Risk of acute myocardial infarction with NSAIDs in real world use : bayesian meta-analysis of individual patient data

OBJECTIVE To characterise the determinants, time course, and risks of acute myocardial infarction associated with use of oral non-steroidal anti-inflammatory drugs (NSAIDs). DESIGN Systematic review followed by a one stage bayesian individual patient data meta-analysis. DATA SOURCES Studies from Canadian and European healthcare databases. REVIEW METHODS Eligible studies were sourced from computerised drug prescription or medical databases, conducted in the general or an elderly population, documented acute myocardial infarction as specific outcome, studied selective cyclo-oxygenase-2 inhibitors (including rofecoxib) and traditional NSAIDs, compared risk of acute myocardial infarction in NSAID users with non-users, allowed for time dependent analyses, and minimised effects of confounding and misclassification bias. EXPOSURE AND OUTCOMES Drug exposure was modelled as an indicator variable incorporating the specific NSAID, its recency, duration of use, and dose. The outcome measures were the summary adjusted odds ratios of first acute myocardial infarction after study entry for each category of NSAID use at index date (date of acute myocardial infarction for cases, matched date for controls) versus non-use in the preceding year and the posterior probability of acute myocardial infarction. RESULTS A cohort of 446 763 individuals including 61 460 with acute myocardial infarction was acquired. Taking any dose of NSAIDs for one week, one month, or more than a month was associated with an increased risk of myocardial infarction. With use for one to seven days the probability of increased myocardial infarction risk (posterior probability of odds ratio >1.0) was 92% for celecoxib, 97% for ibuprofen, and 99% for diclofenac, naproxen, and rofecoxib. The corresponding odds ratios (95% credible intervals) were 1.24 (0.91 to 1.82) for celecoxib, 1.48 (1.00 to 2.26) for ibuprofen, 1.50 (1.06 to 2.04) for diclofenac, 1.53 (1.07 to 2.33) for naproxen, and 1.58 (1.07 to 2.17) for rofecoxib. Greater risk of myocardial infarction was documented for higher dose of NSAIDs. With use for longer than one month, risks did not appear to exceed those associated with shorter durations. CONCLUSIONS All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDS and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.Peer reviewe

Xpert® MTB/RIF assay for extrapulmonary tuberculosis and rifampicin resistance.

