TB Modeling and Translational Epi Group

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- June 2014 -

How can mathematical models advance tuberculosis control in high HIV prevalence settings? (2014). Houben RM., Dowdy DW., Vassall A., Cohen T., Nicol MP., Granich RM., Shea JE., Eckhoff P., Dye C., Kimerling ME., White RG, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 18, 509-14

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Existing approaches to tuberculosis (TB) control have been no more than partially successful in areas with high human immunodeficiency virus (HIV) prevalence. In the context of increasingly constrained resources, mathematical modelling can augment understanding and support policy for implementing those strategies that are most likely to bring public health and economic benefits. In this paper, we present an overview of past and recent contributions of TB modelling in this key area, and suggest a way forward through a modelling research agenda that supports a more effective response to the TB-HIV epidemic, based on expert discussions at a meeting convened by the TB Modelling and Analysis Consortium. The research agenda identified high-priority areas for future modelling efforts, including 1) the difficult diagnosis and high mortality of TB-HIV; 2) the high risk of disease progression; 3) TB health systems in high HIV prevalence settings; 4) uncertainty in the natural progression of TB-HIV; and 5) combined interventions for TB-HIV. Efficient and rapid progress towards completion of this modelling agenda will require co-ordination between the modelling community and key stakeholders, including advocates, health policy makers, donors and national or regional finance officials. A continuing dialogue will ensure that new results are effectively communicated and new policy-relevant questions are addressed swiftly.

A user-friendly, open-source tool to project impact and cost of diagnostic tests for tuberculosis. (2014). Dowdy DW., Andrews JR., Dodd PJ., Gilman RH, eLife, 3

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Most models of infectious diseases, including tuberculosis (TB), do not provide results customized to local conditions. We created a dynamic transmission model to project TB incidence, TB mortality, multidrug-resistant (MDR) TB prevalence, and incremental costs over 5 years after scale-up of nine alternative diagnostic strategies. A corresponding web-based interface allows users to specify local costs and epidemiology. In settings with little capacity for up-front investment, same-day microscopy had the greatest impact on TB incidence and became cost-saving within 5 years if delivered at $10/test. With greater initial investment, population-level scale-up of Xpert MTB/RIF or microcolony-based culture often averted 10 times more TB cases than narrowly-targeted strategies, at minimal incremental long-term cost. Xpert for smear-positive TB had reasonable impact on MDR-TB incidence, but at substantial price and little impact on overall TB incidence and mortality. This user-friendly modeling framework improves decision-makers' ability to evaluate the local impact of TB diagnostic strategies.

Point-of-Care Tests for HIV, Related Coinfections, and Blood-Borne Infections. (2014). Pant Pai N., Peeling RW., Smith BD., Dowdy D, AIDS research and treatment, 2014, 625082

- May 2014 -

Impact of isoniazid preventive therapy for HIV-infected adults in Rio de Janeiro, Brazil: an epidemiological model. (2014). Dowdy DW., Golub JE., Saraceni V., Moulton LH., Cavalcante SC., Cohn S., Pacheco AG., Chaisson RE., Durovni B, Journal of acquired immune deficiency syndromes (1999), 66, 552-8

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BACKGROUND: The potential epidemiological impact of isoniazid preventive therapy (IPT), delivered at levels that could be feasibly scaled up among people living with HIV (PLHIV) in modern, moderate-burden settings, remains uncertain. METHODS: We used routine surveillance and implementation data from a cluster-randomized trial of IPT among HIV-infected clinic patients with good access to antiretroviral therapy in Rio de Janeiro, Brazil, to populate a parsimonious transmission model of tuberculosis (TB)/HIV. We modeled IPT delivery as a constant process capturing a proportion of the eligible population every year. We projected feasible reductions in TB incidence and mortality in the general population and among PLHIV specifically at the end of 5 years after implementing an IPT program. RESULTS: Data on time to IPT fit an exponential curve well, suggesting that IPT was delivered at a rate covering 20% (95% confidence interval: 16% to 24%) of the 2500 eligible individuals each year. By the end of year 5 after modeled program rollout, IPT had reduced TB incidence by 3.0% [95% uncertainty range (UR): 1.6% to 7.2%] in the general population and by 15.6% (95% UR: 15.5% to 36.5%) among PLHIV. Corresponding reductions in TB mortality were 4.0% (95% UR: 2.2% to 10.3%) and 14.3% (14.6% to 33.7%). Results were robust to wide variations in parameter values on sensitivity analysis. CONCLUSIONS: TB screening and IPT delivery can substantially reduce TB incidence and mortality among PLHIV in urban, moderate-burden settings. In such settings, IPT can be an important component of a multi-faceted strategy to feasibly reduce the burden of TB in PLHIV.

