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This study was funded by Chiesi.

Asma eosinofílica greu; Comparació indirecta del tractament; Mepolizumab Severe eosinophilic asthma; Indirect treatment comparison; Mepolizumab Asma eosinofílica severa; Comparación de tratamiento indirecto; Mepolizumab Aim To analyse the cost-effectiveness of MEP with standard of care (SoC) versus other anti-IL-5 therapies approved for the treatment of severe eosinophilic asthma (SEA) patients, within the Spanish National Health System (NHS) perspective. Methods A Markov model with a 4-week cycle length was used to compare MEP with BEN and RES as therapies added to SoC in the management of SEA, in terms of cost per QALY gained and incremental cost-effectiveness ratio (ICER). Costs (€2019) were obtained from public sources, while utilities and transition probabilities were retrieved from literature, e.g. network meta-analysis. Continuation criteria for biological treatment and reduction of oral corticosteroids (OCS) was set at 50% minimum reduction of exacerbation rate. Adverse events related to chronic OCS use included diabetes, osteoporosis, cataracts, acute myocardial infarct, and peptic ulcer. The analysis was performed over a 5-year time horizon from the National Healthcare System (NHCS) perspective, with a yearly discount rate of 3% applied to both costs and QALYs. Probabilistic sensitivity analysis and univariate deterministic sensitivity analysis were performed to address uncertainty around the cost-effectiveness results. Results On top of SoC, the model indicates that MEP is dominant (lower cost, higher benefit) compared to BEN and RES: For BEN and RES, respectively, treatment with MEP had a point estimate of 0.076 and 0.075 additional QALYs, and savings of €3,173.47 and €7,772.95 per patient. The findings were robust to variation as estimated using sensitivity analysis. Conclusions MEP is a cost-effective treatment in comparison with BEN and RES added to SoC for patients with SEA in the Spanish setting. This study was funded by GlaxoSmithKline [Study code: HO-19-19968].

Objective To determine the clinical and economic consequences of inhaled corticosteroid doses and particle size in patients on triple-inhalation therapy for COPD. Methods Patients aged ≥40 years who initiated treatment with multi-inhaler triple-inhaled therapy between 1 January 2015 and 31 March were included and followed for 1 year. Patients were grouped according to inhaled corticosteroid (ICS) dose (low/medium/high) and particle size device (extrafine/non-extrafine particles). Outcome variables were moderate and severe exacerbations, pneumonia and healthcare resource use (HCRU) costs. A multivariate analysis was performed for model correction (p

Melanie Schroeder,1 Nicole Benjamin,2 Laura Atienza,3 Chandroday Biswas,4 Alan Martin,5 John D Whalen,6 José Luis Izquierdo Alonso,7 Juan Antonio Riesco Miranda,8 Juan José Soler-Cataluña,9 Alicia Huerta,3 Afisi S Ismaila10,11 1Value Evidence and Outcomes, GlaxoSmithKline plc., Brentford, UK; 2Global Health Economics, ICON plc., Boston, MA, USA; 3Market Access, GlaxoSmithKline SA, Madrid, Spain; 4Global Health Economics, ICON plc., Bengaluru, Karnataka, India; 5Value Evidence and Outcomes, GlaxoSmithKline plc., Uxbridge, UK; 6Global Health Economics, ICON plc., Abingdon, UK; 7Pneumology, Hospital Universitario de Guadalajara, Guadalajara, Spain; 8Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Servicio de Neumología, Hospital San Pedro de Alcántara, Cáceres, Spain; 9Pneumology Department, Hospital Arnau de Vilanova-Lliria (Valencia), Valencia, Spain; 10Value Evidence and Outcomes, GlaxoSmithKline plc., Collegeville, PA, USA; 11Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Afisi S IsmailaGlaxoSmithKline Plc., 1250 South Collegeville Road, Collegeville, PA 19426-0989, USATel +1 (919) 315 8229Email afisi.s.ismaila@gsk.comPurpose: To evaluate the cost-effectiveness of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) vs twice-daily budesonide/formoterol (BUD/FOR) in patients with symptomatic chronic obstructive pulmonary disease (COPD) at risk of exacerbations, from the Spanish National Healthcare System perspective.Patients and Methods: The validated GALAXY-COPD model was used to simulate disease progression and predict healthcare costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) over a 3-year time horizon for a Spanish population. Patient characteristics from published literature were supplemented by data from FULFIL (NCT02345161), which compared FF/UMEC/VI vs BUD/FOR in patients with symptomatic COPD at risk of exacerbations. Treatment effects, extrapolated to 3 years, were based on Week 24 results in the FULFIL intent-to-treat population, including change in forced expiratory volume in 1 second, St. George’s Respiratory Questionnaire score, and exacerbation rates. Treatment, exacerbations, and COPD management costs (2019€) were informed by Spanish public sources and published literature. A 3% discount rate for costs and benefits was applied. One-way sensitivity and scenario analyses, and probabilistic sensitivity analysis (PSA), were performed.Results: FF/UMEC/VI treatment led to fewer moderate and severe exacerbations (2.126 and 0.306, respectively) vs BUD/FOR (2.608 and 0.515, respectively), with a mean incremental cost of € 69 and gain of 0.107 QALYs, which resulted in an ICER of € 642 per QALY gained. In sensitivity analyses, the ICER was most sensitive to treatment effect variations in exacerbations and healthcare resource utilization/event costs. Overall, 95% of 1000 PSA simulations resulted in an ICER less than € 11,000 per QALY gained for FF/UMEC/VI vs BUD/FOR, confirming robustness of the results. The probability of FF/UMEC/VI being cost-effective vs BUD/FOR was 100% at a willingness-to-pay threshold of € 30,000 per QALY gained.Conclusion: At the accepted Spanish ICER threshold of € 30,000, FF/UMEC/VI represents a cost-effective treatment option vs BUD/FOR in patients with symptomatic COPD at risk of exacerbations.Keywords: cost-utility analysis, health-related quality of life, incremental cost-effectiveness ratio, fluticasone furoate, vilanterol, umeclidinium

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (COVID-19) and can be associated with serious complications, including acute respiratory distress syndrome. This condition is accompanied by a massive release of cytokines, also denominated cytokine storm, development of systemic oxidative stress and a prothrombotic state. In this context, it has been proposed a role for acetylcysteine (NAC) in the management of patients with COVID-19. NAC is a molecule classically known for its mucolytic effect, but it also has direct and indirect antioxidant activity as a precursor of reduced glutathione. Other effects of NAC have also been described, such as modulating the immune and inflammatory response, counteracting the thrombotic state, and having an antiviral effect. The pharmacological activities of NAC and its effects on the mechanisms of disease progression make it a potential therapeutic agent for COVID-19. NAC is safe, tolerable, affordable, and easily available. Moreover, the antioxidant effects of the molecule may even prevent infection and play an important role as a complement to vaccination. Although the clinical efficacy and dosing regimens of NAC have been evaluated in the clinical setting with small series of patients, the results are promising. In this article, we review the pathogenesis of SARS-CoV-2 infection and the current knowledge of the mechanisms of action of NAC across disease stages. We also propose NAC posology strategies to manage COVID-19 patients in different clinical scenarios.

