Initiation Of Anti-tuberculosis Treatment Research Articles

Effect of anti-tuberculosis treatment on thyroid profile in newly detected smear positive pulmonary tuberculosis cases

Background: Tuberculosis being a systemic disease and has a capacity for wide spread dissemination. Present study aims to identify the effects of antituberculous treatment on thyroid profile in new smear positive pulmonary tuberculosis cases.Methods: This study was conducted among 60 new smear positive pulmonary tuberculosis cases attending pulmonary medicine OPD from May 2015 to April 2017. Thyroid function test in the form of free T3, free T4 and TSH was measured before initiating Anti tuberculosis treatment (ATT), at 3 months and at the end of 6 months.Results: Out of 60 patients enrolled in present study, majority were males. Diabetes mellitus was the major co morbidity. Sick euthyroid was found to have decreasing trend during the course of treatment, and hypothyroidism was found to be increasing trend end of 6 months.Conclusions: The common Thyroid Dysfunction seen during the study period was Hypothyroidism and Sick euthyroid. Anti-tuberculous medication preferably Rifampicin probably would explain the cause for these thyroid dysfunctions noticed during the study time. And those patients with significant hypothyroid need to started on thyroid supplements. Among the drugs used for treatment, rifampicin was probably the cause for thyroid dysfunction noticed during the course of treatment. Hence, authors recommend that these patients should be started on thyroid supplements after the diagnosis of significant hypothyroidism.

Diagnostic pathways and direct medical costs incurred by new adult pulmonary tuberculosis patients prior to anti-tuberculosis treatment - Tamil Nadu, India.

BackgroundTuberculosis (TB) patients face substantial delays prior to treatment initiation, and out of pocket (OOP) expenditures often surpass the economic productivity of the household. We evaluated the pre-diagnostic cost and health seeking behaviour of new adult pulmonary TB patients registered at Primary Health Centres (PHCs) in Vellore district, Tamil Nadu, India.MethodsThis descriptive study, part of a randomised controlled trial conducted in three rural Tuberculosis Units from Dec 2012 to Dec 2015, collected data on number of health facilities, dates of visits prior to the initiation of anti-tuberculosis treatment, and direct OOP medical costs associated with TB diagnosis. Logistic regression analysis examined the factors associated with delays in treatment initiation and OOP expenditures.ResultsOf 880 TB patients interviewed, 34.7% presented to public health facilities and 65% patients sought private health facilities as their first point of care. The average monthly individual income was $77.79 (SD 57.14). About 69% incurred some pre-treatment costs at an average of $39.74. Overall, patients experienced a median of 6 days (3–11 IQR) of time to treatment initiation and 21 days (10–30 IQR) of health systems delay. Age ≤ 40 years (aOR: 1.73; CI: 1.22–2.44), diabetes (aOR: 1.63; CI: 1.08–2.44) and first visit to a private health facility (aOR: 17.2; CI: 11.1–26.4) were associated with higher direct OOP medical costs, while age ≤ 40 years (aOR: 0.64; CI: 0.48–0.85) and first visit to private health facility (aOR: 1.79, CI: 1.34–2.39) were associated with health systems delay.ConclusionThe majority of rural TB patients registering at PHCs visited private health facilities first and incurred substantial direct OOP medical costs and delays prior to diagnosis and anti-tuberculosis treatment initiation. This study highlights the need for PHCs to be made as the preferred choice for first point of contact, to combat TB more efficiently.

Sputum bacteriology conversion and treatment outcome of patients with multidrug-resistant tuberculosis.

PurposeMultidrug-resistant tuberculosis (MDR-TB) requires long-term treatment, has a high fatality rate, and constitutes a global threat. Earlier detection of treatment failure is required to predict therapeutic efficacy.Patients and methodsWe enrolled MDR-TB patients consecutively from January 2011 through December 2012 in Lianyungang, China. Sputum smear microscopy tests and sputum cultures were performed once a month for the first 6 months following initiation of antituberculosis treatment and once every 2 months thereafter until the end of therapy. The sensitivity, specificity and area under the receiver operating characteristic curve (AUC) were used with a 95% CI to estimate the role of sputum bacteriology conversion in predicting treatment outcomes.ResultsAmong the 92 MDR-TB patients enrolled in this study, 40.2% had poor treatment outcomes. The median initial sputum bacteriology conversion time was 1 month. Patients having 2-month sputum smear conversions (adjusted odds ratio [OR]: 7.19, 95% CI: 2.60–19.84) or culture conversions (adjusted OR: 2.88, 95% CI: 1.11–7.45) were more likely to experience good outcomes. The sensitivity and specificity obtained when using two-month sputum smear conversions to predict treatment outcomes were 67.6% (95% CI: 50.2–82.0) and 76.4% (95% CI: 63.0–86.8), respectively. The sensitivity and specificity obtained when using 2-month culture conversions to predict treatment outcomes were 48.6% (95% CI: 32.0–65.6) and 74.5% (95% CI: 61.0–85.3), respectively. The AUC for two-month smear conversions was 0.72 (95% CI: 0.62–0.81), significantly higher than that obtained for 2-month culture conversions (0.62, 95% CI: 0.52–0.72) (χ2 = 4.18, P = 0.041).ConclusionThe prognoses of MDR-TB patients displaying persistent sputum positivity were inferior to those for whom sputum bacteriology conversion was observed. Thus, sputum smear conversion results obtained 2 months after treatment initiation may provide a potential means for predicting MDR-TB treatment outcomes.

