Clinical diagnostic utility of IP-10 and LAM antigen levels for the diagnosis of tuberculous pleural effusions in a high burden setting

Background: Current tools for the diagnosis of tuberculosis pleural effusions are sub-optimal. Data about the value of new diagnostic technologies are limited, particularly, in high burden settings. Preliminary case control studies have identified IFN-γ-inducible-10kDa protein (IP-10) as a promising diagnostic marker; however, its diagnostic utility in a day-to-day clinical setting is unclear. Detection of LAM antigen has not previously been evaluated in pleural fluid. Methods: We investigated the comparative diagnostic utility of established (adenosine deaminase [ADA]), more recent (standardized nucleic-acid-amplification-test [NAAT]) and newer technologies (a standardized LAM mycobacterial antigendetection assay and IP-10 levels) for the evaluation of pleural effusions in 78 consecutively recruited South African tuberculosis suspects. All consenting participants underwent pleural biopsy unless contra-indicated or refused. The reference standard comprised culture positivity for M. tuberculosis or histology suggestive of tuberculosis. Principal Findings: Of 74 evaluable subjects 48, 7 and 19 had definite, probable and non-TB, respectively. IP-10 levels were significantly higher in TB vs non-TB participants (p<0.0001). The respective outcomes [sensitivity, specificity, PPV, NPV %] for the different diagnostic modalities were: ADA at the 30 IU/L cut-point [96; 69; 90; 85], NAAT [6; 93; 67; 28], IP-10 at the 28,170 pg/ml ROC-derived cut-point [80; 82; 91; 64], and IP-10 at the 4035 pg/ml cut-point [100; 53; 83; 100]. Thus IP-10, using the ROC-derived cut-point, missed ~20% of TB cases and mis-diagnosed ~20% of non-TB cases. By contrast, when a lower cut-point was used a negative test excluded TB. The NAAT had a poor sensitivity but high specificity. LAM antigendetection was not diagnostically useful. Conclusion: Although IP-10, like ADA, has sub-optimal specificity, it may be a clinically useful rule-out test for tuberculous pleural effusions. Larger multi-centric studies are now required to confirm our findings

Reply to : Cause or consequence?

Funding AstraZeneca funded the SABINA III study; was involved in the study design, protocol development, study conduct and statistical analysis; and was given the opportunity to review this manuscript before submission. Publication support was provided by Michelle Rebello, PhD, of Cactus Life Sciences and funded by AstraZeneca.Peer reviewedPostprin

Short-acting β2-agonist prescriptions are associated with poor clinical outcomes of asthma : the multi-country, cross-sectional SABINA III study

Data sharing Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Acknowledgements Editorial support was provided by Michelle Rebello, PhD, CMPP, of Cactus Life Sciences (part of Cactus Communications, Mumbai, India) in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). This support was fully funded by AstraZeneca. Support statement AstraZeneca funded the study; was involved in the study design, protocol development, study conduct and statistical analysis; and was given the opportunity to review the manuscript before submission. AstraZeneca also funded medical writing support. All authors had full access to all the data, wrote the report and accept responsibility for its publication.Peer reviewedPostprin

Tiotropium improves lung function, exacerbation rate, and asthma control, independent of baseline characteristics including age, degree of airway obstruction, and allergic status

AbstractBackgroundMany patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS) with or without long-acting β2-agonists (LABAs). Tiotropium add-on to ICS plus a LABA has been shown to improve lung function and reduce exacerbation risk in patients with symptomatic asthma.ObjectiveTo determine whether the efficacy of tiotropium add-on therapy is dependent on patients’ baseline characteristics.MethodsTwo randomized, double-blind, parallel-group, twin trials (NCT00772538 and NCT00776984) of once-daily tiotropium Respimat® 5 μg add-on to ICS plus a LABA were performed in parallel in patients with severe symptomatic asthma. Exploratory subgroup analyses of peak forced expiratory volume in 1 s (FEV1), trough FEV1, time to first severe exacerbation, time to first episode of asthma worsening, and seven-question Asthma Control Questionnaire responder rate were performed to determine whether results were influenced by baseline characteristics.Results912 patients were randomized: 456 received tiotropium and 456 received placebo. Tiotropium improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, compared with placebo, independent of baseline characteristics including gender, age, body mass index, disease duration, age at asthma onset, and FEV1 % predicted at screening and reversibility.ConclusionOnce-daily tiotropium 5 μg compared with placebo improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, independent of a broad range of baseline characteristics, as add-on to ICS plus LABAs in patients with severe symptomatic asthma.Trial registryClinicalTrials.gov; numbers NCT00772538 and NCT00776984 URL: www.clinicaltrials.gov

