James D. Chalmers

The Bronchiectasis Severity Index. An International Derivation and Validation Study

RATIONALE There are no risk stratification tools for morbidity and mortality in bronchiectasis. Identifying patients at risk of exacerbations, hospital admissions, and mortality is vital for future research. OBJECTIVES This study describes the derivation and validation of the Bronchiectasis Severity Index (BSI). METHODS Derivation of the BSI used data from a prospective cohort study (Edinburgh, UK, 2008-2012) enrolling 608 patients. Cox proportional hazard regression was used to identify independent predictors of mortality and hospitalization over 4-year follow-up. The score was validated in independent cohorts from Dundee, UK (n = 218); Leuven, Belgium (n = 253); Monza, Italy (n = 105); and Newcastle, UK (n = 126). MEASUREMENTS AND MAIN RESULTS Independent predictors of future hospitalization were prior hospital admissions, Medical Research Council dyspnea score greater than or equal to 4, FEV1 < 30% predicted, Pseudomonas aeruginosa colonization, colonization with other pathogenic organisms, and three or more lobes involved on high-resolution computed tomography. Independent predictors of mortality were older age, low FEV1, lower body mass index, prior hospitalization, and three or more exacerbations in the year before the study. The derived BSI predicted mortality and hospitalization: area under the receiver operator characteristic curve (AUC) 0.80 (95% confidence interval, 0.74-0.86) for mortality and AUC 0.88 (95% confidence interval, 0.84-0.91) for hospitalization, respectively. There was a clear difference in exacerbation frequency and quality of life using the St. Georges Respiratory Questionnaire between patients classified as low, intermediate, and high risk by the score (P < 0.0001 for all comparisons). In the validation cohorts, the AUC for mortality ranged from 0.81 to 0.84 and for hospitalization from 0.80 to 0.88. CONCLUSIONS The BSI is a useful clinical predictive tool that identifies patients at risk of future mortality, hospitalization, and exacerbations across healthcare systems.

C-Reactive Protein Is an Independent Predictor of Severity in Community-acquired Pneumonia

BACKGROUND C-reactive protein (CRP) is an acute phase protein synthesized by the liver primarily in response to interleukin-6. Initial studies have suggested that inflammatory markers may have a role in predicting severity. We investigated whether admission and day 4 CRP could predict severity in community-acquired pneumonia. METHODS A prospective study was carried out over a 2-year period in a large teaching hospital. CRP was measured on admission and on day 4. The outcomes of interest were: 30-day mortality; need for mechanical ventilation and/or inotropic support; development of complicated pneumonia (lung abscess, empyema, or complicated parapneumonic effusion); the value of predictive tests were assessed using multivariate logistic regression. RESULTS There were 570 patients included in the study; 30-day mortality was 9.6%. Low CRP levels showed a high negative predictive value for excluding 30-day mortality (CRP <10 mg/L=100%, CRP <50=99.1%, CRP <100=98.9%, CRP <200=94.9%). Low admission CRP levels <100 mg/L were independently associated with reduced 30-day mortality (odds ratio [OR] 0.18; 0.04-0.85), P=.03; need for mechanical ventilation and/or inotropic support (OR 0.21; 0.14-0.4), P=.002; and complicated pneumonia (OR 0.05; 0.01-0.35), P=.003. A CRP that fails to fall by 50% or more within 4 days of admission is independently associated with increased 30 day mortality (OR 24.5; 6.4-93.4), P <.0001; need for mechanical ventilation and/or inotropic support (OR 7.1; 2.8-17.8), P <.0001 and complicated pneumonia (OR 15.4; 6.32-37.6), P <.0001. CONCLUSIONS Admission CRP <100 mg/L has reduced risk for 30-day mortality, need for mechanical ventilation and/or inotropic support, and complicated pneumonia. Failure of CRP to fall by 50% or more at day 4 leads to an increased risk for 30-day mortality, need for mechanical ventilation and/or inotropic support, and complicated pneumonia. C-reactive protein is an independent marker of severity in community-acquired pneumonia.

Short- and Long-Term Antibiotic Treatment Reduces Airway and Systemic Inflammation in Non–Cystic Fibrosis Bronchiectasis

