ABSTRACT
Background and objective
The relationship between IPF development and environmental factors has not been completely elucidated. Analysing geographic regions of idiopathic pulmonary fibrosis ...(IPF) cases could help identify those areas with higher aggregation and investigate potential triggers. We hypothesize that cross‐analysing location of IPF cases and areas of consistently high air pollution concentration could lead to recognition of environmental risk factors for IPF development.
Methods
This retrospective study analysed epidemiological and clinical data from 503 patients registered in the Observatory IPF.cat from January 2017 to June 2019. Incident and prevalent IPF cases from the Catalan region of Spain were graphed based on their postal address. We generated maps of the most relevant air pollutant PM2.5 from the last 10 years using data from the CALIOPE air quality forecast system and observational data.
Results
In 2018, the prevalence of IPF differed across provinces; from 8.1 cases per 100 000 habitants in Barcelona to 2.0 cases per 100 000 in Girona. The ratio of IPF was higher in some areas. Mapping PM2.5 levels illustrated that certain areas with more industry, traffic and shipping maintained markedly higher PM2.5 concentrations. Most of these locations correlated with higher aggregation of IPF cases. Compared with other risk factors, PM2.5 exposure was the most frequent.
Conclusion
In this retrospective study, prevalence of IPF is higher in areas of elevated PM2.5 concentration. Prospective studies with targeted pollution mapping need to be done in specific geographies to compile a broader profile of environmental factors involved in the development of pulmonary fibrosis.
This study identifies geographic regions of notable air pollution, juxtaposed over locations with higher prevalence of idiopathic pulmonary fibrosis (IPF). Certain areas with elevated air pollutants may be deserving greater analysis for screening of IPF and optimizing early identification. Prospective studies are required for evaluating air pollution as an IPF risk factor.
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Background and objective
Secreted mucins play a key role in antibacterial defence in the airway, but have not previously been characterized in non‐cystic fibrosis (CF) bronchiectasis patients. We aim ...to investigate the relationship between secreted mucins levels and the presence of bacterial colonization due to potentially pathogenic microorganisms (PPM) in the airways of stable bronchiectasis patients.
Methods
Clinically stable bronchiectasis patients were studied prospectively at two centres. Patients with other pulmonary conditions were excluded. Spontaneous sputum was subject to bacterial culture, and secreted mucins (MUC2, MUC5AC and MUC5B) were measured in sputum supernatants by ELISA.
Results
A total of 50 patients were included. PPM were identified from sputum samples in 30 (60%), with Pseudomonas aeruginosa (n = 10) and Haemophilus influenzae (n = 10) as the most common PPM. There were no baseline differences among airway colonized and non‐colonized patients. Patients with airways colonized by PPM presented higher levels of airway MUC2. No differences in MUC5AC levels were found among groups, whereas MUC5B levels were undetectable. Patients with P. aeruginosa colonization expressed the highest levels of MUC2. High levels of MUC2 and MUC5AC are also correlated with disease severity using the Bronchiectasis Severity Index.
Conclusions
Airway MUC2 levels were higher in bronchiectasis patients colonized with PPM compared with those without airway colonization, especially in patients with P. aeruginosa. These findings suggest that airway‐secreted mucins levels may play a role in the pathogenesis of airway infection in non‐CF bronchiectasis.
Secreted mucins are important for airway defence. However, their role in airway bacterial colonization in non‐CF bronchietasis has not been studied previously. Our study demonstrates that airway MUC2 levels are higher in patients with non‐CF bronchiectasis and airway bacterial colonization, especially in those with severe disease and Pseudomonas aeruginosa.