Lecanemab in patients with early Alzheimer\u27s disease: Detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study

BACKGROUND: Lecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early AD. The objective of this analysis is to report results from study 201 blinded period (core), the open-label extension (OLE), and gap period (between core and OLE) supporting the effectiveness of lecanemab. METHODS: The lecanemab study 201 core was a double-blind, randomized, placebo-controlled study of 856 patients randomized to one of five dose regimens or placebo. An OLE of study 201 was initiated to allow patients to receive open-label lecanemab 10mg/kg biweekly for up to 24 months, with an intervening off-treatment period (gap period) ranging from 9 to 59 months (mean 24 months). RESULTS: At 12 and 18 months of treatment in the core, lecanemab 10 mg/kg biweekly demonstrated dose-dependent reductions of brain amyloid measured PET and corresponding changes in plasma biomarkers and slowing of cognitive decline. The rates of clinical progression during the gap were similar in lecanemab and placebo subjects, with clinical treatment differences maintained after discontinued dosing over an average of 24 months in the gap period. During the gap, plasma Aβ42/40 ratio and p-tau181 levels began to return towards pre-randomization levels more quickly than amyloid PET. At OLE baseline, treatment differences vs placebo at 18 months in the randomized period were maintained across 3 clinical assessments. In the OLE, lecanemab 10 mg/kg biweekly treatment produced dose-dependent reductions in amyloid PET SUVr, improvements in plasma Aβ42/40 ratio, and reductions in plasma p-tau181. CONCLUSIONS: Lecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Data indicate that rapid and pronounced amyloid reduction correlates with clinical benefit and potential disease-modifying effects, as well as the potential to use plasma biomarkers to monitor for lecanemab treatment effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT01767311

Obstructive pulmonary disease in patients with previous tuberculosis: Pathophysiology of a community-based cohort

Background. An association between chronic airflow limitation (CAL) and a history of pulmonary tuberculosis (PTB) has been confirmed in epidemiological studies, but the mechanisms responsible for this association are unclear. It is debated whether CAL in this context should be viewed as chronic obstructive pulmonary disease (COPD) or a separate phenotype. Objective. To compare lung physiology and high-resolution computed tomography (HRCT) findings in subjects with CAL and evidence of previous (healed) PTB with those in subjects with smoking-related COPD without evidence of previous PTB. Methods. Subjects with CAL identified during a Burden of Obstructive Lung Disease (BOLD) study performed in South Africa were studied. Investigations included questionnaires, lung physiology (spirometry, body plethysmography and diffusing capacity) and quantitative HRCT scans to assess bronchial anatomy and the presence of emphysema (–200 HU). Findings in subjects with a past history and/or HRCT evidence of PTB were compared with those in subjects without these features. Results. One hundred and seven of 196 eligible subjects (54.6%) were enrolled, 104 performed physiology tests and 94 had an HRCT scan. Based on history and HRCT findings, subjects were categorised as no previous PTB (NPTB, n=31), probable previous PTB (n=33) or definite previous PTB (DPTB, n=39). Subjects with DPTB had a lower diffusing capacity (Δ=–17.7%; p=0.001) and inspiratory capacity (Δ=–21.5%; p=0.001) than NPTB subjects, and higher gas-trapping and fibrosis but not emphysema scores (Δ=+6.2% (p=0.021), +0.36% (p=0.017) and +3.5% (p=0.098), respectively). Conclusions. The mechanisms of CAL associated with previous PTB appear to differ from those in the more common smoking-related COPD and warrant further study..info:eu-repo/semantics/publishedVersio