Clinical predictors for fatal pulmonary embolism in 15520 patients with venous thromboembolism - Findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry

BACKGROUND Clinical predictors for fatal pulmonary embolism (PE) in patients with venous thromboembolism have never been studied. METHODS AND RESULTS Using data from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry about patients with objectively confirmed symptomatic acute venous thromboembolism, we determined independent predictive factors for fatal PE. Between March 2001 and July 2006, 15520 consecutive patients (mean age+/-SD, 66.3+/-16.9 years; 49.7% men) with acute venous thromboembolism were included. Symptomatic deep-vein thrombosis without symptomatic PE was observed in 58.0% (n=9008) of patients, symptomatic nonmassive PE in 40.4% (n=6264), and symptomatic massive PE in 1.6% (n=248). At 3 months, the cumulative rates of overall mortality and fatal PE were 8.65% and 1.68%, respectively. On multivariable analysis, patients with symptomatic nonmassive PE at presentation exhibited a 5.42-fold higher risk of fatal PE compared with patients with deep-vein thrombosis without symptomatic PE (P<0.001). The risk of fatal PE was multiplied by 17.5 in patients presenting with a symptomatic massive PE. Other clinical factors independently associated with an increased risk of fatal PE were immobilization for neurological disease, age >75 years, and cancer. CONCLUSIONS PE remains a potentially fatal disease. The clinical predictors identified in the present study should be included in any clinical risk stratification scheme to optimally adapt the treatment of PE to the risk of the fatal outcome.

Eligibility for and outcome of treatment of latent tuberculosis infection in a cohort of HIV-infected people in Spain

BACKGROUND Previous studies have demonstrated the efficacy of treatment for latent tuberculosis infection (TLTBI) in persons infected with the human immunodeficiency virus, but few studies have investigated the operational aspects of implementing TLTBI in the co-infected population.The study objectives were to describe eligibility for TLTBI as well as treatment prescription, initiation and completion in an HIV-infected Spanish cohort and to investigate factors associated with treatment completion. METHODS Subjects were prospectively identified between 2000 and 2003 at ten HIV hospital-based clinics in Spain. Data were obtained from clinical records. Associations were measured using the odds ratio (OR) and its 95% confidence interval (95% CI). RESULTS A total of 1242 subjects were recruited and 846 (68.1%) were evaluated for TLTBI. Of these, 181 (21.4%) were eligible for TLTBI either because they were tuberculin skin test (TST) positive (121) or because their TST was negative/unknown but they were known contacts of a TB case or had impaired immunity (60). Of the patients eligible for TLTBI, 122 (67.4%) initiated TLTBI: 99 (81.1%) were treated with isoniazid for 6, 9 or 12 months; and 23 (18.9%) with short-course regimens including rifampin plus isoniazid and/or pyrazinamide. In total, 70 patients (57.4%) completed treatment, 39 (32.0%) defaulted, 7 (5.7%) interrupted treatment due to adverse effects, 2 developed TB, 2 died, and 2 moved away. Treatment completion was associated with having acquired HIV infection through heterosexual sex as compared to intravenous drug use (OR:4.6; 95% CI:1.4-14.7) and with having taken rifampin and pyrazinamide for 2 months as compared to isoniazid for 9 months (OR:8.3; 95% CI:2.7-24.9). CONCLUSIONS A minority of HIV-infected patients eligible for TLTBI actually starts and completes a course of treatment. Obstacles to successful implementation of this intervention need to be addressed.

D-dimer levels and 90-day outcome in patients with acute pulmonary embolism with or without cancer.

BACKGROUND: The prognostic value of D-dimer testing in patients with acute pulmonary embolism (PE) has not been thoroughly studied. METHODS: We used the RIETE Registry data to assess the 90-day prognostic value of increased IL Test D-dimer levels at baseline in patients with PE, according to the presence or absence of cancer. RESULTS: As of May 2013, 3,283 patients with acute PE underwent D-dimer testing using IL Test D-dimer. Among 2,588 patients without cancer, those with D-dimer levels in the highest quartile had a higher rate of fatal PE (2.6% vs. 0.9%; p=0.002), fatal bleeding (1.1% vs. 0.3%; p=0.017) and all-cause death (9.1% vs. 4.4%; p<0.001) at 90 days compared with those with levels in the lowest quartiles. Among 695 patients with cancer, those with levels in the highest quartile had a similar rate of fatal PE or fatal bleeding but higher mortality (35% vs. 24%; p<0.01). On multivariate analysis, non-cancer patients with D-dimer levels in the highest quartile had an increased risk for fatal PE (odds ratio [OR]: 3.3; 95% CI: 1.6-6.6), fatal bleeding (OR: 4.3; 95% CI: 1.4-13.7) and all-cause death (OR: 2.1; 95% CI: 1.4-3.1) compared with patients with levels in the lowest quartiles. CONCLUSIONS: Non-cancer patients with acute PE and IL Test D-dimer levels in the highest quartile had an independently higher risk for fatal PE, fatal bleeding and all-cause death at 90 days than those with levels in the lowest quartiles. In patients with cancer, D-dimer levels failed to predict fatal PE or fatal bleeding.

