A double-blind, randomised, placebo-controlled study of roxithromycin and doxycycline combination, roxithromycin alone, or matching placebo for 12 weeks in adults with frequent exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Azithromycin prophylaxis has been shown to reduce COPD exacerbations but there is poor evidence for other antibiotics. We compared exacerbation rates in COPD patients with a history of frequent exacerbations (at least three moderate or severe COPD exacerbations in the past two years) during a 12-week treatment course and over a subsequent 48-week follow up period. RESULTS: 292 patients were randomised to one of three treatments for 12 weeks: roxithromycin 300 mg daily and doxycycline 100 mg daily (n = 101); roxithromycin 300 mg daily (n = 97); or matching placebos (n = 94). There were no differences in the annualised moderate and severe exacerbation rates after treatment with roxithromycin/doxycycline (2.83 (95 % CI 2.37-3.40)) or roxithromycin only (2.69 (2.26-3.21)) compared to placebo (2.5 (2.08-3.03)) (p = 0.352 and p = 0.5832 respectively). Furthermore, there were no differences in the annualised exacerbation rates during 12-week treatment with roxithromycin/doxycycline (1.64 (95 % CI 1.17-2.30)), roxithromycin only (1.75 (1.24-2.41)) or placebo (2.23 (1.68-3.03)) (p = 0.1709 and p = 0.2545 respectively). There were also no significant differences between groups for spirometry or quality of life scores over either the 12-week treatment or 48-week post-treatment periods. Both active treatments were associated with nausea but otherwise adverse events were comparable among treatment groups. CONCLUSIONS: Twelve-weeks of prophylaxis with roxithromycin/doxycycline combination or roxithromycin alone did not reduce COPD exacerbations in patients with history of frequent exacerbations. These findings do not support the use of these antibiotics to prevent exacerbations in COPD patients.

Biomarkers of cardiac dysfunction and mortality from community-acquired pneumonia in adults.

BACKGROUND: Cardiac dysfunction is common in acute respiratory diseases and may influence prognosis. We hypothesised that blood levels of N-terminal B-type natriuretic peptide (NT-proBNP) and high-sensitivity Troponin T would predict mortality in adults with community-acquired pneumonia. METHODS AND FINDINGS: A prospective cohort of 474 consecutive patients admitted with community-acquired pneumonia to two New Zealand hospitals over one year. Blood taken on admission was available for 453 patients and was analysed for NT-proBNP and Troponin T. Elevated levels of NT-proBNP (>220 pmol/L) were present in 148 (33%) and 86 (19%) of these patients respectively. Among the 26 patients who died within 30 days of admission, 23 (89%) had a raised NT-proBNP and 14 (53%) had a raised Troponin T level on admission compared to 125 (29%) and 72 (17%) of the 427 who survived (p values<0.001). Both NT-proBNP and Troponin T predicted 30-day mortality in age-adjusted analysis but after mutual adjustment for the other cardiac biomarker and the Pneumonia Severity Index, a raised N-terminal pro-brain natriuretic peptide remained a predictor of 30-day mortality (OR = 5.3, 95% CI 1.4-19.8, p = 0.013) but Troponin T did not (OR = 1.3, 95% CI 0.5-3.2, p = 0.630). The areas under the receiver-operating curves to predict 30-day mortality were similar for NT-proBNP (0.88) and the Pneumonia Severity Index (0.87). CONCLUSIONS: Elevated N-terminal B-type natriuretic peptide is a strong predictor of mortality from community-acquired pneumonia independent of clinical prognostic indicators. The pathophysiological basis for this is unknown but suggests that cardiac involvement may be an under-recognised determinant of outcome in pneumonia and may require a different approach to treatment. In the meantime, measurement of B-type natriuretic peptides may help to assess prognosis.

Biochemical markers of cardiac dysfunction predict mortality in acute exacerbations of COPD.

