Characteristics and Management of Patients with Refractory or Unexplained Chronic Cough in Outpatient Hospital Clinics in Spain: A Retrospective Multicenter Study.

PURPOSE: Chronic cough (cough that persists for ≥ 8 weeks) can cause a range of physical symptoms and psychosocial effects that significantly impair patients' quality of life. Refractory chronic cough (RCC) and unexplained chronic cough (UCC) are challenging to diagnose and manage, with substantial economic implications for healthcare systems. METHODS: This retrospective multicenter non-interventional study aimed to characterize the profile and health resource consumption of patients with RCC or UCC who attended outpatient clinics at Spanish hospitals. Data were collected from medical records of patients with RCC or UCC for up to 3 years before study inclusion. RESULTS: The patient cohort (n = 196) was representative of the chronic cough population (77.6% female, mean age 58.5 years). Two-thirds of patients (n = 126) had RCC. The most frequently visited doctors were pulmonologists (93.4% of patients) and primary care physicians (78.6%), with a mean of 5 visits per patient over three years' observation. The most common diagnostic tests were chest x-ray (83.7%) and spirometry with bronchodilation (77.0%). The most commonly prescribed treatments were proton pump inhibitors (79.6%) and respiratory medications (87.8%). Antibiotics were prescribed empirically to 56 (28.6%) patients. Differences between RCC or UCC groups related mainly to approaches used to manage cough-associated conditions (gastroesophageal reflux disease, asthma) in patients with RCC. CONCLUSION: RCC and UCC are responsible for high health resource utilization in Spanish hospitals. Specific treatments targeting the pathological processes driving chronic cough may provide opportunities to reduce the associated burden for patients and healthcare systems.

Clinical Features and Outcomes Associated with Bronchial Asthma Among COVID-19 Hospitalized Patients.

Background: The impact of diagnosis treatment and bronchial asthma on coronavirus disease 2019 (COVID-19) associated outcomes remains unclear. Objective: To identify the prevalence and outcomes associated with asthma among hospitalized patients with COVID-19. Methods: Electronic health records of 130 patients with asthma among hospitalized patients with COVID-19 were reviewed. Two subgroups of asthmatic patients were compared according to clinical outcomes during hospitalization. Patients with death results, intubation, and/or need of intensive care unit (ICU) stay were grouped as asthmatic patients with severe COVID-19 outcomes, and the rest were grouped as asthmatic patients with non-severe COVID-19 outcomes. Multivariable analyses were conducted with logistic regression to identify independent risk factors for severe outcomes. Results: The prevalence of asthma in COVID-19 hospitalized patients was 5%. The mean age was 59.4 years and 54% were women. 17% received treatment in GINA step 4-5 asthma at the time of admission. An allergic asthma phenotype was determined in 38%. There was no significant difference in hospital length of stay or need for intubation between asthmatic patients and global COVID-19 admitted patients. 17% of asthmatic patients developed a severe outcome, and 5% had a death result. Elevated Lactate Dehydrogenase (LDH) level, low transcutaneous pulse oximetry (SpO2), the coexistence of atrial fibrillation (AF), and need for moderate or high ICS at admission were independent risk factors for a worse outcome in asthmatics COVID-19 hospitalized patients. Conclusion: The prevalence of asthma in COVID-19 hospitalized patients was 5%, consistent with the asthma prevalence in the general population. The asthmatic patients with the previous prescription of moderate or high doses of ICS and/or coexistence of atrial fibrillation at admission had a higher risk of the severe outcome.

The pan-JAK inhibitor LAS194046 reduces neutrophil activation from severe asthma and COPD patients in vitro.