High prevalence of drug-resistant tuberculosis and other mycobacteria among HIV-infected patients in Brazil: a systematic review

There is a little-noticed trend involving human immunodeficiency virus (HIV)-infected patients suspected of having tuberculosis: the triple-treatment regimen recommended in Brazil for years has been potentially ineffective in over 30% of the cases. This proportion may be attributable to drug resistance (to at least 1 drug) and/or to infection with non-tuberculous mycobacteria. This evidence was not disclosed in official statistics, but arose from a systematic review of a few regional studies in which the diagnosis was reliably confirmed by mycobacterial culture. This paper clarifies that there has long been ample evidence for the potential benefits of a four-drug regimen for co-infected patients in Brazil and it reinforces the need for determining the species and drug susceptibility in all positive cultures from HIV-positive patients.

Pulmonary Sarcoid-like Granulomatosis after Multiple Vaccinations of a Long-term Surviving Patient with Metastatic Melanoma.

Autoimmune side effects are frequent in patients with cancer treated with immune checkpoint-targeting antibodies, but are rare with cancer vaccines. Here, we present a case report on a patient with metastatic melanoma who developed pulmonary sarcoid-like granulomatosis following repetitive vaccinations with peptides and CpG. Despite multiple metastases, including one lesion in the brain, the patient is alive and well more than 13 years after the diagnosis of metastatic disease. The strongly activated tumor-specific CD8(+) T cells showed robust long-term memory and effector functions. It is possible that long-term survival and adverse autoimmune events may become more common for vaccines inducing robust anticancer immune responses as were present in this patient. Cancer Immunol Res; 2(12); 1148-53. ©2014 AACR.

MR and CT imaging of pulmonary valved conduits in children and adolescents: normal appearance and complications.

BACKGROUND: The Contegra® is a conduit made from the bovine jugular vein and then interposed between the right ventricle and the pulmonary artery. It is used for cardiac malformations in the reconstruction of right ventricular outflow tract. OBJECTIVE: To describe both normal and pathological appearances of the Contegra® in radiological imaging, to describe imaging of complications and to define the role of CT and MRI in postoperative follow-up. MATERIALS AND METHODS: Forty-three examinations of 24 patients (17 boys and 7 girls; mean age: 10.8 years old) with Contegra® conduits were reviewed. Anatomical description and measurements of the conduits were performed. Pathological items examined included stenosis, dilatation, plicature or twist, thrombus or vegetations, calcifications and valvular regurgitation. Findings were correlated to the echographic gradient through the conduit when available. RESULTS: CT and MR work-up showed Contegra® stenosis (n = 12), dilatation (n = 9) and plicature or twist (n = 7). CT displayed thrombus or vegetations in the Contegra® in three clinically infected patients. Calcifications of the conduit were present at CT in 12 patients and valvular regurgitation in three patients. The comparison between CT and/or MR results showed a good correlation between the echographic gradient and the presence of stenosis in the Contegra®. CONCLUSION: CT and MR bring additional information about permeability and postoperative anatomy especially when echocardiography is inconclusive. Both techniques depict the normal appearance of the conduit, and allow comparison and precise evaluation of changes in the postoperative follow-up.

Perinatal Hypoxia Enhances Cyclic Adenosine Monophosphate-mediated BKCa Channel Activation in Adult Murine Pulmonary Artery.

Exposure to perinatal hypoxia results in alteration of the adult pulmonary circulation, which is linked among others to alterations in K channels in pulmonary artery (PA) smooth muscle cells. In particular, large conductance Ca-activated K (BKCa) channels protein expression and activity were increased in adult PA from mice born in hypoxia compared with controls. We evaluated long-term effects of perinatal hypoxia on the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway-mediated activation of BKCa channels, using isoproterenol, forskolin, and dibutyryl-cAMP. Whole-cell outward current was higher in pulmonary artery smooth muscle cells from mice born in hypoxia compared with controls. Spontaneous transient outward currents, representative of BKCa activity, were present in a greater proportion in pulmonary artery smooth muscle cells of mice born in hypoxia than in controls. Agonists induced a greater relaxation in PA of mice born in hypoxia compared with controls, and BKCa channels contributed more to the cAMP/PKA-mediated relaxation in case of perinatal hypoxia. In summary, perinatal hypoxia enhanced cAMP-mediated BKCa channels activation in adult murine PA, suggesting that this pathway could be a potential target for modulating adult pulmonary vascular tone after perinatal hypoxia.

