Accurate diagnosis and subsequent treatment of latent tuberculosis infection (LTBI) is essential for TB elimination. However, the absence of a gold standard test for diagnosing LTBI makes assessment ...of the true prevalence of LTBI and the accuracy of diagnostic tests challenging. Bayesian latent class models can be used to make inferences about disease prevalence and the sensitivity and specificity of diagnostic tests using data on the concordance between tests. We performed the largest meta-analysis to date aiming to evaluate the performance of tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) for LTBI diagnosis in various patient populations using Bayesian latent class modelling.
Systematic search of PubMeb, Embase and African Index Medicus was conducted without date and language restrictions on September 11, 2017 to identify studies that compared the performance of TST and IGRAs for LTBI diagnosis. Two IGRA methods were considered: QuantiFERON-TB Gold In Tube (QFT-GIT) and T-SPOT.TB. Studies were included if they reported 2x2 agreement data between TST and QFT-GIT or T-SPOT.TB. A Bayesian latent class model was developed to estimate the sensitivity and specificity of TST and IGRAs in various populations, including immune-competent adults, immune-compromised adults and children. A TST cut-off value of 10 mm was used for immune-competent subjects and 5 mm for immune-compromised individuals.
A total of 157 studies were included in the analysis. In immune-competent adults, the sensitivity of TST and QFT-GIT were estimated to be 84% (95% credible interval CrI 82-85%) and 52% (50-53%), respectively. The specificity of QFT-GIT was 97% (96-97%) in non-BCG-vaccinated and 93% (92-94%) in BCG-vaccinated immune-competent adults. The estimated figures for TST were 100% (99-100%) and 79% (76-82%), respectively. T-SPOT.TB has comparable specificity (97% for both tests) and better sensitivity (68% versus 52%) than QFT-GIT in immune-competent adults. In immune-compromised adults, both TST and QFT-GIT display low sensitivity but high specificity. QFT-GIT and TST are equally specific (98% for both tests) in non-BCG-vaccinated children; however, QFT-GIT is more specific than TST (98% versus 82%) in BCG-vaccinated group. TST is more sensitive than QFT-GIT (82% versus 73%) in children.
This study is the first to assess the utility of TST and IGRAs for LTBI diagnosis in different population groups using all available data with Bayesian latent class modelling. Our results challenge the current beliefs about the performance of LTBI screening tests, and have important implications for LTBI screening policy and practice. We estimated that the performance of IGRAs is not as reliable as previously measured in the general population. However, IGRAs are not or minimally affected by BCG and should be the preferred tests in this setting. Adoption of IGRAs in settings where BCG is widely administered will allow for a more accurate identification and treatment of LTBI.
Drug-resistant tuberculosis (DR-TB) is an ongoing challenge in the Torres Strait Islands (TSI) / Papua New Guinea (PNG) border region. Treatment success rates have historically been poor for patients ...diagnosed with DR-TB, leading to increased transmission. This study aimed to identify variables associated with unfavourable outcome in patients diagnosed with DR-TB to inform programmatic improvements. A retrospective study of all DR-TB cases who presented to Australian health facilities in the Torres Strait between 1 March 2000 and 31 March 2020 was performed. This time period covers four distinct TB programmatic approaches which reflect Australian and Queensland Government decisions on TB management in this remote region. Univariate and multivariate predictors of unfavourable outcome were analysed. Unfavourable outcome was defined as lost to follow up, treatment failure and death. Successful outcome was defined as cure and treatment completion. In total, 133 patients with resistance to at least one TB drug were identified. The vast majority (123/133; 92%) of DR-TB patients had pulmonary involvement; and of these, 41% (50/123) had both pulmonary and extrapulmonary TB. Unfavourable outcomes were observed in 29% (39/133) of patients. Patients living with human immunodeficiency virus, renal disease or diabetes (4/133; 4/133; 3/133) had an increased frequency of unfavourable outcome (p <0.05), but the numbers were small. Among all 133 DR-TB patients, 41% had a low lymphocyte count, which was significantly associated with unfavourable outcome (p <0.05). We noted a 50% increase in successful outcomes achieved in the 2016-2020 programmatic period, compared to earlier periods (OR 5.3, 95% Confidence Interval 1.3, 20.4). Being a close contact of a known TB case was associated with improved outcome. While DR-TB treatment outcomes have improved over time, enhanced surveillance for DR-TB, better cross border collaboration and consistent diagnosis and management of comorbidities and other risk factors should further improve patient care and outcomes.