Non-T2 severe asthma and chronic obstructive pulmonary disease (COPD) are airway chronic inflammatory disorders with a poor response to corticosteroids. LAS194046, a novel pan-Janus kinase (JAK) inhibitor, shows inhibitory effects on T2 allergic lung inflammation in rats. In this work we analyze the effects of LAS194046, fluticasone propionate and their combination in neutrophils from non-T2 severe asthma and COPD patients in vitro. Neutrophils from 23 healthy subjects, 23 COPD and 21 non-T2 severe asthma patients were incubated with LAS194046 (0.01 nM-1 µM), fluticasone propionate (0.1 nM-1 µM) or their combination and stimulated with lipopolysaccharide (LPS 1 µM). LAS194046 shows similar maximal % inhibition and potency inhibiting IL-8, MMP-9 and superoxide anion release in neutrophils from healthy, COPD and asthma. Fluticasone propionate suppresses mediator release only in neutrophils from healthy patients. The combination of LAS194046 with fluticasone propionate shows synergistic anti-inflammatory and anti-oxidant effects. The mechanisms involved in the synergistic effects of this combination include the increase of MKP1 expression, decrease of PI3Kδ, the induction of glucocorticoid response element and the decrease of ERK1/2, P38 and JAK2/STAT3 phosphorylation compared with monotherapies. In summary, LAS194046 shows anti-inflammatory effects in neutrophils from COPD and severe non-T2 asthma patients and induces synergistic anti-inflammatory effects when combined with fluticasone propionate.

In vitro anti-inflammatory effects of AZD8999, a novel bifunctional muscarinic acetylcholine receptor antagonist /ß2-adrenoceptor agonist (MABA) compound in neutrophils from COPD patients.

Recent evidence indicates that AZD8999 (LAS190792), a novel muscarinic acetylcholine receptor antagonist and ß2-adrenoceptor agonist (MABA) in development for chronic respiratory diseases, induces potent and sustained relaxant effects in human bronchi by adressing both muscarinic acetylcholine receptors and ß2-adrenoceptor. However, the anti-inflammatory effects of the AZD8999 monotherapy or in combination with corticosteroids are unknown. This study investigates the anti-inflammatory effects of AZD8999 in monotherapy and combined with fluticasone propionate in neutrophils from healthy and chronic obstructive pulmonary disease (COPD) patients. Peripheral blood neutrophils from healthy and COPD patients were incubated with AZD8999 and fluticasone propionate, individually or in combination, for 1h followed by lipopolysaccharide (LPS) stimulation for 6h. The IL-8, MMP9, IL-1ß, and GM-CSF release was measured in cell culture supernatants. AZD8999 shows ~ 50% maximum inhibitory effect and similar potency inhibiting the released cytokines in neutrophils from healthy and COPD patients. However, while fluticasone propionate suppresses mediator release in neutrophils from healthy patients, COPD neutrophils are less sensitive. The combination of non-effective concentrations of AZD8999 (0.01nM) with non-effective concentrations of fluticasone propionate (0.1nM) shows synergistic anti-inflammatory effects. The studied mechanisms that may be involved in the synergistic anti-inflammatory effects of this combination include the increase of glucocorticoid receptor (GR)α and MKP1 expression, the induction of glucocorticoid response element (GRE) activation and the decrease of ERK1/2, P38 and GR-Ser226 phosphorylations compared with monotherapies. In summary, AZD8999 shows anti-inflammatory effects in neutrophils from COPD patients and induces synergistic anti-inflammatory effects when combined with fluticasone propionate, supporting the use of MABA/ICS combination therapy in COPD.

Mucin 1 deficiency mediates corticosteroid insensitivity in asthma.

BACKGROUND: The loss of corticosteroid efficacy is an important issue in severe asthma management and may lead to poor asthma control and deterioration of airflow. Recent data indicate that Mucin 1 (MUC1) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis, but the role of MUC1 in uncontrolled severe asthma is unknown. The objective was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in asthma. METHODS: Mucin 1 expression was evaluated by real-time PCR in human bronchial epithelial cells (HBEC) and blood neutrophils from uncontrolled severe asthma (n = 27), controlled mild asthma (n = 16), and healthy subjects (n = 13). IL-8, MMP9, and GM-CSF were measured by ELISA in HBEC and neutrophils. An asthma model of ovalbumin (OVA) was used in MUC1 KO and WT C57BL/6 mice according to ARRIVE guidelines. RESULTS: Mucin 1-CT expression was downregulated in bronchial epithelial cells and peripheral blood neutrophils from severe asthma patients compared with mild asthma and healthy subjects (P < 0.05). Daily dose of inhaled corticosteroids (ICS) inversely correlated with MUC1 expression in neutrophils from mild and severe asthma (ρ = -0.71; P < 0.0001). Dexamethasone showed lower anti-inflammatory effects in severe asthma peripheral blood neutrophils and HBECs stimulated with lipopolysaccharide (LPS) than in cells from mild asthma. Glucocorticoid receptor (GR)-α phosphorylated at serine 226 was increased in cells from severe asthma, and the MUC1-CT/GRα complex was downregulated in severe asthma cells. OVA asthma model in MUC1 KO mice was resistant to the anti-inflammatory effects of dexamethasone. CONCLUSION: Mucin 1-CT modulates corticosteroid efficacy in vitro and in vivo asthma models.

