Interleukin (IL)–12 and IL-23 Are Key Cytokines for Immunity against Salmonella in Humans

Patients with inherited deficiency of the interleukin (IL)–12/IL-23–interferon (IFN)–g axis show increased susceptibility to invasive disease caused by the intramacrophage pathogens salmonellae and mycobacteria. We analyzed data on 154 patients with such deficiency. Significantly more patients with IL-12/IL-23–component deficiency had a history of salmonella disease than did those with IFN-g–component deficiency. Salmonella disease was typically severe, extraintestinal, and caused by nontyphoidal serovars. These findings strongly suggest that IL-12/IL-23 is a key cytokine for immunity against salmonella in humans and that IL-12/IL-23 mediates this protective effect partly through IFN-g–independent pathways. Investigation of the IL-12/IL-23–IFN-g axis should be considered in patients with invasive salmonella disease

Evaluation of a point-of-care tuberculosis test-and-treat algorithm on early mortality in people with HIV accessing antiretroviral therapy (TB Fast Track study): study protocol for a cluster randomised controlled trial.

BACKGROUND: Early mortality for HIV-positive people starting antiretroviral therapy (ART) remains high in resource-limited settings, with tuberculosis the most important cause. Existing rapid diagnostic tests for tuberculosis lack sensitivity among HIV-positive people, and consequently, tuberculosis treatment is either delayed or started empirically (without bacteriological confirmation). We developed a management algorithm for ambulatory HIV-positive people, based on body mass index and point-of-care tests for haemoglobin and urine lipoarabinomannan (LAM), to identify those at high risk of tuberculosis and mortality. We designed a clinical trial to test whether implementation of this algorithm reduces six-month mortality among HIV-positive people with advanced immunosuppression. METHODS/DESIGN: The TB Fast Track study is an open, pragmatic, cluster randomised superiority trial, with 24 primary health clinics randomised to implement the intervention or standard of care. Adults (aged ≥18 years) with a CD4 count of 150 cells/μL or less, who have not received any tuberculosis treatment in the last three months, or ART in the last six months, are eligible. In intervention clinics, the study algorithm is used to classify individuals as at high, medium or low probability of tuberculosis. Those classified as high probability start tuberculosis treatment immediately, followed by ART after two weeks. Medium-probability patients follow the South African guidelines for test-negative tuberculosis and are reviewed within a week, to be re-categorised as low or high probability. Low-probability patients start ART as soon as possible. The primary outcome is all-cause mortality at six months. Secondary outcomes include severe morbidity, time to ART start and cost-effectiveness. DISCUSSION: This trial will test whether a primary care-friendly management algorithm will enable nurses to identify HIV-positive patients at the highest risk of tuberculosis, to facilitate prompt treatment and reduce early mortality. There remains an urgent need for better diagnostic tests for tuberculosis, especially for people with advanced HIV disease, which may render empirical treatment unnecessary. TRIAL REGISTRATION: This trial was registered with Current Controlled Trials (identifier: ISRCTN35344604 ) on 12 September 2012

Comparison of laboratory costs of rapid molecular tests and conventional diagnostics for detection of tuberculosis and drug-resistant tuberculosis in South Africa.

BACKGROUND: The World Health Organization has endorsed the use of molecular methods for the detection of TB and drug-resistant TB as a rapid alternative to culture-based systems. In South Africa, the Xpert MTB/Rif assay and the GenoType MTBDRplus have been implemented into reference laboratories for diagnosis of TB and drug-resistance, but their costs have not been fully elucidated. METHODS: We conducted a detailed reference laboratory cost analysis of new rapid molecular assays (Xpert and MTBDRplus) for tuberculosis testing and drug-resistance testing in South Africa, and compared with the costs of conventional approaches involving sputum microscopy, liquid mycobacterial culture, and phenotypic drug sensitivity testing. RESULTS: From a laboratory perspective, Xpert MTB/RIF cost $14.93/sample and the MTBDRplus line probe assay cost$23.46/sample, compared to $16.88/sample using conventional automated liquid culture-based methods. Laboratory costs of Xpert and MTBDRplus were most influenced by cost of consumables (60-80%). CONCLUSIONS: At current public sector pricing, Xpert MTB/RIF and MTBDRplus are comparable in cost to mycobacterial culture and conventional drug sensitivity testing. Overall, reference laboratories must balance costs with performance characteristics and the need for rapid results

Viral infections in interferon-γ receptor deficiency

Interferon-gamma receptor deficiency is a recently described immunodeficiency that is associated with onset of severe mycobacterial infections in childhood. We describe the occurrence of symptomatic and often severe viral infections in 4 patients with interferon-gamma receptor deficiency and mycobacterial disease. The viral pathogens included herpes viruses, parainfluenza virus type 3, and respiratory syncytial virus. We conclude that patients with interferon-gamma receptor deficiency and mycobacterial disease have increased susceptibility to some viral pathogens