COVID-19 is not only a global pandemic and public health crisis; it has also severely affected the global economy and financial markets. Significant reductions in income, a rise in unemployment, and ...disruptions in the transportation, service, and manufacturing industries are among the consequences of the disease mitigation measures that have been implemented in many countries. It has become clear that most governments in the world underestimated the risks of rapid COVID-19 spread and were mostly reactive in their crisis response. As disease outbreaks are not likely to disappear in the near future, proactive international actions are required to not only save lives but also protect economic prosperity.
We present a mathematical model to simulate tuberculosis (TB) transmission in highly endemic regions of the Asia-Pacific, where epidemiology does not appear to be primarily driven by HIV-coinfection. ...The ten-compartment deterministic model captures many of the observed phenomena important to disease dynamics, including partial and temporary vaccine efficacy, declining risk of active disease following infection, the possibility of reinfection both during the infection latent period and after treatment, multidrug resistant TB (MDR-TB) and de novo resistance during treatment. We found that the model could not be calibrated to the estimated incidence rate without allowing for reinfection during latency, and that even in the presence of a moderate fitness cost and a lower value of R0, MDR-TB becomes the dominant strain at equilibrium. Of the modifiable programmatic parameters, the rate of detection and treatment commencement was the most important determinant of disease rates with each respective strain, while vaccination rates were less important. Improved treatment of drug-susceptible TB did not result in decreased rates of MDR-TB through prevention of de novo resistance, but rather resulted in a modest increase in MDR-TB through strain replacement. This was due to the considerably greater relative contribution of community transmission to MDR-TB incidence, by comparison to de novo amplification of resistance in previously susceptible strains.
•We present a model for simulation of programmatic responses to tuberculosis in highly endemic countries of the Asia-Pacific.•The model presented cannot be calibrated to estimated incidence rates without allowing for reinfection during latency.•Even in the presence of a moderate fitness cost, MDR-TB dominates at equilibrium.•Improved treatment of drug-susceptible TB does not result in decreased rates of MDR-TB through prevention of de novo resistance.•Community transmission to MDR-TB incidence contributes markedly more to MDR-TB burden than resistance amplification under our model structure.
Tuberculosis (TB) is the seventh leading cause of morbidity and mortality in Bangladesh. Although the National TB control program (NTP) of Bangladesh is implementing its nationwide TB control ...strategies, more specific and effective single or combination interventions are needed to control drug-susceptible (DS) and multi-drug resistant (MDR) TB. In this study, we developed a two strain TB mathematical model with amplification and fit it to the Bangladesh TB data to understand the transmission dynamics of DS and MDR TB. Sensitivity analysis was used to identify important parameters. We evaluated the cost-effectiveness of varying combinations of four basic control strategies including distancing, latent case finding, case holding and active case finding, all within the optimal control framework. From our fitting, the model with different transmission rates between DS and MDR TB best captured the Bangladesh TB reported case counts. The estimated basic reproduction number for DS TB was 1.14 and for MDR TB was 0.54, with an amplification rate of 0.011 per year. The sensitivity analysis also indicated that the transmission rates for both DS and MDR TB had the largest influence on prevalence. To reduce the burden of TB (both DS and MDR), our finding suggested that a quadruple control strategy that combines distancing control, latent case finding, case holding and active case finding is the most cost-effective. Alternative strategies can be adopted to curb TB depending on availability of resources and policy makers’ decisions.
