Adjunctive pascolizumab in rifampicin-susceptible pulmonary tuberculosis: proof-of-concept, partially-randomised, double-blind, placebo-controlled, dose-escalation trial.

BACKGROUND: Interleukin-4 (IL-4), increased in tuberculosis infection, may impair bacterial killing. Blocking IL-4 confers benefit in animal models. We evaluated safety and efficacy of pascolizumab (humanised anti-IL-4 monoclonal antibody) as adjunctive tuberculosis treatment. METHODS: Participants with rifampicin-susceptible pulmonary tuberculosis received a single intravenous infusion of pascolizumab or placebo; and standard 6-month tuberculosis treatment. Pascolizumab dose increased in successive cohorts: [1] non-randomised 0.05 mg/kg (n = 4); [2] non-randomised 0.5 mg/kg (n = 4); [3] randomised 2.5 mg/kg (n = 9) or placebo (n = 3); [4] randomised 10 mg/kg (n = 9) or placebo (n = 3). Co-primary safety outcome was study-drug-related grade 4 or serious adverse event (G4/SAE); in all cohorts (1-4). Co-primary efficacy outcome was week-8 sputum culture time-to-positivity (TTP); in randomised cohorts (3-4) combined. RESULTS: Pascolizumab levels exceeded IL-4 50% neutralising dose for 8 weeks in 78-100% of participants in cohorts 3-4. There were no study-drug-related G4/SAEs. Median week-8 TTP was 42 days in pascolizumab and placebo groups (p = 0.185). Rate of TTP increase was greater with pascolizumab (difference from placebo 0.011 [95% Bayesian credible interval 0.006 to 0.015] log10TTP/day. CONCLUSIONS: There was no evidence to suggest blocking IL-4 was unsafe. Preliminary efficacy findings are consistent with animal models. This supports further investigation of adjunctive anti-IL-4 interventions for tuberculosis in larger phase 2 trials.

Procalcitonin and antibiotics in moderate-severe acute exacerbation of chronic obstructive pulmonary disease: to use or not to use.

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Acute exacerbations of COPD (AECOPD) are major driver for healthcare utilization with each exacerbation begetting the next exacerbation. It is, therefore, important to treat each episode effectively to prevent the next. However, this can be challenging as AECOPD result from complex interactions between host, environment and infective agents. The benefits of starting antibiotics in AECOPD, which are not life-threatening (e.g. not requiring mechanical ventilation) or not complicated by pneumonia remain controversial. RECENT FINDINGS: The use of procalcitonin to guide antibiotic therapy in AECOPD has gained interest in recent years. The main advantage of this approach is a safe reduction in antibiotic use in a large group of patients, which may potentially translate to several other benefits. These include reduced antibiotic-related side-effects, reduced risk of developing antibiotic-resistant organisms and cost savings. This approach is associated with no increase in mortality or morbidity such as treatment failure, re-admission, admission to ICU. SUMMARY: Procalcitonin-guided antibiotic therapy in AECOPD is a promising and safe approach, which may be ready for the prime time.

Sub-clinical abnormalities detected by PET/MRI in household tuberculosis contacts.

BACKGROUND: The understanding of early events following TB exposure is limited by traditional tests that rely on detection of an immune response to infection, which is delayed, or on imaging tests with low sensitivity for early disease. We investigated for evidence of lung abnormalities in heavily exposed TB contacts using PET/MRI. METHODS: 30 household contacts of 20 index patients underwent clinical assessment, IGRA testing, chest x-ray and PET/MRI scan using 18-F-FDG. MRI images were examined by a radiology/nuclear medicine dual-qualified physician using a standardised report form, while PET/MRI images were examined independently by another radiology/nuclear medicine dual-qualified physician using a similar form. Standardised uptake value (SUV) was quantified for each abnormal lesion. RESULTS: IGRA was positive in 40%. PET/MRI scan was abnormal in 30%, predominantly FDG uptake in hilar or mediastinal lymph nodes and lung apices. We did not identify any relationship between PET/MRI findings and degree of exposure or IGRA status. CONCLUSION: PET-based imaging may provide important insights into the natural history following exposure to TB that may not be available from traditional tests of TB immune response or imaging. The clinical significance of the abnormalities is uncertain and merits further investigation in longitudinal studies.