RE: Severe mental illness at ART initiation is associated with worse retention in care among HIV-infected Ugandan adults by JM Nachega et al. (2013), TMIH 18, pp 53-57. (2014). Nakimuli-Mpungu E., Dowdy DW., Nachega JB, Tropical medicine & international health : TM & IH, 19, 133-4

Population-level impact of shorter-course regimens for tuberculosis: a model-based analysis. (2014). Fofana MO., Knight GM., Gomez GB., White RG., Dowdy DW, PloS one, 9, e96389

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Despite current control efforts, global tuberculosis (TB) incidence is decreasing slowly. New regimens that can shorten treatment hold promise for improving treatment completion and success, but their impact on population-level transmission remains unclear. Earlier models projected that a four-month regimen could reduce TB incidence by 10% but assumed that an entire course of therapy must be completed to derive any benefit. We constructed a dynamic transmission model of TB disease calibrated to global estimates of incidence, prevalence, mortality, and treatment success. To account for the efficacy of partial treatment, we used data from clinical trials of early short-course regimens to estimate relapse rates among TB patients who completed one-third, one-half, two-thirds, and all of their first-line treatment regimens. We projected population-level incidence and mortality over 10 years, comparing standard six-month therapy to hypothetical shorter-course regimens with equivalent treatment success but fewer defaults. The impact of hypothetical four-month regimens on TB incidence after 10 years was smaller than estimated in previous modeling analyses (1.9% [95% uncertainty range 0.6-3.1%] vs. 10%). Impact on TB mortality was larger (3.5% at 10 years) but still modest. Transmission impact was most sensitive to the proportion of patients completing therapy: four-month therapy led to greater incidence reductions in settings where 25% of patients leave care ("default") over six months. Our findings remained robust under one-way variation of model parameters. These findings suggest that novel regimens that shorten treatment duration may have only a modest effect on TB transmission except in settings of very low treatment completion.

A comparative assessment of the price, brands and pack characteristics of illicitly traded cigarettes in five cities and towns in South Africa. (2014). Wherry AE., McCray CA., Adedeji-Fajobi TI., Sibiya X., Ucko P., Lebina L., Golub JE., Cohen JE., Martinson NA, BMJ open, 4, e004562

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OBJECTIVE: The prevalence of illicitly traded cigarettes in South Africa has been reported to be 40-50%. However, these estimates do not account for the more nuanced characteristics of the illicit cigarette trade. With the goal of better understanding contraband cigarettes in South Africa, this study piloted three methods for assessing the price, brands, pack features and smoker's views about illicit cigarettes in five cities/towns. Data were collected in June and July 2012. SETTING: A convenience sample of three South African cities (Johannesburg, Durban and Nelspruit) and two smaller towns (Musina and Ficksburg) were chosen for this study. OUTCOME MEASURES: Three cross-sectional approaches were used to assess the characteristics of contraband cigarettes: (1) a dummy purchase of cigarettes from informal retailers, (2) the collection of discarded cigarette packs and (3) a survey of tobacco smokers. PARTICIPANTS: For the purposes of the survey, 40 self-reported smokers were recruited at taxi ranks in each downtown site. Adults who were over the age of 18 were asked to verbally consent to participate in the study and answer a questionnaire administered by a researcher. RESULTS: The leading reason for labelling a pack as illicit in each city/town was the absence of an excise stamp (28.6% overall), and the least common reason was an illegal tar or nicotine level (11.1% overall). The overall proportion of informal vendors who sold illicit cigarettes was 41%. Singles and packs of 20 were consistently cheaper at informal vendors. Survey participants' responses reflected varied perspectives on illicit cigarettes and purchasing preferences. CONCLUSIONS: Each approach generated an interesting insight into physical aspects of illicit cigarettes. While this pilot study cannot be used to generate generalisable statistics on illicit cigarettes, more systematic surveys of this nature could inform researchers' and practitioners' initiatives to combat illicit and legal cigarette sales and usage.