Substantially Higher and Earlier Occurrence of Anti-Tuberculosis Drug-Related Adverse Reactions in HIV Coinfected Tuberculosis Patients: A Matched-Cohort Study

Little information exists on the frequency, severity, and timing of first-line anti-tuberculosis drug-related adverse events (TB-AEs) in HIV-tuberculosis coinfected (HIV-TB) patients in the antiretroviral therapy (ART) era. This matched-cohort study included HIV-TB patients as cases and HIV-uninfected tuberculosis (non-HIV-TB) patients as controls. Tuberculosis was culture-confirmed in both groups. Cases were matched to controls in a 1:4 ratio on age, sex, and year of diagnosis. TB-AEs were defined as Grade 2 or higher requiring drug discontinuation/regimen change. From 2003 to 2015, 94 cases and 376 controls were analyzed (95% men, 98% Asians). Standard four-drug combination therapy was initiated in 91% of cases and 89% of controls (p = 0.45). Cases had a higher frequency of TB-AE [51% (48/94) vs. 10% (39/376), p < 0.001]. Their major TB-AEs were fever (19%), rash (11%), and neutropenia (11%). TB-AEs were more severe in cases [Grade 3 or higher: cases (71%, 34/48) vs. controls (49%, 19/39), p < 0.001]. The time from treatment initiation to TB-AE was shorter in cases [median 18 (interquartile range 12-28) vs. 27 (15-57) days, p = 0.027], and 73% of TB-AEs in cases occurred within 4 weeks of starting anti-tuberculosis treatment. HIV infection was an independent risk factor for TB-AEs in the multivariate Cox analysis [adjusted HR (aHR): 6.96; 95% confidence interval: 3.93-12.3]. TB-AEs occurred more frequently in HIV-TB than in non-HIV-TB patients, and were more severe. The majority of TB-AEs occurred within 4 weeks of initiating anti-tuberculosis treatment. Because TB-AEs may delay ART initiation, careful monitoring during this period is warranted in coinfected patients.

Time to treatment for rifampicin-resistant tuberculosis: systematic review and meta-analysis.

BACKGROUND:To reduce transmission and improve patient outcomes, rapid diagnosis and treatment of rifampicin-resistant tuberculosis (RR-TB) is required.OBJECTIVE:To conduct a systematic review and meta-analysis assessing time to treatment for RR-TB and variability using diagnostic testing methods and treatment delivery approach.DESIGN:Studies from 2000 to 2015 reporting time to second-line treatment initiation were selected from PubMed and published conference abstracts.RESULTS:From 53 studies, 83 cohorts (13 034 patients) were included. Overall weighted mean time to treatment from specimen collection was 81 days (95%CI 70–91), and was shorter with ambulatory (57 days, 95%CI 40–74) than hospital-based treatment (86 days, 95%CI 71–102). Time to treatment was shorter with genotypic susceptibility testing (38 days, 95%CI 27–49) than phenotypic testing (108 days, 95%CI 98–117). The mean percentage of diagnosed patients initiating treatment was 76% (95%CI 70–83, range 25–100).CONCLUSION:Time to second-line anti-tuberculosis treatment initiation is extremely variable across studies, and often unnecessarily long. Reduced delays are associated with genotypic testing and ambulatory treatment settings. Routine monitoring of the proportion of diagnosed patients initiating treatment and time to treatment are necessary to identify areas for intervention.

Tuberculous Meningitis in Children and Adults: New Insights for an Ancient Foe.