Pneumonia in the tropics.

Pneumonia in the tropics poses a heavy disease burden. The complex interplay of climate change, human migration influences and socio-economic factors lead to changing patterns of respiratory infections in tropical climate but also increasingly in temperate countries. Tropical and poorer countries, especially South East Asia, also bear the brunt of the global tuberculosis (TB) pandemic, accounting for almost one-third of the burden. But, as human migration patterns evolve, we expect to see more TB cases in higher income as well as temperate countries, and rise in infections like scrub typhus from ecotourism activities. Fuelled by the ease of air travel, novel zoonotic infections originating from the tropics have led to global respiratory pandemics. As such, clinicians worldwide should be aware of these new conditions as well as classical tropical bacterial pneumonias such as melioidosis. Rarer entities such as co-infections of leptospirosis and chikungunya or dengue will need careful consideration as well. In this review, we highlight aetiologies of pneumonia seen more commonly in the tropics compared with temperate regions, their disease burden, variable clinical presentations as well as impact on healthcare delivery.

Role of BMI, airflow obstruction, St George's Respiratory Questionnaire and age index in prognostication of Asian COPD.

BACKGROUND AND OBJECTIVE: COPD is a complex condition with a heavy burden of disease. Many multidimensional tools have been studied for their prognostic utility but none has been universally adopted as each has its own limitations. We hypothesize that a multidimensional tool examining four domains, health-related quality of life, disease severity, systemic effects of disease and patient factors, would better categorize and prognosticate these patients. METHODS: We first evaluated 300 patients and found four factors that predicted mortality: BMI, airflow obstruction, St George's Respiratory Questionnaire and age (BOSA). A 10-point index (BOSA index) was constructed and prospectively validated in a cohort of 772 patients with all-cause mortality as the primary outcome. Patients were categorized into their respective BOSA quartile group based on their BOSA score. Multivariate survival analyses and receiver operator characteristic (ROC) curves were used to assess the BOSA index. RESULTS: Patients in BOSA Group 4 were at higher risk of death compared with their counterparts in Group 1 (hazard ratio (HR): 0.29, 95% CI: 0.16-0.51, P < 0.001) and Group 2 (HR: 0.53, 95% CI: 0.34-0.82, P = 0.005). Race and gender did not affect mortality. The area under the ROC curve for BOSA index was 0.690 ± 0.025 while that for Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 was 0.641 ± 0.025 (P = 0.17). CONCLUSION: The BOSA index predicts mortality well and it has at least similar prognostic utility as GOLD 2011 in Asian patients. The BOSA index is a simple tool that does not require complex equipment or testing. It has the potential to be used widely.

Severe community-acquired pneumonia: timely management measures in the first 24 hours.

Mortality rates for severe community-acquired pneumonia (CAP) range from 17 to 48 % in published studies.In this review, we searched PubMed for relevant papers published between 1981 and June 2016 and relevant files. We explored how early and aggressive management measures, implemented within 24 hours of recognition of severe CAP and carried out both in the emergency department and in the ICU, decrease mortality in severe CAP.These measures begin with the use of severity assessment tools and the application of care bundles via clinical decision support tools. The bundles include early guideline-concordant antibiotics including macrolides, early haemodynamic support (lactate measurement, intravenous fluids, and vasopressors), and early respiratory support (high-flow nasal cannulae, lung-protective ventilation, prone positioning, and neuromuscular blockade for acute respiratory distress syndrome).While the proposed interventions appear straightforward, multiple barriers to their implementation exist. To successfully decrease mortality for severe CAP, early and close collaboration between emergency medicine and respiratory and critical care medicine teams is required. We propose a workflow incorporating these interventions.

Obesity, asthma prevalence and IL-4: Roles of inflammatory cytokines, adiponectin and neuropeptide Y.

