Interventions for treating tuberculous pericarditis.

BACKGROUND: Tuberculous pericarditis can impair the heart's function and cause death; long term, it can cause the membrane to fibrose and constrict causing heart failure. In addition to antituberculous chemotherapy, treatments include corticosteroids, drainage, and surgery. OBJECTIVES: To assess the effects of treatments for tuberculous pericarditis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register (27 March 2017); the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library (2017, Issue 2); MEDLINE (1966 to 27 March 2017); Embase (1974 to 27 March 2017); and LILACS (1982 to 27 March 2017). In addition we searched the metaRegister of Controlled Trials (mRCT) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal using 'tuberculosis' and 'pericard*' as search terms on 27 March 2017. We searched ClinicalTrials.gov and contacted researchers in the field of tuberculous pericarditis. This is a new version of the original 2002 review. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search outputs, evaluated study eligibility, assessed risk of bias, and extracted data; and we resolved any discrepancies by discussion and consensus. One trial assessed the effects of both corticosteroid and Mycobacterium indicus pranii treatment in a two-by-two factorial design; we excluded data from the group that received both interventions. We conducted fixed-effect meta-analysis and assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Seven trials met the inclusion criteria; all were from sub-Saharan Africa and included 1959 participants, with 1051/1959 (54%) HIV-positive. All trials evaluated corticosteroids and one each evaluated colchicine, M. indicus pranii immunotherapy, and open surgical drainage. Four trials (1841 participants) were at low risk of bias, and three trials (118 participants) were at high risk of bias.In people who are not infected with HIV, corticosteroids may reduce deaths from all causes (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.59 to 1.09; 660 participants, 4 trials, low certainty evidence) and the need for repeat pericardiocentesis (RR 0.85, 95% CI 0.70 to 1.04; 492 participants, 2 trials, low certainty evidence). Corticosteroids probably reduce deaths from pericarditis (RR 0.39, 95% CI 0.19 to 0.80; 660 participants, 4 trials, moderate certainty evidence). However, we do not know whether or not corticosteroids have an effect on constriction or cancer among HIV-negative people (very low certainty evidence).In people living with HIV, only 19.9% (203/1959) were on antiretroviral drugs. Corticosteroids may reduce constriction (RR 0.55, 0.26 to 1.16; 575 participants, 3 trials, low certainty evidence). It is uncertain whether corticosteroids have an effect on all-cause death or cancer (very low certainty evidence); and may have little or no effect on repeat pericardiocentesis (RR 1.02, 0.89 to 1.18; 517 participants, 2 trials, low certainty evidence).For colchicine among people living with HIV, we found one small trial (33 participants) which had insufficient data to make any conclusions about any effects on death or constrictive pericarditis.Irrespective of HIV status, due to very low certainty evidence from one trial, it is uncertain whether adding M. indicus pranii immunotherapy to antituberculous drugs has an effect on any outcome.Open surgical drainage for effusion may reduce repeat pericardiocentesis In HIV-negative people (RR 0.23, 95% CI 0.07 to 0.76; 122 participants, 1 trial, low certainty evidence) but may make little or no difference to other outcomes. We did not find an eligible trial that assessed the effects of open surgical drainage in people living with HIV.The review authors found no eligible trials that examined the length of antituberculous treatment needed nor the effects of other adjunctive treatments for tuberculous pericarditis. AUTHORS' CONCLUSIONS: For HIV-negative patients, corticosteroids may reduce death. For HIV-positive patients not on antiretroviral drugs, corticosteroids may reduce constriction. For HIV-positive patients with good antiretroviral drug viral suppression, clinicians may consider the results from HIV-negative patients more relevant.Further research may help evaluate percutaneous drainage of the pericardium under local anaesthesia, the timing of pericardiectomy in tuberculous constrictive pericarditis, and new antibiotic regimens.

The diagnostic accuracy of pericardial and urinary lipoarabinomannan (LAM) assays in patients with suspected tuberculous pericarditis.

