TB Modeling and Translational Epi Group

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- April 2015 -

Costs and Consequences of Using Interferon-gamma Release Assays for the Diagnosis of Active Tuberculosis in India. (2015). Little KM., Pai M., Dowdy DW, PloS one, 10, e0124525

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BACKGROUND: There is growing concern that interferon-gamma release assays (IGRAs) are being used off-label for the diagnosis of active tuberculosis (TB) disease in many high-burden settings, including India, where the background prevalence of latent TB infection is high. We analyzed the costs and consequences of using IGRAs for the diagnosis of active TB in India from the perspective of the Indian TB control sector. METHODS AND FINDINGS: We constructed a decision analytic model to estimate the incremental cost and effectiveness of IGRAs for the diagnosis of active TB in India. We compared a reference scenario of clinical examination and non-microbiological tests against scenarios in which clinical diagnosis was augmented by the addition of either sputum smear microscopy, IGRA, or Xpert MTB/RIF. We examined costs (in 2013 US dollars) and consequences from the perspective of the Indian healthcare sector. Relative to sputum smear microscopy, use of IGRA for active TB resulted in 23,700 (95% uncertainty range, UR: 3,800 - 38,300) additional true-positive diagnoses, but at the expense of 315,700 (95% UR: 118,300 - 388,400) additional false-positive diagnoses and an incremental cost of US$49.3 million (95% UR: $34.9 - $58.0 million) (2.9 billion Indian Rupees). Relative to Xpert MTB/RIF (including the cost of treatment for drug resistant TB), use of IGRA led to 400 additional TB cases treated (95% UR: [-8,000] - 16,200), 370,600 (95% UR: 252,200 - 441,700) more false-positive diagnoses, 70,400 (95% UR: [-7,900] - 247,200) fewer disability-adjusted life years averted, and US$14.6 million (95%UR: [-$7.2] - $28.7 million) (854 million Indian Rupees) in additional costs. CONCLUSION: Using IGRAs for diagnosis of active TB in a setting like India results in tremendous overtreatment of people without TB, and substantial incremental cost with little gain in health. These results support the policies by WHO and Standards for TB Care in India, which discourage the use of IGRAs for the diagnosis of active TB in India and similar settings.

The epidemiological advantage of preferential targeting of tuberculosis control at the poor. (2015). Andrews JR., Basu S., Dowdy DW., Murray MB, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 19, 375-80

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Tuberculosis (TB) remains disproportionately concentrated among the poor, yet known determinants of TB reactivation may fail to explain observed disparities in disease rates according to wealth. Reviewing data on TB disparities in India and the wealth distribution of known TB risk factors, we describe how social mixing patterns could be contributing to TB disparities. Wealth-assortative mixing, whereby individuals are more likely to be in contact with others from similar socio-economic backgrounds, amplifies smaller differences in risk of TB, resulting in large population-level disparities. As disparities and assortativeness increase, TB becomes more difficult to control, an effect that is obscured by looking at population averages of epidemiological parameters, such as case detection rates. We illustrate how TB control efforts may benefit from preferential targeting toward the poor. In India, an equivalent-scale intervention could have a substantially greater impact if targeted at those living below the poverty line than with a population-wide strategy. In addition to potential efficiencies in targeting higher-risk populations, TB control efforts would lead to a greater reduction in secondary TB cases per primary case diagnosed if they were preferentially targeted at the poor. We highlight the need to collect programmatic data on TB disparities and explicitly incorporate equity considerations into TB control plans.