BACKGROUND: Retrospective studies suggest that plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin T are often elevated in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) and are associated with increased mortality. These cardiac biomarkers were investigated in an unselected cohort of patients admitted to hospital with exacerbations of COPD. METHODS: Consecutive patients with physician-diagnosed COPD exacerbation but without clinical evidence of acute cardiac disease admitted to a public hospital over a 1 year period were studied prospectively. NT-proBNP and troponin T were measured on admission. The primary end point was all-cause mortality at 30 days. RESULTS: Elevated NT-proBNP (>220 pmol/l) was present in 65/244 patients (27.5%) and significantly predicted 30-day mortality (OR 9.0, 95% CI 3.1 to 26.2, p<0.001). Elevated troponin T (>0.03 µg/l) was found in 40/241 patients (16.6%) and also predicted 30-day mortality (OR 6.3, 95% CI 2.4 to 16.5, p<0.001). These associations persisted after adjusting for other clinical and laboratory predictors of mortality (arterial CO(2) pressure (Paco(2)), body mass index and CURB65 score). NT-proBNP and troponin T levels appeared to have additive associations with mortality: 30-day mortality among patients with abnormalities of both NT-proBNP and troponin T was 15-fold higher than among patients with normal values. CONCLUSION: Elevated levels of NT-proBNP and troponin T are strong predictors of early mortality among patients admitted to hospital with acute exacerbations of COPD independently of other known prognostic indicators. The pathophysiological basis for this is unknown, but indicates that cardiac involvement in exacerbations of COPD may be an important determinant of prognosis.

Predicting early mortality in acute exacerbation of chronic obstructive pulmonary disease using the CURB65 score.

BACKGROUND AND OBJECTIVE: Hospitalization for exacerbation of COPD is associated with a high risk of mortality. A risk-prediction model using information easily obtained on admission could help to identify high-risk individuals. The CURB65 score was developed to predict mortality risk in community acquired pneumonia. A retrospective study found that this score was also associated with mortality in COPD exacerbations. We conducted a prospective study to assess the utility of the CURB65 score in acute COPD exacerbations. METHODS: Consecutive patients with physician diagnosed COPD exacerbations admitted to a public hospital during a 1-year period were studied prospectively. The CURB65 scores were calculated from information obtained at initial hospital presentation. CURB65 = one point each for Confusion, Urea > 7 mmol/L, Respiratory rate ≥ 30/min, low Blood pressure, age ≥ 65 years. RESULTS: 30-day mortality data were available for 249 of 252 patients. CURB65 scores on admission significantly predicted risk of death during the hospital admission and at 30 days. The 30-day mortality by score groups were: low risk (scores 0-1) 2.0% (2/98), moderate risk (score 2) 6.7% (6/90) and high risk (scores 3-5) 21.3% (13/61). CURB65 scores were not predictive of 1-year mortality. CONCLUSIONS: A simple 6-point score based on confusion, blood urea, respiratory rate, blood pressure and age can be used to stratify patients with COPD exacerbation into different management groups. The CURB65 score was as effective in predicting early mortality in our cohort of acute COPD exacerbations as it was in previous cohorts with community acquired pneumonia. Our findings suggest that CURB65 scores can help clinicians to assess patients with exacerbation of COPD.

Lung cancer susceptibility model based on age, family history and genetic variants.

BACKGROUND: Epidemiological and pedigree studies suggest that lung cancer results from the combined effects of age, smoking, impaired lung function and genetic factors. In a case control association study of healthy smokers and lung cancer cases, we identified genetic markers associated with either susceptibility or protection to lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: We screened 157 candidate single nucleotide polymorphisms (SNP) in a discovery cohort of 439 subjects (200 controls and 239 lung cancer cases) and identified 30 SNPs associated with either the healthy smokers (protective) or lung cancer (susceptibility) phenotype. After genotyping this 30 SNP panel in a validation cohort of 491 subjects (248 controls and 207 lung cancers) and, using the same protective and susceptibility genotypes from our discovery cohort, a 20 SNP panel was selected based on replication of SNP associations in the validation cohort. Following multivariate logistic regression analyses, including the selected SNPs from runs 1 and 2, we found age and family history of lung cancer to be significantly and independently associated with lung cancer. Numeric scores were assigned to both the SNP and demographic data, and combined to form a simple algorithm of risk. CONCLUSIONS/SIGNIFICANCE: Significant differences in the distribution of the lung cancer susceptibility score was found between normal controls and lung cancer cases, which remained after accounting for differences in lung function. Validation in other case-control and prospective cohorts are underway to further define the potential clinical utility of this model.

