Eduard Monsó

Variability and effects of bronchial colonisation in patients with moderate COPD

Sputum and lung function were periodically assessed in stable moderate chronic obstructive pulmonary disease (COPD) outpatients to determine relationships between bronchial colonisation and inflammation. Relationships between potentially pathogenic microorganism (PPM) typology, bronchial inflammation (neutrophilia, tumour necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-12) and post-bronchodilator decline in forced expiratory volume in 1u2005s (FEV1) were analysed. PPMs periodically showing the same molecular profile using pulse field gel electrophoresis were considered long-term persistent. Bronchial colonisation was observed in 56 out of 79 follow-up examinations (70.9%) and was mainly due to Haemophilus influenzae, Pseudomonas aeruginosa and enterobacteria (nu200a=u200a47). These PPMs were all related to sputum neutrophilia (p≤0.05, Chi-squared test), and H. influenzae was related to higher levels of IL-1β (pu200a=u200a0.005) and IL-12 (pu200a=u200a0.01), with a dose–response relationship (Spearman’s correlation coefficient of 0.38 for IL-1β (pu200a=u200a0.001), and of 0.32 for IL-12 (pu200a=u200a0.006)). Haemophilus parainfluenzae was not associated with an identifiable inflammatory response. Long-term persistence of the same strain was observed in 12 examinations (21.4%), mainly due to P. aeruginosa or enterobacteria. A neutrophilic bronchial inflammatory response was associated with a statistically significant decline in FEV1 during follow-up (OR 2.67, 95% CI 1.07–6.62). A load-related relationship to bronchial inflammation in moderate COPD was observed for colonisation by H. influenzae, but not for colonisation by H. parainfluenzae.

Region-related risk factors for respiratory symptoms in European and Californian farmers

The aim of this study was to determine the prevalences and regional risk factors for respiratory symptoms in European and Californian farmers. Farmers participating in the 1993–1997 surveys performed in Europe (n=7,188) and California (n=1,839) were included in this cross-sectional study. Respiratory symptoms and farming characteristics were assessed by questionnaire and risk factors associated with symptoms using logistic regression. The prevalences of rhinitis and asthma were lower in European (12.7% and 2.8%) than in Californian farmers (23.9% and 4.7%), but chronic bronchitis and toxic pneumonitis were more prevalent in Europe (10.7% and 12.2%) than in California (4.4% and 2.7%). Respiratory symptoms were associated with poultry and rabbit farming, flower growing and the cultivation of grain and oil plants. Working in Europe was a statistically significant risk factor for chronic bronchitis and toxic pneumonitis. Chronic bronchitis was related to toxic pneumonitis, work inside confinement buildings and greenhouses. Chronic bronchitis and toxic pneumonitis are highly prevalent among European farmers and are mainly attributable to indoor work.

Efficacy of moxifloxacin in the treatment of bronchial colonisation in COPD

This study was designed to investigate the efficacy of moxifloxacin for the eradication of bacterial colonisation of the airways in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Out of 119 stable patients with COPD screened, 40 (mean age 69u2005yrs, mean forced expiratory volume in 1u2005s 50% predicted) were colonised with potentially pathogenic microorganisms (PPMs) and were included in a randomised, double-blind, placebo-controlled trial with moxifloxacin 400u2005mg daily for 5u2005days. Eradication rates were 75% with moxifloxacin and 30% with placebo at 2u2005weeks (pu200a=u200a0.01). Bacterial persistence at 8u2005weeks was still higher (not significantly) in the placebo arm (five (25%) out of 20 versus one (5%) out of 20; pu200a=u200a0.18). The frequencies of acquisition of a new PPM were high and similar in both treatment groups; consequently, the prevalence of colonisation at 8u2005weeks was also similar between treatment arms. No difference was found in the number of patients with exacerbations during the 5-month follow-up. Only the acquisition of a new PPM during follow-up showed a statistically significant relationship with occurrence of an exacerbation. Moxifloxacin was effective in eradicating PPMs in patients with positive sputum cultures. However, most patients were recolonised after 8u2005weeks of follow-up. Acquisition of a new strain of bacteria was associated with an increased risk of developing an exacerbation.