Changes and Clinical Consequences of Smoking Cessation in Patients With COPD: A Prospective Analysis From the CHAIN Cohort.

BACKGROUND: Despite the existing evidence-based smoking cessation interventions, chances of achieving that goal in real life are still low among patients with COPD. We sought to evaluate the clinical consequences of changes in smoking habits in a large cohort of patients with COPD. METHODS: CHAIN (COPD History Assessment in Spain) is a Spanish multicenter study carried out at pulmonary clinics including active and former smokers with COPD. Smoking status was certified by clinical history and co-oximetry. Clinical presentation and disease impact were recorded via validated questionnaires, including the London Chest Activity of Daily Living (LCADL) and the Hospital Anxiety and Depression Scale (HADS). No specific smoking cessation intervention was carried out. Factors associated with and clinical consequences of smoking cessation were analyzed by multivariate regression and decision tree analyses. RESULTS: One thousand and eighty-one patients with COPD were included (male, 80.8%; age, 65.2 [SD 8.9] years; FEV1, 60.2 [20.5]%). During the 2-year follow-up time (visit 2, 906 patients; visit 3, 791 patients), the majority of patients maintained the same smoking habit. Decision tree analysis detected chronic expectoration as the most relevant variable to identify persistent quitters in the future, followed by an LCADL questionnaire (cutoff 9 points). Total anxiety HADS score was the most relevant clinical impact associated with giving up tobacco, followed by the LCADL questionnaire with a cutoff value of 10 points. CONCLUSIONS: In this real-life prospective COPD cohort with no specific antismoking intervention, the majority of patients did not change their smoking status. Our study also identifies baseline expectoration, anxiety, and dyspnea with daily activities as the major determinants of smoking status in COPD. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT01122758; URL: www.clinicaltrials.gov.

Prevalence of persistent blood eosinophilia: relation to outcomes in patients with COPD.

The impact of blood eosinophilia in chronic obstructive pulmonary disease (COPD) remains controversial.To evaluate the prevalence and stability of a high level of blood eosinophils (≥300 cells·µL-1) and its relationship to outcomes, we determined blood eosinophils at baseline and over 2 years in 424 COPD patients (forced expiratory volume in 1 s (FEV1) 60% predicted) and 67 smokers without COPD from the CHAIN cohort, and in 308 COPD patients (FEV1 60% predicted) in the BODE cohort. We related eosinophil levels to exacerbations and survival using Cox hazard analysis.In COPD patients, 15.8% in the CHAIN cohort and 12.3% in the BODE cohort had persistently elevated blood eosinophils at all three visits. A significant proportion (43.8%) of patients had counts that oscillated above and below the cut-off points, while the rest had persistent eosinophil levels <300 cells·µL-1 A similar eosinophil blood pattern was observed in controls. Exacerbation rates did not differ in patients with and without eosinophilia. All-cause mortality was lower in patients with high eosinophils compared with those with values <300 cells·µL-1 (15.8% versus 33.7%; p=0.026).In patients with COPD, blood eosinophils ≥300 cells·µL-1 persisting over 2 years was not a risk factor for COPD exacerbations. High eosinophil count was associated with better survival.

Multi-level differential network analysis of COPD exacerbations.