Murine typhus: a newly recognised problem in the Waikato region of New Zealand.

AIM: To characterise and investigate patients diagnosed with murine typhus in the Waikato District Health Board (DHB) region during 2006. METHOD: We reviewed the hospital and general practitioner records of all patients presenting with clinical and serological evidence of murine typhus. All patients were interviewed by telephone using a semi-structured questionnaire to identify environmental risk factors for infection. A limited, retrospective serosurvey was undertaken and surveillance was enhanced. RESULTS: 12 patients were identified, all had either lived, or spent considerable time, in rural areas; 7 patients had seen rats on their properties 'regularly' and 3 remembered fleabites within the incubation period of the illness. The classic triad of symptoms is fever, headache, and rash--these symptoms were seen in 12, 11, and 8 patients respectively; lethargy, myalgias, nausea, and vomiting were also common. 11 patients had abnormal liver function tests at presentation, and 7 had low platelets. Treatment with doxycycline was associated with a shorter hospital stay. CONCLUSION: Murine typhus has now been confirmed in rural areas throughout the Waikato DHB region. Rats are likely associated with disease in rural communities and rat control is a complex issue. However, a greater awareness of the disease should lead to earlier diagnosis and treatment.

Meningococcal disease deaths and the frequency of antibiotic administration delays.

OBJECTIVE: Meningococcal disease (MCD) remains a medical emergency and a frequent cause of death in previously healthy individuals. We aimed to determine the frequency and cause of delays in antibiotic administration in a cohort of deaths. METHODS: A retrospective chart review was undertaken on 140 hospitalised MCD deaths within New Zealand's serogroup B epidemic (1993-2004). RESULTS: Death after hospital presentation occurred rapidly (median 12 h) with 70% dying within 24 h. Delays of more than 2 h in time-to-antibiotic post hospital presentation occurred in 29%. The major contributors to these delays were the failure to include MCD within the differential diagnosis and prolonged assessment times. Multivariate logistic regression analysis, undertaken by combining study deaths which had meningococcal bacterial load results (n=9) with a survivor cohort (n=126) from a previous study, confirmed bacterial load as a major predictor of death (OR 7.5 per log10 cfu/mL increase; 95% CI 2.2-25.3; p=0.001). A non-significant increased risk of death per hour of antibiotic delay was seen (OR 1.18; 95% CI 0.90-1.55; p=0.22). CONCLUSIONS: Death from MCD occurred rapidly, with many patients not receiving antibiotics at the earliest opportunity. The introduction of recently developed rapid diagnostic markers into the identified delay-intervals could lead to a reduction in time-to-antibiotic and hopefully reduce case-fatality rates.

Effectiveness of beta lactam antibiotics compared with antibiotics active against atypical pathogens in non-severe community acquired pneumonia: meta-analysis.

