A comprehensive analysis of the impact of <i>Pseudomonas aeruginosa</i> colonization on prognosis in adult bronchiectasis

Rationale: Eradication and suppression of Pseudomonas aeruginosa is a key priority in national guidelines for bronchiectasis and is a major focus of drug development and clinical trials. An accurate estimation of the clinical impact of P. aeruginosa in bronchiectasis is therefore essential. Methods: Data derived from 21 observational cohort studies comparing patients with P. aeruginosa colonization with those without it were pooled by random effects meta-analysis. Data were collected for key longitudinal clinical outcomes of mortality, hospital admissions, exacerbations, and lung function decline, along with cross-sectional outcomes such as quality of life. MeasurementsandMainResults: In the aggregate, the included studies comprised 3,683 patients. P. aeruginosa was associated with a highly significant and consistent increase in all markers of disease severity, including mortality (odds ratio [OR], 2.95; 95% confidence interval [CI], 1.98-4.40; P <0.0001), hospital admissions (OR, 6.57; 95% CI, 3.19-13.51; P <0.0001), and exacerbations (mean difference, 0.97/yr; 95% CI, 0.64-1.30; P <0.0001). The patients with P. aeruginosa also had worse quality of life on the basis of their St. George's Respiratory Questionnaire results (mean difference, 18.2 points; 95% CI, 14.7-21.8; P <0.0001). Large differences in lung function and radiological severity were also observed. The definitions of colonization were inconsistent among the studies, but the findings were robust regardless of the definition used. Conclusion: P. aeruginosa is associated with an approximately threefold increased risk of death and an increase in hospital admissions and exacerbations in adult bronchiectasis

Research highlights from the 2018 European Respiratory Society International Congress: Airway disease

The annual European Respiratory Society (ERS) International Congress (held in Paris in 2018) was once again a platform for discussion of the highest-quality scientific research, cutting-edge techniques and innovative new therapies within the respiratory field. This article discusses only some of the high-quality research studies presented at this year’s Congress, with a particular focus on airway diseases including asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis and cough, as presented through Assembly 5 of the ERS (Airway Diseases: Asthma and COPD). The authors establish the key take-home messages of these studies, compare their findings and place them in the context of current understanding.Health Research Boar

Bronchiectasis Rheumatoid Overlap Syndrome Is an Independent Risk Factor for Mortality in Patients With Bronchiectasis:A Multicenter Cohort Study

BACKGROUND: This study assessed if bronchiectasis (BR) and rheumatoid arthritis (RA), when manifesting as an overlap syndrome (BROS), were associated with worse outcomes than other BR etiologies applying the Bronchiectasis Severity Index (BSI). METHODS: Data were collected from the BSI databases of 1,716 adult patients with BR across six centers: Edinburgh, United Kingdom (608 patients); Dundee, United Kingdom (n = 286); Leuven, Belgium (n = 253); Monza, Italy (n = 201); Galway, Ireland (n = 242); and Newcastle, United Kingdom (n = 126). Patients were categorized as having BROS (those with RA and BR without interstitial lung disease), idiopathic BR, bronchiectasis-COPD overlap syndrome (BCOS), and "other" BR etiologies. Mortality rates, hospitalization, and exacerbation frequency were recorded. RESULTS: A total of 147 patients with BROS (8.5% of the cohort) were identified. There was a statistically significant relationship between BROS and mortality, although this relationship was not associated with higher rates of BR exacerbations or BR-related hospitalizations. The mortality rate over a mean of 48 months was 9.3% for idiopathic BR, 8.6% in patients with other causes of BR, 18% for RA, and 28.5% for BCOS. Mortality was statistically higher in patients with BROS and BCOS compared with those with all other etiologies. The BSI scores were statistically but not clinically significantly higher in those with BROS compared with those with idiopathic BR (BSI mean, 7.7 vs 7.1, respectively; P < .05). Patients with BCOS had significantly higher BSI scores (mean, 10.4), Pseudomonas aeruginosa colonization rates (24%), and previous hospitalization rates (58%). CONCLUSIONS: Both the BROS and BCOS groups have an excess of mortality. The mechanisms for this finding may be complex, but these data emphasize that these subgroups require additional study to understand this excess mortality