Longitudinal Analysis of QuantiFERON-TB Gold In-Tube in Children with Adult Household Tuberculosis Contact in South Africa: A Prospective Cohort Study

QuantiFERON-TB Gold In Tube (QFT-GIT) is a tool for detecting M. tuberculosis infection. However, interpretation and utility of serial QFT-GIT testing of pediatric tuberculosis (TB) contacts is not well understood. We compared TB prevalence between baseline and 6 months follow-up using QFT-GIT and tuberculin skin testing (TST) in children who were household contacts of adults with pulmonary TB in South Africa, and explored factors associated with QFT-GIT conversions and reversions.Prospective study with six month longitudinal follow-up.Among 270 enrolled pediatric contacts, 196 (73%) underwent 6-month follow-up testing. The 6-month prevalence estimate of MTB infection in pediatric contacts increased significantly from a baseline of 29% (79/270, 95%CI [24-35]) to 38% (103/270, 95% CI [32-44], p<0.001) using QFT-GIT; prevalence increased from a baseline of 28% (71/254, 95%CI [23-34]) to 33% (88/263, 95%CI [21-32], p = 0.002) using TST. Prevalence estimates were influenced by thresholds for positivity for TST, but not for QFT-GIT. Among 134 children with a negative or indeterminate baseline QFT-GIT, 24 (18%) converted to positive at follow-up; conversion rates did not differ significantly when using more stringent thresholds to define QFT-GIT conversion. Older age >10 years (AOR 8.9 95%CI [1.1-72]) and baseline TST positivity ≥5 mm (AOR 5.2 95%CI [1.2-23]) were associated with QFT-GIT conversion. Among 62 children with a positive baseline QFT-GIT, 9 (15%) reverted to negative; female gender (AOR 18.5 95%CI [1.1-321]; p = 0.04] was associated with reversion, while children with baseline positive TST were less likely to have QFT-GIT reversion (AOR 0.01 95%CI [0.001-0.24]).Among pediatric contacts of adult household TB cases in South Africa, prevalence estimates of TB infection increased significantly from baseline to 6 months. Conversions and reversions occurred among pediatric TB contacts using QFT-GIT, but QFT-GIT conversion rates were less influenced by thresholds used for conversions than were TST conversion rates

The Impact of Expanded Testing for Multidrug Resistant Tuberculosis Using Geontype MTBDRplus in South Africa: An Observational Cohort Study

Globally, multidrug resistant tuberculosis (MDR-TB) remains underdiagnosed. The Genotype MTBDRplus®, a rapid drug susceptibility testing (DST) assay used to detect resistance to isoniazid and rifampicin in the diagnosis of MDR-TB, has good diagnostic accuracy, but its impact on patient outcomes in routine practice is unproven. We assessed the clinical impact of routine DST using MTBDRplus in a single health district in South Africa

Rifapentine Population Pharmacokinetics and Dosing Recommendations for Latent Tuberculosis Infection.

RATIONALE: Rifapentine has been investigated at various doses, frequencies, and dosing algorithms but clarity on the optimal dosing approach is lacking. OBJECTIVES: In this individual participant data meta-analysis of rifapentine pharmacokinetics, we characterize rifapentine population pharmacokinetics, including autoinduction, and determine optimal dosing strategies for short-course rifapentine-based regimens for latent tuberculosis infection. METHODS: Rifapentine pharmacokinetic studies were identified though a systematic review of literature. Individual plasma concentrations were pooled, and non-linear mixed effects modeling was performed. A subset of data was reserved for external validation. Simulations were performed under various dosing conditions including current weight-based methods and alternative methods driven by identified covariates. MEASUREMENTS AND MAIN RESULTS: We identified 9 clinical studies with a total of 863 participants with pharmacokinetic data (n=4301 plasma samples). Rifapentine population pharmacokinetics were described successfully with a one-compartment distribution model. Autoinduction of clearance was driven by rifapentine plasma concentration. The maximum effect was a 72% increase in clearance and was reached after 21 days. Drug bioavailability decreased by 27% with HIV infection, decreased by 28% with fasting, and increased by 49% with a high-fat meal. Body weight was not a clinically relevant predictor of clearance. Pharmacokinetic simulations showed that current weight-based dosing leads to lower exposures in low weight individuals, which can be overcome with flat dosing. In HIV-positive patients, 30% higher doses are required to match drug exposure in HIV-negative patients. CONCLUSIONS: Weight-based dosing of rifapentine should be removed from clinical guidelines and higher doses for HIV-positive patients should be considered to provide equivalent efficacy

Implications of progressive lung damage and post-tuberculosis sequelae for the health benefits of prompt tuberculosis treatment in high HIV prevalence settings: a mathematical modelling analysis

