Introducing the concept of loss of corticosteroid credit in asthma.

The widespread use of systemic corticosteroids (SCS) in asthma is associated with significant comorbidities and mortality. A dose-response relationship for cumulative SCS exposure with most adverse outcomes began at cumulative exposures of 1.0-<2.5 g, equivalent to four lifetime SCS courses. The purpose of creating the SCS credit concept was to increase awareness of the risks of SCS exposure and to promote better therapeutic alternatives. Consuming the lifetime SCS credit of 1.5 g/yr significantly increased morbidity and mortality.

Bronchodilator responsiveness testing with inhaled budesonide/formoterol in asthma.

BACKGROUND: The choice of bronchodilators for responsiveness testing (BRT) is a clinical decision according to ATS/ERS. Since January 2019 we use budesonide/formoterol for BRT in asthma at our center in Argentina. The aim was to compare budesonide/formoterol with salbutamol for BRT in stable asthmatic patients that were followed up in a short-acting beta2 agonist (SABA)-free asthma center. METHODS: From the Hospital database, we found for the same patient at least one BRT using salbutamol 200 µg and another with budesonide/formoterol 320/9 µg. RESULTS: We found similar BRT between salbutamol and budesonide/formoterol in 101 asthmatic individuals (26 males) aged 38.14 ± 16.1 yrs (mean ± Standard deviation). The absolute response was 0.18 ± 0.21 L in FEV1 after salbutamol and 0.20 ± 0.22 L in FEV1 after budesonide/formoterol. Afterwards, we showed 202 patients tested with budesonide/formoterol; the mean absolute response was 0.21 ± 0.22 L in FEV1. There were no unexpected safety findings. CONCLUSIONS: In asthmatic patients, we demonstrated similar efficacy between Budesonide/formoterol and salbutamol for BRT.

It is time to end our love affair with short-acting ß2-agonists in asthma? Yes.

Why not directly eradicate SABA from asthma management? The time to leave behind SABA in asthma management is now. We wasted enough time identifying the key issue in asthma morbidity and mortality. Please, eradicate SABA. https://bit.ly/3DU4mmo.

Treat to target approach for asthma.

Recognition that about half of asthma deaths might be preventable if recommended guidelines are followed suggests that better implementation of established management strategies is needed. However, to achieve a further substantive reduction in asthma mortality, novel strategies will also be required. It is well established that asthma is a disease of chronic inflammation, with episodes of worsening inflammation associated with increased symptoms and/or exacerbations; however, current guidelines paradoxically recommend that initial treatment is only symptomatic, rather than directed at the underlying inflammatory mechanism. The "Treat to target" (TTT) approach has become a popular concept in the medical management of several common chronic conditions, including rheumatoid arthritis (RA), diabetes, hypertension and hyperlipidemia. For example, as part of a TTT approach, rheumatologists recommend methotrexate for RA with onset within 6 months. Applying the TTT approach to asthma, the primary target could be clinical remission and the primary goals as follows: eliminate symptoms and exacerbation risk; prevent airway remodeling; and normalize lung function. To construct a TTT algorithm for chronic asthma, the proposal is to eradicate short-acting ß2-agonists (SABA) at all asthma severity levels and replace SABA with "Anti-Inflammatory Reliever Therapy" (AIR), using inhaled corticosteroids (ICS)/SABA or ICS/formoterol. For individuals with equal to or less than 12 months' history of symptoms, fewer than two symptoms per month, no exacerbations in the last 12 months and normal lung function, the recommendation is early initiation of ICS/SABA or ICS/formoterol as AIR.

The clinical recovery of tuberculosis patients undergoing specific treatment is associated with changes in the immune and neuroendocrine responses.