BACKGROUND: Obesity is associated with asthma risk and severity, but the underlying biological mechanisms are poorly understood. We hypothesized that cytokine markers of systemic inflammation, and adiponectin and neuropeptide Y (NPY) markers of immuno-modulating and neurohormonal regulation are involved in the obesity-asthma association. METHODS: We explored the relationships between body mass index (BMI), C-reactive protein (CRP), IL-6, TNF-α, adiponectin and NPY with asthma prevalence and IL-4 levels in 70 youth with asthma and 69 age- and gender-matched healthy controls using cross-sectional and longitudinal data. RESULTS: Mean BMI level was higher among patients with asthma than healthy controls (p < 0.001). In logistic regression models controlling for potential confounders, independent associations with asthma prevalence were found for obesity (p = 0.001), increasing tertiles of CRP (linear trend p < 0.001), IL-6 (linear trend p < 0.001) and lowest and highest tertiles of TNF-α (quadratic trend p < 0.05), increasing adiponectin (linear p = 0.022) and decreasing tertiles of NPY (linear trend p = 0.001). Among patients with asthma, NPY level was positively correlated with adiponectin (p < 0.05) and TNF-α (p < 0.05), and levels of NPY and IL-6 were significantly associated with IL-4 level at baseline and 1-year follow-up. CONCLUSIONS: The obesity-asthma association was not explained by systemic inflammation. Specifically, CRP, TNF-a, IL-6, NPY and adiponectin were independently associated with asthma prevalence. NPY and IL-6 were associated with IL-4 marker of allergic airway inflammation in asthma and should be further investigated as prognostic markers of asthma outcomes.

IDSA/ATS minor criteria aid pre-intensive care unit resuscitation in severe community-acquired pneumonia.

The effect of employing severity scores to identify severe community-acquired pneumonia (SCAP) cases for early aggressive resuscitation is unknown. Optimising pre-intensive care unit (ICU) care may improve outcomes in patients at risk of SCAP. We conducted a before-and-after study of patients classified into control and intervention groups (January 2004 to December 2007 and January 2008 to December 2010, respectively). Our intervention was two-pronged, using the 2007 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) minor criteria to identify SCAP for aggressive emergency department resuscitation. Patients with SCAP, defined as those with three or more IDSA/ATS minor criteria, were targeted. Differences in mortality, triage and compliance with emergency department resuscitation were compared between the groups. The hospital mortality rate was lower in the intervention versus the control group (5.7% versus 23.8%, p<0.001). On multivariate analysis, the intervention group was associated with lower mortality (OR 0.24, 95% CI 0.09-0.67). ICU admission rates decreased from 52.9% to 38.6% (p=0.008) and inappropriately delayed ICU admissions decreased from 32.0% to 14.8% (p<0.001). There was increased compliance with the aggressive resuscitation protocol after the intervention. A combined intervention, using a pneumonia score to identify those at risk of SCAP early and an aggressive pre-ICU resuscitation protocol may reduce mortality and ICU admissions.

Bedside pleural procedures by pulmonologists and non-pulmonologists: a 3-year safety audit.

BACKGROUND AND OBJECTIVE: Pleural procedures such as tube thoracostomy and chest aspirations are commonly performed and carry potential risks of visceral organ injury, pneumothorax and bleeding. In this context limited information exists on the complication rates when non-pulmonologists perform ultrasound-guided bedside pleural procedures. Bedside pleural procedures in our university hospital were audited to compare complication rates between pulmonologists and non-pulmonologists. METHODS: A combined safety approach using standardized training, pleural safety checklists and ultrasound-guidance was initially implemented in a ∼1000-bed academic medical centre. A prospective audit, over approximately 3.5 years, of all bedside pleural procedures excluding procedures done in operating theatres and radiological suites was then performed. RESULTS: Overall, 529 procedures (295 by pulmonologists; 234 by non-pulmonologists) for 443 patients were assessed. There were 16 (3.0%) procedure-related complications, all in separate patients. These included five iatrogenic pneumothoraces, four dry taps, four malpositioned chest tubes, two significant chest wall bleeds and one iatrogenic hemothorax. There were no differences in complication rates between pulmonologists and non-pulmonologists. Presence of chronic obstructive pulmonary disease (COPD) independently increased the risk of complications by nearly sevenfold. CONCLUSIONS: Results from this study support pleural procedural practice by both pulmonologists and non-pulmonologists in an academic medical centre setting. This is possible with a standard training program, pleural safety checklists and relatively high utilization rates of ultrasound guidance for pleural effusions. Nonetheless, additional vigilance is needed when patients with COPD undergo pleural procedures.