Survival of HIV patients with tuberculosis started on simultaneous or deferred HAART in the THRio cohort, Rio de Janeiro, Brazil. (2014). Saraceni V., Durovni B., Cavalcante SC., Cohn S., Pacheco AG., Moulton LH., Chaisson RE., Golub JE, The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases, 18, 491-5

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BACKGROUND: The timing of highly active antiretroviral therapy (HAART) after a tuberculosis diagnosis in HIV-infected patients can affect clinical outcomes and survival. We compared survival after tuberculosis diagnosis in HIV-infected adults who initiated HAART and tuberculosis therapy simultaneously to those who delayed the start of HAART for at least two months. METHODS: The THRio cohort includes 17,983 patients receiving HIV care in 29 public clinics in Rio de Janeiro, Brazil. HAART-naive patients at the time of a new TB diagnosis between September 2003 and June 2008 were included. Survival was measured in days from diagnosis of TB. We compared survival among patients who initiated HAART within 60 days of TB treatment (simultaneous - ST) to those who started HAART >60 days of TB treatment or never started (deferred - DT). Kaplan-Meier plots and Cox proportional hazards regression analyses were conducted. RESULTS: Of 947 patients diagnosed with TB, 572 (60%) were HAART naive at the time of TB diagnosis; 135 were excluded because of missing CD4 count results. Among the remaining 437 TB patients, 56 (13%) died during follow-up: 25 (10%) among ST patients and 31 (16%) in DT group (p=0.08). ST patients had lower median CD4 counts at TB diagnosis than DT patients (106 vs. 278, p<0.001). Cox proportional hazards utilizing propensity score analysis showed that DT patients were more likely to die (adjusted HR=1.89; 95% CI: 1.05-3.40; p=0.03). CONCLUSION: HAART administered simultaneously with TB therapy was associated with improved survival after TB diagnosis. HAART should be given to patients with HIV-related TB as soon as clinically feasible.

- February 2014 -

Timing of tuberculosis transmission and the impact of household contact tracing. An agent-based simulation model. (2014). Kasaie P., Andrews JR., Kelton WD., Dowdy DW, American journal of respiratory and critical care medicine, 189, 845-52

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RATIONALE: Household contact tracing has recently been endorsed for global tuberculosis (TB) control, but its potential population-level impact remains uncertain. OBJECTIVES: To project the maximum impact of household contact tracing for TB in a moderate-burden setting. METHODS: We developed a stochastic, agent-based simulation model of a simplified TB epidemic, calibrated to a setting of moderate TB incidence. We used data from the literature to generate "community-driven" and "household-driven" scenarios in which 22 and 50% of TB transmission occurred within the household, respectively. In each scenario, we simulated an intervention in which the household members are screened and treated for TB at the time of an index patient's active TB diagnosis. MEASUREMENTS AND MAIN RESULTS: By the time of TB diagnosis, 75 to 95% of initial household infections had already occurred, but only 1.5 to 3.0% of contacts had sufficient time to progress to active TB. With 100% sensitive tracing of all contacts for 5 consecutive years, TB incidence declined by 10 to 15%, with a mean year-over-year decline of 2% per year. Effects were sustained for many years after stopping the intervention. Providing preventive therapy with contact tracing nearly doubled this impact (17-27% decline in incidence). Impact was proportional to sensitivity and coverage; thus, if 50% of contacts were screened with a 50% sensitive test, TB incidence declined by only 0.5% per year. CONCLUSIONS: Household contact tracing is unlikely to transform TB epidemiology in isolation but has the potential, especially with provision of preventive therapy, to augment a comprehensive package of interventions that could substantially reduce the population-level burden of TB.

- January 2014 -

Economic evaluation of laboratory testing strategies for hospital-associated Clostridium difficile infection. (2014). Schroeder LF., Robilotti E., Peterson LR., Banaei N., Dowdy DW, Journal of clinical microbiology, 52, 489-96