Tuberculosis (TB) caused by Mycobacterium tuberculosis is a health problem worldwide. Patients with pulmonary TB show a neuro-immune-endocrine imbalance characterized by an impaired cellular immunity together with increased plasma levels of cortisol, pro- and anti-inflammatory cytokines and markedly decreased dehydroepiandrosterone (DHEA) levels. Extending these findings, we now investigated the immune-endocrine profile of TB patients undergoing specific treatment. Patients (n = 24) were bled at diagnosis (T0), 2, 4, 6 months after treatment initiation and 3 months following its completion. At T0, TB patients showed increased plasma levels of interleukin-6 (IL-6), C reactive protein, interferon-gamma (IFN-γ) and transforming growth factor beta (TGF-ß). These mediators decreased during treatment, reaching levels similar to those from healthy controls (n = 26). Specific treatment led to an increased lymphoproliferative response along with clinical improvement. Newly diagnosed patients had low levels of DHEA, with increased cortisol amounts and cortisol/DHEA ratio, which normalized upon specific treatment. As regards glucocorticoid receptors (GR), TB patients at diagnosis presented a reduced mRNA GRα/GRß ratio in their peripheral blood mononuclear cells. Furthermore, multivariate analysis showed that cortisol/DHEA ratio was positively associated with inflammatory mediators for which this ratio may constitute a disease biomarker. Anti-mycobacterial treatment results in a better immune-endocrine scenario for the control of physiopathological processes accompanying disease development and hence implied in clinical recovery.

Recomendaciones prácticas para el manejo de la crisis asmática en pacientes adultos / Practical Recommendations for the Management of Acute Asthma in Adult Patients

Las exacerbaciones de asma pueden ser graves y ponen en riesgo la vida de los pacientes. En estos casos es fundamental reconocer signos y síntomas de riesgo, incluyendo la medición de la obstrucción al flujo aéreo y la oximetría de pulso, con la finalidad de objetivar la gravedad de la crisis. La administración adecuada del tratamiento incluyendo broncodilatadores, corticoesteroides y oxigenoterapia permite revertir la obstrucción bronquial y preservar la vida del paciente. A pesar de estas premisas básicas en el manejo de la crisis asmática, en nuestro medio se ha detectado recurrentemente una atención defciente de estos eventos. El contar con recomendaciones de fácil implementación, adecuadas a las necesidades locales y desarrolladas por médicos especialistas en medicina respiratoria podría mejorar la calidad de atención de estos pacientes. Con este objetivo se realizó una revisión bibliográfica clasificando la información según el grado de evidencia. Los resultados fueron evaluados por un panel de expertos y se desarrolló un algoritmo de manejo del asma aguda. El algoritmo propone una evaluación inicial en base a signos de severidad, datos de medición del flujo aéreo (FEV1 y/o FPE) y oximetría de pulso que permitirán clasificar las exacerbaciones según su grado de severidad e indicar detalladamente los pasos terapéuticos a seguir en cada caso, como así también los criterios de internación y alta. El uso de estas recomendaciones permitirá una mejor distribución de recursos y optimización del tratamiento de los pacientes atendidos por exacerbaciones de asma.

Asthma exacerbations can be severe and life threatening. In order to assess in a correct and objective way the severity of the exacerbation, it is essential to recognize risk signs and symptoms, including the measurement of airflow obstruction and pulse oximetry. Proper treatment including bronchodilators, corticosteroids, and oxygen can reverse bronchial obstruction and preserve patient's life. Despite these basic facts, inappropriate care in the management of acute asthma events is frequent in Argentina. Recommendations developed by specialists in respiratory medicine, which are easy to implement and adapted to local needs, could improve the quality of care of these patients. In order to accomplish these goals, an exhaustive review of the literature was conducted and the information was classified according to the degree of evidence. The results were evaluated by a panel of experts and an algorithm for the management of acute asthma was designed. This algorithm proposes an initial assessment based on asthma severity including measurement of airflow obstruction (FEV1 and/or PF) and pulse oximetry. Thus, it allows classifying exacerbations by degree of severity, leading to appropriate sequential therapeutic options as well as criteria for admission and discharge. The use of these recommendations is intended to allow a correct management of asthma exacerbations in Argentina and an optimized use of medical resources.