On March 11, 2020, the World Health Organization declared Coronavirus Disease 2019 (COVID-19) a pandemic. Till now, it affected 452.4 million (Spain, 11.18 million) persons all over the world with a total of 6.04 million of deaths (Spain, 100,992). It is observed that 75% of hospitalized COVID-19 patients have at least one COVID-19 associated comorbidity. It was shown that people with underlying chronic illnesses are more likely to get it and grow seriously ill. Individuals with COVID-19 who have a past medical history of cardiovascular disorder, cancer, obesity, chronic lung disease, diabetes, or neurological disease had the worst prognosis and are more likely to develop acute respiratory distress syndrome or pneumonia. COVID-19 can affect the respiratory system in a variety of ways and across a spectrum of levels of disease severity, depending on a person's immune system, age and comorbidities. Symptoms can range from mild, such as cough, shortness of breath and fever, to critical disease, including respiratory failure, shock and multi-organ system failure. So, COVID-19 infection can cause overall worsening of these previous respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease, etc. This review aims to provide information on the impact of the COVID-19 disease on pre-existing lung comorbidities.

espanolIntroduccion. En los ultimos anos se han realizado numerosos avances relacionados con la enfermedad pulmonar obstructiva cronica (EPOC), y sobre todo ha habido frecuentes cambios en las recomendaciones respecto al tratamiento; en concreto sobre la indicacion y uso de corticoides inhalados (CI). Objetivos. El objetivo de este documento es generar recomendaciones actualizadas del uso de los CI con el fin de optimizar el tratamiento de los pacientes que acuden a la consulta de los profesionales de atencion primaria. Material y metodos. Neumologos y medicos de atencion primaria (AP) han participado en este proyecto en todo el territorio nacional, compartiendo experiencias clinicas con el fin de recoger la situacion sobre el manejo de los CI en pacientes con EPOC en cada region, analizando y validando las recomendaciones previamente elaboradas por el Comite Cientifico tras una exhaustiva revision de la evidencia cientifica existente. Resultados. La mayoria de los participantes mostraron su acuerdo con las recomendaciones. Se deberia aumentar la formacion sobre conceptos como exacerbacion de la enfermedad y seguridad de los CI. Es importante individualizar los tratamientos y disminuir la variabilidad de criterios. Hay que aumentar el numero de revisiones periodicas, actualizar los protocolos de tratamiento y hacer hincapie en las recomendaciones de las guias de practica clinica sobre el tratamiento LABA/CI en pacientes ACO (siglas del ingles asthma-COPD overlap)1-4, o con recuento elevado de eosinofilos. Se debe fomentar la implicacion de todos los profesionales sanitarios involucrados en el tratamiento del paciente con EPOC e invertir mas recursos economicos en la educacion sanitaria de los pacientes. Conclusiones. En este proyecto se propone una serie de recomendaciones validadas, discutidas y consensuadas por medicos de AP, en relacion con la correcta identificacion del paciente con EPOC candidato a tratamiento con CI inhalados (paciente exacerbador o ACO) y la seguridad en el uso de estos, que esperamos sean de ayuda en la toma de decisiones de los profesionales sanitarios. EnglishIntroduction. In recent years, many advances have been made related with chronic obstructive pulmonary disease (COPD), and above all frequent changes have taken place in the recommendations regarding its treatment, specifically on the indication and use of inhaled corticosteroids (IC). Objectives. This document aims to generate updated recommendations on the use of ICs in order to optimize the treatment of patients who come to the medical office of the primary care professionals. Materials and methods. Pneumologists and primary care (PC) physicians have participated in this project in all of the national territory, sharing clinical experiences in order to gather information on the situation of the management of ICs in patients with COPD in each region, analyzing and validating the recommendations previously elaborated by the Scientific Committee after a comprehensive review of the existing scientific evidence. Results. The majority of the participants expressed their approval with the recommendations. Training should be increased on concepts such as exacerbation of the disease and safety of the ICs. It is important to tailor the treatments and decrease the variability of criteria. The number of regular reviews needs to be increased as well as the need to update the treatment protocols and to place emphasis on the recommendations of the clinical practice guidelines on the LABA/IC treatment patients with asthma-COPD overlaping1-4 or with elevated eosinophil count. Involvement of all the health care professionals participating in the treatment of the patients with COPD should be encouraged and more economic resources must be invested in the health care education of the patients. Conclusions. A series of validated, discussed and agreed upon recommendations by the PC physicians are proposed in this project in relationship with the correct identification of patients with COPD who are candidates for treatment with inhaled ICs (exacerbator or ACO patients) and the safety of the use of these, which we hope will be of help in the decision making of the health care professionals.