Performance of a Novel Algorithm Using Automated Digital Microscopy for Diagnosing Tuberculosis. (2015). Ismail NA., Omar SV., Lewis JJ., Dowdy DW., Dreyer AW., van der Meulen H., Nconjana G., Clark DA., Churchyard GJ, American journal of respiratory and critical care medicine, 191, 1443-9

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RATIONALE: TBDx automated microscopy is a novel technology that processes digital microscopic images to identify acid-fast bacilli (AFB). Use of TBDx as part of a diagnostic algorithm could improve the diagnosis of tuberculosis (TB), but its performance characteristics have not yet been formally tested. OBJECTIVES: To evaluate the performance of the TBDx automated microscopy system in algorithms for diagnosis of TB. METHODS: Prospective samples from patients with presumed TB were processed in parallel with conventional smear microscopy, TBDx microscopy, and liquid culture. All TBDx-positive specimens were also tested with the Xpert MTB/RIF (GXP) assay. We evaluated the sensitivity and specificity of two algorithms-(1) TBDx-GXP (TBDx with positive specimens tested by Xpert MTB/RIF) and (2) TBDx alone-against the gold standard liquid media culture. MEASUREMENTS AND MAIN RESULTS: Of 1,210 samples, 1,009 were eligible for evaluation, of which 109 were culture positive for Mycobacterium tuberculosis. The TBDx system identified 70 specimens (68 culture positive) as having 10 or more putative AFB (high positive) and 207 (19 culture positive) as having 1-9 putative AFB (low positive). An algorithm in which "low-positive" results on TBDx were confirmed by GXP had 78% sensitivity (85 of 109) and 99.8% specificity (889 of 900), requiring 21% (207 of 1,009) specimens to be processed by GXP. As a stand-alone test, a "high-positive" result on TBDx had 62% sensitivity and 99.7% specificity. CONCLUSIONS: TBDx used in diagnostic algorithms with GXP provided reasonable sensitivity and high specificity for active TB while dramatically reducing the number GXP tests performed. As a stand-alone microscopy system, its performance was equivalent to that of a highly experienced TB microscopist.

- March 2015 -

Drivers and trajectories of resistance to new first-line drug regimens for tuberculosis. (2015). Shrestha S., Knight GM., Fofana M., Cohen T., White RG., Cobelens F., Dowdy DW, Open forum infectious diseases, 1, ofu073

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BACKGROUND: New first-line drug regimens for treatment of tuberculosis (TB) are in clinical trials: emergence of resistance is a key concern. Because population-level data on resistance cannot be collected in advance, epidemiological models are important tools for understanding the drivers and dynamics of resistance before novel drug regimens are launched. METHODS: We developed a transmission model of TB after launch of a new drug regimen, defining drug-resistant TB (DR-TB) as resistance to the new regimen. The model is characterized by (1) the probability of acquiring resistance during treatment, (2) the transmission fitness of DR-TB relative to drug-susceptible TB (DS-TB), and (3) the probability of treatment success for DR-TB versus DS-TB. We evaluate the effect of each factor on future DR-TB prevalence, defined as the proportion of incident TB that is drug-resistant. RESULTS: Probability of acquired resistance was the strongest predictor of the DR-TB proportion in the first 5 years after the launch of a new drug regimen. Over a longer term, however, the DR-TB proportion was driven by the resistant population's transmission fitness and treatment success rates. Regardless of uncertainty in acquisition probability and transmission fitness, high levels (>10%) of drug resistance were unlikely to emerge within 50 years if, among all cases of TB that were detected, 85% of those with DR-TB could be appropriately diagnosed as such and then successfully treated. CONCLUSIONS: Short-term surveillance cannot predict long-term drug resistance trends after launch of novel first-line TB regimens. Ensuring high treatment success of drug-resistant TB through early diagnosis and appropriate second-line therapy can mitigate many epidemiological uncertainties and may substantially slow the emergence of drug-resistant TB.

