Prevalence and clinical significance of respiratory viruses and bacteria detected in tuberculosis patients compared to household contact controls in Tanzania: a cohort study.

OBJECTIVES: To describe the prevalence of respiratory pathogens in tuberculosis (TB) patients and in their household contact controls, and to determine the clinical significance of respiratory pathogens in TB patients. METHODS: We studied 489 smear-positive adult TB patients and 305 household contact controls without TB with nasopharyngeal swab samples within an ongoing prospective cohort study in Dar es Salaam, Tanzania, between 2013 and 2015. We used multiplex real-time PCR to detect 16 respiratory viruses and seven bacterial pathogens from nasopharyngeal swabs. RESULTS: The median age of the study participants was 33 years; 61% (484/794) were men, and 21% (168/794) were HIV-positive. TB patients had a higher prevalence of HIV (28.6%; 140/489) than controls (9.2%; 28/305). Overall prevalence of respiratory viral pathogens was 20.4% (160/794; 95%CI 17.7-23.3%) and of bacterial pathogens 38.2% (303/794; 95%CI 34.9-41.6%). TB patients and controls did not differ in the prevalence of respiratory viruses (Odds Ratio [OR] 1.00, 95%CI 0.71-1.44), but respiratory bacteria were less frequently detected in TB patients (OR 0.70, 95%CI 0.53-0.94). TB patients with both respiratory viruses and respiratory bacteria were likely to have more severe disease (adjusted OR [aOR] 1.6, 95%CI 1.1-2.4; p 0.011). TB patients with respiratory viruses tended to have more frequent lung cavitations (aOR 1.6, 95%CI 0.93-2.7; p 0.089). CONCLUSIONS: Respiratory viruses are common for both TB patients and household controls. TB patients may present with more severe TB disease, particularly when they are co-infected with both bacteria and viruses.

Acute phase proteins and IP-10 as triage tests for the diagnosis of tuberculosis: systematic review and meta-analysis.

OBJECTIVES: We examined the data reported in studies for diagnostic purposes and to discuss whether their intended use could be extended to triage, as rule-in or rule-out tests to select individuals who should undergo further confirmatory tests. METHODS: We searched Scopus, PubMed and Web of Science with the terms 'acute phase proteins,' 'IP-10,' 'tuberculosis,' 'screening' and 'diagnosis,' extracted the sensitivity and specificity of the biomarkers and explored methodologic differences to explain performance variations. Summary estimates were calculated using random-effects models for overall pooled accuracy. The hierarchical summary receiver operating characteristic model was used for meta-analysis. RESULTS: We identified 14, four and one studies for C-reactive protein (CRP), interferon γ-induced protein 10 (IP-10) and alpha-1-acid glycoprotein (AGP). The pooled CRP sensitivity/specificity (95% confidence interval) was 89% (80-96) and 57% (36-65). Sensitivity/specificity were higher in high-tuberculosis-burden countries (90%/64%), HIV-infected individuals (91%/61%) and community-based studies (90%/62%). IP-10 sensitivity/specificity in TB vs. non-TB studies was 85%/63% and in TB and HIV coinfected vs. other lung conditions 94%/21%. However, IP-10 studies included diverse populations and a high risk of bias, resulting in very low-quality evidence. AGP had 86%/93% sensitivity/specificity. CONCLUSIONS: Few studies have evaluated CRP, IP-10 and AGP for the triage of symptomatic patients. Their high sensitivity and moderate specificity warrant further prospective studies exploring whether their combined use could optimize performance.

Tuberculosis among HIV-infected population: incidence and risk factors in rural Tanzania.

BACKGROUND: The incidence of tuberculosis among HIV-infected populations with high CD4 count in high burden countries has not been well studied. OBJECTIVE: To assess the TB incidence in HIV-infected adults and its associated risk factors. METHOD: A cohort study with retrospective review of medical records and prospective follow-up of HIV-infected adult participants attending CTC who were 18-55 years old, had CD4 count more than 250 cells/mm3 in the period of 2008-2010 and were not on ART at enrolment. Cox proportional hazard regression was used to explore the predictors of incident TB. RESULTS: Overall 777 (24%) of 3,279 CTC enrolled HIV-infected adults fulfilled the inclusion criteria of the study. The incidence of TB in the study population ranged from 0.8/100 per person years (PY) at risk (95% CI 0.5-1.3) in the main analysis to 1.7/100 PY at risk (95% CI 1.0-2.6) in sensitivity analyses. Only prior history of TB disease was found to have a significant association with an increased risk of TB, hazard ratio 5.7 (95% CI 2.0-16.4, p value 0.001). CONCLUSION: Tuberculosis incidence among HIV-infected adults with medium/high CD4 count in Bagamoyo is lower than in other high TB burden countries. Previously TB treated patients have a much higher risk of getting TB again than those who never had TB before.