We evaluated the diagnostic accuracy of urinary and pericardial fluid (PF) lipoarabinomannan (LAM) assays in tuberculous pericarditis (TBP). From October 2009 through September 2012, 151 patients with TBP were enrolled. Mycobacterium tuberculosis culture and/or pericardial histology were the reference standard for definite TBP. 49% (74/151), 33.1% (50/151) and 17.9% (27/151) of patients had definite-, probable-, and non-TB respectively; 69.5% (105/151) were HIV positive. LAM ELISA had the following sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, positive predictive value and negative predictive values (95% confidence interval): urinary - 17.4% (9.1-30.7), 93.8% (71.7-98.9), 2.8 (0.1-63.3), 0.9 (0.8-0.9), 88.9% (56.5-98.0), and 28.3% (17.9-41.6); PF - 11.6% (6.0-21.3), 88% (70.0-95.8), 0.9 (0.08-12.0), 1.0 (0.9-1.1), 72.7% (43.4-90.1), and 26.6% (18.2-36.9). Sensitivity increased with a CD4 ≤ 100 cells/mm(3) from 3.5% to 50% (p < 0.001) for urinary LAM ELISA; for urinary LAM strip test, grade 1 and 2 cut-points performed similarly, irrespective of HIV status or CD4 count. For PF LAM strip tests, switching cut-points from grade 1 to 2 significantly reduced test sensitivity (54.5% versus 19.7%; p < 0.001). Urinary and PF LAM assays have low sensitivity but high specificity for diagnosis of TBP. The sensitivity of urinary LAM is increased in HIV-infected patients with a CD4 ≤ 100 cells/mm(3).

Randomized Controlled Trial of Radiation Protection With a Patient Lead Shield and a Novel, Nonlead Surgical Cap for Operators Performing Coronary Angiography or Intervention.

BACKGROUND: Interventional cardiologists receive one of the highest levels of annual occupational radiation exposure. Further measures to protect healthcare workers are needed. METHODS AND RESULTS: We evaluated the efficacy of a pelvic lead shield and a novel surgical cap in reducing operators' radiation exposure. Patients undergoing coronary angiography or percutaneous coronary intervention (n=230) were randomized to have their procedure with or without a lead shield (Ultraray Medical, Oakville, Canada) placed over the patient. During all procedures, operators wore the No Brainer surgical cap (Worldwide Innovations and Technology, Kansas City, KS) designed to protect the head from radiation exposure. The coprimary outcomes for the lead shield comparison were (1) operator dose (µSv) and (2) operator dose indexed for air kerma (µSv/mGy). For the cap comparison, the primary outcome was the difference between total radiation dose (µSv; internal and external to cap). The lead shield use resulted in a 76% reduction in operator dose (mean dose, 3.07; 95% confidence interval [CI], 2.00-4.71 µSv lead shield group versus 12.57; 95% CI, 8.14-19.40 µSv control group; P<0.001). The mean dose indexed for air kerma was reduced by 72% (0.004; 95% CI, 0.003-0.005 µSv/mGy lead shield group versus 0.015; 95% CI, 0.012-0.019 µSv/mGy control group; P<0.001). The cap use resulted in a significant reduction in operator head radiation exposure (mean left temporal difference [external-internal] radiation dose was 4.79 [95% CI, 3.30-6.68] µSv; P<0.001). CONCLUSIONS: The use of a pelvic lead shield and the cap reduced significantly the operator radiation exposure and can be easily incorporated into clinical practice. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02128035.

Radial Versus Femoral Access for Coronary Angiography/Intervention in Women With Acute Coronary Syndromes: Insights From the RIVAL Trial (Radial Vs femorAL access for coronary intervention).

