PZP (pregnancy zone protein) is a broad-spectrum immunosuppressive protein believed to suppress T-cell function during pregnancy to prevent fetal rejection. It has not previously been reported in the ...airway.
To characterize PZP in the bronchiectasis airway, including its relationship with disease severity.
Label-free liquid chromatography/mass spectrometry was performed for sputum protein profiling of patients with bronchiectasis confirmed by high-resolution computed tomography. Results for patients with and without
infection were compared. Sputum and serum PZP was measured by validated ELISA. Airway infection status was established by culture and 16S ribosomal RNA sequencing. Immunofluorescence, ELISA, and electron microscopy were used to identify the cellular source of PZP in neutrophils treated with multiple stimuli.
Elevated PZP was identified by label-free liquid chromatography/mass spectrometry as being associated with
infection. In a validation study of 124 patients, sputum but not serum concentrations of PZP were significantly associated with the Bronchiectasis Severity Index, the frequency of exacerbations, and symptoms. Airway infection with Proteobacteria such as
was associated with higher concentrations of PZP. PZP in sputum was directly related to airway bacterial load. Neutrophils induced to form neutrophil extracellular traps (NETs) with phorbol myristate acetate released high concentrations of PZP
, and fluorescence microscopy confirmed the presence of PZP in NETs, whereas fluorescence and electron microscopy localized PZP to the cytoplasm and nuclei of neutrophils. Effective antibiotic therapy reduced sputum PZP.
PZP is released into NETs. We report a novel link between airway infection, NET formation, and disease severity in bronchiectasis during chronic airway inflammation.
Pulmonary rehabilitation improves exercise capacity and reduces risk of future exacerbation in COPD when performed after an exacerbation. There have been no previous studies of post-exacerbation ...rehabilitation in bronchiectasis.
Parallel group randomized controlled trial compared pulmonary rehabilitation (PR) to standard care (SC) in patients followed an antibiotic treated exacerbation of bronchiectasis. Patients were randomized following a 14 day course of antibiotics was completed. The primary outcome was 6-min walk distance (6 MW) at 8 weeks. Secondary outcomes were time to the next exacerbation, St.Georges Respiratory Questionnaire, COPD CAT score, Leicester cough questionnaire (LCQ) and FEV1 at 8 and 12 weeks post exacerbation.
Forty eight patients were enrolled but only 27 had exacerbations within 12 months of enrolment. Nine patients received pulmonary rehabilitation and 18 received standard care. The 6 MW improved significantly from post-exacerbation to 8 weeks in both groups, with no significant difference between PR and SC- mean difference of 11 m (95% CI -34.3 to 56.3,p = 0.6). Time to the next exacerbation was not significantly different hazard ratio 0.83 (0.31-2.19, p = 0.7). No significant differences were seen between groups in terms of LCQ, CAT, FEV1 or SGRQ between groups. An analysis of probability based on the patients enrolled suggested > 1000 subjects are likely be required to have an > 80% probability of observing a statistically significant difference between PR and SC and any such differences would be likely to be too small to be clinically relevant.
This pilot study identified no significant benefits associated with pulmonary rehabilitation after exacerbations of bronchiectasis.
NCT02179983, registered on Clinicaltrials.gov 29th June 2014.
Background and Purpose
‘Food addiction’ is the subject of intense public and research interest. However, this nosology based on neurobehavioural similarities among obese individuals, patients with ...eating disorders and those with substance use disorders (drug addiction) remains controversial. We thus sought to determine which aspects of disordered eating are causally linked to preclinical models of drug addiction. We hypothesized that extensive drug histories, known to cause addiction‐like brain changes and drug motivation in rats, would also cause addiction‐like food motivation.
Experimental Approach
Rats underwent extensive cocaine, alcohol, caffeine or obesogenic diet histories and were subsequently tested for punishment‐resistant food self‐administration or ‘compulsive appetite’, as a measure of addiction‐like food motivation.
Key Results
Extensive cocaine and alcohol (but not caffeine) histories caused compulsive appetite that persisted long after the last drug exposure. Extensive obesogenic diet histories also caused compulsive appetite, although neither cocaine nor alcohol histories caused excess calorie intake and bodyweight during abstinence. Hence, compulsive appetite and obesity appear to be dissociable, with the former sharing common mechanisms with preclinical drug addiction models.
Conclusion and Implications
Compulsive appetite, as seen in subsets of obese individuals and patients with binge‐eating disorder and bulimia nervosa (eating disorders that do not necessarily result in obesity), appears to epitomize ‘food addiction’. Because different drug and obesogenic diet histories caused compulsive appetite, overlapping dysregulations in the reward circuits, which control drug and food motivation independently of energy homeostasis, may offer common therapeutic targets for treating addictive behaviours across drug addiction, eating disorders and obesity.
Abstract Background Systemic inflammation in bronchiectasis is poorly studied in relation to aetiology and severity. We hypothesized that molecular patterns of inflammation may define particular ...aetiology and severity groups in bronchiectasis. Method We assayed blood concentrations of 31 proteins from 90 bronchiectasis patients (derivation cohort) and conducted PCA to examine relationships between these markers, disease aetiology and severity. Key results were validated in two separate cohorts of 97 and 79 patients from other centres. Results There was significant heterogeneity in protein concentrations across the derivation population. Increasing severity of bronchiectasis (BSI) was associated with increasing fibrinogen (rho = 0.34, p = 0.001 –validated in a second cohort), and higher fibrinogen was associated with worse lung function, Pseudomonas colonisation and impaired health-status. There were generally similar patterns of inflammation in patients with idiopathic and post-infectious disease. However, patients with primary immunodeficiency had exaggerated IL-17 responses, validated in a second cohort (n = 79, immunodeficient 12.82 pg/ml versus idiopathic/post-infectious 4.95 pg/ml, p = 0.001), and thus IL-17 discriminated primary immunodeficiency from other aetiologies (AUC 0.769 (95%CI 0.661–0.877)). Conclusion Bronchiectasis is associated with heterogeneity of systemic inflammatory proteins not adequately explained by differences in disease aetiology or severity. More severe disease is associated with enhanced acute-phase responses. Plasma fibrinogen was associated with bronchiectasis severity in two cohorts, Pseudomonas colonisation and health status, and offers potential as a useful biomarker.