Impact of a palliative care initiative on end-of-life care in the general wards: a before-and-after study.

BACKGROUND: Data on deaths in the general wards of our hospital in 2007 revealed infrequent discussions on end-of-life care and excessive burdensome interventions. AIM: A physician order form to withhold inappropriate life-sustaining interventions was initiated in 2009. The use of the form was facilitated by staff educational sessions and a palliative care consult service. This study aims to evaluate the impact of these interventions in 2010. DESIGN: Retrospective medical chart review with comparisons was made for the following: baseline patient characteristics, orders concerning life-sustaining therapies, treatment provided in last 24 h of life, and discussion of specific life-sustaining therapies with patients and families. SETTINGS/PARTICIPANTS: This study included all adult patients who died in our hospital's general wards in 2007 (N = 683) versus 2010 (N = 714). RESULTS: There was an increase in orders to withhold life-sustaining therapies, such as cardiopulmonary resuscitation (66.2%-80.0%). There was a decrease in burdensome interventions such as antibiotics (44.9%-24.9%) and a small increase in palliative treatments such as analgesia (29.1%-36.7%). There were more discussions on the role of cardiopulmonary resuscitation with conversant patients (4.6%-10.2%) and families (56.5%-79.8%) (p-value all < 0.05). On multivariate analysis, the physician order form independently predicted orders to withhold cardiopulmonary resuscitation. CONCLUSIONS: A multifaceted intervention of a physician order form, educational sessions, and palliative care consult service led to an improvement in documentation of end-of-life discussions and was associated with an increase in such discussions and less burdensome treatments. There were small improvements in the proportion of palliative treatments administered.

Effect of a pleural checklist on patient safety in the ultrasound era.

BACKGROUND AND OBJECTIVE: Bedside ultrasound allows direct visualization of pleural collections for thoracentesis and tube thoracostomy. However, there is little information on patient safety improvement methods with this approach. The effect of a checklist on patient safety for bedside ultrasound-guided pleural procedures was evaluated. METHODS: A prospective study of ultrasound-guided pleural procedures from September 2007 to June 2010 was performed. Ultrasound guidance was routine practice for all patients under the institution's care and the freehand method was used. All operators took a half-day training session on basic thoracic ultrasound and were supervised by more experienced operators. A 14-item checklist was introduced in June 2009. It included systematic thoracic scanning and a safety audit. Clinical and safety data are described before (Phase I) and after (Phase II) the introduction of the checklist. RESULTS: There were 121 patients in Phase I (58.7 ± 18.9 years) and 134 patients in Phase II (60.2 ± 19.6 years). Complications occurred for 10 patients (8.3%) in Phase I (six dry taps, three pneumothoraces, one haemothorax) and for 2 patients (1.5%) in Phase II (one significant bleed, one malposition of chest tube) (P = 0.015). There were no procedure-related deaths. The use of the checklist alone was associated with fewer procedure-related complications. This was independent of thoracostomy rate, pleural effusion size and pleural fluid ultrasound appearance. CONCLUSIONS: A pleural checklist with systematic scanning and close supervision may further enhance safety of ultrasound-guided procedures. This may also help promote safety while trainees are learning to perform these procedures.

"Pivot and Cluster Strategy" in the light of Kahneman's "Decision Hygiene" template.

Pivot and cluster strategy (PCS) is a cognitive forcing strategy designed to achieve diagnostic accuracy through the analytical deployment of a cluster of differential diagnoses (Cluster) specific to the initial most likely diagnosis (Pivot) recalled by a clinical diagnostician. This approach has been widely implemented and has effectively decreased diagnostic errors. Kahneman et al. have introduced innovative notions of noise and decision hygiene. Noise refers to the variance of errors, with numerous individuals' errors in judgment pointing in different directions. They suggest a "Decision Hygiene" (DH) template, w preventative technique meant to reduce noise in decision-making. This paper introduced an interpretation of the existing strategy of PCS from new perspectives of noise and DH, which would allow us to further understand the usefulness of PCS, thereby contributing to a positive effect on the quality of diagnosis.

Female reproductive factors, gene polymorphisms in the estrogen metabolism pathway, and risk of lung cancer in Chinese women.