Summary Background Airway bacterial colonization by potentially pathogenic microorganisms occurs in a proportion of patients with Chronic Obstructive Pulmonary Disease (COPD). It increases airway ...inflammation and influences outcomes negatively. Yet, its diagnosis in clinical practice is not straightforward. The electronic nose is a new non-invasive technology capable of distinguishing volatile organic compound (VOC) breath-prints in exhaled breath. We aim to explore if an electronic nose can reliably discriminate COPD patients with and without airway bacterial colonization. Methods We studied 37 clinically stable COPD patients (67.8 ± 5.2 yrs, FEV1 41 ± 10% ref.) and 13 healthy controls (62.8 ± 5.2 yrs, FEV1 99 ± 10% ref.). The presence of potentially pathogenic microorganisms in the airways of COPD patients ( n = 10, 27%) was determined using quantitative bacterial cultures of protected specimen brush. VOCs breath-prints were analyzed by discriminant analysis on principal component reduction, resulting in cross-validated accuracy values. Area Under Receiver Operating Characteristics (AUROC) was calculated using multiple logistic regression. Results Demographic, functional and clinical characteristics were similar in colonized and non-colonized COPD patients but their VOC breath-prints were different (accuracy 89%, AUROC 0.92, p > 0.0001). Likewise, VOCs breath-prints from colonized (accuracy 88%, AUROC 0.98, p < 0.0001) and non-colonized COPD patients (accuracy 83%, AUROC 0.93, p < 0.0001) were also different from controls. Conclusions An electronic nose can identify the presence of airway bacterial colonization in clinically stable patients with COPD.
Mucins are essential for airway defense against bacteria. We hypothesized that abnormal secreted airway mucin levels would be associated with bacterial colonization in patients with severe chronic ...obstructive pulmonary disease (COPD) Objectives: To investigate the relationship between mucin levels and the presence of potentially pathogenic micro-organisms in the airways of stable patients with severe COPD Methods: Clinically stable patients with severe COPD were examined prospectively. All patients underwent a computerized tomography scan, lung function tests, induced sputum collection, and bronchoscopy with bronchoalveolar lavage (BAL) and protected specimen brush. Patients with bronchiectasis were excluded. Secreted mucins (MUC2, MUC5AC, and MUC5B) and inflammatory markers were assessed in BAL and sputum by ELISA.
We enrolled 45 patients, with mean age (±SD) of 67 (±8) years and mean FEV1 of 41 (±10) % predicted. A total of 31% (n = 14) of patients had potentially pathogenic micro-organisms in quantitative bacterial cultures of samples obtained by protected specimen brush. Patients with COPD with positive cultures had lower levels of MUC2 both in BAL (P = 0.02) and in sputum (P = 0.01). No differences in MUC5B or MUC5AC levels were observed among the groups. Lower MUC2 levels were correlated with lower FEV1 (r = 0.32, P = 0.04) and higher sputum IL-6 (r = -0.40, P = 0.01).
Airway MUC2 levels are decreased in patients with severe COPD colonized by potentially pathogenic micro-organisms. These findings may indicate one of the mechanisms underlying airway colonization in patients with severe COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01976117).
INTRODUCTIONPulmonary nocardiosis (PN) is a severe infection with a high morbidity and mortality that mainly affects immunocompromised patients. In recent years, an increase in PN cases has been ...detected among patients with chronic obstructive pulmonary disease (COPD). The factors that are associated with its presence and determine its prognosis remain unknown.METHODSRetrospective study of COPD patients diagnosed with PN over the period from 1997-2009 at the Hospital de la Santa Creu i Sant Pau, in Barcelona (Spain). Demographic, clinical, microbiological and evolution data were evaluated in all casesRESULTSThirty patients were identified with PN and COPD. Mean age (standard deviation) was 76 (7) years and the mean FEV(1) was 40 (14)%. Chronic respiratory failure was observed in 56,7% patients and 51,7% had received systemic corticosteroid therapy previous to the PN diagnosis. The most common symptoms were cough and dyspnea (90%). Alveolar infiltrates were observed in 60% of the cases. The most frequently isolated Nocardia species was N. cyriacigeorgica (68%). The one-month mortality rate was 17%, while the one-year mortality rate was 33%. The factors associated with mortality within the first year included previous systemic corticosteroid treatment, less than three months of specific antibiotic therapy and active associated neoplasm.CONCLUSIONSPN affects patients with moderate-severe COPD and has high short- and mid-term mortality rates. Previous corticosteroid treatment, specific antibiotic therapy for less than 3 months and active neoplasia were factors associated with mortality.
