaculum maritimum, and Photobacterium damselae of both compounds was tested. In addition, the viability of Sparicotyle chrysophrii larvae was evaluated. Moreover, a diet that consisted of a blend of PTS/PTSO (ALLIUM) was used. A total of 90 gilthead sea bream juveniles were tested against P. damselae subsp. Piscicida after 12 weeks of dietary administration. Furthermore, 150 fish with a rate of 10–15 parasites/fish were fed for 21 days and the number of gill parasites was recorded. All strains were sensitive to both compounds. PTSO showed the highest inhibitory effect against all target strains, while PTS showed higher effectiveness against S. chrysophrii. Fish from ALLIUM group presented the highest probability of survival, increasing up to 91.1%, whereas in the control group, the probability of survival was 66.7%. The number of parasites in the gilthead sea bream decreased in the ALLIUM group over time. These results suggest the inclusion of PTS and PTSO in feed as a natural strategy to prevent antibacterial and antiparasitic fish diseases.

Jose Luis Lopez-Campos,1,2 Carmen Calero-Acuña,1,2 Eduardo Márquez-Martín,1 Esther Quintana Gallego,1,2 Laura Carrasco-Hernández,1 Maria Abad Arranz,1 Francisco Ortega Ruiz1,2 1Virgen del Rocio University Hospital, Biomedicine Institute of Seville (IBiS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Sevilla, Spain; 2Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain Objective: The combination of a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA) in a single inhaler is a viable treatment option for patients with chronic obstructive pulmonary disease (COPD). Here, we systematically review the current knowledge on double bronchodilation for the treatment of COPD, with a specific focus on its efficacy versus placebo and/or monotherapy bronchodilation. Methods: A systematic review of clinical trials investigating LABA/LAMA combination therapies was conducted. Articles were retrieved from PubMed, Embase, and Scopus on June 26, 2016. We specifically selected clinical trials with a randomized controlled or crossover design published in any scientific journal showing the following characteristics: 1) comparison of different LABA/LAMA combinations in a single inhaler for patients with COPD, 2) dose approved in Europe, and 3) focus on efficacy (versus placebo and/or bronchodilator monotherapy) in terms of lung function, respiratory symptoms, or exacerbations. Results: We analyzed 26 clinical trials conducted on 24,338 patients. All LABA/LAMA combinations were consistently able to improve lung function compared with both placebo and bronchodilator monotherapy. Improvements in symptoms were also consistent versus placebo, showing some lack of correlation for some clinical end points and combinations versus monotherapy bronchodilation. Albeit being an exploratory end point, exacerbations showed an improvement with LABA/LAMA combinations over placebo in some trials; however, scarce information was available in comparison with bronchodilator monotherapy in most studies. Conclusion: Our data show consistent improvements for LABA/LAMA combinations, albeit with some variability (depending on the clinical end point, the specific combination, and the comparison group). Clinicians should be aware that these are average differences. All treatments should be tailored at the individual level to optimize clinical outcomes. Keywords: COPD, bronchodilators, efficacy, systematic review

We systematically reviewed the current knowledge on fixed-dose triple therapies for the treatment of chronic obstructive pulmonary disease (COPD), with a specific focus on its efficacy versus single bronchodilation, double fixed dose combinations, and open triple therapies. Articles were retrieved from PubMed, Embase, and Scopus up to 3 August 2018. We selected articles with randomized controlled or crossover design conducted in patients with COPD and published as full-length articles or scientific letters, evaluating triple therapy combinations in a single or different inhaler, and with efficacy data versus monocomponents, double combinations, or open triple therapies. Our systematic search reported 108 articles, of which 24 trials were finally selected for the analysis. A total of 7 studies with fixed dose triple therapy combinations, and 17 studies with open triple therapies combinations. Triple therapy showed improvements in lung function [trough forced expiratory volume (FEV 1) ranging from not significant (NS) to 147 ml], health status using the St. George’s Respiratory Questionnaire [(SGRQ) from NS to 8.8 points], and exacerbations [risk ratio (RR) from NS to 0.59 for all exacerbations] versus single or double therapies with a variability in the response, depending the specific combination, and the comparison group. The proportion of adverse effects was similar between study groups, the exception being the increase in pneumonia for some inhaled corticosteroid (ICS) containing groups. The reviews of this paper are available via the supplementary material section.