The authors examined relations between reproductive factors and 5 estrogen pathway gene polymorphisms (CYP17 rs743572, CYP19A1 rs10046, ERß rs1256049, ERß rs4986938, and COMT rs4680) among 702 Singapore Chinese female lung cancer cases and 1,578 hospital controls, of whom 433 cases (61.7%) and 1,375 controls (87.1%) were never smokers. Parity (per child, odds ratio (OR) = 0.92, 95% confidence interval (CI): 0.87, 0.97) and menstrual cycle length (for ≥30 days vs. <30 days, OR = 0.50, 95% CI: 0.32, 0.80) were inversely associated with lung cancer in never smokers, while age at first birth (for ages 21-25, 26-30, and ≥31 years vs. ≤20 years, ORs were 1.54, 2.17, and 1.30, respectively), age at menopause (for ages 49-51 and ≥52 years vs. ≤48 years, ORs were 1.37 and 1.59; P(trend) = 0.003), and reproductive period (for 31-33, 34-36, 37-39, and ≥40 years vs. ≤30 years, ORs were 1.06, 1.25, 1.45, and 1.47; P(trend) = 0.026) were positively associated. Among smokers, parity was inversely associated with lung cancer, but there was no association with other reproductive factors. The COMT rs4680 A allele was positively associated with lung cancer in never smokers (for G/A or A/A vs. G/G, OR = 1.46, 95% CI: 1.12, 1.90) but not in ever smokers. No associations were seen with other polymorphisms. These results support a risk-enhancing role of estrogens in lung carcinogenesis among never smokers.

Predicting mortality among older adults hospitalized for community-acquired pneumonia: an enhanced confusion, urea, respiratory rate and blood pressure score compared with pneumonia severity index.

BACKGROUND AND OBJECTIVE: Pneumonia Severity Index (PSI) predicts mortality better than Confusion, Urea >7 mmol/L, Respiratory rate >30/min, low Blood pressure: diastolic blood pressure <60 mm Hg or systolic blood pressure <90 mm Hg, and age >65 years (CURB-65) for community-acquired pneumonia (CAP) but is more cumbersome. The objective was to determine whether CURB enhanced with a small number of additional variables can predict mortality with at least the same accuracy as PSI. METHODS: Retrospective review of medical records and administrative data of adults aged 55 years or older hospitalized for CAP over 1 year from three hospitals. RESULTS: For 1052 hospital admissions of unique patients, 30-day mortality was 17.2%. PSI class and CURB-65 predicted 30-day mortality with area under curve (AUC) of 0.77 (95% confidence interval (CI): 0.73-0.80) and 0.70 (95% CI: 0.66-0.74) respectively. When age and three co-morbid conditions (metastatic cancer, solid tumours without metastases and stroke) were added to CURB, the AUC improved to 0.80 (95% CI: 0.77-0.83). Bootstrap validation obtained an AUC estimate of 0.78, indicating negligible overfitting of the model. Based on this model, a clinical score (enhanced CURB score) was developed that had possible values from 5 to 25. Its AUC was 0.79 (95% CI: 0.76-0.83) and remained similar to that of PSI class. CONCLUSIONS: An enhanced CURB score predicted 30-day mortality with at least the same accuracy as PSI class did among older adults hospitalized for CAP. External validation of this score in other populations is the next step to determine whether it can be used more widely.

Economic burden of chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: The aim of this study was to estimate the direct medical costs of COPD in two public health clusters in Singapore from 2005 to 2009. METHODS: Patients aged 40 years and over, who had been diagnosed with COPD, were identified in a Chronic Disease Management Data-mart. Annual utilization of health services in inpatient, specialist outpatient, emergency department and primary care settings was extracted from the Chronic Disease Management Data-mart. Trends in attributable costs, proportions of costs and health-care utilization were analyzed across each level of care. A weighted attribution approach was used to allocate costs to each health-care utilization episode, depending on the relevance of co-morbidities. RESULTS: The mean total cost was approximately $9.9 million per year. Inpatient admissions were the major cost driver, contributing an average of $7.2 million per year. The proportion of hospitalization costs declined from 75% in 2005 to 68% in 2009. Based on the 5-year average, attendances at primary care clinics, emergency department and specialist clinics contributed 3%, 5% and 17%, respectively, of overall COPD costs. On average, 42% of the total cost burden was incurred for the medical management of COPD. The share of cost incurred for the treatment of conditions related and unrelated to COPD were 29% and 26%, respectively, of the total average costs. CONCLUSIONS: COPD is likely to represent a significant burden to the public health system in most countries. The findings are particularly relevant to understanding the allocation of health-care resources and informing appropriate cost containment strategies.

