Robert Rutherford

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-1β 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. Daily sputum and chronic infection with Pseudomonas or other bacteria define clinical phenotypes in bronchiectasis http://ow.ly/W4H9m

Etiology of Non–Cystic Fibrosis Bronchiectasis in Adults and Its Correlation to Disease Severity

RATIONALE Testing for underlying etiology is a key part of bronchiectasis management, but it is unclear whether the same extent of testing is required across the spectrum of disease severity. OBJECTIVES The aim of the present study was to identify the etiology of bronchiectasis across European cohorts and according to different levels of disease severity. METHODS We conducted an analysis of seven databases of adult outpatients with bronchiectasis prospectively enrolled at the bronchiectasis clinics of university teaching hospitals in Monza, Italy; Dundee and Newcastle, United Kingdom; Leuven, Belgium; Barcelona, Spain; Athens, Greece; and Galway, Ireland. All the patients at every site underwent the same comprehensive diagnostic workup as suggested by the British Thoracic Society. MEASUREMENTS AND MAIN RESULTS Among the 1,258 patients enrolled, an etiology of bronchiectasis was determined in 60%, including postinfective (20%), chronic obstructive pulmonary disease related (15%), connective tissue disease related (10%), immunodeficiency related (5.8%), and asthma related (3.3%). An etiology leading to a change in patients management was identified in 13% of the cases. No significant differences in the etiology of bronchiectasis were present across different levels of disease severity, with the exception of a higher prevalence of chronic obstructive pulmonary disease-related bronchiectasis (P < 0.001) and a lower prevalence of idiopathic bronchiectasis (P = 0.029) in patients with severe disease. CONCLUSIONS Physicians should not be guided by disease severity in suspecting specific etiologies in patients with bronchiectasis, although idiopathic bronchiectasis appears to be less common in patients with the most severe disease.

The safety and efficacy of total lymphoid irradiation in progressive bronchiolitis obliterans syndrome after lung transplantation

Total lymphoid irradiation (TLI) has been used to control renal and cardiac allograft rejection. Data evaluating TLI in bronchiolitis obliterans syndrome (BOS), the physiological manifestation of chronic lung allograft rejection, is very limited. We present our single center experience of the safety and efficacy of TLI in controlling progressive BOS in a retrospective study.

Comorbidities and the risk of mortality in patients with bronchiectasis: an international multicentre cohort study.

BACKGROUND Patients with bronchiectasis often have concurrent comorbidities, but the nature, prevalence, and impact of these comorbidities on disease severity and outcome are poorly understood. We aimed to investigate comorbidities in patients with bronchiectasis and establish their prognostic value on disease severity and mortality rate. METHODS An international multicentre cohort analysis of outpatients with bronchiectasis from four European centres followed up for 5 years was done for score derivation. Eligible patients were those with bronchiectasis confirmed by high-resolution CT and a compatible clinical history. Comorbidity diagnoses were based on standardised definitions and were obtained from full review of paper and electronic medical records, prescriptions, and investigator definitions. Weibull parametric survival analysis was used to model the prediction of the 5 year mortality rate to construct the Bronchiectasis Aetiology Comorbidity Index (BACI). We tested the BACI as a predictor of outcomes and explored whether the BACI added further prognostic information when used alongside the Bronchiectasis Severity Index (BSI). The BACI was validated in two independent international cohorts from the UK and Serbia. FINDINGS Between June 1, 2006, and Nov 22, 2013, 1340 patients with bronchiectasis were screened and 986 patients were analysed. Patients had a median of four comorbidities (IQR 2-6; range 0-20). 13 comorbidities independently predicting mortality rate were integrated into the BACI. The overall hazard ratio for death conferred by a one-point increase in the BACI was 1·18 (95% CI 1·14-1·23; p<0·0001). The BACI predicted 5 year mortality rate, hospital admissions, exacerbations, and health-related quality of life across all BSI risk strata (p<0·0001 for mortality and hospital admissions, p=0·03 for exacerbations, p=0·0008 for quality of life). When used in conjunction with the BSI, the combined model was superior to either model alone (p=0·01 for combined vs BACI; p=0·008 for combined vs BSI). INTERPRETATION Multimorbidity is frequent in bronchiectasis and can negatively affect survival. The BACI complements the BSI in the assessment and prediction of mortality and disease outcomes in patients with bronchiectasis. FUNDING European Bronchiectasis Network (EMBARC).