RATIONALE The vicious cycle hypothesis of bronchiectasis argues that bacterial colonization leads to airway inflammation and progressive lung damage. The logical extension of this hypothesis is that acute or chronic antibiotic therapy should improve airway inflammation and clinical outcome. There are little data to support this hypothesis in patients with non-cystic fibrosis (CF) bronchiectasis. OBJECTIVES To determine whether acute or chronic antibiotic therapy improves airway inflammation and clinical outcome in non-CF bronchiectasis. METHODS The relationship between bacterial load and airway and systemic inflammation was investigated in 385 stable patients, 15 stable patients treated with intravenous antibiotics, and 34 patients with an exacerbation of bronchiectasis treated with intravenous antibiotics. Long-term antibiotic therapy was investigated using samples from a 12-month controlled trial of nebulized gentamicin. MEASUREMENTS AND MAIN RESULTS In stable patients, there was a direct relationship between airway bacterial load and markers of airway inflammation (P < 0.0001 for all analyses). High bacterial loads were associated with higher serum intercellular adhesion molecule-1, E-selectin, and vascular cell adhesion molecule-1 (P < 0.05 above bacterial load ≥1 × 10(7) cfu/ml). In stable patients, there was a direct relationship between bacterial load and the risk of subsequent exacerbations (odds ratio, 1.20; 95% confidence interval, 1.11-1.29; P < 0.0001) and severe exacerbations (odds ratio, 1.11; 95% confidence interval, 1.01-1.21; P = 0.02). Short- and long-term antibiotic treatments were associated with reductions in bacterial load, airways, and systemic inflammation. CONCLUSIONS High airway bacterial loads in non-CF bronchiectasis are associated with airway and systemic inflammation and a greater risk of exacerbations. Short- and long-term antibiotic therapy reduce markers of airways and systemic inflammation.

Severity assessment tools for predicting mortality in hospitalised patients with community-acquired pneumonia. Systematic review and meta-analysis

Introduction International guidelines recommend a severity-based approach to management in community-acquired pneumonia. CURB65, CRB65 and the Pneumonia Severity Index (PSI) are the most widely recommended severity scores. The aim of this study was to compare the performance characteristics of these scores for predicting mortality in community-acquired pneumonia. Methods A systematic review and meta-analysis was conducted according to MOOSE (meta-analysis of observational studies in epidemiology) guidelines. PUBMED and EMBASE were searched (1980–2009). 40 studies reporting prognostic information for the PSI, CURB65 and CRB65 severity scores were identified. Performance characteristics were pooled using a random effects model. Relationships between sensitivity and specificity were plotted using summary receiver operator characteristic (sROC) curves. Results All three scores predicted 30 day mortality. The PSI had the highest area under the sROC curve, 0.81 (SE 0.008), compared with CURB65, 0.80 (SE 0.008), p=0.1, and CRB65, 0.79 (0.01), p=0.09. These differences were not statistically significant. Performance characteristics were similar across comparable cut-offs for low, intermediate and high risk for each score. In identifying low risk patients, PSI (groups I and II) had the best negative likelihood ratio 0.08 (0.06–0.12) compared with CURB65 (score 0–1) 0.21 (0.15–0.30) and CRB65 (score 0), 0.15 (0.10–0.22). Conclusion There were no significant differences in overall test performance between PSI, CURB65 and CRB65 for predicting mortality from community-acquired pneumonia.

Epidemiology, Antibiotic Therapy, and Clinical Outcomes in Health Care–Associated Pneumonia: A UK Cohort Study

BACKGROUND The recently introduced concept of health care-associated pneumonia (HCAP), referring to patients with frequent healthcare contacts and at higher risk of contracting resistant pathogens, is controversial. METHODS This prospective observational study recorded the clinical features, microbiology, and outcomes in a UK cohort of hospitalized patients with pneumonia. The primary outcome was 30-day mortality. Logistic regression was used to adjust for confounders when determining the impact of HCAP on clinical outcomes. RESULTS A total of 20.5% of patients met the HCAP criteria. HCAP patients were older than patients with community-acquired pneumonia (CAP) (median 76 y, IQR 65-83 vs 65 y, IQR 48-77; P < .0001) and more frequently had major comorbidities (62.1% vs 45.2%; P < .0001). Patients with HCAP had higher initial severity compared to CAP patients (Pneumonia Severity Index, mean 3.7 [SD 1.1] vs mean 3.1 [SD 1.3]; P < .0001) but also worse functional status using the Eastern Cooperative Oncology Group scale (mean 2.4 [SD 1.44] vs mean 1.4 [SD 1.13]; P < .0001) and more frequently had treatment restrictions such as do not resuscitate orders (59.9% vs 29.8%; P < .0001). Consequently mortality was increased (odds ratio [OR] 2.15 [1.44-3.22]; P = .002) in HCAP patients on univariate analysis. Multivariate analysis suggested this relationship was primarily due to confounders rather than a higher frequency of treatment failure due to resistant organisms (adjusted OR .97 [.61-1.55]; P = .9). The frequencies of Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and Gram-negative Enterobacteriaceae were low in both cohorts. CONCLUSIONS HCAP is common in the United Kingdom and is associated with a high mortality. This increased mortality was primarily related to underlying patient-related factors rather than the presence of antibiotic-resistant pathogens. This study did not establish a clear indication to change prescribing practices in a UK cohort.

Prior statin use is associated with improved outcomes in community-acquired pneumonia.