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Clostridium difficile infection (CDI) is the most common cause of infectious diarrhea in health care settings, and for patients presumed to have CDI, their isolation while awaiting laboratory results is costly. Newer rapid tests for CDI may reduce this burden, but the economic consequences of different testing algorithms remain unexplored. We used decision analysis from the hospital perspective to compare multiple CDI testing algorithms for adult inpatients with suspected CDI, assuming patient management according to laboratory results. CDI testing strategies included combinations of on-demand PCR (odPCR), batch PCR, lateral-flow diagnostics, plate-reader enzyme immunoassay, and direct tissue culture cytotoxicity. In the reference scenario, algorithms incorporating rapid testing were cost-effective relative to nonrapid algorithms. For every 10,000 symptomatic adults, relative to a strategy of treating nobody, lateral-flow glutamate dehydrogenase (GDH)/odPCR generated 831 true-positive results and cost $1,600 per additional true-positive case treated. Stand-alone odPCR was more effective and more expensive, identifying 174 additional true-positive cases at $6,900 per additional case treated. All other testing strategies were dominated by (i.e., more costly and less effective than) stand-alone odPCR or odPCR preceded by lateral-flow screening. A cost-benefit analysis (including estimated costs of missed cases) favored stand-alone odPCR in most settings but favored odPCR preceded by lateral-flow testing if a missed CDI case resulted in less than $5,000 of extended hospital stay costs and <2 transmissions, if lateral-flow GDH diagnostic sensitivity was >93%, or if the symptomatic carrier proportion among the toxigenic culture-positive cases was >80%. These results can aid guideline developers and laboratory directors who are considering rapid testing algorithms for diagnosing CDI.

Tuberculosis: progress and challenges in product development and delivery. (2014). Pai M., Dowdy D, The Lancet. Respiratory medicine, 2, 25-7

Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: A meta-analysis of randomized controlled trials. (2014). Nachega JB., Parienti JJ., Uthman OA., Gross R., Dowdy DW., Sax PE., Gallant JE., Mugavero MJ., Mills EJ., Giordano TP, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 58, 1297-307

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BACKGROUND: Contemporary antiretroviral treatment regimens are simpler than in the past, with lower pill burden and once-daily dosing frequency common. We performed a meta-analysis of randomized controlled trials (RCTs) to investigate the impact of pill burden and once-daily vs twice-daily dosing on ART adherence and virological outcomes. METHODS: A literature search of 4 electronic databases through 31 March 2013 was used. RCTs comparing once-daily vs twice-daily ART regimens that also reported on adherence and virological suppression were included. Study design, study population characteristics, intervention, outcome measures, and study quality were extracted. Study quality was rated using the Cochrane risk-of-bias tool. RESULTS: Nineteen studies met our inclusion criteria (N = 6312 adult patients). Higher pill burden was associated with both lower adherence rates (P = .004) and worse virological suppression (P < .0001) in both once-daily and twice-daily subgroups, although the association with adherence in the once-daily subgroup was not statistically significant. The average adherence was modestly higher in once-daily regimens than twice-daily regimens (weighted mean difference = 2.55%; 95% confidence interval [CI], 1.23 to 3.87; P = .0002). Patients on once-daily regimens did not achieve virological suppression more frequently than patients on twice-daily regimens (relative risk [RR] = 1.01; 95% CI, 0.99 to 1.03; P = .50). Both adherence and viral load suppression decreased over time, but adherence decreased less with once-daily dosing than with twice-daily dosing. CONCLUSIONS: Lower pill burden was associated with both better adherence and virological suppression. Adherence, but not virological suppression, was slightly better with once- vs twice-daily regimens.

Do high rates of empirical treatment undermine the potential effect of new diagnostic tests for tuberculosis in high-burden settings? (2014). Theron G., Peter J., Dowdy D., Langley I., Squire SB., Dheda K, The Lancet. Infectious diseases, 14, 527-32

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In tuberculosis-endemic settings, patients are often treated empirically, meaning that they are placed on treatment based on clinical symptoms or tests that do not provide a microbiological diagnosis (eg, chest radiography). New tests for tuberculosis, such as the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA), are being implemented at substantial cost. To inform policy and rationally drive implementation, data are needed for how these tests affect morbidity, mortality, transmission, and population-level tuberculosis burden. If people diagnosed by use of new diagnostics would have received empirical treatment a few days later anyway, then the incremental benefit might be small. Will new diagnostics substantially improve outcomes and disease burden, or simply displace empirical treatment? Will the extent and accuracy of empirical treatment change with the introduction of a new test? In this Personal View, we review emerging data for how empirical treatment is frequently same-day, and might still be the predominant form of treatment in high-burden settings, even after Xpert implementation; and how Xpert might displace so-called true-positive, rather than false-positive, empirical treatment. We suggest types of studies needed to accurately assess the effect of new tuberculosis tests and the role of empirical treatment in real-world settings. Until such questions can be addressed, and empirical treatment is appropriately characterised, we postulate that the estimated population-level effect of new tests such as Xpert might be substantially overestimated.