OBJECTIVES: The purpose of this study was to determine the efficacy and safety of radial versus femoral access in women undergoing coronary angiography/intervention. BACKGROUND: The risk of bleeding and vascular access site complications are higher in women than in men. METHODS: In a pre-specified RIVAL (RadIal Vs femorAL access for coronary intervention) subgroup analysis, we compared outcomes in women (n=1,861) and men (n=5,160) randomized to radial versus femoral access. RESULTS: Overall, women were at higher risk of major vascular complications compared with men (4.7% vs. 1.7%; p<0.0001). Major vascular complications were significantly reduced with radial access in women (3.1% vs. 6.1%; hazard ratio [HR]: 0.5; 95% confidence interval [CI]: 0.32 to 0.78; p=0.002) and in men (0.7% vs. 2.8%; HR: 0.27; 95% CI: 0.17 to 0.45; p<0.0001; interaction p=0.092). Crossover rates were higher with radial compared with femoral access in women (11.1% vs. 1.9%; HR: 5.88; p<0.0001) and men (6.3% vs. 1.9%; HR: 3.32; p<0.0001; interaction p=0.054). Percutaneous coronary intervention (PCI) success rates were similar irrespective of access site (women: HR: 1.05; p=0.471; men: HR: 1.00; p=0.888; interaction p=0.674), with no differences in PCI complications. In multivariable analyses, female sex was an independent predictor of major vascular complications (HR: 2.39; 95% CI: 1.76 to 3.25; p<0.0001). There were consistent findings for women and men, with no difference for the primary composite endpoint of death, myocardial infarction, stroke, and non-coronary artery bypass grafting bleeding (women: 3.9% vs. 5.0%; HR: 0.77; 95% CI: 0.50 to 1.19; men: 3.54% vs. 3.5%; HR: 1.00; 95% CI: 0.75 to -1.34; interaction p=0.325). CONCLUSIONS: Women undergoing coronary angiography and PCI have a higher risk of vascular access site complications compared with men, and radial access is an effective method to reduce these complications.

Tuberculous Pericarditis is Multibacillary and Bacterial Burden Drives High Mortality.

BACKGROUND: Tuberculous pericarditis is considered to be a paucibacillary process; the large pericardial fluid accumulation is attributed to an inflammatory response to tuberculoproteins. Mortality rates are high. We investigated the role of clinical and microbial factors predictive of tuberculous pericarditis mortality using the artificial intelligence algorithm termed classification and regression tree (CART) analysis. METHODS: Patients were prospectively enrolled and followed in the Investigation of the Management of Pericarditis (IMPI) registry. Clinical and laboratory data of 70 patients with confirmed tuberculous pericarditis, including time-to-positive (TTP) cultures from pericardial fluid, were extracted and analyzed for mortality outcomes using CART. TTP was translated to log10 colony forming units (CFUs) per mL, and compared to that obtained from sputum in some of our patients. FINDINGS: Seventy patients with proven tuberculous pericarditis were enrolled. The median patient age was 35 (range: 20-71) years. The median, follow up was for 11.97 (range: 0·03-74.73) months. The median TTP for pericardial fluid cultures was 22 (range: 4-58) days or 3.91(range: 0·5-8·96) log10CFU/mL, which overlapped with the range of 3.24-7.42 log10CFU/mL encountered in sputum, a multi-bacillary disease. The overall mortality rate was 1.43 per 100 person-months. CART identified follow-up duration of 5·23 months on directly observed therapy, a CD4 + count of ≤ 199.5/mL, and TTP ≤ 14 days (bacillary load ≥ 5.53 log10 CFU/mL) as predictive of mortality. TTP interacted with follow-up duration in a non-linear fashion. INTERPRETATION: Patients with culture confirmed tuberculous pericarditis have a high bacillary burden, and this bacterial burden drives mortality. Thus proven tuberculosis pericarditis is not a paucibacillary disease. Moreover, the severe immunosuppression suggests limited inflammation. There is a need for the design of a highly bactericidal regimen for this condition.

Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis.

BACKGROUND: Tuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered. We evaluated the effects of adjunctive glucocorticoid therapy and Mycobacterium indicus pranii immunotherapy in patients with tuberculous pericarditis. METHODS: Using a 2-by-2 factorial design, we randomly assigned 1400 adults with definite or probable tuberculous pericarditis to either prednisolone or placebo for 6 weeks and to either M. indicus pranii or placebo, administered in five injections over the course of 3 months. Two thirds of the participants had concomitant human immunodeficiency virus (HIV) infection. The primary efficacy outcome was a composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. RESULTS: There was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.77 to 1.18; P=0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; hazard ratio, 1.03; 95% CI, 0.82 to 1.29; P=0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; hazard ratio, 3.27; 95% CI, 1.07 to 10.03; P=0.03, and 1.8% vs. 0.5%; hazard ratio, 3.69; 95% CI, 1.03 to 13.24; P=0.03, respectively), owing mainly to an increase in HIV-associated cancer. CONCLUSIONS: In patients with tuberculous pericarditis, neither prednisolone nor M. indicus pranii had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. (Funded by the Canadian Institutes of Health Research and others; IMPI ClinicalTrials.gov number, NCT00810849.).

