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.

"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.

Diagnosing pulmonary tuberculosis by pooling induced sputum.

INTRODUCTION: Early diagnosis and treatment of pulmonary tuberculosis (PTB) remains fundamental in reducing transmissions and death. Sputum induction is recommended for the diagnosis of pulmonary tuberculosis (PTB) in patients who are unable to expectorate or smear negative. OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy of pooling two induced sputum specimens into one microbiological test over a single day for the diagnosis of PTB. METHODS: We prospectively enrolled consecutive hospitalized adults with suspected PTB from 2009-2016. Two induced sputum specimens were obtained on the same day and pooled together for AFB smear, culture and Xpert MTB/RIF testing. The final diagnosis of PTB was based on a positive culture from any respiratory specimen. All patients were followed up for 3 months. RESULTS: Of 420 patients, 86(20.5%) were diagnosed with PTB based on a positive respiratory culture. The sensitivity, specificity, positive and negative predictive values for pooled induced sputum were 98.8% (CI 93.7-100%), 100% (CI 98.9-100%) and 100% (94.6-100%) and 99.7% (CI 98.1-100%) respectively. Xpert MTB/RIF in pooled induced sputum was positive in 88.4% of the PTB patients. CONCLUSION: In the diagnosis of PTB, testing two induced sputum specimens which were pooled together for one microbiological testing process may be comparable to repeat testing.

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.

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.

Ministry of Health Clinical Practice Guidelines: Chronic Obstructive Pulmonary Disease.

The Ministry of Health (MOH) has updated the Clinical Practice Guidelines on Chronic Obstructive Pulmonary Disease (COPD) to provide doctors and patients in Singapore with evidence-based treatment for COPD. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH Clinical Practice Guidelines on COPD, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: https://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guidelines/cpg_medical.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

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.

Evaluation of a disease management program for COPD using propensity matched control group.

BACKGROUND: Disease management programs (DMPs) have proliferated recently as a means of improving the quality and efficiency of care for patients with chronic illness. These programs include education about disease, optimization of evidence-based medications, information and support from case managers, and institution of self-management principles. Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in Singapore and worldwide. DMP aims to reduce mortality, hospitalizations, and average length of stay in such patients. This study assesses the outcomes of the DMP, comparing the propensity score matched DMP patients with controls. METHODS: DMP patients were compared with the controls, who were COPD patients fulfilling the DMP's inclusion criteria but not included in the program. Control patients were identified from Operations Data Store (ODS) database. The outcomes of interest were average length of stay, number of days admitted to hospital per 100 person days, readmission, and mortality rates per person year. The risk of death and readmission was estimated using Cox, and competing risk regression respectively. Propensity score was estimated to identify the predictors of DMP enrolment. DMP patients and controls were matched on their propensity score. RESULTS: There were 170 matched DMP patients and control patients having 287 and 207 hospitalizations respectively. Program patient had lower mortality than the controls (0.12 vs. 0.27 per person year); cumulative 1-year survival was 91% among program patient and 76% among the control patients. Readmission, and hospital days per 100 person-days was higher for the program patients (0.36 vs. 0.17 per person year), and (2.19 vs. 1.88 per person year) respectively. CONCLUSIONS: Participation in "DMP" was associated with lower all-cause mortality when compared to the controls. This survival gain in the program patients was paradoxically associated with an increase in readmission rate and total hospital days.

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.

Neuropeptide Y associated with asthma in young adults.

OBJECTIVE: Neuropeptide Y, a widely circulating neurotransmitter, plays a pivotal role in energy balance, immunomodulation and asthma, and several NPY polymorphisms are promising genetic risk factors for asthma and obesity. We explored the associations of candidate NPY gene polymorphisms with prevalent asthma and its relationship with obesity in young adult asthma patients free of other chronic medical morbidity. METHODS: Five common gene variants of NPY (rs16147 (-399T/C), rs17149106 (-602G/T), rs16140 (+1000C/G), rs5573 (+1201A/G), rs5574 (+5327C/T)) previously validated to account for most of the NPY expression in vitro and in vivo were investigated in 126 physician-diagnosed asthma patients without other chronic medical morbidity and 182 healthy controls (21-35years). Plasma levels of NPY, adiponectin, and CRP were determined using ELISA, and IL-6 was measured by Luminex in a subgroup of 70 patients and 69 age- and sex-matched healthy controls. RESULTS: In logistic regression models controlling for gender and obesity, the CT genotype of rs5574 (OR=0.54, 95%CI: 0.30-0.89) and the GT genotype of rs17149106 (OR=5.58, 95%CI: 1.09-28.54) were significantly associated with asthma. No significant interaction between NPY SNP polymorphisms and obesity were detected. Plasma NPY level was correlated with adiponectin levels (p<0.05). Compared with the healthy controls, patients with asthma had higher BMI (p<0.001), adiponectin (p<0.05), IL-6 (p=0.001) and CRP (p<0.001), and lower NPY levels (p<0.01). CONCLUSIONS: The CT genotype of rs5574 and the GT genotype of rs17149106 are significantly associated with prevalent asthma.

Prognostic utility of the 2011 GOLD classification and other multidimensional tools in Asian COPD patients: a prospective cohort study.

BACKGROUND: How well the 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification prognosticates for Asian patients with COPD is unknown. OBJECTIVE: The authors aimed to study the predictive utility of the GOLD 2011 classification for exacerbations and mortality as compared with other multidimensional tools in an Asian population. METHODS: In all, 1,110 COPD patients were prospectively followed between March 2008 and March 2013. They were classified using the 2011 and 2007 GOLD guidelines, modified Medical Research Council score, St. George's Respiratory Questionnaire (SGRQ), and Body mass index, Obstruction, Dyspnea (BOD) index. Outcome measures were exacerbations and mortality. Multivariable survival analyses and receiver operating characteristic (ROC) curves were used to assess the different classification systems. RESULTS: Time-to-event analyses demonstrated earlier exacerbations in 2011's GOLD D when compared with GOLD A (hazard ratio [HR] 0.54, 95% confidence interval [CI]: 0.31-0.95, P=0.032) and GOLD B (HR 0.62, 95% CI: 0.45-0.85, P=0.003) and higher mortality when compared with GOLD A (HR 0.37, 95% CI: 0.16-0.88, P=0.025) and GOLD B (HR 0.46, 95% CI: 0.31-0.70, P<0.001). The areas under the ROC curve for GOLD 2011, GOLD 2007, modified Medical Research Council, St. George's Respiratory Questionnaire, and BOD index were 0.62, 0.59, 0.61, 0.60, and 0.61, respectively, for the prediction of exacerbations and 0.71, 0.70, 0.71, 0.71, and 0.72, respectively, for the prediction of mortality (ROC comparator, P>0.05). CONCLUSION: The 2011 GOLD classification predicts exacerbations and mortality moderately well in Asian COPD patients. Its prognostic utility is similar to that of other multidimensional systems.