BACKGROUND: Tuberculosis (TB) is the world's leading infectious cause of death. Extrapulmonary TB accounts for 15% of TB cases, but the proportion is increasing, and over half a million people were newly diagnosed with rifampicin-resistant TB in 2016. Xpert® MTB/RIF (Xpert) is a World Health Organization (WHO)-recommended, rapid, automated, nucleic acid amplification assay that is used widely for simultaneous detection of Mycobacterium tuberculosis complex and rifampicin resistance in sputum specimens. This Cochrane Review assessed the accuracy of Xpert in extrapulmonary specimens. OBJECTIVES: To determine the diagnostic accuracy of Xpert a) for extrapulmonary TB by site of disease in people presumed to have extrapulmonary TB; and b) for rifampicin resistance in people presumed to have extrapulmonary TB. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature (LILACS), Scopus, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number (ISRCTN) Registry, and ProQuest up to 7 August 2017 without language restriction. SELECTION CRITERIA: We included diagnostic accuracy studies of Xpert in people presumed to have extrapulmonary TB. We included TB meningitis and pleural, lymph node, bone or joint, genitourinary, peritoneal, pericardial, and disseminated TB. We used culture as the reference standard. For pleural TB, we also included a composite reference standard, which defined a positive result as the presence of granulomatous inflammation or a positive culture result. For rifampicin resistance, we used culture-based drug susceptibility testing or MTBDRplus as the reference standard. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed risk of bias and applicability using the QUADAS-2 tool. We determined pooled predicted sensitivity and specificity for TB, grouped by type of extrapulmonary specimen, and for rifampicin resistance. For TB detection, we used a bivariate random-effects model. Recognizing that use of culture may lead to misclassification of cases of extrapulmonary TB as 'not TB' owing to the paucibacillary nature of the disease, we adjusted accuracy estimates by applying a latent class meta-analysis model. For rifampicin resistance detection, we performed univariate meta-analyses for sensitivity and specificity separately to include studies in which no rifampicin resistance was detected. We used theoretical populations with an assumed prevalence to provide illustrative numbers of patients with false positive and false negative results. MAIN RESULTS: We included 66 unique studies that evaluated 16,213 specimens for detection of extrapulmonary TB and rifampicin resistance. We identified only one study that evaluated the newest test version, Xpert MTB/RIF Ultra (Ultra), for TB meningitis. Fifty studies (76%) took place in low- or middle-income countries. Risk of bias was low for patient selection, index test, and flow and timing domains and was high or unclear for the reference standard domain (most of these studies decontaminated sterile specimens before culture inoculation). Regarding applicability, in the patient selection domain, we scored high or unclear concern for most studies because either patients were evaluated exclusively as inpatients at tertiary care centres, or we were not sure about the clinical settings.Pooled Xpert sensitivity (defined by culture) varied across different types of specimens (31% in pleural tissue to 97% in bone or joint fluid); Xpert sensitivity was > 80% in urine and bone or joint fluid and tissue. Pooled Xpert specificity (defined by culture) varied less than sensitivity (82% in bone or joint tissue to 99% in pleural fluid and urine). Xpert specificity was ≥ 98% in cerebrospinal fluid, pleural fluid, urine, and peritoneal fluid.Xpert testing in cerebrospinal fluidXpert pooled sensitivity and specificity (95% credible interval (CrI)) against culture were 71.1% (60.9% to 80.4%) and 98.0% (97.0% to 98.8%), respectively (29 studies, 3774 specimens; moderate-certainty evidence).For a population of 1000 people where 100 have TB meningitis on culture, 89 would be Xpert-positive: of these, 18 (20%) would not have TB (false-positives); and 911 would be Xpert-negative: of these, 29 (3%) would have TB (false-negatives).For TB meningitis, ultra sensitivity and specificity against culture (95% confidence interval (CI)) were 90% (55% to 100%) and 90% (83% to 95%), respectively (one study, 129 participants).Xpert testing in pleural fluidXpert pooled sensitivity and specificity (95% CrI) against culture were 50.9% (39.7% to 62.8%) and 99.2% (98.2% to 99.7%), respectively (27 studies, 4006 specimens; low-certainty evidence).For a population of 1000 people where 150 have pleural TB on culture, 83 would be Xpert-positive: of these, seven (8%) would not have TB (false-positives); and 917 would be Xpert-negative: of these, 74 (8%) would have TB (false-negatives).Xpert testing in urineXpert pooled sensitivity and specificity (95% CrI) against culture were 82.7% (69.6% to 91.1%) and 98.7% (94.8% to 99.7%), respectively (13 studies, 1199 specimens; moderate-certainty evidence).For a population of 1000 people where 70 have genitourinary TB on culture, 70 would be Xpert-positive: of these, 12 (17%) would not have TB (false-positives); and 930 would be Xpert-negative: of these, 12 (1%) would have TB (false-negatives).Xpert testing for rifampicin resistanceXpert pooled sensitivity (20 studies, 148 specimens) and specificity (39 studies, 1088 specimens) were 95.0% (89.7% to 97.9%) and 98.7% (97.8% to 99.4%), respectively (high-certainty evidence).For a population of 1000 people where 120 have rifampicin-resistant TB, 125 would be positive for rifampicin-resistant TB: of these, 11 (9%) would not have rifampicin resistance (false-positives); and 875 would be negative for rifampicin-resistant TB: of these, 6 (1%) would have rifampicin resistance (false-negatives).For lymph node TB, the accuracy of culture, the reference standard used, presented a greater concern for bias than in other forms of extrapulmonary TB. AUTHORS' CONCLUSIONS: In people presumed to have extrapulmonary TB, Xpert may be helpful in confirming the diagnosis. Xpert sensitivity varies across different extrapulmonary specimens, while for most specimens, specificity is high, the test rarely yielding a positive result for people without TB (defined by culture). Xpert is accurate for detection of rifampicin resistance. For people with presumed TB meningitis, treatment should be based on clinical judgement, and not withheld solely on an Xpert result, as is common practice when culture results are negative

Evaluating Latent Tuberculosis Infection Test Performance Using Latent Class Analysis in a TB and HIV Endemic Setting.

BACKGROUND: Given the lack of a gold standard for latent tuberculosis infection (LTBI) and paucity of performance data from endemic settings, we compared test performance of the tuberculin skin test (TST) and two interferon-gamma-release assays (IGRAs) among health-care workers (HCWs) using latent class analysis. The study was conducted in Cape Town, South Africa, a tuberculosis and human immunodeficiency virus (HIV) endemic setting Methods: 505 HCWs were screened for LTBI using TST, QuantiFERON-gold-in-tube (QFT-GIT) and T-SPOT.TB. A latent class model utilizing prior information on test characteristics was used to estimate test performance. RESULTS: LTBI prevalence (95% credible interval) was 81% (71-88%). TST (10 mm cut-point) had highest sensitivity (93% (90-96%)) but lowest specificity (57%, (43-71%)). QFT-GIT sensitivity was 80% (74-91%) and specificity 96% (94-98%), and for TSPOT.TB, 74% (67-84%) and 96% (89-99%) respectively. Positive predictive values were high for IGRAs (90%) and TST (99%). All tests displayed low negative predictive values (range 47-66%). A composite rule using both TST and QFT-GIT greatly improved negative predictive value to 90% (range 80-97%). CONCLUSION: In an endemic setting a positive TST or IGRA was highly predictive of LTBI, while a combination of TST and IGRA had high rule-out value. These data inform the utility of LTBI-related immunodiagnostic tests in TB and HIV endemic settings