Lifetime occupational exposure to dusts, gases and fumes is associated with bronchitis symptoms and higher diffusion capacity in COPD patients.

Background Occupational exposure to dusts, gases and fumes has been associated with reduced FEV1 and sputum production in COPD patients. The effect of occupational exposure on other characteristics of COPD, especially those reflecting emphysema, has not been studied in these patients. Methods We studied 338 patients hospitalized for a first exacerbation of COPD in 9 Spanish hospitals, obtaining full occupational history in a face-to-face interview; job codes were linked to a job exposure matrix for semi-quantitative estimation of exposure to mineral/biological dust, and gases/fumes for each job held. Patients underwent spirometry, diffusing capacity testing and analysis of gases in stable conditions. Quality of life, dyspnea and chronic bronchitis symptoms were determined with a questionnaire interview. A high- resolution CT scan was available in 133 patients. Results 94% of the patients included were men, with a mean age of 68(8.5) years and a mean FEV1% predicted 52 (16). High exposure to gases or fumes was associated with chronic bronchitis, and exposure to mineral dust and gases/fumes was associated with higher scores for symptom perception in the St. George’s questionnaire. No occupational agent was associated with a lower FEV1. High exposure to all occupational agents was associated with better lung diffusion capacity, in long-term quitters. In the subgroup with CT data, patients with emphysema had 18% lower DLCO compared to those without emphysema. Conclusions In our cohort of COPD patients, high exposure to gases or fumes was associated with chronic bronchitis, and high exposure to all occupational agents was consistently associated with better diffusion capacity in long-term quitters.

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 72u2005h of hospitalisation and during clinical stability, at least 3u2005months 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. This is the first study to investigate COPD exacerbations using multi-level differential network analysis http://ow.ly/uYlW30eMpwR

Influence of Dynamic Leaks in Volume-Targeted Pressure Support Noninvasive Ventilation: A Bench Study

INTRODUCTION: The effect of leaks on volume-targeted pressure support noninvasive ventilation mode has only been tested with continuous simulated leaks. The objective of the study was to assess the influence of random leaks occurring either during inspiration or expiration. METHODS: Analysis of the volume-targeted pressure support mode in 6 commercial ventilators with single-limb circuits and intentional leak in a bench study (restrictive model). Unintentional leaks were introduced through a mechanical system during inspiration (threshold valve with 2 levels of leaks) or during expiration (active valve). Results of delivered tidal volume (VT) and pressure support were externally recorded. A pre-set VT of 550 mL was programmed, with a wide range of pressure support values. RESULTS: All the ventilators showed a deviation of delivered versus programmed VT below 10% in the period without unintentional leaks. In the model with unintentional inspiratory leaks, a progressive drop in delivered VT and pressure support was observed for all ventilators. The reduction in the delivered VT for the highest inspiratory leak ranged between 21 and 40%, corresponding to a decrease in pressure support between 3.09 and 10.15 cm H2O after 5 min. Conversely, in the expiratory model, increases in delivered VT and pressure support were observed, ranging between 16 and 33% and between 2.7 and 6.5 cm H2O, respectively. CONCLUSIONS: The introduction of random leaks influences the performance of commercial ventilators with single-limb circuits and intentional leak. The decrease in delivered VT with inspiratory leaks reaches a magnitude that may have clinically important impacts.