Unilateral lobar pulmonary edema.

INTRODUCTION: Pulmonary edema is usually bilateral, but unilateral lobar pulmonary edema can also be encountered in clinical practice. CLINICAL PICTURE: We describe a case of unilateral lobar pulmonary edema in a patient without known cardiac history. It was first presentation of underlying cardiac disease in our patient and was difficult to differentiate from pneumonia. CONCLUSION: Unilateral pulmonary edema can mimic as pneumonia. Clinician should be aware of differential diagnosis of pulmonary edema, otherwise it can lead to unnecessary investigation and delay in starting definitive treatment.

Polymorphisms in inflammatory pathway genes, host factors and lung cancer risk in Chinese female never-smokers.

Inflammation appears to be important in lung carcinogenesis among smokers, but its role among never-smokers is not well established. We hypothesized that inflammatory medical conditions and gene polymorphisms interact to increase lung cancer risk in never-smokers. We interviewed 433 Singaporean female never-smoker lung cancer patients and 1375 hospital controls, and evaluated six polymorphisms in the interleukin 1-ß, interleukin 6 (IL6), cyclooxygenase-2, peroxisome proliferator-activated receptor-γ and interleukin 1-ß receptor antagonist (IL1RN) genes. Tuberculosis was associated with a non-significant elevated risk of lung cancer [odds ratio (OR) 1.58, 95% confidence interval (CI) 0.95-2.62]. There was no effect of asthma, atopy or chronic productive cough individually. However, the presence of one or more of these conditions (asthma, cough or atopy) increased risk (OR 2.24, 95%CI 1.15-4.38) in individuals possessing the T/T genotype at interleukin 1-ß -31T/C, but not in those possessing the C/T (OR 0.87, 95%CI 0.51-1.57) or C/C genotypes (OR 0.58, 95%CI 0.27-1.27), and in individuals having the *2 variable number of tandem repeat allele of IL1RN [OR 5.09 (1.39-18.67)], but not in those without (OR 0.93, 95%CI 0.63-1.35). The IL6-634 G allele increased the risk of lung cancer (OR 1.44, 95%CI 1.07-1.94). Lung cancer risk also increased with the number of polymorphism sites where at least 1 'risk' allele was present [interleukin 1-ß -31T/C (T allele), IL1RN (*2 allele) and IL6-634C/G (G allele)] among those with asthma, cough or atopy (Ptrend 0.001) but not in those without (Ptrend 0.47). Our results suggest that the effect of inflammatory medical conditions on lung cancer in never-smokers is modulated by host genetic susceptibility and will need to be confirmed in other studies conducted in similar populations.

Meat consumption and risk of lung cancer among never-smoking women.

The relationship between diet and lung cancer, apart from the protective effect of fruit and vegetables, is poorly understood. Reports on the role of dietary components such as meat are inconsistent, and few studies include sufficient numbers of nonsmokers. We examined the relationship between meat consumption and never-smoking lung cancer in a hospital-based case-control study of Singapore Chinese women, a population with low smoking prevalence. Three hundred and ninety-nine cases and 815 controls were recruited, of whom 258 cases and 712 controls were never smokers. A standardized questionnaire (which included a food frequency questionnaire module) was administered by trained interviewers. Among these never smokers, fruit and vegetable intake were inversely associated with lung cancer risk. Seventy-two percent of meat consumed was white meat (chicken or fish). Meat consumption overall was inversely associated with lung cancer [adjusted odds ratio (OR), 0.88, 0.59 for second, third tertiles, P (trend) = .012]. An inverse relationship between fish consumption and lung cancer (adjusted OR, 0.81, 0.47 for 2nd, 3rd tertiles, P (trend) < .001) was observed. No association was seen between consumption of processed meats and lung cancer, nor between dietary heterocyclic amines and lung cancer. Our data suggest that fish consumption may be protective against lung cancer in never smokers.