Abstract Introduction Pulmonary nocardiosis (PN) is a severe infection with a high morbidity and mortality that mainly affects immunocompromised patients. In recent years, an increase in PN cases has ...been detected among patients with chronic obstructive pulmonary disease (COPD). The factors that are associated with its presence and determine its prognosis remain unknown. Methods Retrospective study of COPD patients diagnosed with PN over the period from 1997 to 2009 at the Hospital de la Santa Creu i Sant Pau, in Barcelona (Spain). Demographic, clinical, microbiological and evolution data were evaluated in all cases. Results Thirty patients were identified with PN and COPD. Mean age (standard deviation) was 76 (7) years and the mean FEV1 was 40 (14)%. Chronic respiratory failure was observed in 56.7% patients and 51.7% had received systemic corticosteroid therapy previous to the PN diagnosis. The most common symptoms were cough and dyspnea (90%). Alveolar infiltrates were observed in 60% of the cases. The most frequently isolated Nocardia species was N. cyriacigeorgica (68%). The one-month mortality rate was 17%, while the one-year mortality rate was 33%. The factors associated with mortality within the first year included previous systemic corticosteroid treatment, less than three months of specific antibiotic therapy and active associated neoplasm. Conclusions PN affects patients with moderate-severe COPD and has high short- and mid-term mortality rates. Previous corticosteroid treatment, specific antibiotic therapy for less than 3 months and active neoplasia were factors associated with mortality.
La malaltia pulmonar obstructiva crònica (MPOC) representa un problema sanitari de primer ordre, donada la seva elevada prevalença, que és una causa creixent de morbi-mortalitat arreu del món i ...donada l’elevada despesa sanitària que representa.
Diversos estudis amb tècniques invasives han demostrat que el 30-50% dels pacients amb MPOC greu clínicament estables presenten bactèries potencialment patògenes (BPP) a la seva via aèria, fet que es relaciona amb més inflamació, una major pèrdua de funció pulmonar i amb aguditzacions més freqüents i greus.
En l’actualitat però, no és conegut per què uns pacients amb MPOC són més susceptibles que d’altres a la colonització bacteriana. Per contra, està ben establerta la importància dels mecanismes de defensa innats del sistema respiratori, com són les mucines per mantenir la via aèria estèril. Per altra banda, el diagnòstic de la presència bacteriana a la via aèria en aquests pacients es realitza mitjançant el cultiu d’esput, que és un mètode no invasiu àmpliament estès en la pràctica clínica diària però que presenta importants limitacions.
La hipòtesi de la tesi postula que les mucines (mecanismes de defensa pulmonar) estan alterades en alguns pacients amb MPOC greu, fet que els fa més susceptibles a ser colonitzats per BPP. I que els mètodes diagnòstics no invasius com la Tomografia Computeritzada d´Alta Resolució (TACAR) o el nas electrònic (e-nose) poden facilitar-ne el seu diagnòstic.
Per a estudiar els objectius proposats, es van dissenyar 3 estudis prospectius en el quals es van incloure pacients amb MPOC moderada-greu en fase d’estabilitat clínica (> 8 setmanes sense agudització) i sense altra patologia respiratòria concomitant. En tots els pacients es va realitzar l’obtenció de mostra d’esput induït, una fibrobroncoscòpia amb rentada broncoalveolar (RBA) i es van recollir variables demogràfiques i de funcionalisme pulmonar. Es va realitzar l’estudi microbiològic de les mostres respiratòries. En el primer estudi es va realitzar determinació de les mucines, dels pèptids antimicrobians i de les citocines inflamatòries. En el segon estudi es realitzava l’adquisició d’imatges pulmonars mitjançant la TACAR i determinació de signes radiològics d’infecció. En el darrer estudi, es van determinar els compostos orgànics volàtils (COVs) en l’aire exhalat mitjançant el nas electrònic.
Com a resultats es va detectar que l’expressió disminuïda de la mucina 2 (MUC 2) a la via aèria s’associava a la colonització bacteriana bronquial i a una major inflamació de la via aèria (determinada pels nivells de IL-6). Es va observar que existia una relació inversa entre els nivells de IL-6 a la via aèria i els nivells de mucina 2. En l’estudi de la TACAR, es va observar que aquesta no detectava diferències en els patrons radiològics estudiats entre els subjectes amb colonització respecte aquells sense colonització. Per altra banda l’e-nose, sí va mostrar una correcta capacitat per classificar els MPOC en colonitzats i no colonitzats, amb una sensibilitat del 82% i una especificitat del 96%.