Determinants of false-negative results in non-small-cell lung cancer staging by endobronchial ultrasound-guided needle aspiration

OBJECTIVESnFalse-negative results of endobronchial ultrasound-guided transbronchial needle aspiration in non-small-cell lung cancer staging have shown significant variability in previous studies. The aim of this study was to identify procedure- and tumour-related determinants of endobronchial ultrasound-guided transbronchial needle aspiration false-negative results.nnnMETHODSnWe conducted a prospective study that included non-small-cell lung cancer patients staged as N0/N1 by endobronchial ultrasound-guided transbronchial needle aspiration and undergoing therapeutic surgery. The frequency of false-negative results in the mediastinum was calculated. Procedure-related, first, and tumour-related, second, determinants of false-negative results in stations reachable and non-reachable by endobronchial ultrasound were determined by multivariate logistic regression.nnnRESULTSnFalse-negative endobronchial ultrasound-guided transbronchial needle aspiration results were identified in 23 of 165 enrolled patients (13.9%), mainly in stations reachable by endobronchial ultrasound (17 cases, 10.3%). False-negative results were related to the extensiveness of endobronchial ultrasound sampling: their prevalence was low (2.4%) when sampling of three mediastinal stations was satisfactory, but rose above 10% when this requirement was not fulfilled (P = 0.043). In the multivariate analysis, abnormal mediastinum on computer tomography/positron emission tomography [odds ratio (OR) 7.77, 95% confidence interval (CI) 2.19-27.51, P = 0.001] and extensiveness of satisfactory sampling of mediastinal stations (OR 0.37, 95% CI 0.16-0.89, P = 0.026) were statistically significant risk factors for false-negative results in stations reachable by endobronchial ultrasound. False-negative results in non-reachable nodes were associated with a left-sided location of the tumour (OR 10.11, 95% CI 1.17-87.52, P = 0.036).nnnCONCLUSIONSnThe presence of false-negative ultrasound-guided transbronchial needle aspiration results were observed in nearly 15% of non-small-cell lung cancer patients but in only 3% when satisfactory samples were obtained from three mediastinal stations. False-negative results in stations reachable by endobronchial ultrasound were associated with the extensiveness of sampling, and in stations out of reach of endobronchial ultrasound with left-sided tumours. These results suggest that satisfactory sampling of at least three mediastinal stations by EBUS-TBNA may be a quality criterion to be recommended for EBUS-TBNA staging.

Specific IgA and metalloproteinase activity in bronchial secretions from stable chronic obstructive pulmonary disease patients colonized by Haemophilus influenzae

BackgroundHaemophilus influenzae is the most common colonizing bacteria of the bronchial tree in chronic obstructive pulmonary disease (COPD), and positive cultures for this potentially pathogenic microorganism (PPM) has been associated with local inflammation changes that may influence the relationships between H. influenzae and the bronchial mucosa.MethodsA cross-sectional analysis of stable COPD patients enrolled in the Phenotype and Course of Chronic Obstructive Pulmonary Disease (PAC-COPD) Study, focusing on bronchial colonization by H. influenzae, was performed. Specific IgA against the PPM was measured by optical density, and metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) using ELISA in sputum samples. Levels in patients colonized by H. influenzae and non-colonized patients were compared.ResultsSputum supernatant for the measurement of specific IgA against H. influenzae was available from 54 stable COPD patients, who showed levels of specific IgA significantly lower in colonized (n=21) than in non-colonized patients (n=33) (15 [4-37] versus 31 [10-75], p=0.033, Mann-Whitney U test). Proenzyme MMP-9 was measured in 44 patients, and it was higher in colonized (n=12, 1903 [1488-6699] ng/ml) than in non-colonized patients (n=32, 639 [373-972] ng/ml) (p<0.001, Mann-Whitney U test). Active form of MMP-9 was also higher in colonized (126 [25-277] ng/ml) than in non-colonized patients (39 [14-68] ng/ml) (p=0.021, Mann-Whitney U test), and the molar ratio between proenzyme MMP-9 and TIMP-1 was above 1 (2.1 [0.1-12.5]) in colonized patients, significantly higher than the ratio found in non-colonized patients (0.2 [0.08-0.5]) (p=0.030, Mann-Whitney U test).ConclusionsClinically stable COPD patients colonized by H. influenzae had lower levels of specific IgA against the microorganism and higher values of the active form of MMP-9 in their sputum supernatant than non-colonized patients. Bronchial colonization by H. influenzae may cause structural changes in the extracellular matrix through a defective defense and the production of active metalloproteinases.