Tuberculous meningitis is the most devastating manifestation of infection with Mycobacterium tuberculosis and represents a medical emergency. Approximately one half of tuberculous meningitis patients die or suffer severe neurologic disability. The goal of this review will be to review the pathogenic, clinical, and radiologic features of tuberculous meningitis and to highlight recent advancements in translational and clinical science. Pharmacologic therapy includes combination anti-tuberculosis drug regimens and adjunctive corticosteroids. It is becoming clear that a successful treatment outcome depends on an immune response that is neither too weak nor overly robust, and genetic determinants of this immune response may identify which patients will benefit from adjunctive corticosteroids. Recent clinical trials of intensified anti-tuberculosis treatment regimens conducted in Indonesia and Vietnam, motivated by the pharmacologic challenges of treating M. tuberculosis infections of the central nervous system, have yielded conflicting results regarding the survival benefit of intensified treatment regimens. More consistent findings have been observed regarding the relationship between initial anti-tuberculosis drug resistance and mortality among tuberculous meningitis patients. Prompt initiation of anti-tuberculosis treatment for all suspected cases remains a key aspect of management. Priorities for research include the improvement of diagnostic testing strategies and the optimization of host-directed and anti-tuberculosis therapies.

Low Frequency of Acquired Isoniazid and Rifampicin Resistance in Rifampicin-Susceptible Pulmonary Tuberculosis in a Setting of High HIV-1 Infection and Tuberculosis Coprevalence.

We estimated the incidence of acquired isoniazid and rifampicin resistance in rifampicin-susceptible tuberculosis in a setting of high human immunodeficiency virus type 1 (HIV-1) infection and tuberculosis coprevalence. GeneXpert MTB/RIF-confirmed patients with rifampicin-susceptible tuberculosis were recruited at antituberculosis treatment initiation in Khayelitsha, South Africa. Liquid culture and adherence assessment were performed at 2 and 5-6 months. MTBDRplus was performed on mycobacteria-positive cultures to ascertain acquired drug resistance (ADR). Spoligotyping and whole-genome sequencing were performed to ascertain homogeneity between baseline isolates and isolates with ADR. Baseline isolates were retrospectively tested for isoniazid monoresistance. An electronic database review was performed to ascertain tuberculosis recurrences. A total of 306 participants (62% with HIV-1 coinfection, of whom 71% received antiretroviral therapy) were recruited. Ascertainment of outcomes was complete for 284 participants. Five acquired a resistant Mycobacterium tuberculosis strain during or subsequent to treatment. One strain was confirmed to have ADR, 2 were confirmed as causing exogenous reinfection, and 2 were unrecoverable for genotyping. Incident ADR was estimated to have ranged from 0.3% (95% confidence interval [CI], .1%-1.9%; 1 of 284 participants) to 1% (95% CI, .2%-3%; 3 of 284 participants). Seventeen of 279 baseline isolates (6.1%; 95% CI, 3.6%-9.6%) had isoniazid monoresistance (13 of 17 had an inhA promoter mutation), but 0 of 17 had amplified resistance. Treatment with standardized antituberculosis regimens dosed daily throughout, high uptake of antiretroviral therapy, and low prevalence of isoniazid monoresistance were associated with a low frequency of ADR.

A retrospective study on primary anti-tuberculosis drug resistance in patients with acquired immunodeficiency syndrome and tuberculosis

Objective To investigate primary anti-tuberculosis drug resistance in patients with acquired immunodeficiency syndrome (AIDS) and tuberculosis in Chongqing area. Methods Clinical data of 119 patients with AIDS and tuberculosis were retrospectively collected. Anti-tuberculosis drug resistance rates were analyzed according to drug susceptibility testing, and their correlations with CD4+ T lymphocytes counts, initially treatment or retreatment and clinical forms of tuberculosis were also analyzed. Comparison between groups was analyzed by χ2 test. Results Thirty-eight patients (31.9%) showed anti-tuberculosis drug resistance among the 119 patients with completed results of drug susceptibility testing results. The percentages of mono-resistance, poly-resistance, multi-drug resistance (MDR) and extensive drug resistance (XDR) were 11.7%, 7.6%, 6.7% and 5.9%, respectively. The resistance rate of isoniazid (22.7%, 28/119) was the highest among first-line anti-tuberculosis drugs and that of pasiniazide (11.0%, 14/119) was the highest among second-line drugs. Drug resistance rates among patients with different levels of CD4+ T lymphocytes counts did not differ significantly (the cut-off of CD4+ T lymphocytes count was 50/μL: χ2=0.545, P=0.461; cut-off value was 100/μL: χ2=0.652, P=0.420). Patents with milliary pulmonary tuberculosis had a significantly higher drug resistance rate (64.0%) than those with secondary pulmonary tuberculosis (27.6%). Conclusions The prevalence of anti-tuberculosis drug resistance prior to anti-tuberculosis treatment initiation is high among AIDS patients with tuberculosis in Chongqing area. Patients with milliary pulmonary tuberculosis tend to have higher anti-tuberculosis drug resistance, but drug resistance does not appear to correlate with CD4+ T lymphocytes counts. Key words: Acquired immunodeficiency syndrome; Tuberculosis; Coinfection; Anti-tuberculosis drug resistance