Resumen Objetivo Describir un acuerdo entre expertos basado en la evidencia y la experiencia sobre los aspectos mas relevantes del paciente exacerbador con EPOC. Metodos Se siguio la metodologia Delphi. Tras revisar la evidencia por un comite cientifico y 60 expertos, se elaboro un cuestionario con 3 apartados: diagnostico del paciente exacerbador; tratamiento, y proceso asistencial. La encuesta fue respondida online en 2 rondas por 60 neumologos. El grado de acuerdo siguio la escala Likert de 1 (total desacuerdo) a 9 (total acuerdo), definiendose acuerdo y desacuerdo como una puntuacion de 7-9 o 1-3, respectivamente, otorgada por mas de dos tercios de los participantes. Resultados Se incluyeron un total de 48 aseveraciones, una anadida en la segunda ronda. Hubo consenso en 37 (78,7%) tras la primera ronda (acuerdo), y en 43 (89,5%) tras la segunda (42 acuerdo y 1 desacuerdo). Las afirmaciones con mayor proporcion de expertos en el rango de acuerdo se refirieron a que, en el paciente exacerbador, la infeccion bronquial cronica favorece el deterioro de la funcion pulmonar (93,1%), a que no se deben retirar los broncodilatadores de larga duracion (93,1%), a la conveniencia de personalizar el tratamiento si se dan nuevas exacerbaciones pese a un tratamiento broncodilatador optimo (96,6%), o al cuidado y manejo de este paciente, que debe ser coordinado entre atencion primaria y neumologia (93,1%) y controlado en programas integrados especificos multicomponente (94,8%). Conclusiones La informacion proporcionada por este consenso puede facilitar el diagnostico y tratamiento del paciente exacerbador con EPOC en nuestro ambito.

[EN] The application of low ozone dosage to minimize the problems caused by filamentous foaming was evaluated in two bioreactors of an urban wastewater treatment plant. Filamentous and nitrifying bacteria, as well as protist and metazoa, were monitored throughout a one-year period by FISH and conventional microscopy to examine the effects of ozone application on these specific groups of microorganisms. Multivariate data analysis was used to determine if the ozone dosage was a key factor determining the low carbon and nitrogen removal efficiencies observed throughout the study period, as well as to evaluate its impact on the biological communities monitored. The results of this study suggested that ozonation did not significantly affect the COD removal efficiency, although it had a moderate effect on ammonia removal efficiency. Filamentous bacteria were the community most influenced by ozone (24.9% of the variance explained by ozone loading rate), whilst protist and metazoa were less affected (11.9% of the variance explained). Conversely, ozone loading rate was not a factor in determining the nitrifying bacterial community abundance and composition, although this environmental variable was correlated with ammonia removal efficiency. The results of this study suggest that different filamentous morphotypes were selectively affected by ozone. (C) 2019 Elsevier Ltd. All rights reserved., This work was supported by grant from the Entitat de Sanejament d Aigües (EPSAR). P. Barbarroja acknowledges support from MINECO grant PTA2014-09555-I.

[EN] In this study, 16S rRNA gene amplicon sequencing was performed to identify bulking filamentous bacteria in an industrial wastewater treatment plant that threats effluents of bioethanol production process from cereal cooking. The presence of Pseudonocardia sp. was confirmed by comparing the 16SrRNA of the most abundantly amplified sequence (OTU; 12.35%) with corresponding nucleotides present in two genomic databases. The Pseudonocardia species identified was closely related to Pseudonocardia spinosa. Over 50 different types of filamentous microorganisms have been found to cause problems with bulking and foaming, but Pseudonocardia has, until now, not been described to be among them. In addition, the 16S rRNA dataset was analyzed to reveal bacterial community composition during sludge bulking. Candidatus Competibacter was identified as the second most abundant sequence (OTU, 10.04%). Comparative data from samples obtained before and after appearance of Pseudonocardia suggest that a decrease in nutrients could be one of the main factors affecting sludge bulking generated by this species. The outcomes of this study are expected to provide an important insight into the role of Pseudonocardia in bulking in industrial wastewater treatment plants.

Helicobacter pylori is one of the most concerning emerging waterborne pathogens. It has been suggested that it could survive in water inside free-living amoebae (FLA), but nobody has studied this relationship in the environment yet. Thus, we aimed to detect viable H. pylori cells from inside FLA in water samples. Sixty-nine wastewater and 31 drinking water samples were collected. FLA were purified and identified by PCR and sequencing. For exclusively detecting H. pylori inside FLA, samples were exposed to sodium hypochlorite and assayed by specific PMA-qPCR, DVC-FISH and culture. FLA were detected in 38.7% of drinking water and 79.7% of wastewater samples, even after disinfection. In wastewater, Acanthamoeba spp. and members of the family Vahlkampfiidae were identified. In drinking water, Acanthamoeba spp. and Echinamoeba and/or Vermamoeba were present. In 39 (58.2%) FLA-positive samples, H. pylori was detected by PMA-qPCR. After DVC-FISH, 21 (31.3%) samples harboured viable H. pylori internalized cells. H. pylori was cultured from 10 wastewater samples. To our knowledge, this is the first report that demonstrates that H. pylori can survive inside FLA in drinking water and wastewater, strongly supporting the hypothesis that FLA could play an important role in the transmission of H. pylori to humans.

[EN] Viruses (e.g., noroviruses and hepatitis A and E virus), bacteria (e.g., Salmonella spp. and pathogenic Escherichia coli) and protozoa (e.g., Cryptosporidium parvum and Giardia intestinalis) are well-known contributors to food-borne illnesses linked to contaminated fresh produce. As agricultural irrigation increases the total amount of water used annually, reclaimed water is a good alternative to reduce dependency on conventional irrigation water sources. European guidelines have established acceptable concentrations of certain pathogens and/or indicators in irrigation water, depending on the irrigation system used and the irrigated crop. However, the incidences of food-borne infections are known to be underestimated and all the different pathogens contributing to these infections are not known. Next-generation sequencing (NGS) enables the determination of the viral, bacterial and protozoan populations present in a water sample, providing an opportunity to detect emerging pathogens and develop improved tools for monitoring the quality of irrigation water. This is a descriptive study of the virome, bacteriome and parasitome present in different irrigation water sources. We applied the same concentration method for all the studied samples and specific metagenomic approaches to characterize both DNA and RNA viruses, bacteria and protozoa. In general, most of the known viral species corresponded to plant viruses and bacteriophages. Viral diversity in river water varied over the year, with higher bacteriophage prevalences during the autumn and winter. Reservoir water contained Enterobacter cloacae, an opportunistic human pathogen and an indicator of fecal contamination, as well as Naegleria australiensis and Naegleria clarki. Hepatitis E virus and Naegleria fowleri, emerging human pathogens, were detected in groundwater. Reclaimed water produced in a constructed wetland system presented a virome and bacteriome that resembled those of freshwater samples (river and reservoir water). Viral, bacterial and protozoan pathogens were occasionally detected in the different irrigation water sources included in this study, justifying the use of improved NGS techniques to get a comprehensive evaluation of microbial species and potential environmental health hazards associated to irrigation water., This work was supported through a grant funded by the Spanish Ministry of Economy and Competitiveness (MINECO) in the frame of the collaborative international consortium JPIW2013-095-C03-01, JPIW2013-095-C03-02 and JPIW2013-095-C03-03 of the Water Challenges for a Changing World Joint Programming Initiative (Water JPI) Pilot Call and partially by AGL2017-86797-C2-1-R. Silvia Bofill-Mas is a Serra-Hunter fellow at the University of Barcelona.