The WHO's draft HCV elimination targets propose an 80% reduction in incidence and a 65% reduction in HCV-related deaths by 2030. We estimate the treatment scale-up required and cost-effectiveness of ...reaching these targets among injecting drug use (IDU)-acquired infections using Australian disease estimates.
A mathematical model of HCV transmission, liver disease progression and treatment among current and former people who inject drugs (PWID). Treatment scale-up and the most efficient allocation to priority groups (PWID or patients with advanced liver disease) were determined; total healthcare and treatment costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) compared with inaction were calculated.
5662 (95% CI 5202 to 6901) courses per year (30/1000 IDU-acquired infections) were required, prioritised to patients with advanced liver disease, to reach the mortality target. 4725 (3278-8420) courses per year (59/1000 PWID) were required, prioritised to PWID, to reach the incidence target; this also achieved the mortality target, but to avoid clinically unacceptable HCV-related deaths an additional 5564 (1959-6917) treatments per year (30/1000 IDU-acquired infections) were required for 5 years for patients with advanced liver disease. Achieving both targets in this way cost $A4.6 ($A4.2-$A4.9) billion more than inaction, but gained 184 000 (119 000-417 000) QALYs, giving an ICER of $A25 121 ($A11 062-$A39 036) per QALY gained.
Achieving WHO elimination targets with treatment scale-up is likely to be cost-effective, based on Australian HCV burden and demographics. Reducing incidence should be a priority to achieve both WHO elimination goals in the long-term.
Tuberculosis (TB) transmission often occurs within a household or community, leading to heterogeneous spatial patterns. However, apparent spatial clustering of TB could reflect ongoing transmission ...or co-location of risk factors and can vary considerably depending on the type of data available, the analysis methods employed and the dynamics of the underlying population. Thus, we aimed to review methodological approaches used in the spatial analysis of TB burden.
We conducted a systematic literature search of spatial studies of TB published in English using Medline, Embase, PsycInfo, Scopus and Web of Science databases with no date restriction from inception to 15 February 2017. The protocol for this systematic review was prospectively registered with PROSPERO ( CRD42016036655 ).
We identified 168 eligible studies with spatial methods used to describe the spatial distribution (n = 154), spatial clusters (n = 73), predictors of spatial patterns (n = 64), the role of congregate settings (n = 3) and the household (n = 2) on TB transmission. Molecular techniques combined with geospatial methods were used by 25 studies to compare the role of transmission to reactivation as a driver of TB spatial distribution, finding that geospatial hotspots are not necessarily areas of recent transmission. Almost all studies used notification data for spatial analysis (161 of 168), although none accounted for undetected cases. The most common data visualisation technique was notification rate mapping, and the use of smoothing techniques was uncommon. Spatial clusters were identified using a range of methods, with the most commonly employed being Kulldorff's spatial scan statistic followed by local Moran's I and Getis and Ord's local Gi(d) tests. In the 11 papers that compared two such methods using a single dataset, the clustering patterns identified were often inconsistent. Classical regression models that did not account for spatial dependence were commonly used to predict spatial TB risk. In all included studies, TB showed a heterogeneous spatial pattern at each geographic resolution level examined.
A range of spatial analysis methodologies has been employed in divergent contexts, with all studies demonstrating significant heterogeneity in spatial TB distribution. Future studies are needed to define the optimal method for each context and should account for unreported cases when using notification data where possible. Future studies combining genotypic and geospatial techniques with epidemiologically linked cases have the potential to provide further insights and improve TB control.
From October 2014 to February 2019, local authorities in Townsville, North Queensland, Australia continually introduced Wolbachia-infected mosquitoes to control seasonal outbreaks of dengue ...infection. In this study, we develop a mathematical modelling framework to estimate the effectiveness of this intervention as well as the relative dengue transmission rates of Wolbachia-infected and wild-type mosquitoes. We find that the transmission rate of Wolbachia-infected mosquitoes is reduced approximately by a factor of 20 relative to the uninfected wild-type population. In addition, the Townsville Wolbachia release program led to a 65% reduction in predicted dengue incidence during the release period and over 95% reduction in the 24 months that followed. Finally, to investigate the potential impact of other Wolbachia release programs, we use our estimates of relative transmissibility to calculate the relationship between the reproductive number of dengue and the proportion of Wolbachia-infected mosquitoes in the vector population.