- February 2015 -

C-reactive protein (CRP), interferon gamma-inducible protein 10 (IP-10), and lipopolysaccharide (LPS) are associated with risk of tuberculosis after initiation of antiretroviral therapy in resource-limited settings. (2015). Tenforde MW., Gupte N., Dowdy DW., Asmuth DM., Balagopal A., Pollard RB., Sugandhavesa P., Lama JR., Pillay S., Cardoso SW., Pawar J., Santos B., Riviere C., Mwelase N., Kanyama C., Kumwenda J., Hakim JG., Kumarasamy N., Bollinger R., Semba RD., Campbell TB., Gupta A, PloS one, 10, e0117424

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OBJECTIVE: The association between pre-antiretroviral (ART) inflammation and immune activation and risk for incident tuberculosis (TB) after ART initiation among adults is uncertain. DESIGN: Nested case-control study (n = 332) within ACTG PEARLS trial of three ART regimens among 1571 HIV-infected, treatment-naive adults in 9 countries. We compared cases (participants with incident TB diagnosed by 96 weeks) to a random sample of controls (participants who did not develop TB, stratified by country and treatment arm). METHODS: We measured pre-ART C-reactive protein (CRP), EndoCab IgM, ferritin, interferon gamma (IFN-gamma), interleukin 6 (IL-6), interferon gamma-inducible protein 10 (IP-10), lipopolysaccharide (LPS), soluble CD14 (sCD14), tumor necrosis factor alpha (TNF-alpha), and CD4/DR+/38+ and CD8/DR+/38+ T cells. Markers were defined according to established cutoff definitions when available, 75th percentile of measured values when not, and detectable versus undetectable for LPS. Using logistic regression, we measured associations between biomarkers and incident TB, adjusting for age, sex, study site, treatment arm, baseline CD4 and log10 viral load. We assessed the discriminatory value of biomarkers using receiver operating characteristic (ROC) analysis. RESULTS: Seventy-seven persons (4.9%) developed incident TB during follow-up. Elevated baseline CRP (aOR 3.25, 95% CI: 1.55-6.81) and IP-10 (aOR 1.89, 95% CI: 1.05-3.39), detectable plasma LPS (aOR 2.39, 95% CI: 1.13-5.06), and the established TB risk factors anemia and hypoalbuminemia were independently associated with incident TB. In ROC analysis, CRP, albumin, and LPS improved discrimination only modestly for TB risk when added to baseline routine patient characteristics including CD4 count, body mass index, and prior TB. CONCLUSION: Incident TB occurs commonly after ART initiation. Although associated with higher post-ART TB risk, baseline CRP, IP-10, and LPS add limited value to routine patient characteristics in discriminating who develops active TB. Besides determining ideal cutoffs for these biomarkers, additional biomarkers should be sought that predict TB disease in ART initiators.

- January 2015 -

Postarrival Tuberculosis Screening of High-Risk Immigrants at a Local Health Department. (2015). Nuzzo JB., Golub JE., Chaulk P., Shah M, American journal of public health, 105, 1432-8

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OBJECTIVES: We sought to characterize postimmigration tuberculosis (TB) care for Class B immigrants and refugees at the Baltimore City Health Department TB program (BCHD), and to determine the proportion of immigrants with active TB or latent TB infection (LTBI) in this high-risk population. METHODS: We conducted a retrospective chart review of Class B immigrants and refugees who reported to the BCHD for postimmigration TB evaluation from 2010 to 2012. RESULTS: We reviewed the clinical records of 153 Class B immigrants; 4% were diagnosed with active TB and 53% were diagnosed with LTBI. Fifty percent of active TB cases were culture positive, and 67% were asymptomatic; 100% received and completed active TB therapy at the BCHD. Among those diagnosed with LTBI, 87% initiated LTBI therapy and 91% completed treatment. CONCLUSIONS: The high prevalence of active TB and LTBI found among Class B immigrants underscore the importance for postarrival TB screening. The absence of reported symptoms among the majority of active cases identified during this study suggest that reliance on symptom-based screening protocols to prompt sputa testing may be inadequate for identifying active TB among this high-risk group.