Pharmacokinetics, Tolerability, and Bacteriological Response of Rifampin Administered at 600, 900, and 1,200 Milligrams Daily in Patients with Pulmonary Tuberculosis.

In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.).

Blood and urine inducible protein 10 as potential markers of disease activity.

SETTING: Blood interferon-γ inducible protein 10 (IP-10) has been proposed as a biomarker of disease activity for both tuberculosis (TB) and human immunodeficiency virus (HIV) infection. Urine IP-10 has been detected in adults with active TB, and its level decreases after successful anti-tuberculosis treatment. OBJECTIVE: To evaluate blood and urine IP-10 as biomarker of disease activity. DESIGN: Patients with HIV-TB and active TB were enrolled. Individuals with HIV infection only and healthy donors were included as controls. Blood and urine IP-10 levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Of 39 active TB patients enrolled, 24 were HIV-infected and 15 were HIV-uninfected. Of 87 control subjects without active TB, 54 were HIV-infected and 33 were HIV-uninfected. IP-10 analysis was performed in patients with concomitant blood and urine sample collection. Blood IP-10 was associated with active TB, regardless of HIV infection status; urine IP-10 levels were increased in active TB patients, although the difference was significant in HIV-infected individuals only. Finally, in HIV-infected patients, both blood and urine IP-10 levels were inversely correlated with CD4 T-cell counts. CONCLUSION: These findings suggest that IP-10 could be used as a biomarker for disease activity (inflammation).

Screening for pulmonary tuberculosis in a Tanzanian prison and computer-aided interpretation of chest X-rays.

SETTING: Tanzania is a high-burden country for tuberculosis (TB), and prisoners are a high-risk group that should be screened actively, as recommended by the World Health Organization. Screening algorithms, starting with chest X-rays (CXRs), can detect asymptomatic cases, but depend on experienced readers, who are scarce in the penitentiary setting. Recent studies with patients seeking health care for TB-related symptoms showed good diagnostic performance of the computer software CAD4TB. OBJECTIVE: To assess the potential of computer-assisted screening using CAD4TB in a predominantly asymptomatic prison population. DESIGN: Cross-sectional study. RESULTS: CAD4TB and seven health care professionals reading CXRs in local tuberculosis wards evaluated a set of 511 CXRs from the Ukonga prison in Dar es Salaam. Performance was compared using a radiological reference. Two readers performed significantly better than CAD4TB, three were comparable, and two performed significantly worse (area under the curve 0.75 in receiver operating characteristics analysis). On a superset of 1321 CXRs, CAD4TB successfully interpreted >99%, with a predictably short time to detection, while 160 (12.2%) reports were delayed by over 24 h with conventional CXR reading. CONCLUSION: CAD4TB reliably evaluates CXRs from a mostly asymptomatic prison population, with a diagnostic performance inferior to that of expert readers but comparable to local readers.