Mycobacterium w Immunotherapy for Treating Pulmonary Tuberculosis - a Systematic Review.

BACKGROUND: Tuberculosis (TB) remains a global health catastrophe. Mycobacterium w is a heat-killed immune-modulating vaccine designed to attenuate the effects of TB, reduce time to sputum conversion, and thereby decrease transmission and improve cure rates. OBJECTIVES: To evaluate Mycobacterium w (M w) immunotherapy as an adjunct to chemotherapy in participants with pulmonary TB (PTB). SEARCH STRATEGY: In January 2012, we performed both a database search, a handsearch and corresponded with experts in the field. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of M w immunotherapy versus placebo (or no control) for participants with PTB. DATA COLLECTION AND ANALYSIS: Two of the authors (SP and ZK) independently extracted data. Dichotomous outcomes were analysed using risk ratios (RR) and 95% confidence intervals (CI). OUTCOMES: The primary outcome was to determine the effect of M w therapy on sputum conversion. Secondary outcomes were to determine the frequency of adverse reactions. MAIN RESULTS: Three trials (four papers) involving 368 participants were included. All four papers had methodological flaws. Overall, 173 participants received M w and 168 participants received placebo or no control. M w immunotherapy was effective at reducing time to sputum conversion at days 15 (RR 2.31; 95% CI 1.75 to 3.06; P < 0.001) and 30 (RR 1.83; 95% CI 1.12 to 2.98; P = 0.02). After day 30, benefit was only demonstrated in the category II TB (re-treatment). CONCLUSIONS: The meta-analysis suggests benefit as regards the time to sputum conversion. The available data on M w immunotherapy for participants with PTB are however methodologically flawed. We advise that M w be investigated in a well-structured, randomised controlled trial.

Determinants of PCR performance (Xpert MTB/RIF), including bacterial load and inhibition, for TB diagnosis using specimens from different body compartments.

The determinants of Xpert MTB/RIF sensitivity, a widely used PCR test for the diagnosis of tuberculosis (TB) are poorly understood. We compared culture time-to-positivity (TTP; a surrogate of bacterial load), MTB/RIF TB-specific and internal positive control (IPC)-specific C(T) values, and clinical characteristics in patients with suspected TB who provided expectorated (n = 438) or induced sputum (n = 128), tracheal aspirates (n = 71), bronchoalveolar lavage fluid (n = 152), pleural fluid (n = 76), cerebral spinal fluid (CSF; n = 152), pericardial fluid (n = 131), or urine (n = 173) specimens. Median bacterial load (TTP in days) was the strongest associate of MTB/RIF positivity in each fluid. TTP correlated with C(T) values in pulmonary specimens but not extrapulmonary specimens (Spearman's coefficient 0.5043 versus 0.1437; p = 0.030). Inhibition affected a greater proportion of pulmonary specimens than extrapulmonary specimens (IPC C(T) > 34: 6% (47/731) versus 1% (4/381; p < 0.0001). Pulmonary specimens had greater load than extrapulmonary specimens [TTPs (interquartile range) of 11 (7-16) versus 22 (18-33.5) days; p < 0.0001]. HIV-infection was associated with a decreased likelihood of MTB/RIF-positivity in pulmonary specimens but an increased likelihood in extrapulmonary specimens. Mycobacterial load, which displays significant variation across different body compartments, is the main determinant of MTB/RIF-positivity rather than PCR inhibition. MTB/RIF C(T) is a poor surrogate of load in extrapulmonary specimens.

Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous pericarditis compared to adenosine deaminase and unstimulated interferon-γ in a high burden setting: a prospective study.