[EN] The wide diversity of irrigation water sources (i.e., drinking water, groundwater, reservoir water, river water) includes reclaimed water as a requested measure for increasing water availability, but it is also a challenge as pathogen exposure may increase. This study evaluates the level of microbial contamination in different irrigation waters to improve the knowledge and analyses management measures for safety irrigation. Over a one-year period, the occurrence of a set of viruses, bacteria and protozoa, was quantified and the performance of a wetland system, producing reclaimed water intended for irrigation, was characterized. Human fecal pollution (HAdV) was found in most of the irrigation water types analysed. Hepatitis E virus (HEV), an emerging zoonotic pathogen, was present in groundwater where porcine contamination was identified (PAdV). The skin-carcinoma associated Merkel cell polyomavirus (MCPyV), was found occasionally in river water. Noroviruses were detected, as expected, in winter, in river water and reclaimed water. Groundwater, river water and reservoir water also harboured potential bacterial pathogens, like Helicobacter pylori, Legionella spp. and Aeromonas spp. that could be internalized and viable inside amoebas like Acanthamoeba castellanii, which was also detected. Neither Giardia cysts, nor any Cryptosporidium oocysts were detected. The wetland system removed 3 Log(10) of viruses and 5 Log(10) of bacteria, which resembled the river water quality. Irrigation waters were prone to variable contamination levels and according to the European guidance documents, the E. coli (EC) levels were not always acceptable. Sporadic detection of viral pathogens as NoV GII and HAdV was identified in water samples presenting lower EC than the established limit (100MNP/100 mL). When dealing with reclaimed water as a source of irrigation the analysis of some viral parameters, like HAdV during the peak irrigation period (summer and spring) or NoV during the coldest months, could complement existing water management tools based on bacterial indicators., Thiswork was partially funded by a grant fromthe Spanish Ministry of Economy and Competitiveness (MINECO) in the frame of the collaborative international consortium JPIW2013-095-C03-01, JPIW2013095-C03-02 and JPIW2013-095-C03-03 of the Water Challenges for a Changing World Joint Programming Initiative (Water JPI) Pilot Call and partially by AGL2017-86797-C2-1-R. Silvia Bofill-Mas is a SerraHunter fellow at the University of Barcelona. Special thanks to E. Fores, E. Anfruns, and X. Romero from Granollers city council, for the valuable information and help during the sampling campaign.

PURPOSE Diabetes mellitus (DM) is associated with long-term cardiovascular complications, including ischemic heart disease (IHD). Nonetheless, DM may directly impair myocardial and lung structure and function. The aim of this study was to assess the impact of type 2 DM (T2DM) and glycemic control on cardiopulmonary exercise capacity in patients with IHD. METHODS The study involved a cross-sectional analysis of 91 consecutive patients (57 ± 10 yr, 90% men) who underwent a cardiopulmonary exercise test at the beginning of an exercise-based standard phase-II cardiac rehabilitation program, 2 to 3 mo after an acute coronary syndrome. Association of T2DM with cardiopulmonary exercise test parameters was assessed using multiple linear regression analysis controlling for prespecified potential confounders. RESULTS There were 26 (29%) diabetic subjects among IHD patients included in the study. After adjustment, T2DM was an independent predictor of a reduced peak oxygen uptake ((Equation is included in full-text article.)O2peak) (P = .005), a reduced pulse O2 trajectory (P = .001), a steeper minute ventilation to carbon dioxide output (VE/(Equation is included in full-text article.)CO2) slope (P = .046), and an increased dead space-to-tidal volume ratio (VD/VT) at peak exercise (P = .049). Glycated hemoglobin (HbA1c) levels were significantly associated with a reduced forced expiratory volume in the first second of expiration (FEV1) (P = .013), VE (P = .001), and VT (P = .007). (Equation is included in full-text article.)O2peak (P trend < .001), (Equation is included in full-text article.)O2 at anaerobic threshold (P trend < .001), and pulse O2 trajectory (P trend < .001) decreased among HbA1c tertiles. CONCLUSIONS Patients with IHD and a previous diagnosis of T2DM had a reduced aerobic capacity and a ventilation- perfusion mismatch compared with nondiabetic patients. Poor glycemic control in men further deteriorates aerobic capacity probably due to ventilatory inefficiency.

Treated sludge from wastewater treatment plants (WWTPs) is commonly used in agriculture as fertilizers and to amend soils. The most significant health hazard for sewage sludge relates to the wide range of pathogenic microorganisms such as protozoa parasites.The objective of this study was to collect quantitative data on Cryptosporidium oocysts and Giardia cysts in the treated sludge in wastewater treatment facilities in Spain. Sludge from five WWTPs with different stabilization processes has been analysed for the presence of Cryptosporidium and Giardia in the raw sludge and after the sludge treatment. A composting plant (CP) has also been assessed. After a sedimentation step, sludge samples were processed and (oo)cysts were isolated by immunomagnetic separation (IMS) and detected by immunofluorescence assay (IFA). Results obtained in this study showed that Cryptosporidium oocysts and Giardia cysts were present in 26 of the 30 samples (86.6%) of raw sludge samples. In treated sludge samples, (oo)cysts have been observed in all WWTP's analysed (25 samples) with different stabilization treatment (83.3%). Only in samples from the CP no (oo)cysts were detected. This study provides evidence that (oo)cysts are present in sewage sludge-end products from wastewater treatment processes with the negative consequences for public health., We appreciate the financial support provided by Entidad Publica Saneamiento Aguas (EPSAR).