BACKGROUND Statins have potent anti-inflammatory effects in laboratory studies of pulmonary inflammation. We investigated whether statin users had improved outcome when admitted with community-acquired pneumonia. METHODS We carried out a prospective observational study of patients admitted to the hospital with community-acquired pneumonia between January 2005 and November 2007. The use of statins, angiotensin-converting enzyme inhibitors, beta-blockers, and aspirin were recorded. The outcomes of interest were 30-day mortality, need for mechanical ventilation or inotropic support, and the development of complicated pneumonia. RESULTS On multivariate logistic regression, statin use was associated with significantly lower 30-day mortality (adjusted odds ratio [AOR] 0.46, 95% confidence interval [CI], 0.25-0.85, P=.01) and development of complicated pneumonia (AOR 0.44, 95% CI, 0.25-0.79, P=.006). There was no effect on requirement of mechanical ventilation or inotropic support (AOR 0.93, 95% CI, 0.49-1.76, P=.8). Patients prescribed statins had more severe pneumonia (median Pneumonia Severity Index 4, interquartile range [IQR] 3-4) compared with patients not prescribed cardiovascular drugs (median Pneumonia Severity Index 3, IQR 2-4, P < .0001). Despite this, C-reactive protein levels on admission were significantly lower in patients prescribed statins (median 119 mg/L, IQR 46-215) compared with patients prescribed no cardiovascular drugs (182 mg/L, IQR 66-326, P < .0001). On multivariate logistic regression, statin use was independently protective against a C-reactive protein that failed to fall by 50% or more at day 4 (AOR 0.50, 95% CI 0.27-0.92, P=.02). CONCLUSIONS Statin use is associated with reduced markers of systemic inflammation and improved outcomes in patients admitted with community-acquired pneumonia.

Healthcare associated pneumonia does not accurately identify potentially resistant pathogens: a systematic review and meta-analysis

BACKGROUND The 2005 American Thoracic Society/Infectious Diseases Society of America guidelines introduced a concept of healthcare-associated pneumonia (HCAP) to define patients at higher risk of antibiotic-resistant pathogens, thus requiring broad spectrum therapy. There has been no systematic evaluation of the ability of this definition to identify antibiotic-resistant pathogens. METHODS We conducted a systematic review and meta-analysis of studies comparing the frequency of resistant pathogens (defined as methicillin-resistant Staphylococcus aureus, Enterobacteriaceae, and Pseudomonas aeruginosa) in populations with HCAP compared with populations with community-acquired pneumonia (CAP). Predictive accuracy was evaluated using the area under the receiver operator characteristic curve (AUC). The frequencies of pathogens in each group were pooled using a random effects model. RESULTS Twenty-four studies were included (n = 22 456). Overall study quality was poor. HCAP was associated with an increased risk of methicillin-resistant S. aureus (odds ratio [OR], 4.72; 95% confidence interval [CI], 3.69-6.04) enterobactericeae (OR, 2.11; 95% CI, 1.69-2.63), and P. aeruginosa (OR, 2.75; 95% CI, 2.04-3.72; all P < .0001), but these analyses were confounded by publication bias. The discriminatory ability of HCAP for resistant pathogens was low (AUC, 0.70; 95% CI, 0.69-0.71) and was lower in high-quality (AUC, 0.66; 95% CI, 0.62-0.70) and prospective studies (AUC, 0.64; 95% CI 0.62-0.66). After adjustment for age and comorbidities, mortality was not increased in HCAP (OR, 1.20; 95% CI, 0.85-1.70; P = .30). CONCLUSIONS The HCAP concept is based on predominantly low-quality evidence and does not accurately identify resistant pathogens. Mortality in HCAP does not appear to be due to a higher frequency of resistant pathogens.

Management of bronchiectasis in adults

Formerly regarded as a rare disease, bronchiectasis is now increasingly recognised and a renewed interest in the condition is stimulating drug development and clinical research. Bronchiectasis represents the final common pathway of a number of infectious, genetic, autoimmune, developmental and allergic disorders and is highly heterogeneous in its aetiology, impact and prognosis. The goals of therapy should be: to improve airway mucus clearance through physiotherapy with or without adjunctive therapies; to suppress, eradicate and prevent airway bacterial colonisation; to reduce airway inflammation; and to improve physical functioning and quality of life. Fortunately, an increasing body of evidence supports interventions in bronchiectasis. The field has benefited greatly from the introduction of evidence-based guidelines in some European countries and randomised controlled trials have now demonstrated the benefit of long-term macrolide therapy, with accumulating evidence for inhaled therapies, physiotherapy and pulmonary rehabilitation. This review provides a critical update on the management of bronchiectasis focussing on emerging evidence and recent randomised controlled trials. Bronchiectasis is a rapidly developing field: review of recent RCTs and progress towards developing new therapies http://ow.ly/JXGWM

A Comprehensive Analysis of the Impact of Pseudomonas aeruginosa 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. MEASUREMENTS AND MAIN RESULTS 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. Georges 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.

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