- December 2014 -

Cost-effectiveness of tuberculosis screening and isoniazid treatment in the TB/HIV in Rio (THRio) Study. (2014). Azadi M., Bishai DM., Dowdy DW., Moulton LH., Cavalcante S., Saraceni V., Pacheco AG., Cohn S., Chaisson RE., Durovni B., Golub JE, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 18, 1443-8

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OBJECTIVE: To estimate the incremental cost-effectiveness of tuberculosis (TB) screening and isoniazid preventive therapy (IPT) among human immunodeficiency virus (HIV) infected adults in Rio de Janeiro, Brazil. DESIGN: We used decision analysis, populated by data from a cluster-randomized trial, to project the costs (in 2010 USD) and effectiveness (in disability-adjusted life years [DALYs] averted) of training health care workers to implement the tuberculin skin test (TST), followed by IPT for TST-positive patients with no evidence of active TB. This intervention was compared to a baseline of usual care. We used time horizons of 1 year for the intervention and 20 years for disease outcomes, with all future DALYs and medical costs discounted at 3% per year. RESULTS: Providing this intervention to 100 people would avert 1.14 discounted DALYs (1.57 undiscounted DALYs). The median estimated incremental cost-effectiveness ratio was $2273 (IQR $1779-$3135) per DALY averted, less than Brazil's 2010 per capita gross domestic product (GDP) of $11,700. Results were most sensitive to the cost of providing the training. CONCLUSION: Training health care workers to screen HIV-infected adults with TST and provide IPT to those with latent tuberculous infection can be considered cost-effective relative to the Brazilian GDP per capita.

Risk factors for delirium: are systematic reviews enough?. (2014). Brown CH 4th., Dowdy D, Critical care medicine, 43, 232-3

- November 2014 -

Long-term protection from isoniazid preventive therapy for tuberculosis in HIV-infected patients in a medium-burden tuberculosis setting: the TB/HIV in Rio (THRio) study. (2014). Golub JE., Cohn S., Saraceni V., Cavalcante SC., Pacheco AG., Moulton LH., Durovni B., Chaisson RE, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 60, 639-45

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BACKGROUND: The duration of protection against tuberculosis provided by isoniazid preventive therapy is not known for human immunodeficiency virus (HIV)-infected individuals living in settings of medium tuberculosis incidence. METHODS: We conducted an individual-level analysis of participants in a cluster-randomized, phased-implementation trial of isoniazid preventive therapy. HIV-infected patients who had positive tuberculin skin tests (TSTs) were followed until tuberculosis diagnosis, death, or administrative censoring. Nelson-Aalen cumulative hazard plots were generated and hazards were compared using the log-rank test. Cox proportional hazards models were fitted to investigate factors associated with tuberculosis diagnosis. RESULTS: Between 2003 and 2009, 1954 patients with a positive TST were studied. Among these, 1601 (82%) initiated isoniazid. Overall tuberculosis incidence was 1.39 per 100 person-years (PY); 0.53 per 100 PY in those who initiated isoniazid and 6.52 per 100 PY for those who did not (adjusted hazard ratio [aHR], 0.17; 95% confidence interval [CI], .11-.25). Receiving antiretroviral therapy at time of a positive TST was associated with a reduced risk of tuberculosis (aHR, 0.69; 95% CI, .48-1.00). Nelson-Aalen plots of tuberculosis incidence showed a constant risk, with no acceleration in 7 years of follow-up for those initiating isoniazid preventive therapy. CONCLUSIONS: Isoniazid preventive therapy significantly reduced tuberculosis risk among HIV-infected patients with a positive TST. In a medium-prevalence setting, 6 months of isoniazid in HIV-infected patients with positive TST reduces tuberculosis risk over 7 years of follow-up, in contrast to results of studies in higher-burden settings in Africa.

