Michal Shteinberg

The EMBARC European bronchiectasis registry: Protocol for an international observational study

Bronchiectasis is one of the most neglected diseases in respiratory medicine. There are no approved therapies and few large-scale, representative epidemiological studies. The EMBARC (European Multicentre Bronchiectasis Audit and Research Collaboration) registry is a prospective, pan-European observational study of patients with bronchiectasis. The inclusion criterion is a primary clinical diagnosis of bronchiectasis consisting of: 1) a clinical history consistent with bronchiectasis; and 2) computed tomography demonstrating bronchiectasis. Core exclusion criteria are: 1) bronchiectasis due to known cystic fibrosis; 2) age <18 years; and 3) patients who are unable or unwilling to provide informed consent. The study aims to enrol 1000 patients by April 2016 across at least 20 European countries, and 10 000 patients by March 2020. Patients will undergo a comprehensive baseline assessment and will be followed up annually for up to 5 years with the goal of providing high-quality longitudinal data on outcomes, treatment patterns and quality of life. Data from the registry will be available in the form of annual reports. and will be disseminated in conference presentations and peer-reviewed publications. The European Bronchiectasis Registry aims to make a major contribution to understanding the natural history of the disease, as well as guiding evidence-based decision making and facilitating large randomised controlled trials. The European Bronchiectasis Registry will recruit 10 000 patients over 5 years http://ow.ly/Ul7Pd

Binding of Activated Cyclosome to p13 suc1 USE FOR AFFINITY PURIFICATION

Previous studies have indicated that a ∼1,500-kDa complex, designated the cyclosome or anaphase-promoting complex, has a regulated cyclin-ubiquitin ligase activity that targets cyclin B for degradation at the end of mitosis. The cyclosome is inactive in the interphase of the embryonic cell cycle and is converted to the active form in late mitosis in a phosphorylation-dependent process initiated by protein kinase Cdc2-cyclin B. We show here that the active, phosphorylated form of the cyclosome from clam oocytes binds to p13 suc1 , a protein known to associate with Cdc2. The following evidence indicates that the binding of the cyclosome to p13 suc1 is not mediated via the Cdc2-cyclin B complex: (a) activated cyclosome binds to p13 suc1 -Sepharose following its separation from Cdc2-cyclin B by gel filtration chromatography; (b) cyclosome from interphase extracts, activated by a kinase in which cyclin B has been replaced by an N-terminally truncated derivative fused to glutathione S-transferase, binds well to p13 suc1 -Sepharose but not to glutathione-agarose. An alternative possibility, that the phosphorylated cyclosome binds directly to a phosphate-binding site of p13 suc1 , is supported by the observation that the cyclosome is efficiently eluted from p13 suc1 -Sepharose by phosphate-containing compounds. This information was utilized to develop a procedure for the affinity purification of the cyclosome. A factor abundant in the fraction not adsorbed to p13 suc1 -Sepharose stimulates the activity of purified cyclosome. It is suggested that binding of Suc1 may have a role in the regulation of cyclosome activity.

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 “frequent exacerbator phenotype” 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 follow‐up. 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.

Clinical Characteristics and Outcomes of Patients with Clinically Unsuspected Pulmonary Embolism versus Patients with Clinically Suspected Pulmonary Embolism

Background: The routine use of multidetector computed tomography has led to increased detection of unsuspected pulmonary embolism (UPE), with questionable benefit for diagnosis and treatment. Objective: The purpose of this work was to compare the clinical characteristics and prognosis of patients with UPE to patients with suspected PE (SPE). Methods: We retrospectively reviewed the charts of patients diagnosed with PE in a community-based university hospital between the years 2002 and 2007. UPE was defined as PE detected on CT scans performed for indications other than suspicion of PE. We compared patients with UPE to patients with SPE for differences in clinical features, electrocardiogram, imaging and echocardiographic findings. We also assessed the long-term outcomes using electronic patient records. Results: Of 500 patients with PE, 408 had SPE and 92 had UPE. Patients with UPE were similar to patients with SPE regarding age and sex distribution. Malignancy was more prevalent in UPE patients (39 vs. 23%, p < 0.0068). UPE patients had significantly less tachypnea (37 vs. 57%, p = 0.0005), dyspnea (47 vs. 87%, p < 0.0001), chest pain (19 vs. 42%, p < 0.0001) and hypoxemia (36 vs. 55%, p = 0.0011). Mortality was higher in UPE patients (70.3 vs. 53%, p = 0.0029). The hazard ratio after adjustment for confounders including age, sex and malignancy was 1.546 (95% CI: 1.139–2.099, p = 0.0052). Conclusions: We suggest that UPE is more prevalent in patients with a malignancy and is associated with higher mortality despite a less severe clinical presentation. UPE may be a marker of poor prognosis.

The independent contribution of Pseudomonas aeruginosa 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<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. Frequent exacerbations are the key determinants of long-term outcome in patients with chronic Pseudomonas aeruginosa infection http://ow.ly/WjPZ30h67rL

Major respiratory adverse events after laparascopic gastric banding surgery for morbid obesity.