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.
Prolonged antibiotic courses are common in patients with lower respiratory tract infections (LRTIs) and contribute to antibiotic resistance and side effects. This study describes a multidisciplinary ...intervention to reduce antibiotic duration in LRTI patients.
This was a prospective before-and-after intervention study conducted from November 2011 to December 2012. Antibiotic duration was recorded for 6 months for all LRTI admissions (pneumonia, exacerbation of chronic obstructive pulmonary disease, exacerbation of asthma, and other LRTIs), followed by the introduction of an intervention intended to reduce the duration of antibiotic treatment. The intervention incorporated an antibiotic duration based on the CURB65 score, automatic stop dates and pharmacist feedback to prescribers.
Two hundred and eighty-one patients were included in the pre-intervention group and 221 in the post-intervention group. The intervention resulted in a reduction in the duration of antibiotic treatment from 8.3 to 6.8 days (P < 0.001, 18.1% relative reduction). The rate of antibiotic-related adverse effects reduced from 31% to 19% (P = 0.03, 39.3% relative reduction). There was no increase in mortality or length of stay
A simple intervention can significantly reduce antibiotic duration and antibiotic-related side effects.
Abstract Background Identification of chronic Pseudomonas aeruginosa (PA) infection is important in the management of bronchiectasis, but requires repeated sputum sampling. We hypothesized that serum ...anti-PA IgG antibodies could diagnose chronic PA infection at a single visit. Methods Clinically stable bronchiectasis patients were studied prospectively. Chronic PA infection was defined as 2 or more positive sputum samples at least 3 months apart and/or failure to clear PA following eradication treatment. Baseline serum anti-PA IgG was determined by a validated ELISA kit. Results A total of 408 patients were included. Sixty of them (14.7%) had chronic PA infection and had higher anti-PA IgG levels (median 6.2 vs. 1.3 units, p < 0.001). Antibody levels showed direct significant correlations with exacerbation frequency, the bronchiectasis severity index and sputum inflammatory markers. Fifty-seven patients with chronic PA infection had a positive test, giving 95% sensitivity, 74.4% specificity and AUROC of 0.87. During follow-up, 38 patients had a new PA isolation. Eradication at 12 months was achieved in 89.5% of subjects with a negative antibody test and 15.8% of patients with a positive test. Conclusions Anti-PA IgG test is highly accurate to detect chronic PA infection in bronchiectasis patients. In addition, it may be a marker of disease severity and treatment response.
Abstract Introduction Randomized controlled trials (RCTs) for bronchiectasis have experienced difficulties with recruitment and in reaching their efficacy end-points. To estimate the generalizability ...of such studies we applied the eligibility criteria for major RCTs in bronchiectasis to 6 representative observational European Bronchiectasis cohorts. Methods Inclusion and exclusion criteria from 10 major RCTs were applied in each cohort. Demographics and outcomes were compared between patients eligible and ineligible for RCTs. Results 1672 patients were included. On average 33.0% were eligible for macrolide trials, 15.0% were eligible for inhaled antibiotic trials, 15.9% for the DNAse study and 47.7% were eligible for a study of dry powder mannitol. Within these groups, some trials were highly selective with only 1–9% of patients eligible. Eligible patients were generally more severe with higher mortality during follow-up (mean 17.2 vs 9.0% for macrolide studies, 19.2%% vs 10.7% for inhaled antibiotic studies), and a higher frequency of exacerbations than ineligible patients. As up to 93% of patients were ineligible for studies, however, numerically more deaths and exacerbations occurred in ineligible patient across studies (mean 56% of deaths occurred in ineligible patients across all studies). Conclusion Our data suggest that patients enrolled in RCT's in bronchiectasis are only partially representative of patients in clinical practice. The majority of mortality and morbidity in bronchiectasis occurs in patients ineligible for many current trials.
Abstract Introduction Although bronchiectasis particularly affects people ≥65 years of age, data describing clinical characteristics of the disease in this population are lacking. This study aimed at ...evaluating bronchiectasis features in older adults and elderly, along with their clinical outcomes. Methods This was a secondary analysis of six European databases of prospectively enrolled adult outpatients with bronchiectasis. Bronchiectasis characteristics were compared across three study groups: younger adults (18–65 years), older adults (66–75 years), and elderly (and ≥76 years). 3-year mortality was the primary study outcome. Results Among 1258 patients enrolled (median age: 66 years; 42.5% males), 50.9% were ≥65 years and 19.1 ≥ 75 years old. Elderly patients were more comorbid, had worse quality of life and died more frequently than the others. Differences were detected among the three study groups with regard to neither the etiology nor the severity of bronchiectasis, nor the prevalence of chronic infection with P. aeruginosa . In multivariate regression model, age (OR: 1.05; p-value: <0.0001), low BMI (OR: 2.63; p-value: 0.02), previous hospitalizations (OR: 2.06; p-value: 0.006), and decreasing FEV1 (OR: 1.02; p-value: 0.001) were independent predictors of 3-year mortality, after adjustment for covariates. Conclusion Bronchiectasis does not substantially differ across age groups. Poor outcomes in elderly patients with bronchiectasis might be directly related to individual's frailty that should be further investigated in clinical studies.
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