How much is tuberculosis screening worth? Estimating the value of active case finding for tuberculosis in South Africa, China, and India. (2014). Azman AS., Golub JE., Dowdy DW, BMC medicine, 12, 216

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BACKGROUND: Current approaches are unlikely to achieve the aggressive global tuberculosis (TB) control targets set for 2035 and beyond. Active case finding (ACF) may be an important tool for augmenting existing strategies, but the cost-effectiveness of ACF remains uncertain. Program evaluators can often measure the cost of ACF per TB case detected, but how this accessible measure translates into traditional metrics of cost-effectiveness, such as the cost per disability-adjusted life year (DALY), remains unclear. METHODS: We constructed dynamic models of TB in India, China, and South Africa to explore the medium-term impact and cost-effectiveness of generic ACF activities, conceptualized separately as discrete (2-year) campaigns and as continuous activities integrated into ongoing TB control programs. Our primary outcome was the cost per DALY, measured in relationship to the cost per TB case actively detected and started on treatment. RESULTS: Discrete campaigns costing up to $1,200 (95% uncertainty range [UR] 850-2,043) per case actively detected and started on treatment in India, $3,800 (95% UR 2,706-6,392) in China, and $9,400 (95% UR 6,957-13,221) in South Africa were all highly cost-effective (cost per DALY averted less than per capita gross domestic product). Prolonged integration was even more effective and cost-effective. Short-term assessments of ACF dramatically underestimated potential longer term gains; for example, an assessment of an ACF program at 2 years might find a non-significant 11% reduction in prevalence, but a 10-year evaluation of that same intervention would show a 33% reduction. CONCLUSIONS: ACF can be a powerful and highly cost-effective tool in the fight against TB. Given that short-term assessments may dramatically underestimate medium-term effectiveness, current willingness to pay may be too low. ACF should receive strong consideration as a basic tool for TB control in most high-burden settings, even when it may cost over $1,000 to detect and initiate treatment for each extra case of active TB.

- October 2014 -

Modeling of novel diagnostic strategies for active tuberculosis - a systematic review: current practices and recommendations. (2014). Zwerling A., White RG., Vassall A., Cohen T., Dowdy DW., Houben RM, PloS one, 9, e110558

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INTRODUCTION: The field of diagnostics for active tuberculosis (TB) is rapidly developing. TB diagnostic modeling can help to inform policy makers and support complicated decisions on diagnostic strategy, with important budgetary implications. Demand for TB diagnostic modeling is likely to increase, and an evaluation of current practice is important. We aimed to systematically review all studies employing mathematical modeling to evaluate cost-effectiveness or epidemiological impact of novel diagnostic strategies for active TB. METHODS: Pubmed, personal libraries and reference lists were searched to identify eligible papers. We extracted data on a wide variety of model structure, parameter choices, sensitivity analyses and study conclusions, which were discussed during a meeting of content experts. RESULTS & DISCUSSION: From 5619 records a total of 36 papers were included in the analysis. Sixteen papers included population impact/transmission modeling, 5 were health systems models, and 24 included estimates of cost-effectiveness. Transmission and health systems models included specific structure to explore the importance of the diagnostic pathway (n = 4), key determinants of diagnostic delay (n = 5), operational context (n = 5), and the pre-diagnostic infectious period (n = 1). The majority of models implemented sensitivity analysis, although only 18 studies described multi-way sensitivity analysis of more than 2 parameters simultaneously. Among the models used to make cost-effectiveness estimates, most frequent diagnostic assays studied included Xpert MTB/RIF (n = 7), and alternative nucleic acid amplification tests (NAATs) (n = 4). Most (n = 16) of the cost-effectiveness models compared new assays to an existing baseline and generated an incremental cost-effectiveness ratio (ICER). CONCLUSION: Although models have addressed a small number of important issues, many decisions regarding implementation of TB diagnostics are being made without the full benefits of insight from mathematical models. Further models are needed that address a wider array of diagnostic and epidemiological settings, that explore the inherent uncertainty of models and that include additional epidemiological data on transmission implications of false-negative diagnosis and the pre-diagnostic period.