Patients with chronic obstructive pulmonary disease (COPD) often suffer episodes of exacerbation (ECOPD) that impact negatively the course of their disease. ECOPD are heterogeneous events of unclear pathobiology and non-specific diagnosis. Network analysis is a novel research approach that can help unravelling complex biological systems. We hypothesised that the comparison of multi-level (i.e., clinical, physiological, biological, imaging and microbiological) correlation networks determined during ECOPD and convalescence can yield novel patho-biologic information.In this proof-of-concept study we included 86 patients hospitalised because of ECOPD in a multicentre study in Spain. Patients were extensively characterised both during the first 72 h of hospitalisation and during clinical stability, at least 3 months after hospital discharge.We found that 1) episodes of ECOPD are characterised by disruption of the network correlation observed during convalescence; and 2) a panel of biomarkers that include increased levels of dyspnoea, circulating neutrophils and C-reactive protein (CRP) has a high predictive value for ECOPD diagnosis (AUC 0.97).We conclude that ECOPD 1) are characterised by disruption of network homeokinesis that exists during convalescence; and 2) can be identified objectively by using a panel of three biomarkers (dyspnoea, circulating neutrophils and CRP levels) frequently determined in clinical practice.

Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients.

BACKGROUND: Inhaled corticosteroid (ICS) with long-acting beta-2 agonists is a well-documented combination therapy for chronic obstructive pulmonary disease (COPD) based on its additive anti-inflammatory properties. By contrast, the recommendation of ICS in combination with long-acting muscarinic antagonist (LAMA) is not evidence-based. In this study, neutrophils obtained from COPD patients were used to compare the anti-inflammatory effects of aclidinium bromide (a long-acting muscarinic antagonist) with corticosteroids and their potential additive effect. METHODS: Human sputum and blood neutrophils were isolated from healthy individuals (n = 37), patients with stable COPD (n = 52) and those with exacerbated COPD (n = 16). The cells were incubated with corticosteroid fluticasone propionate (0.1 nM-1 µM), aclidinium bromide (0.1 nM-1 µM) or a combination thereof and stimulated with 1 µg of lipopolysaccharide/ml or 5 % cigarette smoke extract. Levels of the pro-inflammatory mediators interleukin-8, matrix metalloproteinase-9, CCL-5, granulocyte-macrophage colony-stimulating factor and interleukin-1ß were measured and the mechanisms of corticosteroid resistance evaluated at the end of the incubation. RESULTS: The non-neuronal cholinergic system was over-expressed in neutrophils from COPD patients, as evidenced by increases in the expression of muscarinic receptors (M2, M4 and M5), choline acetyltransferase and vesicular acetylcholine transporter. Aclidinium bromide demonstrated anti-inflammatory effects on neutrophils from COPD patients, reversing their resistance to corticosteroids. Additive effects of combined aclidinium bromide and fluticasone propionate in blocking M2 receptor levels, inhibiting phosphoinositide 3-kinase-δ and enhancing the glucocorticoid response element transcription factor were demonstrated and were accompanied by an increase in the corticosteroid-induced expression of anti-inflammatory-related genes. CONCLUSIONS: LAMAs potentiate the anti-inflammatory effects of corticosteroids in neutrophils from COPD patients in vitro, thus providing a scientific rationale for their use in combination with corticosteroids in the treatment of COPD.

Chronic Cough.

Chronic cough (CC), or cough lasting more than 8 weeks, has attracted increased attention in recent years following advances that have changed opinions on the prevailing diagnostic and therapeutic triad in place since the 1970s. Suboptimal treatment results in two thirds of all cases, together with a new notion of CC as a peripheral and central hypersensitivity syndrome similar to chronic pain, have changed the approach to this common complaint in routine clinical practice. The peripheral receptors involved in CC are still a part of the diagnostic triad. However, both convergence of stimuli and central nervous system hypersensitivity are key factors in treatment success.

Role of tetrahydrobiopterin in pulmonary vascular remodelling associated with pulmonary fibrosis.