Synopsis Wastewater reuse is a current practice in many countries with water scarcity which poses a significant source of infection to humans through the raw consumption of leafy greens. Current pathogens detected in reused wastewater are not contemplated in existing guidelines. However, information on concentration, dose-response relationships and disease burden for all waterborne pathogens in treated wastewater is scarce. The application of probabilistic models as quantitative microbial risk assessment (QMRA) and consumer safety margin for estimating the risk of infection associated with consuming raw vegetables irrigated with wastewater are helpful tools.

Objective: To describe an evidence- and experience-based expert consensus on the most relevant issues of patients with COPD exacerbations. Methods: The Delphi technique was used. Evidence was reviewed by a scientific committee and 60 experts. A questionnaire was prepared containing 3 sections: diagnosis of the exacerbator; treatment, and healthcare processes. The survey was answered in 2 rounds by 60 pneumologists on an online platform. Statements were scored on a Likert scale from 1 (total disagreement) to 9 (total agreement). Agreement and disagreement were defined as a score of 7-9 or 1-3, respectively, given by more than two thirds of the participants. Results: A total of 48 statements were included, one of which was added in the second round. Consensus was reached in 37 items (78.7%) after the first round (agreement), and in 43 (89.5%) after the second round (42 agreement, 1 disagreement). The statements with the highest proportion of experts agreeing were as follows: in exacerbators, chronic bronchial infection favors lung function decline (93.1%); long-acting bronchodilators should not be withdrawn (93.1%); treatment must be personalized if new exacerbations occur despite optimal bronchodilator treatment (96.6%); management must be coordinated between primary care and the respiratory medicine department (93.1%), and patients must be followed up in specific integrated multicomponent programs (94.8%). Conclusions: The findings of this study could assist in the diagnosis and treatment of COPD exacerbators in our area. (C) 2019 SEPAR. Published by Elsevier Espana, S.L.U. All rights reserved.

Inhalable medications for patients with asthma and chronic obstructive pulmonary disease (COPD) can be confusing even for health care professionals because of the multitude of available devices each with different operating principles. Dry powder inhalers (DPI) are a valuable option for almost all of the patients with asthma or COPD. Based on recorded patient inspiratory profiles, the peak inspiratory flow requirement of 30 L min−1 of high-resistance devices does not usually pose any practical limitations for the patients. Suboptimal adherence and errors in device handling are common and require continuous checking and patient education in order to avoid these pitfalls of all inhalation therapy. The aim of this opinion paper is to describe the working principles of DPIs and to summarise their key properties in order to help prescribing the correct inhaler for each patient. Funding: Orion Pharma.

Free-living amoebae (FLA) are ubiquitous microorganisms commonly found in water. They can act as Trojan Horses for some amoebaresistant bacteria (ARB). Helicobacter pylori is a pathogenic bacteria, suggested to be transmitted through water, which could belong to the ARB group. In this work, a co-culture assay of H. pylori and Acanthamoeba castellanii, one of the most common FLA, was carried out to identify the presence and survival of viable and potentially infective forms of the bacteria internalized by the amoeba. Molecular techniques including FISH, DVC-FISH, qPCR and PMA-qPCR were used to detect the presence of internalized and viable H. pylori. After 24 h in coculture and disinfection treatment to kill extra-amoebic bacteria, viable H. pylori cells were observed inside A. castellanii. When PMAqPCR was applied to the co-culture samples, only DNA from internalized H. pylori cells was detected, whereas qPCR amplified total DNA from the sample. By the combined DVC-FISH method, the viability of H. pylori cells in A. castellanii was observed. Both specific techniques provided evidence, for the first time, that the pathogen is able to survive chlorination treatment in occurrence with A. castellanii and could be very useful methods for performing further studies in environmental samples., The work has also been partially funded by AGL2014-53875-R grant (Ministerio de Economia y Competitividad, Spain) and the "Recovery and joint resources from I+D+i of VLC/CAMPUS program" - MECD (International Excellence Campus Program)

[EN] Understanding waterborne protozoan parasites (WPPs) diversity has important implications in public health. In this study, we evaluated a NGS-based method as a detection approach to identify simultaneously most important WPPs using 18S rRNA high-throughput sequencing. A set of primers to target the V4 18S rRNA region of WPPs such as Cryptosporidium spp., Giardia sp., Blastocystis sp., Entamoeba spp, Toxoplasma sp. and free-living amoebae (FLA) was designed. In order to optimize PCR conditions before sequencing, both a mock community with a defined composition of representative WPPs and a real water sample inoculated with specific WPPs DNA were prepared. Using the method proposed in this study, we have detected the presence of Giardia intestinalis, Acanthamoeba castellanii, Toxoplasma gondii, Entamoeba histolytica and Blastocystis sp. at species level in real irrigation water samples. Our results showed that untreated surface irrigation water in open fields can provide an important source of WPPs. Therefore, the methodology proposed in this study can establish a basis for an accurate and effective diagnostic of WPPs to provide a better understanding of the risk associated to irrigation water., This work was supported through the project funded by the Spanish Ministry of Economy and Competitiveness (MINECO) in the frame of the collaborative international consortium JPIW2013-095-C03-02 of the Water Challenges for a Changing World Joint Programming Initiative (Water JPI) Pilot Call. R. Perez acknowledges support from MINECO program "Promocion de Empleo Joven e Implantacion de la Garantia Juvenil en I + D + i".

[EN] The presence of Cryptosporidium and Giardia in waste water is a main concern because water reuse for irrigation can jeopardize human health. Spanish Legislation for water reuse does not oblige to analyze the presence of both pathogens Cryptosporidium and Giardia in reused water for irrigation. Therefore, the objective of this paper is to determine the influence of wastewater treatment in the increase of the consumer safety margin in relation to the presence of Cryptosporidium and Giardia in leafy green vegetables. With this aim in mind, a total of 108 samples from raw (influent) and treated wastewater (effluent) from three wastewater treatment plants in Spain were analysed according to USEPA Method 1623. Effluent results show that Cryptosporidium oocysts average counts ranged from 1.38 to 2.6/L oocysts and Giardia cysts ranged from 0.6 to 1.7/L cysts, which means a removal values of 2.7 log, 2.5 log and 1.8 log for Cryptosporidium oocysts and 1 log, 2 log and 2.2 log for Giardia cysts in the three wastewater treatment plants analysed. In relation to safety margin the highest probability that exposure exceed the dose response was observed for Giardia. In addition, the sensitivity analysis showed that (oo) cysts concentration present in the leafy green vegetables and the human dose-response were the most influential inputs in the safety margin obtained., We thank EPSAR for authorizing us sampling of WWTP and the personnel of WWTP for providing with WWTP samples. We also thank members of GAMASER for concentrating the secondary and tertiary WWTP samples with the Envirocheck capsules. This study has been supported by the Spanish Ministry of Economy and Competitiveness (MINECO), in the frame of the collaborative international consortium WATERJPI2013-095-C03-02-METAWATER of the Water Challenges for a Changing World Joint Programming Initiative (Water JPI) Pilot Call.