A novel protein-based prognostic signature improves risk stratification to guide clinical management in early-stage lung adenocarcinoma patients: A protein-based prognostic signature for early-stage lung ADC

Each of the pathological stages (I–IIIa) of surgically resected non‐small‐cell lung cancer has hidden biological heterogeneity, manifested as heterogeneous outcomes within each stage. Thus, the finding of robust and precise molecular classifiers with which to assess individual patient risk is an unmet medical need. Here, we identified and validated the clinical utility of a new prognostic signature based on three proteins (BRCA1, QKI, and SLC2A1) to stratify early‐stage lung adenocarcinoma patients according to their risk of recurrence or death. Patients were staged according to the new International Association for the Study of Lung Cancer (IASLC) staging criteria (8th edition, 2018). A test cohort (nu2009=u2009239) was used to assess the value of this new prognostic index (PI) based on the three proteins. The prognostic signature was developed by Cox regression with the use of stringent statistical criteria (TRIPOD: Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis). The model resulted in a highly significant predictor of 5‐year outcome for disease‐free survival (pu2009<u20090.001) and overall survival (pu2009<u20090.001). The prognostic ability of the model was externally validated in an independent multi‐institutional cohort of patients (nu2009=u2009114, pu2009=u20090.021). We also demonstrated that this molecular classifier adds relevant information to the gold standard TNM‐based pathological staging, with a highly significant improvement of the likelihood ratio. We subsequently developed a combined PI including both the molecular and the pathological data that improved the risk stratification in both cohorts (pu2009≤u20090.001). Moreover, the signature may help to select stage I–IIA patients who might benefit from adjuvant chemotherapy. In summary, this protein‐based signature accurately identifies those patients with a high risk of recurrence and death, and adds further prognostic information to the TNM‐based clinical staging, even when the new IASLC 8th edition staging criteria are applied. More importantly, it may be a valuable tool for selecting patients for adjuvant therapy. Copyright

Tumor-associated metabolic and inflammatory responses in early stage non-small cell lung cancer: Local patterns and prognostic significance

INTRODUCTIONnNon-small cell lung cancer (NSCLC) patients diagnosed in early stage and surgically-treated have five-year mortality rate >20%. The identification of biomarkers able to predict progression and death may help to identify patients needing closer follow-up.nnnMETHODSnA retrospective cohort of early-stage surgically-treated NSCLC patients enrolled in the International Association for the Study of Lung Cancer (IASLC) Staging Project was created, and tissue Microarrays (TMAs) were constructed with tumor and non-tumor lung tissue. Pentose phosphate pathway (PPP) proteins (transketolase [TKT] and transketolase-like 1 [TKTL1]), inflammatory markers (cyclooxygenase-2 [COX-2], tumor necrosis factor alpha [TNF-α], interleukin 1 beta [IL1β], nuclear factor kappa-light-chain-enhancer of activated B cells [NFκB]-p65 and antigen Ki-67), and programmed death-ligand 1 (PDL1) were measured by immunohistochemistry.nnnRESULTSnNSCLC patients with adenocarcinoma (ADC) or squamous cell carcinoma (SCC) were included in the study (nu202f=u202f199). TKT and TKTL1 were significantly higher in ADC than in non-tumor tissue (pu202f<u202f0.001). Higher values were also observed in NSCLC for all the inflammatory markers, with figures >30% above those of non-tumor tissue (pu202f<u202f0.001). PDL1 analysis showed a higher percentage of positivity in ADC than in non-tumor tissue (pu202f<u202f0.001). Multivariate Cox proportional hazards modeling confirmed that high IL1β level in tumor tissue was independently associated with 3-year mortality in NSCLC [HRu202f=u202f2.05, 95% CI (1.1-3.7), pu202f=u202f0.019], a relationship driven by ADC subtype.nnnCONCLUSIONnThis study confirms an increase in metabolic activity and an inflammatory response in tumor tissue of early stage NSCLC, and a significant relationship between high levels of IL1β in the tumor and poor prognosis in ADC.