Clinical phenotypes in adult patients with bronchiectasis

Bronchiectasis is a heterogeneous disease. This study aimed at identifying discrete groups of patients with different clinical and biological characteristics and long-term outcomes. This was a secondary analysis of five European databases of prospectively enrolled adult outpatients with bronchiectasis. Principal component and cluster analyses were performed using demographics, comorbidities, and clinical, radiological, functional and microbiological variables collected during the stable state. Exacerbations, hospitalisations and mortality during a 3-year follow-up were recorded. Clusters were externally validated in an independent cohort of patients with bronchiectasis, also investigating inflammatory markers in sputum. Among 1145 patients (median age 66 years; 40% male), four clusters were identified driven by the presence of chronic infection with Pseudomonas aeruginosa or other pathogens and daily sputum: "Pseudomonas" (16%), "Other chronic infection" (24%), "Daily sputum" (33%) and "Dry bronchiectasis" (27%). Patients in the four clusters showed significant differences in terms of quality of life, exacerbations, hospitalisations and mortality during follow-up. In the validation cohort, free neutrophil elastase activity, myeloperoxidase activity and interleukin-1\u3b2 levels in sputum were significantly different among the clusters. Identification of four clinical phenotypes in bronchiectasis could favour focused treatments in future interventional studies designed to alter the natural history of the disease

Ers international congress 2022:Highlights from the respiratory infections assembly

The European Respiratory Society International Congress took place both in person, in Barcelona, Spain, and online in 2022. The congress welcomed over 19 000 attendees on this hybrid platform, bringing together exciting updates in respiratory science and medicine from around the world. In this article, Early Career Members of the Respiratory Infections Assembly (Assembly 10) summarise a selection of sessions across a broad range of topics, including presentations on bronchiectasis, nontuberculous mycobacteria, tuberculosis, cystic fibrosis and coronavirus disease 2019

Intermittent prophylactic antibiotics for bronchiectasis (Review)