Asthma-COPD ovelap (ACO) is an umbrella term that encompasses patients with COPD and eosinophilic inflammation (e-COPD) and smoking asthmatics with non-fully reversible airflow obstruction (SA). We compared the clinical characteristics and the inflammatory profile of e-COPD and SA. Patients classified as e-COPD were older and more often male and showed significantly impaired pulmonary function (likely explained by a heavier smoking habit). On the contrary, SA had more atopic features, more reversibility of airflow obstruction and higher IgE levels. The concentrations of IL-5, IL-13, IL-8, IL-6, TNF-alpha, IL17 in serum were similar between the 2 groups. However, Th2-related biomarkers (periostin, FeNO and blood eosinophils) shower higher median values in e-COPD patients. Our findings reinforce the notion that ACO is a heterogeneous disorder and, as a consequence, it might be unacceptable to offer the same treatment for two related but different conditions., The project was endorsed by the COPD and Asthma Research Board (PII de EPOC y asma) of the Spanish Society of Pneumology and Thoracic Surgery (SEPAR). The project was partially funded by the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Ministerio de Economia y Competitividad (FIS 15/01263) and by an unrestricted grant from Chiesi Espana S.A.U.

Resumen En los ultimos anos existe un creciente interes por las acciones extraoseas de la vitamina D. En este articulo revisamos la fisiologia de la vitamina D, los aspectos fisiopatologicos asociados a su deficit y la evidencia existente sobre su papel etiopatogenico en enfermedades respiratorias. Teniendo en cuenta las acciones pleiotropicas de la vitamina D, existe plausibilidad biologica sobre un potencial papel patogenico del deficit de esta vitamina en el desarrollo de diversas enfermedades respiratorias. Sin embargo, los numerosos estudios epidemiologicos que han encontrado asociacion entre niveles bajos de vitamina D y mayor riesgo de desarrollar diversas enfermedades respiratorias o de conllevar un peor pronostico no permiten demostrar causalidad. Los analisis post hoc de algunos ensayos clinicos, especialmente en enfermedad pulmonar obstructiva cronica (EPOC) y asma, parecen demostrar que ciertos subtipos de pacientes podrian beneficiarse de la correccion del deficit de vitamina D. En este sentido, resultara interesante averiguar si las variantes geneticas implicadas en el metabolismo de la vitamina D pueden explicar las diferencias interindividuales encontradas en cuanto al efecto del deficit de vitamina D y la respuesta a su correccion. En ultimo termino, solo los ensayos clinicos adecuadamente disenados permitiran determinar si los suplementos de 25-OH D pueden tener un efecto preventivo o mejorar la evolucion de las distintas enfermedades respiratorias en las que se ha descrito asociacion epidemiologica entre su pronostico y el deficit de esta vitamina.

a b s t r a c t Objectives: To analyze the clinical utility and economic impact of conventional transbronchial needle aspiration (TBNA) in patients with diagnosis of bronchogenic carcinoma (BC) and mediastinal lymphadenopathies in thoracic computed tomography (CT). To assess the predictive factors of valid aspirations. Patients and methods: Retrospective observational study between 2006 and 2011 of all TBNA performed in patients with final diagnosis of BC and accessible hilar or mediastinal lymphadenopathies on thoracic CT. Results: We performed TBNA on 267 lymphadenopathies of 192 patients. In 34.9% of patients, two or more lymph nodes were biopsied. Valid aspirations were obtained in 153 patients (79.7%) that were diagnostic in 124 (64.6%). Multivariate analysis showed that factors associated with valid or diagnostic results are the diameter of the lymph node and the number of lymph nodes explored. TBNA was the only endoscopic technique that provided the diagnosis of BC in 54 patients (28.1%). Staging mediastinoscopy was avoided in 67.6% of patients. The prevalence of mediastinal lymph node involvement was 74.4%, sensitivity of TBNA was 86.2% and negative predictive value was 63.6%. Including mediastinoscopy and other avoided diagnostic techniques, TBNA saved 451.57 D per patient.

The objective of this study is to analyze the clinical characteristics of two COPD patient populations: one diagnosed using the lower limit of normal (LLN) and another diagnosed by the GOLD criteria. We also compared the population excluded by the LLN criterion with a non-COPD control population. The COPD patients determined with the LLN criterion presented significantly lower levels of FEV1/FVC at 0.55 (0.8) vs 0.66 (0.2), P = .000; FEV1 44.9% (14) vs 53.8% (13), P = .000, and FVC 64.7% (17) vs 70.4%, P=.04. The two COPD groups presented more frequent ER visits in the last year (57% and 52% of the patients, respectively, compared with 11.9% of the control group), without any statistically significant differences between the two. This same pattern was observed in the number of ER visits in the last year: 1.98 (1.6), 1.84 (1.5), and 1.18 (0.7), respectively. When we analyzed the prevalence of the comorbidities that are most frequently associated COPD, there was a clear increase in the percentage of patients who presented associated disorders compared with the control group. Nevertheless, these differences were not very relevant between the two COPD groups. The differences also were not relevant between both COPD groups in the pharmacological prescription profile. In conclusion, the use of the LLN as a criterion for establishing the diagnosis of COPD, compared with the GOLD criteria, excludes a population with important clinical manifestations and with a high consumption of health-care resources. Before its implementation, the relevance of applying this criterion in clinical practice should be analyzed.