Do we need to detect isoniazid resistance in addition to rifampicin resistance in diagnostic tests for tuberculosis? (2014). Denkinger CM., Pai M., Dowdy DW, PloS one, 9, e84197

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BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is resistant to both rifampicin (RIF) and isoniazid (INH). Whereas many TB diagnostics detect RIF-resistance, few detect INH-monoresistance, which is common and may increase risk of acquired MDR-TB. Whether inclusion of INH-resistance in a first-line rapid test for TB would have an important impact on MDR-TB rates remains uncertain. METHODS: WE DEVELOPED A TRANSMISSION MODEL TO EVALUATE THREE TESTS IN A POPULATION SIMILAR TO THAT OF INDIA: a rapid molecular test for TB, the same test plus RIF-resistance detection ("TB+RIF"), and detection of RIF and INH-resistance ("TB+RIF/INH"). Our primary outcome was the prevalence of INH-resistant and MDR-TB at ten years. RESULTS: Compared to the TB test alone and assuming treatment of all diagnosed MDR cases, the TB+RIF test reduced the prevalence of MDR-TB among all TB cases from 5.5% to 3.8% (30.6% reduction, 95% uncertainty range, UR: 17-54%). Despite using liberal assumptions about the impact of INH-monoresistance on treatment outcomes and MDR-TB acquisition, expansion from TB+RIF to TB+RIF/INH lowered this prevalence only from 3.8% to 3.6% further (4% reduction, 95% UR: 3-7%) and INH-monoresistant TB from 15.8% to 15.1% (4% reduction, 95% UR: (-8)-19%). CONCLUSION: When added to a rapid test for TB plus RIF-resistance, detection of INH-resistance has minimal impact on transmission of TB, MDR-TB, and INH-monoresistant TB.

Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. (2014). Pai M., Denkinger CM., Kik SV., Rangaka MX., Zwerling A., Oxlade O., Metcalfe JZ., Cattamanchi A., Dowdy DW., Dheda K., Banaei N, Clinical microbiology reviews, 27, 3-20

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Identification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-gamma) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate a cellular immune response to M. tuberculosis. Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosis infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers.

- November 2013 -

Rapid molecular testing for TB to guide respiratory isolation in the U.S.: a cost-benefit analysis. (2013). Millman AJ., Dowdy DW., Miller CR., Brownell R., Metcalfe JZ., Cattamanchi A., Davis JL, PloS one, 8, e79669

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BACKGROUND: Respiratory isolation of inpatients during evaluation for TB is a slow and costly process in low-burden settings. Xpert MTB/RIF (Xpert) is a novel molecular test for tuberculosis (TB) that is faster and more sensitive but substantially more expensive than smear microscopy. No previous studies have examined the costs of molecular testing as a replacement for smear microscopy in this setting. METHODS: We conducted an incremental cost-benefit analysis comparing the use of a single negative Xpert versus two negative sputum smears to release consecutive adult inpatients with presumed TB from respiratory isolation at an urban public hospital in the United States. We estimated all health-system costs and patient outcomes related to Xpert implementation, diagnostic evaluation, isolation, hospitalization, and treatment. We performed sensitivity and probabilistic uncertainty analyses to determine at what threshold the Xpert strategy would become cost-saving. RESULTS: Among a hypothetical cohort of 234 individuals undergoing evaluation for presumed active TB annually, 6.4% had culture-positive TB. Compared to smear microscopy, Xpert reduced isolation bed utilization from an average of 2.7 to 1.4 days per patient, leading to a 48% reduction in total annual isolation bed usage from 632 to 328 bed-days. Xpert saved an average of $2,278 (95% uncertainty range $1582-4570) per admission, or $533,520 per year, compared with smear microscopy. CONCLUSIONS: Molecular testing for TB could provide substantial savings to hospitals in high-income countries by reducing respiratory isolation usage and overall length of stay.