A piece of my mind. Healthy but harmed. (2014). Dowdy DW, JAMA, 312, 1399-400

Clinical effectiveness and cost-effectiveness of HIV pre-exposure prophylaxis in men who have sex with men: risk calculators for real-world decision-making. (2014). Chen A., Dowdy DW, PloS one, 9, e108742

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BACKGROUND: Oral pre-exposure prophylaxis (PrEP) can be clinically effective and cost-effective for HIV prevention in high-risk men who have sex with men (MSM). However, individual patients have different risk profiles, real-world populations vary, and no practical tools exist to guide clinical decisions or public health strategies. We introduce a practical model of HIV acquisition, including both a personalized risk calculator for clinical management and a cost-effectiveness calculator for population-level decisions. METHODS: We developed a decision-analytic model of PrEP for MSM. The primary clinical effectiveness and cost-effectiveness outcomes were the number needed to treat (NNT) to prevent one HIV infection, and the cost per quality-adjusted life-year (QALY) gained. We characterized patients according to risk factors including PrEP adherence, condom use, sexual frequency, background HIV prevalence and antiretroviral therapy use. RESULTS: With standard PrEP adherence and national epidemiologic parameters, the estimated NNT was 64 (95% uncertainty range: 26, 176) at a cost of $160,000 (cost saving, $740,000) per QALY--comparable to other published models. With high (35%) HIV prevalence, the NNT was 35 (21, 57), and cost per QALY was $27,000 (cost saving, $160,000), and with high PrEP adherence, the NNT was 30 (14, 69), and cost per QALY was $3,000 (cost saving, $200,000). In contrast, for monogamous, serodiscordant relationships with partner antiretroviral therapy use, the NNT was 90 (39, 157) and cost per QALY was $280,000 ($14,000, $670,000). CONCLUSIONS: PrEP results vary widely across individuals and populations. Risk calculators may aid in patient education, clinical decision-making, and cost-effectiveness evaluation.

- September 2014 -

Active case finding of tuberculosis (TB) in an emergency room in a region with high prevalence of TB in Brazil. (2014). Silva DR., Muller AM., Tomasini Kda S., Dalcin Pde T., Golub JE., Conde MB, PloS one, 9, e107576

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SETTING: Public hospital emergency room (ER) in Porto Alegre, Brazil, a setting with high prevalence of tuberculosis (TB) and human immunodeficiency virus (HIV) infection. OBJECTIVE: To determine the prevalence of PTB, using a symptom based active case finding (ACF) strategy in the ER of a public hospital in an area with high prevalence of TB and HIV, as well as variables associated with pulmonary TB diagnosis. METHODS: Cross sectional study. All patients >/= 18 years seeking care at the ER were screened for respiratory symptoms and those with cough >/= 2 weeks were invited to provide a chest radiograph and two unsupervised samples of sputum for acid-fast bacilli smear and culture. RESULTS: Among 31,267 admissions, 6,273 (20.1%) reported respiratory symptoms; 197 reported cough >/= 2 weeks, of which pulmonary TB was diagnosed in 30. In multivariate analysis, the variables associated with a pulmonary tuberculosis diagnosis were: age (OR 0.94, 95% CI: 0.92-0.97; p<0.0001), sputum production (OR 0.18, 95% CI 0.06-0.56; p = 0.003), and radiographic findings typical of TB (OR 12.11, 95% CI 4.45-32.93; p<0.0001). CONCLUSIONS: This study identified a high prevalence of pulmonary TB among patients who sought care at the emergency department of a tertiary hospital, emphasizing the importance of regular screening of all comers for active TB in this setting.