Predictors of discordant latent tuberculosis infection test results amongst South African health care workers

Background The tuberculin skin test (TST) and interferon-gamma-release-assays (IGRAs) are utilized in screening programmes for presumed latent tuberculosis infection (LTBI) in health care workers (HCWs). However, inter-test comparison yields high rates of discordance, which is poorly understood. The aim of the study was therefore to identify factors associated with discordance amongst HCWs in a TB and HIV endemic setting. Methods 505 HCWs were screened for LTBI in South Africa using the TST and two IGRA assays (QuantiFERON-TB-Gold-In-Tube (QFT-GIT) and TSPOT.TB). Factors associated with discordance were analyzed using a multinomial logistic regression model. Results TST-IGRA discordance was negatively associated with longer duration of employment for both TSPOT.TB (OR = 0.92; 95% confidence interval (CI) 0.85–0.99) and QFT-GIT (OR = 0.90; 95% CI 0.84–0.96). Marked test discordance occurred in HIV-infected individuals who were more likely to have TSPOT.TB + ve / TST-ve discordance (OR 4.44; 95% CI 1.14–17.27) or TSPOT.TB + ve / QFT-GIT-ve test discordance (OR 5.72; 95% CI 1.95–16.78). Those engaged in home care were less likely to have QFT-GIT + ve/TSPOT.TB -ve / discordance (OR 0.32; 95% CI 0.10–0.95). Conclusion The marked TST-IGRA and IGRA-IGRA discordance in HIV-infected individuals suggest greater sensitivity of TSPOT.TB in immunocompromised persons or potential greater reactivity of TSPOT.TB in this population

Commercial Serological Tests for the Diagnosis of Active Pulmonary and Extrapulmonary Tuberculosis: An Updated Systematic Review and Meta-Analysis

An up-to-date systematic review and meta-analysis by Karen Steingart and colleagues confirms that commercially available serological tests do not provide an accurate diagnosis of tuberculosis

Xpert MTB/RIF and Xpert Ultra assays for pulmonary tuberculosis and rifampicin resistance in adults irrespective of signs or symptoms of pulmonary tuberculosis.

Objectives This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To determine the accuracy of Xpert MTB/RIF and Xpert Ultra for screening for tuberculosis in adults irrespective of signs or symptoms of pulmonary tuberculosis in the general population (i.e. low‐risk population). To determine the accuracy of Xpert MTB/RIF and Xpert Ultra for screening of pulmonary tuberculosis in adults in the following high‐risk groups. People living with HIV. Household contacts of people with tuberculosis. Patients residing in high‐tuberculosis‐burden settings attending primary health facilities. Homeless people. Miners. People with diabetes mellitus. People who abuse alcohol. Smokers. People residing in prisons. Healthcare workers. To determine the accuracy of Xpert MTB/RIF and Xpert Ultra for the detection of rifampicin resistance in the general population and in the high‐risk groups and settings described above. Secondary objectives To compare the accuracy of Xpert MTB/RIF and Xpert Ultra in the above high‐risk groups and settings. To investigate potential sources of heterogeneity in accuracy estimates, including the percentage of participants with tuberculosis symptoms, tuberculosis burden, tuberculosis/HIV burden, and MDR‐TB burden

Tuberculosis Infection among Young Nursing Trainees in South India

BackgroundAmong healthcare workers in developing countries, nurses spend a large amount of time in direct contact with tuberculosis (TB) patients, and are at high risk for acquisition of TB infection and disease. To better understand the epidemiology of nosocomial TB among nurses, we recruited a cohort of young nursing trainees at Christian Medical College, a large, tertiary medical school hospital in Southern India.Methodology/Principal FindingsAmong 535 nursing students enrolled in 2007, 468 gave consent to participate, and 436 underwent two-step tuberculin skin testing (TST). [...] (50.2%, 95% CI: 45.4–55.0) were TST positive using the 10 mm or greater cut-off. Based on the LCA, the prevalence of LTBI was 47.8% (95% credible interval 17.8% to 65.6%). In the multivariate analysis, TST positivity was strongly associated with time spent in health care, after adjusting for age at entry into healthcare.ConclusionsOur study showed a high prevalence of LTBI even in young nursing trainees. With the recent TB infection control (TBIC) policy guidance from the World Health Organization as the reference, Indian healthcare providers and the Indian Revised National TB Control Programme will need to implement TBIC interventions, and enhance capacity for TBIC at the country level. Young trainees and nurses, in particular, will need to be targeted for TBIC interventions

Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in people living with HIV

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows: To determine the diagnostic accuracy of abdominal ultrasound as a standalone test for detecting abdominal TB or disseminated TB with abdominal involvement in HIV‐positive adults