Resumen El objetivo de este estudio es analizar las caracteristicas clinicas de 2 poblaciones de pacientes con EPOC, una diagnosticada utilizando el limite inferior de la normalidad (LIN) y otra por criterio GOLD, y comparar la poblacion excluida por el criterio LIN con una poblacion control sin EPOC. Los pacientes con EPOC por criterio LIN presentaban valores significativamente mas bajos de FEV1/FVC 0,55 (0,8) vs 0,66 (0,2), p = 0,000; de FEV1 44,9% (14) vs 53,8% (13), p = 0,000, y de FVC 64,7% (17) vs 70,4% p 0,04. Los 2 grupos de EPOC presentaron una mayor frecuentacion en urgencias en el ultimo ano (57 y 52% de los pacientes, respectivamente, frente al 11,9% del grupo control), sin que hubiera diferencias estadisticamente significativas entre ambos. Este mismo patron se observo en el numero de visitas a urgencias en el ultimo ano: 1,98 (1,6), 1,84 (1,5) y 1,18 (0,7), respectivamente. Cuando se analizo la prevalencia de las comorbilidades que mas frecuentemente se asocian a EPOC se detecto, frente al grupo control, un claro incremento en el porcentaje de pacientes que presentaban trastornos asociados; sin embargo, estas diferencias fueron poco relevantes entre los dos grupos de EPOC. Las diferencias tampoco fueron relevantes entre ambos grupos de EPOC en el perfil de prescripcion farmacologica. Como conclusion, el uso del LIN como criterio para establecer el diagnostico de EPOC, frente al criterio GOLD, excluye una poblacion con importantes manifestaciones clinicas y con un elevado consumo de recursos sanitarios. Antes de su implementacion debe analizarse la relevancia de aplicar este criterio en la practica clinica.

Resumen A pesar de que las recomendaciones de las principales guias clinicas han restringido las indicaciones de los corticoides inhalados en la enfermedad pulmonar obstructiva cronica (EPOC), actualmente mas del 80% de los pacientes estan recibiendo este tratamiento en Espana, en su mayoria con dosis elevadas. Una revision detallada de la literatura no justifica el uso de estas dosis elevadas, posicionamiento que esta de acuerdo con las recomendaciones de la FDA. Una revaloracion de su seguridad, la consistencia de los datos de eficacia, que muestran resultados similares con dosis moderadas, y una mejor seleccion de los pacientes exige un replanteamiento del uso de este tratamiento en el paciente con EPOC.

Vibrio vulnificus is an opportunistic human pathogen that may cause gastroenteritis, severe necrotizing soft-tissue infections and primary septicaemia, with a high lethality rate. Illness is associated to ingestion of seafood or to the exposure of contaminated water. The aim of this work was to determine the occurrence of V. vulnificus in water and seafood samples from a coastal area near the Mediterranean (Valencia, Spain). A TaqMan probe-based real-time PCR assay was optimised and applied to 22 sea water, 42 raw sewage and 40 seafood samples. Results were compared with those obtained for culture isolation. The detection level of the PCR assay was 10 CFU g⁻¹ in inoculated samples. Seven seawater, four shellfish and six wastewater samples were positive by real time PCR. V. vulnificus was isolated from two oyster, three sea water and two wastewater samples. All the strains were obtained after 20 h enrichment, except for wastewater strains, which were isolated directly from the sample. To our knowledge, this is the first report on the isolation of V. vulnificus from sewage in Spain. Our results about the presence of V. vulnificus in food and environmental samples are strong enough to consider that the organism may represent a human health hazard in our geographical area.

Pollution of water by sewage and run-off from farms produces a serious public health problem in many countries. Viruses, along with bacteria and protozoa in the intestine or in urine are shed and transported through the sewer system. Even in highly industrialized countries, pathogens, including viruses, are prevalent throughout the environment. Molecular methods are used to monitor viral, bacterial, and protozoan pathogens, and to track pathogen- and source-specific markers in the environment. Molecular techniques, specifically polymerase chain reaction-based methods, provide sensitive, rapid, and quantitative analytical tools with which to study such pathogens, including new or emerging strains. These techniques are used to evaluate the microbiological quality of food and water, and to assess the efficiency of virus removal in drinking and wastewater treatment plants. The range of methods available for the application of molecular techniques has increased, and the costs involved have fallen. These developments have allowed the potential standardization and automation of certain techniques. In some cases they facilitate the identification, genotyping, enumeration, viability assessment, and source-tracking of human and animal contamination. Additionally, recent improvements in detection technologies have allowed the simultaneous detection of multiple targets in a single assay. However, the molecular techniques available today and those under development require further refinement in order to be standardized and applicable to a diversity of matrices. Water disinfection treatments may have an effect on the viability of pathogens and the numbers obtained by molecular techniques may overestimate the quantification of infectious microorganisms. The pros and cons of molecular techniques for the detection and quantification of pathogens in water are discussed.

Antecedentes Existe poca informacion sobre el manejo clinico de pacientes ingresados en hospitales publicos espanoles con un diagnostico de exacerbacion de enfermedad pulmonar obstructiva cronica. AUDIPOC es una auditoria clinica sobre el manejo de exacerbacion de EPOC en Espana. Objetivos Validar la adecuacion y validez de los instrumentos de medicion de las variables propuestas en AUDIPOC Espana (estudio preliminar) y verificar su viabilidad en un medio complejo con hospitales de tamano, recursos y organizacion diferentes (estudio piloto). Material y metodos El estudio preliminar se realizo en 4 hospitales y 213 casos. El estudio piloto en 30 hospitales de 6 comunidades autonomas y 1.203 casos. Resultados Los resultados de ambos estudios contribuyeron a mejorar el diseno y los metodos y organizacion del estudio AUDIPOC, incluyendo un mejor entrenamiento de los responsables hospitalarios, una nueva clasificacion de hospitales, la incorporacion de nuevas variables y la creacion de una oficina de coordinacion y gestion del proyecto. Conclusiones El estudio AUDIPOC es viable y preve reclutar 10.000 pacientes en 142 hospitales de todas las Comunidades Autonomas.