Bold thinking for bold results: modeling the elimination of tuberculosis. (2014). Azman AS., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 18, 883

Impact and cost-effectiveness of current and future tuberculosis diagnostics: the contribution of modelling. (2014). Dowdy DW., Houben R., Cohen T., Pai M., Cobelens F., Vassall A., Menzies NA., Gomez GB., Langley I., Squire SB., White R, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 18, 1012-8

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The landscape of diagnostic testing for tuberculosis (TB) is changing rapidly, and stakeholders need urgent guidance on how to develop, deploy and optimize TB diagnostics in a way that maximizes impact and makes best use of available resources. When decisions must be made with only incomplete or preliminary data available, modelling is a useful tool for providing such guidance. Following a meeting of modelers and other key stakeholders organized by the TB Modelling and Analysis Consortium, we propose a conceptual framework for positioning models of TB diagnostics. We use that framework to describe modelling priorities in four key areas: Xpert((R)) MTB/RIF scale-up, target product profiles for novel assays, drug susceptibility testing to support new drug regimens, and the improvement of future TB diagnostic models. If we are to maximize the impact and cost-effectiveness of TB diagnostics, these modelling priorities should figure prominently as targets for future research.

Reproducibility of interferon gamma (IFN-gamma) release Assays. A systematic review. (2014). Tagmouti S., Slater M., Benedetti A., Kik SV., Banaei N., Cattamanchi A., Metcalfe J., Dowdy D., van Zyl Smit R., Dendukuri N., Pai M., Denkinger C, Annals of the American Thoracic Society, 11, 1267-76

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RATIONALE: Interferon gamma (IFN-gamma) release assays for latent tuberculosis infection result in a larger-than-expected number of conversions and reversions in occupational screening programs, and reproducibility of test results is a concern. OBJECTIVES: Knowledge of the relative contribution and extent of the individual sources of variability (immunological, preanalytical, or analytical) could help optimize testing protocols. METHODS: We performed a systematic review of studies published by October 2013 on all potential sources of variability of commercial IFN-gamma release assays (QuantiFERON-TB Gold In-Tube and T-SPOT.TB). The included studies assessed test variability under identical conditions and under different conditions (the latter both overall and stratified by individual sources of variability). Linear mixed effects models were used to estimate within-subject SD. MEASUREMENTS AND MAIN RESULTS: We identified a total of 26 articles, including 7 studies analyzing variability under the same conditions, 10 studies analyzing variability with repeat testing over time under different conditions, and 19 studies reporting individual sources of variability. Most data were on QuantiFERON (only three studies on T-SPOT.TB). A considerable number of conversions and reversions were seen around the manufacturer-recommended cut-point. The estimated range of variability of IFN-gamma response in QuantiFERON under identical conditions was +/-0.47 IU/ml (coefficient of variation, 13%) and +/-0.26 IU/ml (30%) for individuals with an initial IFN-gamma response in the borderline range (0.25-0.80 IU/ml). The estimated range of variability in noncontrolled settings was substantially larger (+/-1.4 IU/ml; 60%). Blood volume inoculated into QuantiFERON tubes and preanalytic delay were identified as key sources of variability. CONCLUSIONS: This systematic review shows substantial variability with repeat IFN-gamma release assays testing even under identical conditions, suggesting that reversions and conversions around the existing cut-point should be interpreted with caution.

The impact of novel tests for tuberculosis depends on the diagnostic cascade. (2014). Sun AY., Denkinger CM., Dowdy DW, The European respiratory journal, 44, 1366-9

Modeling the impact of novel diagnostic tests on pediatric and extrapulmonary tuberculosis. (2014). Denkinger CM., Kampmann B., Ahmed S., Dowdy DW, BMC infectious diseases, 14, 477