Contexte : La Tanzanie est lourdement frappée par la tuberculose (TB) et les prisonniers sont un groupe à haut risque qui devrait bénéficier d'un dépistage actif, comme le recommande l'Organisation Mondiale de la Santé. Les algorithmes de dépistage qui débutent par une radiographie pulmonaire peuvent détecter des cas asymptomatiques, mais ils requièrent des lecteurs de radiographies expérimentés, qui sont rares dans le contexte pénitentiaire. Des études récentes sur des patients sollicitant des soins pour des symptômes liés à la TB ont mis en évidence une bonne performance diagnostique du logiciel CAD4TB.Objectif : Evaluer le potentiel d'un dépistage assisté par ordinateur en utilisant CAD4TB au sein d'une population carcérale en majorité asymptomatique.Schéma : Étude transversale.Résultats : CAD4TB et sept professionnels de santé lisant des radiographies dans des services de TB locaux ont évalué un ensemble de 511 radiographies pulmonaires provenant de la prison d'Ukonga à Dar es Salaam et les performances ont été comparées grâce à une radiographie de référence. Deux lecteurs ont été significativement plus performants que CAD4TB, trois ont été comparables et deux ont été significativement moins bons (zone sous la courbe de 0,75 dans l'analyse ROC ­fonction d'efficacité du receveur). Sur un ensemble de 1321 radiographies pulmonaires, CAD4TB en a interprété avec succès plus de 99% avec un délai de détection prévisible court, tandis que 160 (12,2%) réponses ont été retardées de plus de 24 h avec la méthode de lecture conventionnelle.Conclusion : CAD4TB évalue de manière fiable les radiographies pulmonaires dans une population en majorité asymptomatique de détenus, avec une performance diagnostique inférieure à celle de lecteurs experts mais comparable à celle des lecteurs locaux.

Marco de referencia: Tanzania es un país con una alta tasa de morbilidad por tuberculosis (TB) y las personas en los establecimientos penitenciarios constituyen un grupo de alto riesgo de contraer la enfermedad; en esta población se debe practicar la detección sistemática activa como lo recomienda la Organización Mundial de la Salud. Los algoritmos de detección cuya etapa inicial es la radiografía de tórax pueden detectar los casos asintomáticos, pero su eficacia depende de la experiencia del profesional que interpreta las imágenes y esta competencia es escasa en los entornos penitenciarios. Algunos estudios recientes de pacientes que buscan atención sanitaria por síntomas asociados con la TB han revelado un buen rendimiento diagnóstico con la utilización del programa informático CAD4TB. Objetivo: Evaluar la utilidad de la detección sistemática de la TB asistida por el programa CAD4TB, en una población penitenciaria en su mayoría asintomática.Método: Fue este un estudio de tipo transversal.Resultados: Siete profesionales de atención sanitaria de los servicios locales de TB analizaron 511 radiografías de tórax provenientes de la prisión de Ukonga, en Dar es-Salam, con la ayuda del programa CAD4TB; se preparó un conjunto de referencia radiográfica de lectura con el fin de evaluar el rendimiento diagnóstico. El desempeño de dos de los lectores fue significativamente superior al resultado del programa CAD4TB, tres lectores obtuvieron una puntuación comparable al programa y en dos lectores se observó un rendimiento significativamente inferior (área bajo la curva: 0,75 en el análisis de eficacia diagnóstica). En un conjunto especial de 1321 radiografías de tórax el programa CAD4TB interpretó eficazmente más del 99%, con un corto lapso previsible hasta la detección, en contraste con la lectura clásica de las radiografías que dio lugar a un retraso superior a 24 horas en 160 informes (12,2%).Conclusión: El programa CAD4TB realizó una evaluación fiable de las radiografías provenientes de una población penitenciaria en su mayor parte asintomática. El rendimiento diagnóstico del programa fue inferior al rendimiento de los lectores expertos, pero comparable con el rendimiento de los lectores locales.

Ascertaining in vivo virulence of Mycobacterium tuberculosis lineages in patients in Mbeya, Tanzania.

We evaluated the relationship between the degree of immunodeficiency indicated by the number of circulating CD4+ T-cells and Mycobacterium tuberculosis lineages identified by spoligotyping and mycobacterial interspersed repetitive units-variable number of tandem repeats genotyping in human immunodeficiency virus (HIV) infected individuals with pulmonary tuberculosis from Mbeya, Tanzania. Of M. tuberculosis strains from 129 patients, respectively 55 (42.6%) and 37 (28.7%) belonged to Latin American Mediterranean and Delhi/Central-Asian lineages, while 37 (28.7%) patients were infected with other strains. There was no difference in the distribution of M. tuberculosis lineages among patients with early or advanced stages of HIV infection (P = 0.785), indicating that the virulence of strains from these lineages may not be substantially different in vivo.

Performance of the Xpert® MTB/RIF assay in an active case-finding strategy: a pilot study from Tanzania.