Physical complications in acute lung injury survivors: a two-year longitudinal prospective study. (2013). Fan E., Dowdy DW., Colantuoni E., Mendez-Tellez PA., Sevransky JE., Shanholtz C., Himmelfarb CR., Desai SV., Ciesla N., Herridge MS., Pronovost PJ., Needham DM, Critical care medicine, 42, 849-59

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OBJECTIVE: Survivors of severe critical illness frequently develop substantial and persistent physical complications, including muscle weakness, impaired physical function, and decreased health-related quality of life. Our objective was to determine the longitudinal epidemiology of muscle weakness, physical function, and health-related quality of life and their associations with critical illness and ICU exposures. DESIGN: A multisite prospective study with longitudinal follow-up at 3, 6, 12, and 24 months after acute lung injury. SETTING: Thirteen ICUs from four academic teaching hospitals. PATIENTS: Two hundred twenty-two survivors of acute lung injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At each time point, patients underwent standardized clinical evaluations of extremity, hand grip, and respiratory muscle strength; anthropometrics (height, weight, mid-arm circumference, and triceps skin fold thickness); 6-minute walk distance, and the Medical Outcomes Short-Form 36 health-related quality of life survey. During their hospitalization, survivors also had detailed daily evaluation of critical illness and related treatment variables. Over one third of survivors had objective evidence of muscle weakness at hospital discharge, with most improving within 12 months. This weakness was associated with substantial impairments in physical function and health-related quality of life that persisted at 24 months. The duration of bed rest during critical illness was consistently associated with weakness throughout 24-month follow-up. The cumulative dose of systematic corticosteroids and use of neuromuscular blockers in the ICU were not associated with weakness. CONCLUSIONS: Muscle weakness is common after acute lung injury, usually recovering within 12 months. This weakness is associated with substantial impairments in physical function and health-related quality of life that continue beyond 24 months. These results provide valuable prognostic information regarding physical recovery after acute lung injury. Evidence-based methods to reduce the duration of bed rest during critical illness may be important for improving these long-term impairments.

Tuberculosis control in a socially vulnerable area: a community intervention beyond DOT in a Brazilian favela. (2013). Soares EC., Vollmer WM., Cavalcante SC., Pacheco AG., Saraceni V., Silva JS., Neves GR., Golub JE., Efron AR., Durovni B., Chaisson RE, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 17, 1581-6

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OBJECTIVES: To evaluate the population-based impact of a comprehensive intervention to strengthen tuberculosis (TB) control in Rocinha, the largest urban slum in Rio de Janeiro, Brazil. DESIGN: In July 2003, 40 lay persons were hired and trained as community health workers to supervise treatment, implement educational activities and establish a supportive social network for anti-tuberculosis treatment. Between July 2005 and June 2008, a door-to-door active case finding campaign was conducted. Data were obtained from the Brazilian National Reporting System, which collects information from the TB notification form for every reported case. RESULTS: Between January 2001 and December 2008, 2623 TB cases were reported, 852 before and 1771 after the start of the program. Following the intervention, treatment success rates increased (67.6% vs. 83.2%, P < 0.001) and default rates dropped (17.8% vs. 5.5%, P < 0.001). Compared to the pre-intervention period, the TB case rate declined by an average of 39 cases per 100,000 population per 6 months (P = 0.003) in the post-intervention period, although this may have been due to secular trends already in place at the start of the intervention. Case rates declined from 591/100,000 in 2001 to 496/100,000 in 2008. CONCLUSION: With proper planning and effective community involvement, a successful intervention can lead to high cure rates and may contribute to a decrease in TB notification rates.

Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial. (2013). Theron G., Zijenah L., Chanda D., Clowes P., Rachow A., Lesosky M., Bara W., Mungofa S., Pai M., Hoelscher M., Dowdy D., Pym A., Mwaba P., Mason P., Peter J., Dheda K, Lancet (London, England), 383, 424-35