En conclusió, els nivells disminuïts de la MUC 2 a la via aèria es relacionen amb la colonització bacteriana bronquial i amb valors més elevats d’inflamació. La TACAR no permet detectar els individus amb BPP a la via aèria, mentre que el nas electrònic sí permet detectar aquells pacients amb MPOC que tenen colonització bronquial.
Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity, mortality and resource use worldwide.
Several studies using invasive diagnostic tools showed that 30-50 % of patients with clinically stable COPD have potentially pathogenic bacteria (PPB) in their airway, which is associated with more inflammation, a higher decrease in lung function and more frequent and severe exacerbations.
However, it is not known why some patients with COPD are more susceptible than others to bacterial airway colonization. It is well established the importance of respiratory system innate defense mechanisms, such as mucins to maintain the airway sterile. On the other hand, sputum culture is a non-invasive diagnostic tool for airway bacterial colonization. Even though is a widespread method in daily clinical practice it has important limitations.
The hypothesis of the thesis postulates that mucin levels are altered in some patients with severe COPD, which makes them more likely to be colonized by PPB. In addition, we postulate that new non-invasive techniques such as the High Resolution Computed Tomography (HRCT) and the electronic nose (e- nose), may facilitate bacterial colonization diagnosis.
Three prospective studies were designed. Inclusion criteria were patients with moderate to severe COPD clinically stable (> 8 weeks without exacerbation) with no other concomitant respiratory disease. In all patients demographic variables and lung function data were collected, induced sputum sample was obtained and a bronchoscopy with broncoalveolar lavage (BAL) was performed. We performed microbiological study of the respiratory samples. In the first study mucin levels, antimicrobial peptides levels and inflammatory cytokines levels were determined. In the second study HRCT images were analysed for radiological signs of infection. In the last study the volatile organic compounds (VOCs) in the exhaled air were studied by the electronic nose.
In result, it was found that decreased levels of airway mucin 2 were associated with bacterial colonization and increased airway inflammation (determined by IL- 6 levels). It was noted that there was an inverse relationship between IL- 6 levels and airway mucin 2 levels. In the second study no differences in HRCT imaging patterns were detected among subjects with and those without bronchial colonization. The e-nose instead, was able to classify COPD patients in colonized and non- colonized with a sensitivity of 82 % and a specificity of 96%.
In conclusion, low airway MUC 2 levels in severe COPD patients were associated with airway bacterial colonization and higher levels of inflammation (IL-6). HRCT is not usefull in the detection of potentially pathogenic bacteria in the airway of COPD patients. The e-nose detects those COPD patients with bronchial colonization.
Single-agent PD-1/PD-L1 inhibitors have shown limited efficacy in unselected mCRPC. The evidence of a survival benefit with sipuleucel-T and ipilimumab, provides a rationale to study further ...increasing immunogenicity in mCRPC through combinations.
Safety and efficacy avelumab plus carboplatin was investigated in a single-arm Phase Ib study in mCRPC, progressing to at least one taxane and one androgen-receptor inhibitor. The primary endpoint was safety. Secondary endpoints included PSA/radiographic responses, progression-free survival (PFS) and overall survival (OS). Germline/somatic mutation analysis was performed.
In total, 26 patients were included. Patients were heavily pretreated: 76.9% received ≥3 and 42.3% ≥4 prior lines. A DNA damage repair (DDR) alteration was found in three patients (11.5%). The safety profile was acceptable with 73% Grade 3-4 treatment-related adverse events. PSA response rate ≥50% was seen in 7.7% of patients. The objective response rate was 17.6%, including one complete response (5.9%). Two of these responders had a known DDR alteration (one BRCA2, one ATM). The median response duration was 6 months. Median radiographic PFS was 6.6 months (95% CI 4.28-9.01), and median OS 10.6 months (95% CI 6.68-NR).
Avelumab plus carboplatin has an acceptable safety profile and was associated with a prolonged OS given the heavily pretreated population.
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