Development of a simple binary response questionnaire to identify airflow obstruction in a smoking population in Argentina.

The CODE questionnaire (COPD detection questionnaire), a simple, binary response scale (yes/no), screening questionnaire, was developed for the identification of patients with chronic obstructive pulmonary disease (COPD). We conducted a survey of 468 subjects with a smoking history in 10 public hospitals in Argentina. Patients with a previous diagnosis of COPD, asthma and other respiratory illness were excluded. Items that measured conceptual domains in terms of characteristics of symptoms, smoking history and demographics data were considered. 96 (20.5%) subjects had a diagnosis of COPD according to the 2010 Global Initiative for Chronic Obstructive Lung Disease strategy document. The variables selected for the final questionnaire were based on univariate and multivariate analyses and clinical criteria. Finally, we selected the presence or absence of six variables (age ≥50 years, smoking history ≥30 pack-years, male sex, chronic cough, chronic phlegm and dyspnoea). Of patients without any of these six variables (0 points), none had COPD. The ability of the CODE questionnaire to discriminate between subjects with and without COPD was good (the area under the receiver operating characteristic curve was 0.75). Higher scores were associated with a greater probability of COPD. The CODE questionnaire is a brief, accurate questionnaire that can identify smoking individuals likely to have COPD.

Changes in the immune and endocrine responses of patients with pulmonary tuberculosis undergoing specific treatment.

We evaluated immune and endocrine status following antituberculosis treatment in HIV-negative patients with newly diagnosed tuberculosis (TB). Treatment led to a decrease in IL-6, IL-1ß, and C-reactive protein levels. Cortisol levels decreased throughout the anti-TB treatment, particularly after 4 months, but changes were less pronounced than those seen in proinflammatory mediators. Specific therapy resulted in increased dehydroepiandrosterone (DHEA) levels, which peaked after 4 months and started to decline after 6 months of treatment, reaching levels below those detected at inclusion. In contrast, in most patients, dehydroepiandrosterone sulfate (DHEAS) levels remained unchanged, although a trend toward increased concentrations was observed in a few cases 3 months after the treatment was finished. Specific therapy also resulted in more balanced cortisol/DHEA and cortisol/DHEAS ratios. Etiologic treatment involves favorable immune and endocrine changes, which may account for its beneficial effects.

mRNA expression of alpha and beta isoforms of glucocorticoid receptor in peripheral blood mononuclear cells of patients with tuberculosis and its relation with components of the immunoendocrine response.

We have analyzed the expression of glucocorticoid receptor (GR) isoforms by real time RT-qPCR in PBMCs from 19 controls (HCo) and 28 TB patients (8 mild; 12 moderate; 8 severe), HIV(-) and similar sex and age distribution. mRNA hGRα/ß ratios were found higher in TB patients respect to those in HCo. However, when analyzing for disease severity such overall trend was at the expense of mild and moderate patients, with severe cases showing a lower mRNA hGRα/ß ratio with respect to the other patient groups. This suggested some degree of resistance to endogenous glucocorticoids in patients with severe TB, since hGRαα dimer mediates the biological functions of GC, with the GRß isoform acting as an inhibitor of GC activity. Levels of IL-6, IL-18, IFN-γ and Cortisol were significantly increased in severe and moderate cases, whereas DHEA values were found decreased in them (p<0.05 respect to HCo). Analysis on the relationship between plasma levels of these immuno-endocrine mediators with the mRNA expression of hGRα and hGRß showed that IL-6 was positively associated with hGRα in mild TB patients (p<0.01), whereas a negative correlation between IFN-γ and hGRß was observed in severe cases (p<0.01). As regard to hormones, DHEA was positively associated with hGRα in moderate and severe cases (p<0.01). This group also showed a negative correlation between hGRα and Cortisol/DHEA ratios (p<0.05). Changes in the systemic levels of cytokine and adrenal hormones are likely to affect GR expression in a differential fashion and according to the amount of pulmonary involvement.