BACKGROUND Laparoscopic adjustable gastric banding surgery has become one of the most common restrictive surgical procedures for treatment of morbid obesity worldwide. Although short-term respiratory complications are well known, long-term data is scarce. We investigated the manifestations of major pulmonary complications showed at least six months after the procedure. METHODS A retrospective cohort study was conducted at a tertiary university medical center in the five years period of 2006-2010. We included every patient who had had major respiratory complication who needed hospitalization, at least 6 months after laparoscopic adjustable gastric banding procedure. Demographic, pre-operative and post-operative clinical data were collected. We documented respiratory symptoms, results of physical examination, pulmonary function tests, and imaging as well as therapies given and outcome. RESULTS Out of 2100 patients who underwent LAGB, thirty subjects, mean age of 45.7 (range 29-64) with an equal number of males and females were included. Mean interval between operation and onset of respiratory symptoms was 51.5 months (range 10-150 months). All had dyspeptic complaints which included: regurgitation, fullness after meals, dysphagia and food aspiration with esophageal dilatation. Major respiratory complications included aspiration pneumonia (19) including pulmonary abscess (4) and empyema (2), exacerbation of asthma (3) and hemoptysis (1). Additionally we documented the emergence of chronic diseases such as interstitial lung disease (5) and bronchiectasis (3). One patient developed acute respiratory distress syndrome due to aspiration pneumonia and eventually died in the intensive care unit. The main mode of therapy was deflation of the gastric band. Those who refused to deflate or remove the gastric banding continued to suffer from dyspeptic and respiratory symptoms including recurrent pulmonary abscess. CONCLUSION Although laparoscopic adjustable gastric banding surgery has few short-term risks and is highly effective at achieving weight reduction, we found an increased risk for major respiratory complications in the long-term period. The obesity epidemic and the increased use of surgical techniques to treat obesity will most likely lead to an increase in the incidence of long-term post-operative respiratory complications. This entity is probably under-reported and needs further research into how to reduce its incidence and morbidity.

Eradication failure of newly acquired Pseudomonas aeruginosa isolates in cystic fibrosis

Eradication of Pseudomonas aeruginosa (PA) is critical in cystic fibrosis (CF) patients. OBJECTIVES To determine eradication success rate of newly acquired PA and to identify characteristics associated with eradication failure. METHODS In an observational study, data from patients with newly acquired PA infection from 2007 to 2013 were collected. Clinical variables were compared in patients with and without successful eradication for ≥1year. RESULTS Of 183 patients out of 740 (25%) from 7 CF Centers that had newly acquired PA, eradication succeeded in 72%. Patients with the highest risk of failure had multi-resistant PA, fewer sputum cultures taken, were older, and were diagnosed at a later age. The risk of eradication failure increased by 1.3% with each year of delayed CF diagnosis; successful eradication increased by 17% with each additional sputum culture taken. CONCLUSIONS Delayed detection of PA infection leading to delayed treatment and growth of multi-resistant organisms is associated with eradication failure.

Use of Inhaled Tobramycin in Cystic Fibrosis

Chronic infection with Pseudomonas aeruginosa is associated with poor outcomes in patients with cystic fibrosis (CF). It leads to a reduced quality of life, acceleration of the decline in lung function, and increased frequency and severity of pulmonary exacerbations. Tobramycin, administered by inhalation as a long-term therapy, decreases bacterial density in airways, reduces exacerbation frequency, and improves quality of life and lung function in patients with chronic P. aeruginosa infection. In the last decade, tobramycin inhalation has become an important contributor to CF treatment as a means to control chronic infection and as a first-line treatment for the eradication of early acquisition of P. aeruginosa. Recently, a dry powder inhalation (DPI) form of tobramycin has become available, which is more convenient for administration and has comparable efficacy to the tobramycin solution. This DPI, the Podhaler™ (Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA), requires less time for treatment delivery and is more portable than a nebulizer, and so is a welcome additional therapeutic option for many patients.

Standardised classification of the aetiology of bronchiectasis using an objective algorithm

Bronchiectasis (BE) is a chronic and progressive respiratory disease with multiple possible causes [1, 2]. Many require a specific therapy and thus, a systematic aetiologic evaluation is recommended by guidelines [3]. Studies have shown wide heterogeneity in the proportion of different aetiologies identified among centres [4–8], which can be partially justified because of geographical risks factors, but may also reflect variations in testing practice or in the definitions of aetiology used [9]. The proportion of patients classified as idiopathic varies (26–74%) across the literature, and this variability is likely to be somewhat linked to a lack of use of a standard aetiological algorithm [4–8]. The use of a standardised aetiological algorithm in bronchiectasis can improve the diagnosis of underlying cause http://ow.ly/5dga30gxrq3

Changes of CFTR functional measurements and clinical improvements in cystic fibrosis patients with non p.Gly551Asp gating mutations treated with ivacaftor

Ivacaftor, a CFTR potentiator, has been found to improve CFTR function and clinical outcomes in patients with cystic fibrosis (CF) gating mutations. We investigated the effects of ivacaftor on CFTR functional measurement in CF patients carrying gating mutations other than p.Gly551Asp. Two siblings aged 13 and 12 carrying the p.Ser549Asn mutation, two sisters (45 and 43years old) compound heterozygotes for p.Asp1152His and p.Gly1244Glu, a 37year old man homozygous for the p.Gly1244Glu mutation, and a 7year old girl with p.Arg352Gln and p.Gly1244Glu mutations commenced treatment with ivacaftor. NPD was performed in all the patients and approached normal for four patients who had also clinical improvement (p.Ser549Asn compound heterozygotes, and p.Asp1152His/p.Gly1244Glu siblings). Beta-adrenergic sweat chloride secretion performed in thep.Asp1152His/p.Gly1244Glu patients improved significantly. The p.Gly1244Glu mutation homozygous patient, who had undergone an ileal resection with ileostomy and enterocutaneous fistula, did not respond clinically to ivacaftor and did not modify his sweat test. These results highlight the importance of different CFTR activity measurements to explore CFTR modulator efficacy.