Background: Bronchiectasis is a common but under‐diagnosed chronic disorder characterised by permanent dilation of the airways arising from a cycle of recurrent infection and inflammation. Symptoms including chronic, persistent cough and productive phlegm are a significant burden for people with bronchiectasis, and the main aim of treatment is to reduce exacerbation frequency and improve quality of life. Prophylactic antibiotic therapy aims to break this infection cycle and is recommended by clinical guidelines for adults with three or more exacerbations a year, based on limited evidence. It is important to weigh the evidence for bacterial suppression against the prevention of antibiotic resistance and further evidence is required on the safety and efficacy of different regimens of intermittently administered antibiotic treatments for people with bronchiectasis. Objectives: To evaluate the safety and efficacy of intermittent prophylactic antibiotics in the treatment of adults and children with bronchiectasis. Search methods: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted searches on 6 September 2021, with no restriction on language of publication. Selection criteria: We included randomised controlled trials (RCTs) of at least three months' duration comparing an intermittent regime of prophylactic antibiotics with placebo, usual care or an alternate intermittent regimen. Intermittent prophylactic administration was defined as repeated courses of antibiotics with on‐treatment and off‐treatment intervals of at least 14 days' duration. We included adults and children with a clinical diagnosis of bronchiectasis confirmed by high resolution computed tomography (HRCT), plain film chest radiograph, or bronchography and a documented history of recurrent chest infections. We excluded studies where participants received high dose antibiotics immediately prior to enrolment or those with a diagnosis of cystic fibrosis, allergic bronchopulmonary aspergillosis (ABPA), primary ciliary dyskinesia, hypogammaglobulinaemia, sarcoidosis, or a primary diagnosis of COPD. Our primary outcomes were exacerbation frequency and serious adverse events. We did not exclude studies on the basis of review outcomes. Data collection and analysis: We analysed dichotomous data as odds ratios (ORs) or relative risk (RRs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures expected by Cochrane. We conducted GRADE assessments for the following primary outcomes: exacerbation frequency; serious adverse events and secondary outcomes: antibiotic resistance; hospital admissions; health‐related quality of life. Main results: We included eight RCTs, with interventions ranging from 16 to 48 weeks, involving 2180 adults. All evaluated one of three types of antibiotics over two to six cycles of 28 days on/off treatment: aminoglycosides, ß‐lactams or fluoroquinolones. Two studies also included 12 cycles of 14 days on/off treatment with fluoroquinolones. Participants had a mean age of 63.6 years, 65% were women and approximately 85% Caucasian. Baseline FEV1 ranged from 55.5% to 62.6% predicted. None of the studies included children. Generally, there was a low risk of bias in the included studies. Antibiotic versus placebo: cycle of 14 days on/off. Ciprofloxacin reduced the frequency of exacerbations compared to placebo (RR 0.75, 95% CI 0.61 to 0.93; I2 = 65%; 2 studies, 469 participants; moderate‐certainty evidence), with eight people (95% CI 6 to 28) needed to treat for an additional beneficial outcome. The intervention increased the risk of antibiotic resistance more than twofold (OR 2.14, 95% CI 1.36 to 3.35; I2 = 0%; 2 studies, 624 participants; high‐certainty evidence). Serious adverse events, lung function (FEV1), health‐related quality of life, and adverse effects did not differ between groups. Antibiotic versus placebo: cycle of 28 days on/off. Antibiotics did not reduce overall exacerbation frequency (RR 0.92, 95% CI 0.82 to 1.02; I2 = 0%; 8 studies, 1695 participants; high‐certainty evidence) but there were fewer severe exacerbations (OR 0.59, 95% CI 0.37 to 0.93; I2 = 54%; 3 studies, 624 participants), though this should be interpreted with caution due to low event rates. The risk of antibiotic resistance was more than twofold higher based on a pooled analysis (OR 2.20, 95% CI 1.42 to 3.42; I2 = 0%; 3 studies, 685 participants; high‐certainty evidence) and consistent with unpooled data from four further studies. Serious adverse events, time to first exacerbation, duration of exacerbation, respiratory‐related hospital admissions, lung function, health‐related quality of life and adverse effects did not differ between study groups. Antibiotic versus usual care. We did not find any studies that compared intermittent antibiotic regimens with usual care. Cycle of 14 days on/off versus cycle of 28 days on/off. Exacerbation frequency did not differ between the two treatment regimens (RR 1.02, 95% CI 0.84 to 1.24; I2 = 71%; 2 studies, 625 participants; moderate‐certainty evidence) However, inconsistencies in the results from the two trials in this comparison indicate that the apparent aggregated similarities may not be reliable. There was no evidence of a difference in antibiotic resistance between groups (OR 1.00, 95% CI 0.68 to 1.48; I2 = 60%; 2 studies, 624 participants; moderate‐certainty evidence). Serious adverse events, adverse effects, lung function and health‐related quality of life did not differ between the two antibiotic regimens. Authors' conclusions: Overall, in adults who have frequent chest infections, long‐term antibiotics given at 14‐day on/off intervals slightly reduces the frequency of those infections and increases antibiotic resistance. Intermittent antibiotic regimens result in little to no difference in serious adverse events. The impact of intermittent antibiotic therapy on children with bronchiectasis is unknown due to an absence of evidence, and further research is needed to establish the potential risks and benefits

The independent contribution of <i>Pseudomonas aeruginosa</i> infection to long-term clinical outcomes in bronchiectasis

Pseudomonas aeruginosa is responsible for chronic infection in many bronchiectasis patients but it is not known whether it is associated with worse clinical outcomes independent of the underlying severity of disease. This study analysed data from 2596 bronchiectasis patients included from 10 different bronchiectasis clinical centres across Europe and Israel, with a 5-year follow-up period. Prevalence of P. aeruginosa chronic infection and its independent impact on exacerbations, hospitalisations, quality of life and mortality was assessed. The prevalence of P. aeruginosa chronic infection was 15.0% (n=389). P. aeruginosa was associated with a higher mortality in a univariate analysis (hazard ratio (HR) 2.02; 95% (confidence interval) CI 1.53-2.66; p&lt;0.0001) but an independent impact on mortality was not found in a multivariate analysis (HR 0.98; 95% CI 0.70-1.36; p=0.89). P. aeruginosa was independently associated with increased mortality only in patients with frequent exacerbations (two or more per year) (HR 2.03; 95% CI 1.36-3.03; p=0.001). An independent association with worse quality of life of 7.46 points (95% CI 2.93-12.00; p=0.001) was found in a multivariable linear regression. P. aeruginosa was therefore found to be independently associated with exacerbation frequency, hospital admissions and worse quality of life. Mortality was increased in patients with P. aeruginosa particularly in the presence of frequent exacerbations