BACKGROUND: Pulmonary hypertension in idiopathic pulmonary fibrosis (IPF) is indicative of a poor prognosis. Recent evidence suggests that tetrahydrobiopterin (BH4), the cofactor of nitric oxide synthase (NOS), is involved in pulmonary hypertension and that pulmonary artery endothelial-to-mesenchymal transition (EnMT) may contribute to pulmonary fibrosis. However, the role of BH4 in pulmonary remodelling secondary to pulmonary fibrosis is unknown. This study examined the BH4 system in plasma and pulmonary arteries from patients with IPF as well as the antiremodelling and antifibrotic effects of the BH4 precursor sepiapterin in rat bleomycin-induced pulmonary fibrosis and in vitro EnMT models. METHODS: BH4 and nitrotyrosine were measured by high-performance liquid chromatography and ELISA, respectively. Expression of sepiapterin reductase (SPR), GTP cyclohydrolase 1 (GCH-1), endothelial NOS (eNOS) and inducible NOS (iNOS) were measured by quantitative PCR and immunohistochemistry. RESULTS: BH4 plasma levels were downregulated in patients with IPF compared with controls while nitrites, nitrates and nitrotyrosine were upregulated. GCH-1 and eNOS were absent in pulmonary arteries of patients with IPF; however, iNOS expression increased while SPR expression was unchanged. In rats, oral sepiapterin (10 mg/kg twice daily) attenuated bleomycin-induced pulmonary fibrosis, mortality, vascular remodelling and pulmonary hypertension by increasing rat plasma BH4, decreasing plasma nitrotyrosine and increasing vascular eNOS and GCH-1 expression. Both transforming growth factor ß1 and endothelin-1 induced EnMT by decreasing BH4 and eNOS expression. In vitro administration of sepiapterin increased endothelial BH4 and inhibited EnMT in human pulmonary artery endothelial cells. CONCLUSIONS: Targeting the BH4 synthesis 'salvage pathway' with sepiapterin may be a new therapeutic strategy to attenuate pulmonary hypertension in IPF.

[Economic cost of treating the patient with asthma in Spain: the AsmaCost study]. / Coste económico del paciente asmático en España (estudio AsmaCost).

OBJECTIVE: This analysis of the cost of asthma in Spain includes both direct health care costs and indirect costs arising from illness. PATIENTS AND METHODS: Prospective, 12-month observational cohort study of adult patients with asthma diagnosed according to the guidelines of the Global Initiative for Asthma (GINA) and the adapted Spanish criteria (GEMA). We recorded information on health care resources utilized (medications, medical visits, emergency care, hospital admissions, and tests) and indirect costs (patient travel or transfer costs and workdays lost). RESULTS: A total of 627 patients throughout Spain were studied. Of these, 21.2% had intermittent asthma, 24.6% mild asthma, 27.6% moderate asthma, and 26.6% severe asthma. The total societal cost of asthma (including indirect costs) was euro1726 (95% confidence interval [CI], euro1314-euro2154) per patient annually. Indirect costs accounted for 11.2% of the total. The cost to the National Health Service was euro1533 (95% CI, euro1133-euro1946) per patient annually. The cost of asthma was higher for patients older than 65 years (euro2079) and for those with more severe disease (euro959 for intermittent asthma; euro1598, mild asthma; euro1553, moderate asthma; and euro2635 severe asthma). Based on these findings, the total annual cost of asthma in Spain is estimated to be euro1480 million (95% CI, euro382-euro2565 million) for patients with demonstrated bronchial hyperreactivity and euro3022 million (95% CI, euro2472-euro3535 million) for patients diagnosed based on symptoms alone. CONCLUSIONS: The average annual cost of asthma in adults in Spain comes to euro1726 per patient, considering both direct and indirect costs. The average annual cost per patient to the National Health Service is euro1533.

[Clinical characteristics of the fatal and near-fatal asthma in Alternaria alternata sensitized patients]. / Características clínicas de las crisis de asma de riesgo vital en los pacientes sensibilizados a Alternaria alternata.