Background: Untreated pulmonary tuberculosis causes ongoing lung damage, which can persist after treatment. Conventional modelling approaches for assessing tuberculosis health effects might not fully capture these mechanisms. We evaluated how tuberculosis-associated lung damage and post-tuberculosis sequelae affect the lifetime health consequences of tuberculosis in high HIV prevalence settings. Methods: We developed a microsimulation model (computer simulations that reproduce disease natural history and intervention effects for sampled individuals) representing dynamic changes in lung function for individuals evaluated for tuberculosis in routine clinical settings. We parametrised the model with data (from a previously published study) for three African countries with a high burden of tuberculosis and HIV: Uganda, Kenya, and South Africa, and estimated lifetime health outcomes under prompt, delayed, and no tuberculosis treatment scenarios. We compared results to earlier modelling approaches that omit progressive lung damage and post-tuberculosis sequelae. Findings: We estimated a 5·1 years (95% uncertainty interval 3·8–6·4) reduction in life expectancy due to tuberculosis with prompt treatment, 7·7 years (5·5–10·1) with delayed treatment, and 18·5 years (15·5–20·6) with no treatment. Estimated per-person disability-adjusted life-years (DALYs) from tuberculosis were 11·4 years (8·9–14·2) with prompt treatment, 17·1 years (13·1–22·1) with delayed treatment, and 37·7 years (34·3–40·3) with no treatment. Compared with individuals without HIV, individuals with HIV had a greater proportion of tuberculosis-attributable deaths, but fewer life-years lost to tuberculosis. Post-tuberculosis DALYs represented 52·5% of total DALYs with prompt treatment, 42·7% with delayed treatment, and 9·1% with no treatment. Modelling approaches that omit progressive lung damage and post-tuberculosis sequelae underestimated lifetime health losses of tuberculosis by 48–57% and underestimated the benefits of prompt treatment by 45–64%. Interpretation: Delayed initiation of tuberculosis treatment causes greater lung damage and higher mortality risks during and after the disease episode than prompt treatment. In settings with coprevalent tuberculosis and HIV, accounting for these factors substantially increased estimates of the lifetime disease burden and life expectancy loss caused by tuberculosis. These findings imply greater health effects and cost-effectiveness for interventions to prevent tuberculosis and achieve earlier treatment initiation than indicated in previous analytical approaches. Funding: US National Institutes of Health

Pharmacokinetic-Pharmacodynamic Evidence From a Phase 3 Trial to Support Flat-Dosing of Rifampicin for Tuberculosis

BACKGROUND: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes. METHODS: We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models; and all trial-defined safety outcomes using logistic regression. RESULTS: Our model-derived rifampicin exposure ranged from 4.57 mg · h/L to 140.0 mg · h/L with a median of 41.8 mg · h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to the weight-banded dose. Exposure-efficacy analysis (n = 680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared with those with exposure above the median. Exposure-safety analysis (n = 722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events or serious adverse events. CONCLUSIONS: Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard-of-care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation

Tuberculosis among health care workers in KwaZulu-Natal, South Africa: a retrospective cohort analysis

Background Tuberculosis (TB) is an occupational hazard for health care workers (HCWs) who are at greater risk of developing TB than the general population. The objective of this study was to compare the difference in TB incidence among HCWs with versus without a history of working in TB wards, to estimate the incidence of TB among HCWs, and to identify risk factors for TB disease in HCWs. Methods A retrospective cohort study (January 2006 to December 2010) was conducted in three district hospitals in KwaZulu-Natal, South Africa. Data were abstracted via chart review from occupational health medical records. Bivariate and multivariate analyses were performed using a Poisson multilevel mixed model. Results Of 1,313 (92%) medical charts reviewed with data on location of work documented, 112 (9%) cases of TB were identified. Among HCWs with TB 14 (13%) had multidrug-resistant TB. Thirty-six (32%) were cured, 33 (29%) completed treatment, and 13 (12%) died. An increased incidence of TB was reported for HCWs with a history of working in TB wards (incidence rate ratio [IRR] 2.03, 95% CI 1.11-3.71), pediatric wards (IRR 1.82 95% CI 1.07-3.10), outpatient departments (IRR 2.08 95% CI 1.23-3.52), and stores/workshop (IRR 2.38 95% CI 1.06-5.34) compared with those without such a history. HCWs living with HIV had a greater incidence of TB (IRR 3.2, 95% CI 1.54-6.66) than HIV-negative HCWs. TB incidence among HCWs was approximately two-fold greater than that of the general population over the study period. Conclusions HCWs working in a TB ward had an increased incidence of TB. However, a greater incidence of TB was also found in HCWs working in other wards including pediatric wards, outpatient departments and stores. We also identified a greater incidence of TB among HCWs than the general population. These findings further support the need for improved infection control measures not only in TB or drug-resistant TB wards or areas perceived to be at high-risk but also throughout hospitals to protect HCWs. Additionally, it is recommended for occupational health services to routinely screen HCWs for TB and provide HCWs with access to care for TB and HIV