Characterization of the “frequent exacerbator phenotype” in bronchiectasis

Rationale: Exacerbations are key events in the natural history of bronchiectasis, but clinical predictors and outcomes of patients with frequently exacerbating disease are not well described. Objectives: To establish if there is a \u201cfrequent exacerbator phenotype\u201d in bronchiectasis and the impact of exacerbations on long-term clinical outcomes. Methods: We studied patients with bronchiectasis enrolled from 10 clinical centers in Europe and Israel, with up to 5 years of follow-up. Patients were categorized by baseline exacerbation frequency (zero, one, two, or three or more per year). The repeatability of exacerbation status was assessed, as well as the independent impact of exacerbation history on hospitalizations, quality of life, and mortality. Measurements and Main Results: A total of 2,572 patients were included. Frequent exacerbations were the strongest predictor of future exacerbation frequency, suggesting a consistent phenotype.The incident rate ratios for future exacerbations were 1.73 (95% confidence interval [CI], 1.47-2.02; P, 0.0001) for one exacerbation per year, 3.14 (95% CI, 2.70-3.66; P, 0.0001) for two exacerbations, and 5.97 (95% CI, 5.27-6.78; P, 0.0001) for patients with three or more exacerbations per year at baseline. Additional independent predictors of future exacerbation frequency were Haemophilus influenzae and Pseudomonas aeruginosa infection, FEV1, radiological severity of disease, and coexisting chronic obstructive pulmonary disease. Patients with frequently exacerbating disease had worse quality of life and were more likely to be hospitalized during followup. Mortality over up to 5 years of follow-up increased with increasing exacerbation frequency. Conclusions: The frequent exacerbator phenotype in bronchiectasis is consistent over time and shows high disease severity, poor quality of life, and increased mortality during follow-up

Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis.

Rationale: In cystic fibrosis the major cause of morbidity and mortality is lung disease characterized by inflammation and infection. The influence of sphingolipid metabolism is poorly understood with a lack of studies using human airway model systems. Objectives: To investigate sphingolipid metabolism in cystic fibrosis and the effects of treatment with recombinant human acid ceramidase on inflammation and infection. Methods: Sphingolipids were measured using mass spectrometry in fully-differentiated cultures of primary human airway epithelial cells and co-cultures with Pseudomonas aeruginosa. In situ activity assays, Western blotting and quantitative polymerase chain reaction were used to investigate function and expression of ceramidase and sphingomyelinase. Effects of treatment with recombinant human acid ceramidase on sphingolipid profile and inflammatory mediator production were assessed in cell cultures and murine models. Measurements and Main Results: Ceramide is increased in cystic fibrosis airway epithelium due to differential function of enzymes regulating sphingolipid metabolism. Sphingosine, a metabolite of ceramide with antimicrobial properties, is not upregulated in response to Pseudomonas aeruginosa by cystic fibrosis airway epithelia. Tumor necrosis factor receptor 1 is increased in the apical membrane of cystic fibrosis epithelia and activates NF-κB signaling, generating inflammation. Treatment with recombinant human acid ceramidase, to decrease ceramide, reduced both inflammatory mediator production and susceptibility to infection. Conclusions: Sphingolipid metabolism is altered in airway epithelial cells cultured from people with cystic fibrosis. Treatment with recombinant acid ceramidase ameliorates the two pivotal features of cystic fibrosis lung disease, inflammation and infection, and thus represents a therapeutic approach worthy of further exploration. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)