Multidimensional severity assessment in bronchiectasis: an analysis of seven European cohorts

Introduction Bronchiectasis is a multidimensional disease associated with substantial morbidity and mortality. Two disease-specific clinical prediction tools have been developed, the Bronchiectasis Severity Index (BSI) and the FACED score, both of which stratify patients into severity risk categories to predict the probability of mortality. Methods We aimed to compare the predictive utility of BSI and FACED in assessing clinically relevant disease outcomes across seven European cohorts independent of their original validation studies. Results The combined cohorts totalled 1612. Pooled analysis showed that both scores had a good discriminatory predictive value for mortality (pooled area under the curve (AUC) 0.76, 95% CI 0.74 to 0.78 for both scores) with the BSI demonstrating a higher sensitivity (65% vs 28%) but lower specificity (70% vs 93%) compared with the FACED score. Calibration analysis suggested that the BSI performed consistently well across all cohorts, while FACED consistently overestimated mortality in ‘severe’ patients (pooled OR 0.33 (0.23 to 0.48), p<0.0001). The BSI accurately predicted hospitalisations (pooled AUC 0.82, 95% CI 0.78 to 0.84), exacerbations, quality of life (QoL) and respiratory symptoms across all risk categories. FACED had poor discrimination for hospital admissions (pooled AUC 0.65, 95% CI 0.63 to 0.67) with low sensitivity at 16% and did not consistently predict future risk of exacerbations, QoL or respiratory symptoms. No association was observed with FACED and 6 min walk distance (6MWD) or lung function decline. Conclusion The BSI accurately predicts mortality, hospital admissions, exacerbations, QoL, respiratory symptoms, 6MWD and lung function decline in bronchiectasis, providing a clinically relevant evaluation of disease severity.

Efficacy of nebulised colomycin in patients with non-cystic fibrosis bronchiectasis colonised with Pseudomonas aeruginosa

Colonisation with Pseudomonas aeruginosa is a feature of bronchiectasis and is associated with more severe disease and lower quality of life.1 Nebulised colomycin, a polymixin, bactericidal antibiotic with potent activity against most Gram-negative organisms, including P aeruginosa , is frequently employed in these patients, but evidence is lacking for this approach. We have retrospectively assessed the efficacy of nebulised colomycin in P aeruginosa -colonised patients receiving a minimum of 6 months treatment. Patients who received concomitant prophylactic macrolide treatment for >4 weeks were excluded. Bronchiectasis was confirmed in all patients by standard high-resolution CT criteria, and all received nebulised colomycin 1–2 megaunits twice daily through a standard jet nebuliser …

Prevalence of coeliac disease in patients with sarcoidosis.

Objective Susceptibility to sarcoidosis and coeliac disease has been linked to the class II haplotype HLA-DR3, DQ2, and an association between the two disorders has been suggested. As a pilot study, we have sought to determine the prevalence of coeliac disease in a cohort of Irish patients with sarcoidosis. Design Prospective, case-controlled study. Methods One hundred and two sarcoid patients (47 males, 55 females) from the west of Ireland and 105 (52 males, 53 females) healthy, ethnically matched, controls underwent interview and screening for coeliac disease and human leucocyte antigen typing by serology. Those with elevated anti-gliadin IgA (AGA) and/or positive endomysial antibody (EMA) were offered small intestinal biopsy. Results Three (3%) sarcoid patients had a prior diagnosis of coeliac disease. A further 12 (12%) patients and four (4%) controls had elevated AGA (P = 0.047), of whom three and one, respectively, had positive EMA. Small intestinal biopsy in 11 patients and three controls confirmed coeliac disease in one individual each, giving a prevalence of coeliac disease in patients compared with controls of 4/102 (4%) versus 1/105 (1%) (P = 0.21). Sensitivity and specificity of EMA and elevated AGA in sarcoid patients was 100% and 50%, and 50% and 9%, respectively. Of the four affected sarcoid patients, three carried HLA-DR3, DQ2 and one carried DR5 (12), DR7, DQ2. Conclusion We have demonstrated a moderately increased prevalence of coeliac disease in Irish patients with sarcoidosis, which we feel justifies future screening of our sarcoid population. Estimation of EMA is recommended and should be restricted to those with susceptible haplotypes.

The generalizability of bronchiectasis randomized controlled trials: A multicentre cohort study.

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 RCTs 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.

Hiatal hernias are correlated with increased severity of non-cystic fibrosis bronchiectasis.

Hiatal hernias (HH) are associated with gastro‐oesophageal reflux and may contribute to lung disease severity. We aimed to evaluate the prevalence of HH among stable non‐cystic fibrosis bronchiectasis (NCFB) patients and determine associations with disease severity.

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.