Tiotropium and risk for fatal and nonfatal cardiovascular events in patients with chronic obstructive pulmonary disease: systematic review with meta-analysis.

BACKGROUND: There are safety concerns regarding the use of anticholinergics in the COPD patient population. The purpose of this review was to evaluate the cardiovascular risk of regular use of inhaled tiotropium bromide in patients with COPD of any severity. METHODS: Systematic searches were conducted in MEDLINE, EMBASE, the Cochrane Controlled Trials Register, manufactures' trial register, and FDA databases, without language restriction. Primary outcomes were a composite of major adverse cardiovascular events, cardiovascular mortality, and nonfatal myocardial infarction (MI) or stroke during the treatment period. Relative risks (RR) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I2 statistic. RESULTS: Nineteen randomized controlled trials (18,111 participants) were selected. There was no difference in the incidence of adverse cardiovascular events (RR=0.96; 95% CI, 0.82-1.12, I2=6%). Among individual components of the composite outcome, tiotropium did not significantly increase the risk of cardiovascular death (RR=0.93; 95% CI, 0.73-1.20, I2=1%), nonfatal MI (RR=0.84; 95% CI, 0.64-1.09, I2=0%), and nonfatal stroke (RR=1.04; 95% CI, 0.78-1.39, I2=0%). A smoking history of > or = 55 pack-years presented a trend to a higher rate of cardiovascular adverse events in patients receiving tiotropium. CONCLUSIONS: Compared with control (placebo or salmeterol), tiotropium did not significantly increase the risk of adverse major cardiovascular events among COPD patients. Subgroup analysis suggested that smoking history can modify the risk of cardiovascular adverse events.

Hospitalizaciones por asma aguda durante el período 1994-2004 en Argentina y Uruguay: el estudio EAGLE / Hospitalizations for acute asthma during the period 1994-2004 in Argentina and Uruguay: the EAGLE study

Introducción: El objetivo de este estudio consistió en un análisis de la base de datos del proyecto EAGLE (características de los pacientes hospitalizados por asma) limitado a la Argentina y el Uruguay. Pacientes y métodos: Para evaluar los cambios producidos en los asmáticos hospitalizados en Argentina y Uruguay, fueron revisadas las historias clínicas de 215 pacientes (15-69 años de edad) hospitalizados en 4 centros médicos durante los años 1994, 1999 y 2004. Resultados: Si bien se verificó una reducción significativa en el uso de teofilinas, la utilización de corticoides inhalados fue baja (16% de todos los pacientes) y se mantuvo incambiada. Se verificó una tendencia a una disminución en el tiempo de hospitalización (10.5 días en 1994 a 8.2 días en 2004, p = 0.2). La tasa global de mortalidad para todos los pacientes estudiados durante los tres años fue 1.4% correspondiendo a un total de 3 fallecimientos. Por el contrario el uso de espirometría o flujo espiratorio máximo en urgencias se mantuvo por debajo del 60% de los pacientes hospitalizados. Globalmente, un 29% de todos los pacientes hospitalizados fueron ingresados a una unidad de cuidados intensivos. Conclusiones: Aunque este estudio sugiere algunas mejoras en el manejo del asma tanto durante el período intercrisis como durante las exacerbaciones, todavía subsisten importantes carencias tanto en Argentina como en Uruguay.(AU)

Introduction: The objective of this study was to assess the data base of project EAGLE (characteristics of the patients hospitalized because of asthma) in Argentina and Uruguay. Patients and Methods: In order to evaluate the changes produced in asthma hospitalizations in Argentina and Uruguay, the records of 215 patients (15-69 years old) admitted for acute asthma at third level hospitals during the years of 1994, 1999, and 2004 were reviewed. Results: Although a the use of theophylline was significantly decreased, the utilization of inhaled corticosteroids was low (16% of all patients) and remained unchanged during the study period. There was a trend towards a reduction in the length of hospital stay (from 10.5 days in 1994, to 8.2 days in 2004, p = 0.2). The overall case fatality rate for all patients admitted during the study period was 1.4% (3 deaths). The use of spirometry or peak expiratory flow measurements in the emergency room was registered in less of 60% of hospitalized patients. Overall, 29% of hospitalized patients required admission into an intensive care unit. Conclusions: Although this study suggests some improvements in the management of asthma in the period between severe exacerbations and during hospitalization, suboptimal case management is still common in Argentina and Uruguay.(AU)