Altered Sensorium and ST Segment Elevation: Atypical Manifestations of Hypercalcemia in a Renal Transplant Patient With Mycobacterium Avium Intracellulare (MAI)

SESSION TITLE: Student/Resident Case Report Poster - Critical Care I SESSION TYPE: Student/Resident Case Report Poster PRESENTED ON: Tuesday, October 25, 2016 at 01:30 PM - 02:30 PM INTRODUCTION: Hypercalcemia secondary to granulomatous diseases is a known cause of hypercalcemia. This case describes hypercalcemia secondary to MAI in a renal transplant patient treated emergently with hemodialysis with resolution of symptoms and calcium. ST segment elevation in inferior leads was also noted on electrocardiogram(EKG). CASE PRESENTATION: A 75 year old woman presented to the ED with altered sensorium and slurred speech, which developed after a hemodialysis treatment. On examination, she was disoriented and noted to have matted cervical lymphadenopathy. Lab results showed a corrected calcium of 13.74 mg/dl. Cardiac enzymes were negative and 12 lead EKG(Fig-1) revealed ST segment elevation in leads II, III and aVF. The patient underwent emergent dialysis, calcitonin was administered with correction of hypercalcemia. PTH was 38.5pg/ml, TSH was 2.27 U/ml, Vitamin D2 was <8ng/ml, vitamin D3 was 91 ng/ml and Alkaline Phosphatase 159 IU/L. CT Neck w/ IV contrast (Fig-2) demonstrated large cystic/necrotic enhancing lymph nodes. Cultures from a draining lymph node grew multiple acid fast bacilli, which on further microbiological analysis (Fig-3) revealed MAI. The patient was treated with Azithromycin and Rifabutin. Pamidronate was continued once weekly. The patient’s EKG also normalized. DISCUSSION: Hypercalcemia is a metabolic emergency noted in approximately 0.5% hospitalized patients1. The principal mechanism of hypercalcemia in granulomatous disease has been attributed to uninhibited production of 1,25 (OH)2 Vitamin D from extra-renal sources. Alveolar macrophages independently produce 1 a hydroxylase, leading to increased 1,25 (OH)2 Vitamin D and low vitamin D1. Glucocorticoids, chloroquine, ketoconazole and bisphosphonates have been used to treat hypercalcemia secondary to MAI, however some patients required hemodialysis. ST segment elevation is a rare finding of hypercalcemia found on electrocardiography. Disseminated MAI infection leading to hypercalcemia is rare. CONCLUSIONS: To our knowledge hypercalcemia is a rare complication resulting from disseminated MAI infection. Our patient also had atypical findings of ST segment elevation on EKG warranting the need for close cardiac monitoring in such patients. Reference #1: Roussos, A, Lagogianni, Gonis, A, Ilias I, Kazi, D, Patsopoulos, Philippou, N. Hypercalcemia in Greek patients with tuberculosis before the initiation of anti-tuberculosis treatment. Respiratory Medicine, 2001;95,187-190. Reference #2: Sharma, OP. Hypercalcemia in granulomatous disorders: a clinical review. Current Opinion in Pulmonary Medicine 2000, 6:442-447. Reference #3: L. Littmann, L. Taylor, and W. D. Brearley, ST-segment elevation: a common finding in severe hypercalcemia. Journal of Electrocardiology, vol. 40, no. 1, pp. 60-62, 2007. DISCLOSURE: The following authors have nothing to disclose: Shyam Shankar, Karan Wats, Hitesh Raheja, Ishan Malhotra, Nupur Uppal, Mangalore Amith Shenoy, Stephan Kamholz No Product/Research Disclosure Information

Burden of disease and risk factors for death among children treated for tuberculosis in Malawi.

Tuberculosis (TB) is a leading cause of childhood death. Patient-level data on pediatric TB in Malawi that can be used to guide programmatic interventions are limited. To describe pediatric TB case burden, disease patterns, treatment outcomes, and risk factors for death and poor outcome. We conducted a retrospective cohort study utilizing routine data. Odds ratios (ORs) for factors associated with poor outcome and death were calculated using generalized estimating equations. Children represented 8% (371/4642) of TB diagnoses. The median age was 7 years (interquartile range 2.8-11); 32.8% (113/345) were human immunodeficiency virus (HIV) infected. Of these, 54.0% were on antiretroviral therapy (ART) at the time of anti-tuberculosis treatment (ATT) initiation, 21.2% started ART during ATT, and 24.8% had no documented ART. The treatment success rate was 77.3% (11.2% cured, 66.1% completed treatment), with 22.7% experiencing poor outcomes (9.5% died, 13.2% were lost to follow-up). Being on ART at the time of ATT initiation was associated with increased odds of death compared to beginning ART during treatment (adjusted OR 2.75, 95%CI 1.27-5.96). Children represent a small proportion of diagnosed TB cases and experience poor outcomes. Higher odds of death among children already on ART raises concerns over the management of these children. Further discussion of and research into pediatric-specific strategies is required to improve case finding and outcomes.