Background It is often stated that the lifetime risk of developing active TB after an index infection is 5% to 10%, one-half of which accrues in the 2 to 5 years following infection. The goal of this ...study was to determine whether such estimates are consistent with local programmatic data. Methods This study included close contacts of individuals with active pulmonary TB notified in the Australian state of Victoria from January 1, 2005, to December 31, 2013, who we deemed to have been infected as a result of their exposure. Survival analysis was first performed on the assumption of complete follow-up through to the end of the study period. The analysis was then repeated with imputation of censorship for migration, death, and preventive treatment, using local mortality and migration data combined with programmatic data on the administration of preventive therapy. Results Of 613 infected close contacts, 67 (10.9%) developed active TB during the study period. Assuming complete follow-up, the 1,650-day cumulative hazard was 11.5% (95% CI, 8.9-14.1). With imputation of censorship for death, migration, and preventive therapy, the median 1,650-day cumulative hazard over 10,000 simulations was 14.5% (95% CI, 11.1-17.9). Most risk accrued in the first 5 months after infection, and risk was greatest in the group aged < 5 years, reaching 56.0% with imputation, but it was also elevated in older children (27.6% in the group aged 5-14 years). Conclusions The risk of active TB following infection is several-fold higher than traditionally accepted estimates, and it is particularly high immediately following infection and in children.
Low doses of acetyl salicylic acid, acting through 15-epi-lipoxin A4, have been shown to be anti-inflammatory in human studies. The manifold effects of acetyl salicylic acid on human physiology ...potentially may benefit patients with the systemic inflammatory response syndrome after sepsis or tissue trauma. We sought to determine whether acetyl salicylic acid administration at the time of development of systemic inflammatory response syndrome is associated with reduced mortality.
Retrospective cohort study of consecutive intensive care unit admissions between April 2000 and November 2009.
Australian tertiary referral center.
Seven-thousand nine-hundred forty-five intensive care unit admissions examined.
The probability of in-hospital death during admissions in which individuals were identified as having systemic inflammatory response syndrome or sepsis was analyzed according to whether they were administered acetyl salicylic acid. Propensity analysis that matched all patients for their probability of being prescribed acetyl salicylic acid was undertaken. Among 5523 patients with a first episode of systemic inflammatory response syndrome, 2082 were administered acetyl salicylic acid in a 24-hr period around the time of systemic inflammatory response syndrome recognition. Propensity analysis showed a 10.9% mortality for acetyl salicylic acid users and 17.2% mortality in the propensity-matched nonusers (absolute risk difference -6.2%; 95% confidence interval -9.5% to -3.5%). Propensity matching also found that acetyl salicylic acid administration was associated with increased risk of renal injury (6.2% vs. 2.9%; absolute risk difference 13.3%; 95% confidence interval 2.5% to 5.0%). In the 970 patients with proven sepsis, acetyl salicylic acid administration was associated with a lower mortality (27.4% vs. 42.2%; absolute risk difference -14.8%; 95% confidence interval -18.9% to -8.6%) after propensity matching. This quasi-experimental study cannot establish a causal association between acetyl salicylic acid and death from systemic inflammatory response syndrome or sepsis. Unrecognized confounders may remain but numerous covariates are included in the analyses.
Our study shows a strong association between acetyl salicylic acid and survival in intensive care unit systemic inflammatory response syndrome and sepsis patients. The effect of acetyl salicylic acid treatment on mortality of patients with systemic inflammatory response syndrome and sepsis needs to be evaluated with prospective randomized intervention studies.
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