OBJECTIVE: To systematically compare beta lactam antibiotics with antibiotics active against atypical pathogens in the management of community acquired pneumonia. DATA SOURCES: Medline, Embase, Cochrane register of controlled trials, international conference proceedings, drug registration authorities, and pharmaceutical companies. Review methods Double blind randomised controlled monotherapy trials comparing beta lactam antibiotics with antibiotics active against atypical pathogens in adults with community acquired pneumonia. Primary outcome was failure to achieve clinical cure or improvement. RESULTS: 18 trials totalling 6749 participants were identified, with most patients having mild to moderate community acquired pneumonia. The summary relative risk for treatment failure in all cause community acquired pneumonia showed no advantage of antibiotics active against atypical pathogens over beta lactam antibiotics (0.97, 95% confidence interval 0.87 to 1.07). Subgroup analysis was undertaken in those with a specific diagnosis involving atypical pathogens. We found a significantly lower failure rate in patients with Legionella species who were treated with antibiotics active against atypical pathogens (0.40, 0.19 to 0.85). Equivalence was seen for Mycoplasma pneumoniae (0.60, 0.31 to 1.17) and Chlamydia pneumoniae (2.32, 0.67 to 8.03). CONCLUSIONS: Evidence is lacking that clinical outcomes are improved by using antibiotics active against atypical pathogens in all cause non-severe community acquired pneumonia. Although such antibiotics were superior in the management of patients later shown to have legionella related pneumonia, this pathogen was rarely responsible for pneumonia within the included trials. beta lactam agents should remain the antibiotics of initial choice in adults with non-severe community acquired pneumonia.

The potential role of procalcitonin in the emergency department management of febrile young adults during a sustained meningococcal epidemic.

OBJECTIVE: To prospectively investigate the diagnostic characteristics of procalcitonin as an aid in the diagnosis of meningococcal disease in febrile young adults presenting to the Waikato Hospital emergency department during a sustained meningococcal epidemic. METHODS: The study population were emergency department patients aged 14-40 years presenting with either a temperature > or = 38.0 degrees C without an obvious focus of infection, or symptoms consistent with meningococcal disease. All had procalcitonin levels, N. meningitidis PCR, blood +/- CSF cultures. RESULTS: One hundred and eighty-three patients presented with undifferentiated febrile illness over a 9 month study period. Nine were subsequently shown to have meningococcal disease. A positive procalcitonin (> or = 0.5 ng/mL) had a sensitivity of 100% (CI 66.4-100), specificity 89% (CI 83.1-93.1), negative predictive value 100% (CI 97.6-100) and positive predictive value 32% (CI 15.9-52.4) for meningococcal disease. CONCLUSIONS: The finding of a procalcitonin level > or = 0.5 ng/mL in young adults with undifferentiated fever indicates an increased chance that the presenting illness may be meningococcal disease. In New Zealand's continuing meningococcal epidemic empirical antibiotics should be strongly considered in those with elevated procalcitonin levels in the hope of reducing meningococcal disease deaths due to delays in antibiotic administration.

Evaluation of a PCR assay for detection of Streptococcus pneumoniae in respiratory and nonrespiratory samples from adults with community-acquired pneumonia.

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia, but it is undoubtedly underdiagnosed. We used a nested PCR assay (targeting the pneumolysin gene) to detect S. pneumoniae DNA in multiple sample types from 474 adults with community-acquired pneumonia and 183 control patients who did not have pneumonia. Plasma or buffy coat samples were PCR positive in only 6 of the 21 patients with positive blood cultures for S. pneumoniae and in 12 other patients (4 of whom had no other laboratory evidence of S. pneumoniae infection). Buffy coat samples from two control patients (neither having evidence of S. pneumoniae infection), but no control plasma samples, were PCR positive. Although pneumococcal antigen was detected in the urine from 120 of 420 (29%) patients, only 4 of 227 (2%) urine samples tested were PCR positive. Overall, 256 of 318 (81%) patients had PCR-positive sputum samples, including 58 of 59 samples from which S. pneumoniae was cultured. Throat swab samples from 229 of 417 (55%) patients were PCR positive and, in those who produced sputum, 96% also had positive PCR results from sputum. Throat swabs from 73 of 126 (58%) control patients were also PCR positive. We conclude that the pneumolysin PCR assay adds little to existing diagnostic tests for S. pneumoniae and is unable to distinguish colonization from infection when respiratory samples are tested.