Hypothyroidism during second-line treatment of multidrug-resistant tuberculosis: a prospective study.

Hypothyroidism is an adverse effect of certain anti-tuberculosis drugs. This is a prospective study of the frequency and possible pathomechanisms associated with hypothyroidism due to second-line treatment of multidrug-resistant tuberculosis. Fifty human immunodeficiency virus negative patients and 20 controls were included. All participants underwent ultrasonography of the thyroid and measurement of thyroid stimulating hormone (TSH). TSH levels were checked every 3 months. If hypothyroidism was present, T3, T4 and thyroid peroxidase autoantibodies were measured, and imaging extended to scintigraphy and repeated ultrasonography. Before treatment, 7 patients (14%) and 1 control (5%) were hypothyreotic. During the first 6 months of treatment, TSH levels increased in 41 patients (82%), 39 (78%) had values above the normal range and 19 (38%) had overt hypothyroidism. As none of the patients had signs of autoimmune thyroiditis, interaction with anti-tuberculosis drugs was assumed to be the cause of hypothyroidism. Nine patients died during treatment, all of whom had developed hypothyroidism. In seven, the metabolic situation at their death was known, and they had become euthyreotic following levothyroxine substitution. TSH levels should be checked before initiating anti-tuberculosis treatment and after 3 and 6 months to start timely replacement of levothyroxine. Further studies are needed to elucidate the exact pathomechanism involved in hypothyroidism and whether hypothyroidism can be used as predictor of treatment failure.

Isoniazid hair concentrations in children with tuberculosis: a proof of concept study.

Assessing treatment adherence and quantifying exposure to anti-tuberculosis drugs among children is challenging. We undertook a 'proof of concept' study to assess the drug concentrations of isoniazid (INH) in hair as a therapeutic drug monitoring tool. Children aged <12 years initiated on a thrice-weekly treatment regimen including INH (10 mg/kg) for newly diagnosed tuberculosis were enrolled. INH concentrations in hair were measured using liquid chromatography-tandem mass spectrometry at 1, 2, 4 and 6 months after initiating anti-tuberculosis treatment. We found that INH hair concentrations in all children on thrice-weekly INH were detectable and displayed variability across a dynamic range.

Diagnosis of Abdominal Tuberculosis Needs Attention.

Dear Editor, We read with keen interest the article titled BStudy of surgical emergencies of tubercular abdomen in developing countries^ by Wani et al. published in the May–June 2015 issue of the Indian Journal of Surgery. The authors have presented 50 patients of tubercular abdomen. The inclusion criteria for patient selection and the diagnostic criteria used to label the patient as a case of abdominal tuberculosis (AT) has not been specified. The authors mentioned rates of positivity of PCR and IgM ELISA for blood and ascitic fluid and its sensitivity. The details of test-kit used for IgM ELISA have not been mentioned. Absolute number of tests on ascitic fluid is not mentioned; ascites was present in a small proportion of patients (n=8). It is not mentioned what gold standard was used for calculating sensitivity for these tests. The authors have not taken into consideration the specificity of these tests for diagnosis of AT. Histopathology test was reported to confirm the diagnosis in 97.8 % patients; however, the histopathological criteria for diagnosing AT have not been mentioned. The proportion of patients who required surgery on failure of initial conservative antituberculosis treatment (ATT) has not been mentioned. Clarification on these points will enhance the value of the observations. A number of tests are being used for confirming the clinical diagnosis of AT. AT being an infective disease, the demonstration of Mycobacterium tuberculosis (MT) from the abdominal lesions would be an ideal criterion for diagnosis; however, the yield ofMTon tissue sections is poor [1]. The demonstration of AFB on Ziehl-Nielsen staining or demonstration of caseating granulomas in abdominal specimen is the next acceptable level of evidence for diagnosis for AT. Diagnosis on the basis of nonspecific granulomas would be a matter of conjecture as several other diseases—notably Crohn’s disease, Ulcerative colitis, Salmonella, Yersinea, Histoplasma capsulatum, and Mycobacteriun capsulatum infection—can produce granulomas in the intestine, lymph nodes, and/or peritoneum. It is difficult to establish evidence-based diagnosis of AT due to difficulty in obtaining specimen for testing and low positivity of accepted criteria. The CT scan is a valuable adjunct in diagnosing ATas it can document typical lesions in intestine, lymph nodes, and omentum, and collections of exudates in abdomen. CT facilitates image guided FNAC and aspiration to collect specimen for cytological / microbiological tests . Demonstration of MT, AFB, caseating granulomas in specimens from other organ/systems like sputum, urine, and FNAC from extra-abdominal lymph nodes, and biopsy from endometrium may corroborate the CT and increase the level of confidence of the diagnosis of AT. Laparoscopy has an important role in demonstrating the typical abdominal lesions and facilitating collection of exudates/tissue specimen for testing. Commercial serological tests provide inconsistent and imprecise findings resulting in highly variable values for sensitivity and specificity. WHO has strongly recommended that these tests not be used for the diagnosis of pulmonary and extrapulmonary TB [2]. Reported high positivity of PCR from blood (72%) is an interesting finding, and its value in diagnosis of AT needs further evaluation. Empirical treatment with ATT should be prescribed only after due diligence, based on available * Bhupendra Kumar Jain bhupendrakjain@gmail.com

Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial

HIV-associated tuberculosis is difficult to diagnose and results in high mortality. Frequent extra-pulmonary presentation, inability to obtain sputum, and paucibacillary samples limits the usefulness of nucleic-acid amplification tests and smear microscopy. We therefore assessed a urine-based, lateral flow, point-of-care, lipoarabinomannan assay (LAM) and the effect of a LAM-guided anti-tuberculosis treatment initiation strategy on mortality. We did a pragmatic, randomised, parallel-group, multicentre trial in ten hospitals in Africa--four in South Africa, two in Tanzania, two in Zambia, and two in Zimbabwe. Eligible patients were HIV-positive adults aged at least 18 years with at least one of the following symptoms of tuberculosis (fever, cough, night sweats, or self-reported weightloss) and illness severity necessitating admission to hospital. Exclusion criteria included receipt of any anti-tuberculosis medicine in the 60 days before enrolment. We randomly assigned patients (1:1) to either LAM plus routine diagnostic tests for tuberculosis (smear microscopy, Xpert-MTB/RIF, and culture; LAM group) or routine diagnostic tests alone (no LAM group) using computer-generated allocation lists in blocks of ten. All patients were asked to provide a urine sample of at least 30 mL at enrolment, and trained research nurses did the LAM test in patients allocated to this group using the Alere Determine tuberculosis LAM Ag lateral flow strip test (Alere, USA) at the bedside on enrolment. On the basis of a positive test result, the nurses made a recommendation for initiating anti-tuberculosis treatment. The attending physician made an independent decision about whether to start treatment or not. Neither patients nor health-care workers were masked to group allocation and test results. The primary endpoint was 8-week all-cause mortality assessed in the modified intention-to-treat population (those who received their allocated intervention). This trial is registered with ClinicalTrials.gov, number NCT01770730. Between Jan 1, 2013, and Oct 2, 2014, we screened 8728 patients and randomly assigned 2659 to treatment (1336 to LAM, 1323 to no LAM). 108 patients did not receive their allocated treatment, mainly because they did not meet the inclusion criteria, and 23 were excluded from analysis, leaving 2528 in the final modified intention-to-treat analysis (1257 in the LAM group, 1271 in the no LAM group). Overall all-cause 8-week mortality occurred in 578 (23%) patients, 261 (21%) in LAM and 317 (25%) in no LAM, an absolute reduction of 4% (95% CI 1-7). The risk ratio adjusted for country was 0·83 (95% CI 0·73-0·96), p=0·012, with a relative risk reduction of 17% (95% CI 4-28). With the time-to-event analysis, there were 159 deaths per 100 person-years in LAM and 196 per 100 person-years in no LAM (hazard ratio adjusted for country 0·82 [95% CI 0·70-0·96], p=0·015). No adverse events were associated with LAM testing. Bedside LAM-guided initiation of anti-tuberculosis treatment in HIV-positive hospital inpatients with suspected tuberculosis was associated with reduced 8-week mortality. The implementation of LAM testing is likely to offer the greatest benefit in hospitals where diagnostic resources are most scarce and where patients present with severe illness, advanced immunosuppression, and an inability to self-expectorate sputum. European Developing Clinical Trials Partnership, the South African Medical Research Council, and the South African National Research Foundation.