BACKGROUND: Tuberculous pericarditis (TBP) is associated with high morbidity and mortality, and is an important treatable cause of heart failure in developing countries. Tuberculous aetiology of pericarditis is difficult to diagnose promptly. The utility of the new quantitative PCR test (Xpert MTB/RIF) for the diagnosis of TBP is unknown. This study sought to evaluate the diagnostic accuracy of the Xpert MTB/RIF test compared to pericardial adenosine deaminase (ADA) and unstimulated interferon-gamma (uIFNγ) in suspected TBP. METHODS: From October 2009 through September 2012, 151 consecutive patients with suspected TBP were enrolled at a single centre in Cape Town, South Africa. Mycobacterium tuberculosis culture and/or pericardial histology served as the reference standard for definite TBP. Receiver-operating-characteristic curve analysis was used for selection of ADA and uIFNγ cut-points. RESULTS: Of the participants, 49% (74/151) were classified as definite TBP, 33% (50/151) as probable TBP and 18% (27/151) as non TBP. A total of 105 (74%) participants were human immunodeficiency virus (HIV) positive. Xpert-MTB/RIF had a sensitivity and specificity (95% confidence interval (CI)) of 63.8% (52.4% to 75.1%) and 100% (85.6% to 100%), respectively. Concentration of pericardial fluid by centrifugation and using standard sample processing did not improve Xpert MTB/RIF accuracy. ADA (≥35 IU/L) and uIFNγ (≥44 pg/ml) both had a sensitivity of 95.7% (88.1% to 98.5%) and a negative likelihood ratio of 0.05 (0.02 to 0.10). However, the specificity and positive likelihood ratio of uIFNγ was higher than ADA (96.3% (81.7% to 99.3%) and 25.8 (3.6 to 183.4) versus 84% (65.4% to 93.6%) and 6.0 (3.7 to 9.8); P = 0.03) at an estimated background prevalence of TB of 30%. The sensitivity and negative predictive value of both uIFNγ and ADA were higher than Xpert-MT/RIF (P < 0.001). CONCLUSIONS: uIFNγ offers superior accuracy for the diagnosis of microbiologically confirmed TBP compared to the ADA assay and the Xpert MTB/RIF test.

Rationale and design of the Investigation of the Management of Pericarditis (IMPI) trial: a 2 × 2 factorial randomized double-blind multicenter trial of adjunctive prednisolone and Mycobacterium w immunotherapy in tuberculous pericarditis.

BACKGROUND: In spite of antituberculosis chemotherapy, tuberculous (TB) pericarditis causes death or disability in nearly half of those affected. Attenuation of the inflammatory response in TB pericarditis may improve outcome by reducing cardiac tamponade and pericardial constriction, but there is uncertainty as to whether adjunctive immunomodulation with corticosteroids and Mycobacterium w (M. w) can safely reduce mortality and morbidity. OBJECTIVES: The primary objective of the IMPI Trial is to assess the effectiveness and safety of prednisolone and M. w immunotherapy in reducing the composite outcome of death, constriction, or cardiac tamponade requiring pericardial drainage in 1,400 patients with TB pericardial effusion. DESIGN: The IMPI trial is a multicenter international randomized double-blind placebo-controlled 2 × 2 factorial study. Eligible patients are randomly assigned to receive oral prednisolone or placebo for 6 weeks and M. w injection or placebo for 3 months. Patients are followed up at weeks 2, 4, and 6 and months 3 and 6 during the intervention period and 6-monthly thereafter for up to 4 years. The primary outcome is the first occurrence of death, pericardial constriction, or cardiac tamponade requiring pericardiocentesis. The secondary outcome is safety of immunomodulatory treatment measured by effect on opportunistic infections (eg, herpes zoster) and malignancy (eg, Kaposi sarcoma) and impact on measures of immunosuppression and the incidence of immune reconstitution disease. CONCLUSIONS: IMPI is the largest trial yet conducted comparing adjunctive immunotherapy in pericarditis. Its results will define the role of adjunctive corticosteroids and M. w immunotherapy in patients with TB pericardial effusion.