Identification of Mycobacterium tuberculosis complex based on amplification and sequencing of the oxyR pseudogene from stored Ziehl-Neelsen-stained sputum smears in Brazil

A cross-sectional analysis of stored Ziehl-Neelsen (ZN)-stained sputum smear slides (SSS) obtained from two public tuberculosis referral laboratories located in Juiz de Fora, Minas Gerais, was carried out to distinguish Mycobacterium bovis from other members of the Mycobacterium tuberculosis complex (MTC). A two-step approach was used to distinguish M. bovis from other members of MTC: (i) oxyR pseudogene amplification to detect MTC and, subsequently, (ii) allele-specific sequencing based on the polymorphism at position 285 of this gene. The oxyR pseudogene was successfully amplified in 100 of 177 (56.5%) SSS available from 99 individuals. No molecular profile of M. bovis was found. Multivariate analysis indicated that acid-fast bacilli (AFB) results and the source laboratory were associated (p < 0.05) with oxyR pseudogene amplification. SSS that were AFB++ SSS showed more oxyR pseudogene amplification than those with AFB0, possibly due to the amount of DNA. One of the two source laboratories presented a greater chance of oxyR pseudogene amplification, suggesting that differences in sputum conservation between laboratories could have influenced the preservation of DNA. This study provides evidence that stored ZN-SSS can be used for the molecular detection of MTC.

Impact of laboratory cross-contamination on molecular epidemiology studies of tuberculosis.

Laboratory cross-contamination by Mycobacterium tuberculosis is known to be responsible for the misdiagnosis of tuberculosis, but its impact on other contexts has not been analyzed. We present the findings of a molecular epidemiology analysis in which the recent transmission events identified by a genotyping reference center were overestimated as a result of unnoticed laboratory cross-contamination in the original diagnostic laboratories.

Hospital volume and patient outcomes in pulmonary embolism.

BACKGROUND: In numerous high-risk medical and surgical conditions, a greater volume of patients undergoing treatment in a given setting or facility is associated with better survival. For patients with pulmonary embolism, the relation between the number of patients treated in a hospital (volume) and patient outcome is unknown. METHODS: We studied discharge records from 186 acute care hospitals in Pennsylvania for a total of 15 531 patients for whom the primary diagnosis was pulmonary embolism. The study outcomes were all-cause mortality in hospital and within 30 days after presentation for pulmonary embolism and the length of hospital stay. We used logistic models to study the association between hospital volume and 30-day mortality and discrete survival models to study the association between in-hospital mortality and time to hospital discharge. RESULTS: The median annual hospital volume for pulmonary embolism was 20 patients (interquartile range 10-42). Overall in-hospital mortality was 6.0%, whereas 30-day mortality was 9.3%. In multivariable analysis, very-high-volume hospitals (> or = 42 cases per year) had a significantly lower odds of in-hospital death (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.51-0.99) and of 30-day death (OR 0.71, 95% CI 0.54-0.92) than very-low-volume hospitals (< 10 cases per year). Although patients in the very-high-volume hospitals had a slightly longer length of stay than those in the very-low-volume hospitals (mean difference 0.7 days), there was no association between volume and length of stay. INTERPRETATION: In hospitals with a high volume of cases, pulmonary embolism was associated with lower short-term mortality. Further research is required to determine the causes of the relation between volume and outcome for patients with pulmonary embolism.

Detection of rifampin-resistant genotypes in Mycobacterium tuberculosis by reverse hybridization assay

We used a colorimetric reverse dot blot hybridization (CRDH) assay to detect the presence of mutations in a specific region of the rpoB gene, associated with rifampin (RIF) resistance, in a panel of 156 DNAs extracted from 103 RIF-sensitive and 53 RIF-resistant cultures of Mycobacterium tuberculosis. When compared with the antimicrobial susceptibility test (AST), the sensitivity and specificity of the CRDH were 92.3% and 98.1%, respectively. When compared with sequencing, the sensitivity and specificity of the CRDH were 90.6% and 100%, respectively. To evaluate the performance of the assay directly in clinical specimens, 30 samples from tuberculosis patients were used. For these samples, the results of the CRDH were 100% consistent with the results of the AST and sequencing. These results indicate that the rate of concordance of the CRDH is high when compared to conventional methods and sequencing data. The CRDH can be successfully applied when a rapid test is required for the identification of RIF resistance in M. tuberculosis.