Tuberculosis-related mortality in people living with HIV in Europe and Latin America: an international cohort study

Management of tuberculosis in patients with HIV in eastern Europe is complicated by the high prevalence of multidrug-resistant tuberculosis, low rates of drug susceptibility testing, and poor access to antiretroviral therapy (ART). We report 1 year mortality estimates from a multiregional (eastern Europe, western Europe, and Latin America) prospective cohort study: the TB:HIV study. Consecutive HIV-positive patients aged 16 years or older with a diagnosis of tuberculosis between Jan 1, 2011, and Dec 31, 2013, were enrolled from 62 HIV and tuberculosis clinics in 19 countries in eastern Europe, western Europe, and Latin America. The primary endpoint was death within 12 months after starting tuberculosis treatment; all deaths were classified according to whether or not they were tuberculosis related. Follow-up was either until death, the final visit, or 12 months after baseline, whichever occurred first. Risk factors for all-cause and tuberculosis-related deaths were assessed using Kaplan-Meier estimates and Cox models. Of 1406 patients (834 in eastern Europe, 317 in western Europe, and 255 in Latin America), 264 (19%) died within 12 months. 188 (71%) of these deaths were tuberculosis related. The probability of all-cause death was 29% (95% CI 26-32) in eastern Europe, 4% (3-7) in western Europe, and 11% (8-16) in Latin America (p<0·0001) and the corresponding probabilities of tuberculosis-related death were 23% (20-26), 1% (0-3), and 4% (2-8), respectively (p<0·0001). Patients receiving care outside eastern Europe had a 77% decreased risk of death: adjusted hazard ratio (aHR) 0·23 (95% CI 0·16-0·31). In eastern Europe, compared with patients who started a regimen with at least three active antituberculosis drugs, those who started fewer than three active antituberculosis drugs were at a higher risk of tuberculosis-related death (aHR 3·17; 95% CI 1·83-5·49) as were those who did not have baseline drug-susceptibility tests (2·24; 1·31-3·83). Other prognostic factors for increased tuberculosis-related mortality were disseminated tuberculosis and a low CD4 cell count. 18% of patients were receiving ART at tuberculosis diagnosis in eastern Europe compared with 44% in western Europe and 39% in Latin America (p<0·0001); 12 months later the proportions were 67% in eastern Europe, 92% in western Europe, and 85% in Latin America (p<0·0001). Patients with HIV and tuberculosis in eastern Europe have a risk of death nearly four-times higher than that in patients from western Europe and Latin America. This increased mortality rate is associated with modifiable risk factors such as lack of drug susceptibility testing and suboptimal initial antituberculosis treatment in settings with a high prevalence of drug resistance. Urgent action is needed to improve tuberculosis care for patients living with HIV in eastern Europe. EU Seventh Framework Programme.

The impact of immune disturbances on the failure of antituberculosis treatment.

Background and aimTuberculosis is an infectious disease caused by Mycobacterium tuberculosis complex, with an evolution and treatment outcome determined by the interaction between the mycobacterial and human genotypes. Various deficiencies of innate immune response starting from the first encounter of M. tuberculosis with lung cells endanger host infection control due to decreased triggering of cellular immune resistance and disturbed humoral immunity. Disturbed cell mediated immunity, known as the basic immune response in tuberculous infection, contributes to the deficient generation of central necrosis granuloma, consequently being responsible for severe clinical aspects and low final outcome. The tuberculosis patient’s immune assessment is important before treatment initiation, for establishing the risk reduction measures and increasing success rate.Material and methodsThe immune study was conducted on 54 new pulmonary tuberculosis cases with treatment failure, 34 new pulmonary tuberculosis cases that successfully ended the treatment and 50 healthy group individuals. Immune assays performed were: blastic transformation of lymphocytes induced by different antigens, quantitatitve assessment of cellular immunity through CD4+ T cell and CD8+ T cell phenotyping, humoral immunity - through immunoglobulin isotyping, innate resistance – through phagocyte activity of neutrophils, the titter of anti-tuberculosis antibodies and the serum level of circulating immune complexes. Investigations were performed at the onset the treatment and at the end of intensive phase of the standard anti-tuberculosis treatment.ResultsImmune disturbances evidenced in patients with treatment failure were: important deficiencies of cellular immunity, hyperactivity of humoral immunity and deficiencies of innate immunity. High predictive value for treatment failure showed the indices: deficiency of T lymphocytes count (OR=62.5) and T helper count (OR=12.5), high level of circulating immune complexes (OR=9.801), deficiency of innate resistance (decreased phagocytating index OR=2.875).ConclusionsFor increasing the treatment success rate, the study of immune disturbances must be performed before of antituberculosis treatment initiation, especially of cellular immunity for the early start of immune adaptive treatment.