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BACKGROUND: Extrapulmonary tuberculosis (EPTB) and most pediatric TB cannot be diagnosed using sputum-based assays. The epidemiological impact of different strategies to diagnose EPTB and pediatric TB is unclear. METHODS: We developed a dynamic epidemic model of TB in a hypothetical population with epidemiological characteristics similar to India. We evaluated the impact of four alternative diagnostic test platforms on adult EPTB and pediatric TB mortality over 10 years: (1) Nucleic acid amplification test optimized for diagnosis of EPTB ("NAAT-EPTB"); (2) NAAT optimized for pediatric TB ("NAAT-Peds"); (3) more deployable NAAT for sputum-based diagnosis of adult pulmonary TB ("point-of-care (POC) sputum NAAT"); and (4) more deployable NAAT capable of diagnosing all forms of TB using non-invasive, non-sputum specimens ("POC non-sputum NAAT"). RESULTS: NAAT-EPTB lowered adult EPTB mortality by a projected 7.6% (95% uncertainty range [UR]: 6.5-8.8%). NAAT-Peds lowered pediatric TB mortality by 6.8% (UR: 4.9-8.4%). POC sputum NAAT, though only able to diagnose pulmonary TB, reduced projected pediatric TB deaths by 13.3% (UR: 4.6-15.7%) and adult EPTB deaths by 8.4% (UR 2.0-9.3%) simply by averting transmission of disease. POC non-sputum NAAT had the greatest effect, lowering pediatric TB mortality by 34.7% (UR: 26.8-38.7), and adult EPTB mortality by 38.5% (UR: 30.7-41.2). The relative impact of a POC sputum NAAT (i.e., enhanced deployability) versus NAAT-EPTB (i.e., enhanced ability to specifically diagnose TB-NSP) on adult EPTB mortality depends most strongly on factors that influence transmission, with settings of higher transmission (e.g., higher per-person transmission rate, lower diagnostic rate) favoring POC sputum NAAT. CONCLUSION: Although novel tests for pediatric TB and EPTB are likely to reduce TB mortality, major reductions in pediatric and EPTB incidence and mortality also require better diagnostic tests for adult pulmonary TB that reach a larger population.

- August 2014 -

Cost-effectiveness of novel algorithms for rapid diagnosis of tuberculosis in HIV-infected individuals in Uganda. (2014). Shah M., Dowdy D., Joloba M., Ssengooba W., Manabe YC., Ellner J., Dorman SE, AIDS (London, England), 27, 2883-92

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OBJECTIVE: Xpert MTB/RIF ('Xpert') and urinary lateral-flow lipoarabinomannan (LF-LAM) assays offer rapid tuberculosis (TB) diagnosis. This study evaluated the cost-effectiveness of novel diagnostic algorithms utilizing combinations of Xpert and LF-LAM for the detection of active TB among people living with HIV. DESIGN: Cost-effectiveness analysis using data from a comparative study of LF-LAM and Xpert, with a target population of HIV-infected individuals with signs/symptoms of TB in Uganda. METHODS: A decision-analysis model compared multiple strategies for rapid TB diagnosis:sputum smear-microscopy; sputum Xpert; smear-microscopy combined with LF-LAM; and Xpert combined with LF-LAM. Primary outcomes were the costs and DALY's averted for each algorithm. Cost-effectiveness was represented using incremental cost-effectiveness ratios (ICER). RESULTS: Compared with an algorithm of Xpert testing alone, the combination of Xpert with LF-LAM was considered highly cost-effective (ICER $57/DALY-averted) at a willingness to pay threshold of Ugandan GDP per capita. Addition of urine LF-LAM testing to smear-microscopy was a less effective strategy than Xpert replacement of smear-microscopy, but was less costly and also considered highly cost-effective (ICER $33 per DALY-averted) compared with continued usage of smear-microscopy alone. Cost-effectiveness of the Xpert plus LF-LAM algorithm was most influenced by HIV/ART costs and life-expectancy of patients after TB treatment. CONCLUSION: The addition of urinary LF-LAM to TB diagnostic algorithms for HIV-infected individuals is highly cost-effective compared with usage of either sputum smear-microscopy or Xpert alone.

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