Aims: This study describes an approach for genotyping Giardia cysts obtained from wastewater treatment plants (WTPs) in Spain using real-time PCR (qPCR) in combination with immunomagnetic beads. Methods and Results: A 50-cycle amplification of a 74-bp fragment of the Giardia beta-giardin gene was adopted from a previous qPCR method. Additionally, two locked nucleic acid (LNA) probes were designed (LNA P434 P1 for assemblage A and LNA P434 H3 for assemblage B). All 16 wastewater samples analysed were positive with the immunofluorescence assay (IFA). Assemblage A was detected in all WTP samples using primer–LNA probe P434 P1 set. Giardia duodenalis identification was confirmed by PCR–RFLP analysis and sequencing of the β-giardin gene in the water samples found positive by IFA and qPCR. Among the 16 assemblage A isolates that were sequenced, two subtypes were identified; 11 corresponded to the A2 subgenotype, whereas three corresponded to the subgenotype A3. A mixture of subgenotypes was found in the remaining two isolates. Conclusions: The newly developed qPCR assays were able to discern G. duodenalis assemblages A and B in wastewater. Significance and Impact of the Study: The real-time PCR assays provided a rapid method for detection and one-step genotyping of G. duodenalis from wastewater samples, and its application would contribute to understanding the distribution and abundance of G. duodenalis assemblages A and B in wastewater.

Patients with chronic obstructive pulmonary disease (COPD) and associated bronchitis are at higher risk of exacerbations, which are a major cause of morbidity and impaired quality of life. Moreover, exacerbations are associated with more rapid disease progression and higher mortality. The typical symptoms of chronic bronchitis (chronic cough and sputum production) are correlated with inflammatory markers in COPD. Roflumilast is an anti-inflammator y drug belonging to the novel therapeutic class of phosphodiesterase-4 inhibitors and is the first drug to be developed for the treatment of a specific COPD phenotype (COPD associated with chronic bronchitis). The results of clinical trials indicate that, in patients with COPD associated with chronic bronchitis and a history of exacerbations, roflumilast improves pulmonary function and reduces the symptoms and frequency of exacerbations requiring medical intervention. This effect is maintained when regular treatment with a long-acting bronchodilator or an inhaled corticosteroid is added.

In the last decade, various studies have suggested that chronic obstructive pulmonary disease (COPD) could favor the development of ischemic heart disease. Several observational and case-control studies have confirmed that patients with COPD have a higher risk of cardiovascular disorders. However, this increased risk could be largely explained by a greater prevalence of classical risk factors. Currently, there are no data to indicate a causal relation between COPD and cardiovascular disease and the concept of systemic inflammation as a common pathogenic mechanism has not been demonstrated. Equally, there is insufficient evidence to conclude that some drugs, such as statins or inhaled corticoids, could decrease cardiovascular risk in patients with COPD by reducing systemic inflammation. Currently, these drugs should only be recommended if patients show specific indications for their use.

Although chronic obstructive pulmonary disease (COPD) is characterized by poorly reversible, chronic airfl ow obstruction, from the clinical point of view we must continue to make progress in the diagnosis and management of these patients so that spirometry is not the only technique used. Understanding that COPD is a heterogeneous process and that patient complexity usually increases due to the presence of comorbidities will allow more individualized strategies to be designed, which may improve control of the process. The TORCH and UPLIFT trials have shown that current treatment can improve important aspects of the disease, including mortality. However, the fi nalizing of these two large trials has generated a current of opinion favoring a more individually-tailored approach that should include all the factors -both pulmonary and extrapulmonary- that can modify the patient's form of presentation. Although we are witnessing a change in the therapeutic approach to COPD, future treatment will probably be based on studies performed in specifi c patient subgroups and on clarifying the interrelation between COPD and other diseases that are common in these patients. Greater knowledge of the pathogenesis of the disease may improve pharmacological treatment but drugs that, by themselves, alter the short- and long- term course of COPD are not on the horizon. However, a more patient-focussed approach may be the main tool available to physicians to increase quality of life -and possibly survival- in these patients.

Objetivo La enfermedad cardiovascular es una causa de muerte frecuente en los pacientes con enfermedad pulmonar obstructiva cronica (EPOC). No esta claro si el exceso de comorbilidad cardiovascular se relaciona con un incremento de factores de riesgo clasicos o si, por el contrario, la EPOC puede considerarse un factor de riesgo independiente. El objetivo de este estudio ha sido analizar la prevalencia de factores de riesgo y comorbilidad cardiovascular en una poblacion atendida en la comunidad por presentar EPOC. Pacientes y metodos Se ha realizado un estudio multicentrico, concurrente y transversal, en el que se incluyo a 572 pacientes con diagnostico confirmado de EPOC. Se recogieron datos de factores de riesgo y comorbilidad cardiovascular extraidos de la historia clinica del centro. Resultados El valor medio ± desviacion estandar del volumen espiratorio forzado en el primer segundo era del 53,7 ± 16,85% y la relacion volumen espiratorio forzado en el primer segundo/capacidad vital forzada del 57,9 ± 10,9%. La prevalencia de hipertension arterial era del 53%, la de obesidad del 27%, la de dislipemia del 26% y la de diabetes del 23%. La prevalencia de factores de riesgo no se relaciono con la gravedad de la enfermedad, pero si habia una tendencia de asociacion con la edad. La prevalencia de cardiopatia isquemica fue del 16,4%, la de enfermedad cerebrovascular del 7% y la de enfermedad vascular periferica del 17%. La prevalencia de comorbilidad vascular no se relaciono con la gravedad de la enfermedad, pero si con la edad y los factores de riesgo clasicos. Conclusiones Los pacientes con EPOC muestran una elevada prevalencia de factores de riesgo cardiovascular. La prevalencia de enfermedad cardiovascular y cerebrovascular excede la comunicada en poblacion general. No se ha observado relacion entre la gravedad de la obstruccion al flujo aereo y la presencia de comorbilidad cardiovascular.

A new Aeromonas bioassay is described to assess the potential harmful effects of the glyphosate-based herbicide, Roundup, in the Albufera lake, a protected area near Valencia. Viability markers as membrane integrity, culturability and beta-galactosidase production of Aeromonas caviae were studied to determine the influence of the herbicide in the bacterial cells. Data from the multifactor analysis of variance test showed no significant differences (P>0.05) between A. caviae counts of viability markers at the studied concentrations (0, 50 and 100 mg l-1 of glyphosate). The effects of Roundup on microbial biota present in the lake were assessed by measuring the number of indigenous mesophilic Aeromonas in presence of different amounts of the herbicide at 0, 50 and 100 mg l-1 of glyphosate. In samples containing 50 and 100 mg l-1 of glyphosate a significant (P