Hospitalizaciones por asma aguda durante el período 1994-2004 en Argentina y Uruguay: el estudio EAGLE / Hospitalizations for acute asthma during the period 1994-2004 in Argentina and Uruguay: the EAGLE study

Introducción: El objetivo de este estudio consistió en un análisis de la base de datos del proyecto EAGLE (características de los pacientes hospitalizados por asma) limitado a la Argentina y el Uruguay. Pacientes y métodos: Para evaluar los cambios producidos en los asmáticos hospitalizados en Argentina y Uruguay, fueron revisadas las historias clínicas de 215 pacientes (15-69 años de edad) hospitalizados en 4 centros médicos durante los años 1994, 1999 y 2004. Resultados: Si bien se verificó una reducción significativa en el uso de teofilinas, la utilización de corticoides inhalados fue baja (16% de todos los pacientes) y se mantuvo incambiada. Se verificó una tendencia a una disminución en el tiempo de hospitalización (10.5 días en 1994 a 8.2 días en 2004, p = 0.2). La tasa global de mortalidad para todos los pacientes estudiados durante los tres años fue 1.4% correspondiendo a un total de 3 fallecimientos. Por el contrario el uso de espirometría o flujo espiratorio máximo en urgencias se mantuvo por debajo del 60% de los pacientes hospitalizados. Globalmente, un 29% de todos los pacientes hospitalizados fueron ingresados a una unidad de cuidados intensivos. Conclusiones: Aunque este estudio sugiere algunas mejoras en el manejo del asma tanto durante el período intercrisis como durante las exacerbaciones, todavía subsisten importantes carencias tanto en Argentina como en Uruguay.

Introduction: The objective of this study was to assess the data base of project EAGLE (characteristics of the patients hospitalized because of asthma) in Argentina and Uruguay. Patients and Methods: In order to evaluate the changes produced in asthma hospitalizations in Argentina and Uruguay, the records of 215 patients (15-69 years old) admitted for acute asthma at third level hospitals during the years of 1994, 1999, and 2004 were reviewed. Results: Although a the use of theophylline was significantly decreased, the utilization of inhaled corticosteroids was low (16% of all patients) and remained unchanged during the study period. There was a trend towards a reduction in the length of hospital stay (from 10.5 days in 1994, to 8.2 days in 2004, p = 0.2). The overall case fatality rate for all patients admitted during the study period was 1.4% (3 deaths). The use of spirometry or peak expiratory flow measurements in the emergency room was registered in less of 60% of hospitalized patients. Overall, 29% of hospitalized patients required admission into an intensive care unit. Conclusions: Although this study suggests some improvements in the management of asthma in the period between severe exacerbations and during hospitalization, suboptimal case management is still common in Argentina and Uruguay.

Safety of long-acting beta-agonists in stable COPD: a systematic review.