Spoligotyping of clinical Mycobacterium tuberculosis isolates from the state of Minas Gerais, Brazil

We performed spoligotyping on 114 strains of the Mycobacterium tuberculosis (Mtb) complex that had been isolated from patients in Minas Gerais Health Units during 2004. A total of 82/114 (72%) clinical isolates were clustered and 32/114 (28%) were unique. Seven shared types containing nine strains were newly created. A total of nine patterns corresponded to unreported orphan strains, as evaluated against all of the strains recorded in the SITVIT2 proprietary database in the Institut Pasteur de la Guadeloupe. The major clades were composed of isolates that belong to the following genotypes: Latin-America and Mediterranean (63/114, 55.3%) (the ill-defined T superfamily) (12/114, 10.5%), Haarlem (8/114, 7%), X clade (6/114, 5.3%), S clade (3/114, 2.6%) and the East-African Indian and Manu types, each with 1/114 (0.9%) isolates. A considerable number of strains (n = 20, 17.5%) showed patterns that did not fall within any of the previously described major clades. We conclude the bulk of tuberculosis (TB) (92/114, 80.7%) in our location is recent evolutionary strains that belong to the principal genetic groups 2/3. Further studies on epidemiology of TB are required to understand Mtb biodiversity and TB transmission in this region.

A rapid detection of multidrug-resistant Mycobacterium tuberculosis by a nitrate reductase assay on blood agar

The susceptibility of 49 Mycobacterium tuberculosis clinical isolates to isoniazid (INH) and rifampisin (RIF) (28 multi-drug resistant-tuberculosis samples) was determined by a nitrate reductase assay (NRA) on blood agar. Agreement between the NRA and other testing methods was found to be 93.8% for both INH and RIF. The sensitivity, specificity, positive predictive value and negative predictive value for INH were 92.8%, 94.2%, 86.6% and 97%, respectively. The sensitivity, specificity, positive predictive value and negative predictive value for RIF were 90.4%, 96.4%, 95% and 93.1%. In conclusion, we show here that blood agar can be used effectively for the NRA test.

Comparison of spoligotyping, mycobacterial interspersed repetitive units typing and IS6110-RFLP in a study of genotypic diversity of Mycobacterium tuberculosis in Delhi, North India

The aim of the present study was to compare polymerase chain reaction (PCR)-based methods - spoligotyping and mycobacterial interspersed repetitive units (MIRU) typing - with the gold-standard IS6110 restriction fragment length polymorphism (RFLP) analysis in 101 isolates of Mycobacterium tuberculosis to determine the genetic diversity of M. tuberculosis clinical isolates from Delhi, North India. Spoligotyping resulted in 49 patterns (14 clusters); the largest cluster was composed of Spoligotype International Types (SITs)26 [Central-Asian (CAS)1-Delhi lineage], followed by SIT11 [East-African-Indian (EAI) 3-Indian lineage]. A large number of isolates (75%) belonged to genotypic lineages, such as CAS, EAI and Manu, with a high specificity for the Indian subcontinent, emphasising the complex diversity of the phylogenetically coherent M. tuberculosis in North India. MIRU typing, using 11 discriminatory loci, was able to distinguish between all but two strains based on individual patterns. IS6110-RFLP analysis (n = 80 strains) resulted in 67 unique isolates and four clusters containing 13 strains. MIRUs discriminated all 13 strains, whereas spoligotyping discriminated 11 strains. Our results validate the use of PCR-based molecular typing of M. tuberculosis using repetitive elements in Indian isolates and demonstrate the usefulness of MIRUs for discriminating low-IS6110-copy isolates, which accounted for more than one-fifth of the strains in the present study.

Clinical data and molecular analysis of Mycobacterium tuberculosis isolates from drug-resistant tuberculosis patients in Goiás, Brazil

Drug resistance is one of the major concerns regarding tuberculosis (TB) infection worldwide because it hampers control of the disease. Understanding the underlying mechanisms responsible for drug resistance development is of the highest importance. To investigate clinical data from drug-resistant TB patients at the Tropical Diseases Hospital, Goiás (GO), Brazil and to evaluate the molecular basis of rifampin (R) and isoniazid (H) resistance in Mycobacterium tuberculosis. Drug susceptibility testing was performed on 124 isolates from 100 patients and 24 isolates displayed resistance to R and/or H. Molecular analysis of drug resistance was performed by partial sequencing of the rpoB and katGgenes and analysis of the inhA promoter region. Similarity analysis of isolates was performed by 15 loci mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing. The molecular basis of drug resistance among the 24 isolates from 16 patients was confirmed in 18 isolates. Different susceptibility profiles among the isolates from the same individual were observed in five patients; using MIRU-VNTR, we have shown that those isolates were not genetically identical, with differences in one to three loci within the 15 analysed loci. Drug-resistant TB in GO is caused by M. tuberculosis strains with mutations in previously described sites of known genes and some patients harbour a mixed phenotype infection as a consequence of a single infective event; however, further and broader investigations are needed to support our findings.