In this pilot study, we evaluated the Xpert® MTB/RIF assay in an active case-finding strategy, using two spot sputum samples collected within a 1-hour interval from household contacts of smear-positive TB index cases. Tuberculosis (TB) confirmed by culture served as the reference standard. Among 219 enrolled contacts, the yield of active TB was 2.3%. While the sensitivity of smear microscopy was 60% (95%CI 14.7-94.7), Xpert MTB/RIF achieved a sensitivity of 100% (95%CI 47.81-100.0). All culture-confirmed cases tested positive by Xpert MTB/RIF on the first submitted sample, suggesting that the evaluation of only one sample could be sufficient for TB diagnosis in this context.

Evaluation of Diagnos TB AG, a flow-through immunoassay for rapid detection of pulmonary tuberculosis.

We evaluated the diagnostic performance of the Diagnos TB AG immunoassay in 171 Tanzanians with suspected pulmonary tuberculosis (TB). The sensitivity and specificity, and positive and negative predictive values of the rapid test for the detection of pulmonary TB in this population were respectively 60.0%, 33.3%, 40.3% and 52.6%. In its current configuration, this test will not help overcome difficulties in the rapid diagnosis of TB.

MR-guided interstitial laser-induced thermotherapy of hepatic metastasis combined with arterial blood flow reduction: technique and first clinical results in an open MR system.

The feasibility and safety of percutaneous laser-induced thermotherapy (LITT) of liver metastases in an open low-field magnetic resonance imaging (MRI) system combined with microsphere-modulated blood flow reduction were tested. Nd:YAG laser therapy with an internally cooled laser applicator was performed under local anesthesia on 20 patients with 34 liver metastases. To increase the effectiveness of LITT, degradable starch microspheres were injected into the proper hepatic artery through an MR-visible catheter initially inserted under fluoroscopy. Near real-time imaging was used for positioning the laser applicator. A T1-weighted gradient-echo breath-hold sequence was used for catheter localization and temperature monitoring. The volumes of the liver metastases and the thermonecroses were determined. MRI-guided LITT could be performed in all patients with no clinically relevant complications. Intraprocedural imaging underestimated the extent of thermonecrosis. In conclusion, percutaneous LITT of liver metastases after injection of starch microspheres is both technically feasible and safe in an open MRI system. J. Magn. Reson. Imaging 2001;13:31-36.

MR imaging-guided biliary drainage in an open low-field system: first clinical experiences.

PURPOSE: To test the feasibility of MR imaging (MRI)-guided percutaneous biliary drainages in patients using an open MR-system. METHODS: 6 patients with mechanical cholestasis underwent MRI-guided puncture and catheterization of the biliary system following intervention planning with magnetic resonance cholangiography (MRC) in an open low-field MR system. Data on the number of punctures required, success in establishing external and internal drainage, and total procedure time were compared to those of 6 patients who underwent biliary drainage with fluoroscopic guidance. RESULTS: MRC facilitated intervention planning in all patients. Near-real-time MR imaging enabled interactive positioning of the devices. The bile ducts were punctured under MRI control in three patients in the first, in two in the second, and in one in the third attempt. MRI-guided puncture was faster than the fluoroscopic procedure. Catheterization for external drainage was successful in all patients. Passing the obstructions was not possible under MRI guidance. The procedure time for MRI-guided catheterization was longer than in the conventional technique. CONCLUSION: MRI-guidance allows reliable placement of an external biliary drainage in an open low-field MR system.

[Laser-induced thermotherapy (LITT) for liver metastasis in an open 0.2T MRI]. / Laserinduzierte Thermotherapie (LITT) von Lebermetastasen in einem offenen 0,2T MRT.

OBJECTIVE: To test the feasibility and safety of the laser-induced thermotherapy (LITT) for liver metastases in open MR imaging system operating at 0.2 Tesla. METHOD: Laser therapy using the Nd:YAG laser was performed on 25 patients with a total of 41 liver metastases. An open low-field MRI scanner was used for puncture, positioning of the laser applicator, and monitoring the therapy. A true FISP sequence was used to track the puncture in close to real-time. Localization diagnostics and temperature monitoring were aided by T1-weighted gradient echo sequences in the breath-holding technique. In the first follow up after 24-48 hours, a contrast-enhanced T1-weighted gradient-echo sequence was performed in an MRI scanner at 1.5T. The pre-, intra- and postinterventional volumes of the liver metastases as well as the thermolesions and the thermonecroses were determined. RESULTS: LITT in an open MRI system was technically feasible in all patients with no clinically relevant complications. The mean volumes of the thermolesions measured during intervention in low-field MRI were lower than the volumes of the thermonecroses measured after intervention in high-field MRI. CONCLUSION: The technique presented here of laser-induced thermotherapy for liver metastases in an open MRI system is technically feasible and safe.