BACKGROUND: Some studies have suggested that use of long-acting beta(2)-agonists (LABAs) leads to an increased risk for adverse events in patients with stable COPD. The purpose of this review was to assess the safety, and secondarily the efficacy of LABAs. METHODS: The authors conducted a systematic review with metaanalysis of randomized clinical trials (> or = 1 month in duration) in the published literature that have compared LABAs with placebo or anticholinergics in stable poorly reversible and reversible COPD. RESULTS: MEDLINE, EMBASE, CINAHL, and the Cochrane Controlled Trials Register were searched to identify 27 studies. LABAs reduced severe exacerbations compared with placebo (relative risk [RR], 0.78; 95% confidence interval [CI], 0.67 to 0.91). There was no significant difference between LABA and placebo groups in terms of respiratory deaths (RR, 1.09; 95% CI, 0.45 to 2.64). Use of LABAs with inhaled corticosteroids reduced the risk of respiratory death compared with LABAs alone (RR, 0.35; 95% CI, 0.14 to 0.93). Patients receiving LABAs showed significant benefits in airflow limitation measures, health-related quality of life, and use of rescue medication. Finally, tiotropium decreased the incidence of severe COPD exacerbations compared with LABAs (RR, 0.52; 95% CI, 0.31 to 0.87). CONCLUSION: This review supports the beneficial effects of the use of LABAs in patients with stable moderate-to-severe COPD, and did not confirm previous data about an increased risk for respiratory deaths. Also, our analysis suggests the superiority of tiotropium over LABAs for the treatment of stable COPD patients.

Encuesta en 8 regiones de Argentina sobre manejo pre-hospitalario de la crisis de asma / Survey of eight regions of Argentina regarding the pre-hospital management of acute asthma

El manejo correcto pre-hospitalario de la crisis asmática sería la medida más provechosa para reducir las muertes por asma. En él influyen el nivel de conocimientos y la aplicación de las guías por parte de los médicos a cargo. Con el objetivo de evaluar la aplicación de guías y su conocimiento, se distribuyó una encuesta anónima a médicos en las reuniones con tele conferencia satelital organizadas por un laboratorio en 2005. La encuesta permitía obtener un puntaje de 0 a 10 para calificar a los participantes. De las 8 regiones del país se obtuvieron 243 encuestas para analizar. El rango del año de graduación fue de 1965 a2005. Los encuestados refirieron atender en total 1523 pacientes en las últimas 4 semanas. El puntaje promedio de toda la muestra fue 7.13 ± 1.83. El promedio más alto fue alcanzado por los neumonólogos (9% del total de encuestados), con una diferencia significativa según el test de Tukey-Kramer de comparación múltiple, entre neumonólogos versus médicos generalistas (6%) y médicos sin especialidad (37%; p<0.05). El 82% manifestó tomar decisiones en base a guías. Aunque, llamativamente, el 50% no usaba medidor de flujo pico; el 45% no administraba anticolinérgicos inhalatorios; el 41% modificaba totalmente sus decisiones ante una crisis asmática en el primer trimestre del embarazo y un 29.5% no indicaba agonistas beta2 inhalados cuando la crisis presentaba un pulso mayorde 120/min. Un 14.9% usaba ansiolíticos sublinguales. La ciudad con mayor puntaje fue Bariloche. Se concluye que exceptuando a los neumonólogos, los resultados de esta encuesta muestran un puntaje no aceptable de calidad de atención pre-hospitalaria.

Asthma mortality could be reduced by improving acute asthma management inpre-hospital setting. Generally, it is difficult to carry out the recommendations of guidelines.In order to assess this issue and the physicians’ knowledge of acute asthma treatment, we designed a score between cero and ten points in a written survey to be distributed during a satellital conference in 8 regions of Argentina in 2005. We collected a total of 243 samples for analysis. Participants assisted a total of 1523 patients in the last 4 weeks. They had been graduated as MD, between 1965 and 2005. The designed score showed a mean 7.13± 1.83. Strikingly, 82% of the inquired participants answered that they follow the guidelines; while 50% did not use Peak Flow Meters. Furthermore, 45% did not administer inhaled anticholinergic bronchodilators. In case of acute asthma and pregnancy 41% absolutely modified their management. When the pulse was greater than 120/min, 29.5% of theparticipants did not indicate inhaled beta2 agonists and 14.9% used sublingua sedatives.Pulmonologists (9% of all participants) achieved a significant higher mean score in comparison with general practitioners. Bariloche city obtained the highest score. We concluded that with the exception of pulmonologists, these results showed an unacceptablequality of the pre-hospital management of acute asthma.