Diagnostic value of Cobas Amplicor MTB and Rotorgene Real Time PCR for tuberculous meningitis: A six-year retrospective study

Objective: Tuberculous meningitis (TBM) is the most severe and lethal form of tuberculosis (TB).Bacteriologic confirmation of TBM is difficult and slow. Therefore, most patients receive antituberculosis treatment based only on clinical and cerebrospinal fluid (CSF) characteristics. Rapid diagnosis of TBM is important to decrease morbidity and mortality. The aim of the study was to demonstrate that COBAS Amplicor MTB and Rotorgene Real Time (RT) PCR is a rapid method of diagnosing TBM before and after initiating anti-tuberculosis treatment. Methods: A retrospective study was conducted between December 2002 and January 2009 in 468 patients with suspected TBM. Clinical specimens were collected from different hospitals in Ankara. All specimens were evaluated by smear microscopy and culture methods with Lowenstein-Jensen (LJ) and MGIT culture system. Results: Using culture results as a gold standard, the sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) were 71.0%, 98.8%, 97.8% and 75.0%, respectively, for COBAS Amplicor MTB and 80%, 98.9%, 99.0% and 80.0%, respectively, for Rotorgene RT PCR. Statistical analysis showed no significant differences between the COBAS Amplicor MTB and Rotorgene RT PCR (p≥0.05). All isolates were susceptible to isoniazid, rifampin, streptomycin, and ethambutol with proportion method in LJ medium. All isolates were defined as LAM7-TUR by spoligotyping. Conclusion: Retrospective analysis of COBAS Amplicor MTB and Rotorgene RT PCR found that both tests are effective in rapidly diagnosing MTB using CSF. It was concluded that Rotorgene RT PCR test is more sensitive (81.0%) than COBAS Amplicor MTB (71.0%). J Microbiol Infect Dis 2015;5(4): 156-161 Key words: Tuberculous meningitis, COBAS Amplicor MTB, Rotorgene Real Time PCR

Late paradoxical lymph node enlargement during and after anti-tuberculosis treatment in non-HIV-infected patients.

A tertiary referral centre in South Korea. To investigate the incidence, clinical characteristics and outcomes of late paradoxical response (>4 months after the initiation of anti-tuberculosis treatment) during and after anti-tuberculosis treatment in non-human immunodeficiency virus (HIV) infected patients with lymph node tuberculosis (TB). We retrospectively reviewed the medical records of non-HIV-infected patients with lymph node TB between 1997 and 2007, and prospectively enrolled patients with newly diagnosed lymph node TB between 2008 and 2013. Of 467 patients with confirmed and probable lymph node TB, 83 (18%) displayed a paradoxical response: 57 of these (69%) were classified as early and 26 (31%) as late paradoxical response. Patients with late paradoxical response (median 12 months) received more prolonged anti-tuberculosis treatment than those with early (median 9 months, P < 0.001) or no paradoxical response (median 9 months, P < 0.001). The frequency of post-treatment lymph node enlargement increased progressively from those without any paradoxical response (6%), through those with an early response (12%) to those with a late response (23%). Paradoxical response presents late in about one third of non-HIV-infected patients with lymph node TB who experience a response. Although anti-tuberculosis treatment is commonly prolonged in patients with late paradoxical response, post-treatment lymph node enlargement is more frequent in these patients.

Highlights of the third edition of Chinese guidelines for AIDS diagnosis and treatment(2015)

The third edition of Chinese guidelines for AIDS diagnosis and treatment was launched in 2015 by AIDS Professional Group, Society of Infectious Diseases, Chinese Medical Association. New edition emphasizes the importance of timely initiation of anti-retroviral therapy(ART). Like other guidelines, this edition recommends that once the HIV infection is confirmed, the ART should be initiated timely. For patients with HIV and opportunistic infections, once the infections are under control, the ART should be initiated without delay. For AIDS patients complicated with tuberculosis whose CD4 cell counts are less than 200/μL, the ART should start within 2 weeks after the initiation of anti-tuberculosis treatment. In this guideline, the drugs with severe toxicities and poor tolerance are excluded, and new drugs are added such as rilpivrine (RPV) and atazanavir (ATV) because of less toxicity and higher HIV depression effect; and 3TC+TDF+EFV is recommended as the first line regimen. As for children with HIV infection, especially for those less than 5 years, once the infection is confirmed the ART should be initiated immediately. For the prevention of HIV mother to children transmission, new edition recommends that HIV-infected pregnant women start ART early and keep on ART all their lives.

Early stationary phase culture supernatant accelerates growth of sputum cultures collected after initiation of anti-tuberculosis treatment

We investigated the effect of Mycobacterium tuberculosis culture supernatant added to sputum cultures collected during the first 8 weeks of anti-tuberculosis treatment. With ongoing treatment duration, time to culture positivity decreased significantly in supernatant-enriched cultures, possibly due to stimulation of dormant or slowly metabolizing M. tuberculosis cells.