Adam T. Hill

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.

Assessment of airway neutrophils by sputum colour: correlation with airways inflammation

BACKGROUND Airway inflammation, with recruitment of neutrophils to the airway lumen, results in purulent secretions and a variety of potential adverse consequences for patients with chronic bronchitis and bronchiectasis. We hypothesised that gradations of sputum colour would correlate directly with the myeloperoxidase content of sputum and with various other indicators of the activity and consequences of bronchial diseases. METHODS To test this hypothesis, we quantified sputum colour by reference to a sensitive nine point colour chart and correlated this assessment with indices of a number of inflammatory mediators in sputum. RESULTS The results indicate that standardised visual measurements of sputum colour correlated strongly with myeloperoxidase, interleukin 8, leucocyte elastase (both activity and total quantity), sputum volume, protein leak, and secretory leucocyte proteinase inhibitor (p<0.001 for all). In addition, there was a strong direct correlation between leucocyte elastase and both myeloperoxidase (p<0.003) and sputum volume (p<0.001), but a strong negative correlation with secretory leucocyte proteinase inhibitor (p<0.001). CONCLUSIONS These results indicate that sputum colour graded visually relates to the activity of the underlying markers of bronchial inflammation. The results of this simple visual analysis of sputum provides guidance concerning underlying inflammation and its damaging potential. It also provides a useful scientific tool for improving the monitoring of chronic airways diseases and response to treatment.

A randomised crossover trial of chest physiotherapy in non-cystic fibrosis bronchiectasis

Regular chest physiotherapy is advocated in non-cystic fibrosis bronchiectasis despite little evidence supporting its routine use. This study aimed to establish the efficacy of regular chest physiotherapy in non-cystic fibrosis bronchiectasis compared with no regular chest physiotherapy. 20 patients not practising regular chest physiotherapy were enrolled in a randomised crossover trial of 3 months of twice daily chest physiotherapy using an oscillatory positive expiratory pressure device compared with 3 months of no chest physiotherapy. The primary end-point was the Leicester Cough Questionnaire (LCQ). Additional outcomes included 24-h sputum volume, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), forced expiratory flow at 25–75% of FVC (FEF25–75%), maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), exercise capacity, sputum microbiology and St Georges Respiratory Questionnaire (SGRQ). The treatment effect was estimated using the differences of the pairs of observations from each patient. There was a significant improvement in all domains and total LCQ score with regular chest physiotherapy (median (interquartile range) total score improvement 1.3 (-0.17–3.25) units; p = 0.002). 24-h sputum volume increased significantly with regular chest physiotherapy (2 (0–6) mL; p = 0.02), as did exercise capacity (40 (15–80) m; p = 0.001) and SGRQ total score (7.77 (-0.99–14.5) unit improvement; p = 0.004). No significant differences were seen in sputum bacteriology, FEV1, FVC, FEF25–75%, MIP or MEP. Regular chest physiotherapy in non-cystic fibrosis bronchiectasis has small, but significant benefits.

Risk factors for complicated parapneumonic effusion and empyema on presentation to hospital with community-acquired pneumonia.

Background: The aim of this study was to identify key factors on admission predicting the development of complicated parapneumonic effusion or empyema in patients admitted with community-acquired pneumonia. Methods: A prospective observational study of patients admitted with community-acquired pneumonia in NHS Lothian, UK, was conducted. Multivariate regression analyses were used to evaluate factors that could predict the development of complicated parapneumonic effusion or empyema, including admission demographics, clinical features, laboratory tests and pneumonia-specific (Pneumonia Severity Index (PSI), CURB65 (New onset confusion, urea >7 mmol/l, Respiratory rate ≥30 breaths/min, Systolic blood pressure < 90 mm Hg and/or diastolic blood pressure ≤60 mm Hg and age ≥65 years) and CRB65 (New onset confusion, Respiratory rate ≥30 breaths/min, Systolic blood pressure <90 mm Hg and/or diastolic blood pressure ≤60 mm Hg and age ≥65 years)) and generic sepsis scoring systems (APACHE II (Acute Physiology and Chronic Health Evaluation II), SEWS (standardised early warning score) and systemic inflammatory response syndrome (SIRS)). Results: 1269 patients were included in the study and 92 patients (7.2%) developed complicated parapneumonic effusion or empyema. The pneumonia-specific and generic sepsis scoring systems had no value in predicting complicated parapneumonic effusion or empyema. Multivariate logistic regression identified albumin <30 g/l adjusted odds ratio (AOR) 4.55 (95% CI 2.45 to 8.45, p<0.0001), sodium <130 mmol/l AOR 2.70 (1.55 to 4.70, p = 0.0005), platelet count >400×109/l AOR 4.09 (2.21 to 7.54, p<0.0001), C-reactive protein >100 mg/l AOR 15.7 (3.69 to 66.9, p<0.0001) and a history of alcohol abuse AOR 4.28 (1.87 to 9.82, p  =  0.0006) or intravenous drug use AOR 2.82 (1.09 to 7.30, p = 0.03) as independently associated with development of complicated parapneumonic effusion or empyema. A history of chronic obstructive pulmonary disease was associated with decreased risk, AOR 0.18 (0.06 to 0.53, p = 0.002). A 6-point scoring system using these combined variables had good discriminatory value: area under the receiver operator characteristic curve (AUC) 0.84 (95% CI 0.81 to 0.86, p<0.0001). Conclusion: This study has identified seven clinical factors predicting the development of complicated parapneumonic effusion or empyema. Independent validation is needed.

Comprehensive molecular testing for respiratory pathogens in community-acquired pneumonia

This is the first time a comprehensive, multipathogen, quantitative and qualitative molecular approach for respiratory bacteria and viruses has been compared with traditional diagnostic methods on a large hospitalized pneumonia cohort, with estimation of potential effects on antibiotic prescribing.