BACKGROUND AND OBJECTIVE: Some studies have pointed to Alternaria alternata as a trigger of fatal and near-fatal asthma (NFA) crises. The objective of this study was to determine the clinical characteristics of fatal and NFA crisis in patients sensitized to Alternaria. PATIENTS AND METHOD: One hundred ninety four patients with fatal or NFA attacks were enrolled in a multicenter (33 Spanish hospitals), prospective study. We gathered the characteristics and clinical course of the crises. We performed the following tests: spirometry, prick-test to common allergens, and specific IgE to Alternaria when patients were in stable condition. The sensitization test to Alternaria was performed when the prick-test and/or specific IgE levels were positive. RESULTS: Twenty (10%) patients were sensitized to Alternaria. When compared to non-sensitized patients, Alternaria sensitized patients were significantly younger, 35 (15) vs 50 (21) years old (p<0.001); their hospital admission length was shorter, 6.5 (5.5) against 9 (7) days (p=0.039); they had a higher number of deaths or severe neurological sequelae, 15 vs 3% (p=0.026); they had a higher sensitization frequency to the remaining allergens, 68 against 22% (p=0.003); and they exhibited a fewer bronchodilation response upon inhaled salbutamol, 6 vs 10% (p=0.013). CONCLUSIONS: The clinical characteristics of Alternaria sensitised, fatal-and NFA-patients, seem to identify a particular phenotype. Specific avoidance strategies could be useful to prevent fatal and NFA attacks.

Determinants of dyspnea in patients with different grades of stable asthma.

Dyspnea is a main feature of symptomatology in asthma, and its perception does not necessarily correlates well with airway obstruction. The aim of this study was twofold: (1) to identify factors determining the subjective degree of dyspnea in patients with different grades of stable bronchial asthma and (2) to compare various clinical methods existing for grading dyspnea. The investigation comprised 153 outpatients with stable asthma. The parameters studied were the following: demographic characteristic of subjects, baseline dyspnea score by means of three clinical instruments (baseline dyspnea index [BDI], Medical Research Council [MRC] scale, and modified Borg scale), asthma severity, standard measures of physiologic lung function, anxiety, depression, subconscious illness attention, and asthma-related quality of life (HRQOL). The dyspnea scores were all significantly interrelated (r=0.77-0.85, p<0.001). The three clinical scales for grading dyspnea were significantly correlated with the same parameters: airflow obstruction, lung hyperinflation, emotional factors, HRQOL, age, age at asthma onset, asthma duration, female gender, clinical severity, and lower economical, and educational levels. Multiple regression analysis showed that independent factors determining clinical dyspnea scores were: age, airway obstruction, and emotional status. Moreover, in patients with severe asthma, lung hyperinflation helped to explain the individual dyspnea score. These data suggest that clinical methods are appropriate for evaluating the impact of dyspnea on daily activities of asthmatic patients. BDI, MRC, and Borg clinical dyspnea scales showed similarly information in subjects with asthma. Independently of asthma severity, older age, airway obstruction, and psychological disturbance were associated with higher degree of dyspnea. However, if subjects had severe airway obstruction, lung hyperinflation was a major determinant of baseline dyspnea score.

Gender differences in health-related quality of life among patients with asthma.

This study has a twofold objective: 1) to explore to what extent suffering from asthma affects the HRQL of men and women differently at several stages of disease severity and 2) to analyze whether the informed poorer HRQL of asthmatic women is related to their higher scores on instruments measuring emotionally disordered symptoms. One hundred fifty-one outpatient asthmatics (84 women and 67 men) completed the Spanish versions of the Asthma Quality of Life questionnaire (AQL), as well as anxiety and depression inventories. A full history, physical examination, and pulmonary function test were performed on all subjects. Patients were classified into one of four asthma severity categories following the criteria of the Global Initiative on Asthma (GINA). There were no gender differences in sociodemographic variables, asthma duration, GINA, FEV1 or dyspnea. However, women showed a poorer HRQL than men, as well as high degrees of anxiety and depression. When these data were reanalyzed taking into account the four groups of asthma severity, women only reported a poorer HRQL than men at the intermittent asthma level. The gender differences on depression and anxiety scores were maintained at the three lower severity levels, but not at the most severe asthma degree. When depression and anxiety scores were partialed out, the AQL scores maintained significant relationships with asthma severity, dyspnea, and FEV1, both in women and men. Therefore, only in men were there also relationships among AQL and sociodemographic data. The best predictor of the women's HRQL was the dyspnea score, whereas in men it was the asthma severity (GINA).