Magnetic resonance-guided vascular catheterization: feasibility using a passive tracking technique at 0.2 Telsa in a pig model.

The objective of this study was to demonstrate in an animal model the feasibility of a passive tracking technique for catheter visualization of magnetic resonance (MR)-guided endovascular procedures. All experiments were performed in a 0.2 Tesla open MR system. Susceptibility-based catheters and guide wires were introduced into the aorta and were advanced selectively into the splenic and renal arteries under MR guidance. Based on a previously acquired contrast-enhanced magnetic resonance angiography (MRA) data set, the catheter positioning was performed by using a single-slice true fast imaging with steady state precession (FISP) sequence with a frame rate of 1.3 seconds. Contrast-enhanced MRA was performed in all animals. All catheters were advanced without complications into the aorta and were introduced into the proximal parts of the right renal and splenic arteries under MR guidance. Catheter manipulations were more difficult in the distal parts of these vessels due to the more complex anatomy. Passive catheter tracking is a valuable and technically robust alternative to active tracking methods, because it does not require additional hardware and, thus, can be implemented and used easily with any open MR imaging system. J. Magn. Reson. Imaging 1999;10:841-844.

Localization of a ventricular tachycardia-focus with multichannel magnetocardiography and three-dimensional current density reconstruction.

The objective of this case report is to determine the accurate localization of a malignant ventricular tachycardia (VT) focus by combining multichannel magnetocardiographic (MCG) information with morphologic data. The localization was obtained by calculating the three-dimensional current density distribution (3D-CDD) on the left ventricular surface. To estimate the accuracy of this localization technique, examinations of a healthy volunteer were additionally performed. The MCG-signals were recorded in a magnetically shielded room by a 49-channel magnetogradiometer. The corresponding morphologic information was recorded by magnetic resonance tomography (MRT). The coordinate systems were matched with the help of markers. The 3D-CDD was calculated by the Philips CURRY software package. The origin of a malignant VT determined by X-ray images of the ablation catheter position during the electrophysiological examination (EPE), was used as the gold standard. This was then compared with the localization results obtained by the 3D-CDD. It was found that the localization coordinates showed a difference of less than 10 mm.

In vivo measurement of endothelium-dependent vasodilation with substance P in man.

Endothelial cells synthesize and metabolize vasoactive substances which are involved in the regulation of vascular tone. Among these factors, the endothelium-derived nitric oxide (NO) appears to be of major importance. Many studies observed an impairment of the generation, release, or the diffusion of endothelial NO across the vascular intima in laboratory animals with various experimental diseases such as hypercholesterolemia, atherosclerosis and hypertension. In human coronary arteries obtained from explanted hearts impaired endothelium-dependent relaxations were measured in atherosclerotic segments. The hypothesis of a decreased NO mediated vasodilation in patients with coronary artery disease was further underscored by in vivo studies in man using intracoronary infusions of the endothelium-dependent vasodilator acetylcholine and quantitative coronary angiographic measurements of the diameter changes. From these observations it was assumed that endothelial dysfunction, in particular a profound inability of the coronary endothelium to relax via NO dependent mechanisms may play an important role in the pathogenesis of abnormal coronary vasomotion. However, further investigations in man reveal that the ability of the coronary endothelium of patients with coronary artery disease or vasospastic angina to produce endothelial NO is less affected as judged from the effects of acetylcholine. In recent investigations a largely preserved endothelial function could be measured in these patients when the endothelium-dependent vasodilator substance P was used as a tool for the measurement of NO dependent relaxation. Thus, endothelial dysfunction does not appear to serve as a major cause of abnormal vasoconstriction in coronary artery disease or vasospastic angina in man.