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BACKGROUND: The Xpert MTB/RIF test for tuberculosis is being rolled out in many countries, but evidence is lacking regarding its implementation outside laboratories, ability to inform same-day treatment decisions at the point of care, and clinical effect on tuberculosis-related morbidity. We aimed to assess the feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing at primary-care health-care facilities in southern Africa. METHODS: In this pragmatic, randomised, parallel-group, multicentre trial, we recruited adults with symptoms suggestive of active tuberculosis from five primary-care health-care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. Eligible patients were randomly assigned using pregenerated tables to nurse-performed Xpert MTB/RIF at the clinic or sputum smear microscopy. Participants with a negative test result were empirically managed according to local WHO-compliant guidelines. Our primary outcome was tuberculosis-related morbidity (measured with the TBscore and Karnofsky performance score [KPS]) in culture-positive patients who had begun anti-tuberculosis treatment, measured at 2 months and 6 months after randomisation, analysed by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT01554384. FINDINGS: Between April 12, 2011, and March 30, 2012, we randomly assigned 758 patients to smear microscopy (182 culture positive) and 744 to Xpert MTB/RIF (185 culture positive). Median TBscore in culture-positive patients did not differ between groups at 2 months (2 [IQR 0-3] in the smear microscopy group vs 2 [0.25-3] in the MTB/RIF group; p=0.85) or 6 months (1 [0-3] vs 1 [0-3]; p=0.35), nor did median KPS at 2 months (80 [70-90] vs 90 [80-90]; p=0.23) or 6 months (100 [90-100] vs 100 [90-100]; p=0.85). Point-of-care MTB/RIF had higher sensitivity than microscopy (154 [83%] of 185 vs 91 [50%] of 182; p=0.0001) but similar specificity (517 [95%] 544 vs 540 [96%] of 560; p=0.25), and had similar sensitivity to laboratory-based MTB/RIF (292 [83%] of 351; p=0.99) but higher specificity (952 [92%] of 1037; p=0.0173). 34 (5%) of 744 tests with point-of-care MTB/RIF and 82 (6%) of 1411 with laboratory-based MTB/RIF failed (p=0.22). Compared with the microscopy group, more patients in the MTB/RIF group had a same-day diagnosis (178 [24%] of 744 vs 99 [13%] of 758; p<0.0001) and same-day treatment initiation (168 [23%] of 744 vs 115 [15%] of 758; p=0.0002). Although, by end of the study, more culture-positive patients in the MTB/RIF group were on treatment due to reduced dropout (15 [8%] of 185 in the MTB/RIF group did not receive treatment vs 28 [15%] of 182 in the microscopy group; p=0.0302), the proportions of all patients on treatment in each group by day 56 were similar (320 [43%] of 744 in the MTB/RIF group vs 317 [42%] of 758 in the microscopy group; p=0.6408). INTERPRETATION: Xpert MTB/RIF can be accurately administered by a nurse in primary-care clinics, resulting in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment. However, the benefits did not translate into lower tuberculosis-related morbidity, partly because of high levels of empirical-evidence-based treatment in smear-negative patients. FUNDING: European and Developing Countries Clinical Trials Partnership, National Research Foundation, and Claude Leon Foundation.

- October 2013 -

Population-level impact of active tuberculosis case finding in an Asian megacity. (2013). Dowdy DW., Lotia I., Azman AS., Creswell J., Sahu S., Khan AJ, PloS one, 8, e77517

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BACKGROUND: The potential population-level impact of private-sector initiatives for tuberculosis (TB) case finding in Southeast Asia remains uncertain. In 2011, the Indus Hospital TB Control Program in Karachi, Pakistan, undertook an aggressive case-finding campaign that doubled notification rates, providing an opportunity to investigate potential population-level effects. METHODS: We constructed an age-structured compartmental model of TB in the intervention area. We fit the model using field and literature data, assuming that TB incidence equaled the estimated nationwide incidence in Pakistan (primary analysis), or 1.5 times greater (high-incidence scenario). We modeled the intervention as an increase in the rate of formal-sector TB diagnosis and evaluated the potential impact of sustaining this rate for five years. RESULTS: In the primary analysis, the five-year intervention averted 24% (95% uncertainty range, UR: 18-30%) of five-year cumulative TB cases and 52% (95% UR: 45-57%) of cumulative TB deaths. Corresponding reductions in the high-incidence scenario were 12% (95% UR: 8-17%) and 27% (95% UR: 21-34%), although the absolute number of lives saved was higher. At the end of five years, TB notification rates in the primary analysis were below their 2010 baseline, incidence had dropped by 45%, and annual mortality had fallen by 72%. About half of the cumulative impact on incidence and mortality could be achieved with a one-year intervention. CONCLUSIONS: Sustained, multifaceted, and innovative approaches to TB case-finding in Asian megacities can have substantial community-wide epidemiological impact.

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