Diagnostic Tests For Tuberculosis Research Articles

Magnitude and Reasons for Gaps in Tuberculosis Diagnostic Testing and Treatment Initiation: An Operational Research Study from Dakshina Kannada, South India

BackgroundIn India, ensuring all Persons with Presumptive TB (PPTB) undergo TB diagnostic tests and initiating all diagnosed TB patients on treatment are two major implementation challenges.ObjectivesIn a coastal district of Karnataka state, South India, to (1) determine the number and proportion of PPTB who did not undergo any TB diagnostic test, and the number and proportion of TB patients who were not initiated on treatment (2) explore the facilitators and barriers in TB diagnostic testing and treatment initiation from health care providers’ perspective.MethodsFor objective-1, we used a cross-sectional design involving review of data of PPTB enrolled for care during January– March 2019 and for objective-2, we used a qualitative design involving key informant interviews of health care providers.ResultsOf 8822 PPTB patients enrolled for evaluation of TB, 767 (9%) had not undergone any TB diagnostic test. In those who had undergone any TB diagnostic test, a total of 822 were diagnosed with TB and of them, 26 (3%) were not initiated on treatment. Cartridge-based nucleic acid amplification tests was used as a diagnostic test only among 1188 (13.5%) PPTB patients. The gaps in diagnostic testing were due to: non-availability of doctors/lab-technicians, inadequate knowledge about TB diagnostic tests among health care providers, reluctance of patients to undergo the TB diagnostic tests due to stigma/confidentiality issues and sub-optimal engagement of private health facilities for TB control.ConclusionAbout 9% of PPTB not undergoing any test for TB and 3% of the TB patients not initiated on treatment are of major concern. Revised National TB Control Programme needs to address the identified barriers to improve the process of TB diagnosis and treatment initiation.

Predicting the impact of patient and private provider behavior on diagnostic delay for pulmonary tuberculosis patients in India: A simulation modeling study.

BackgroundTuberculosis (TB) incidence in India continues to be high due, in large part, to long delays experienced by patients before successful diagnosis and treatment initiation, especially in the private sector. This diagnostic delay is driven by patients’ inclination to switch between different types of providers and providers’ inclination to delay ordering of accurate diagnostic tests relevant to TB. Our objective is to quantify the impact of changes in these behavioral characteristics of providers and patients on diagnostic delay experienced by pulmonary TB patients.Methods and findingsWe developed a discrete event simulation model of patients’ diagnostic pathways that captures key behavioral characteristics of providers (time to order a test) and patients (time to switch to another provider). We used an expectation-maximization algorithm to estimate the parameters underlying these behavioral characteristics, with quantitative data encoded from detailed interviews of 76 and 64 pulmonary TB patients in the 2 Indian cities of Mumbai and Patna, respectively, which were conducted between April and August 2014. We employed the estimated model to simulate different counterfactual scenarios of diagnostic pathways under altered behavioral characteristics of providers and patients to predict their potential impact on the diagnostic delay. Private healthcare providers including chemists were the first point of contact for the majority of TB patients in Mumbai (70%) and Patna (94%). In Mumbai, 45% of TB patients first approached less-than-fully-qualified providers (LTFQs), who take 28.71 days on average for diagnosis. About 61% of these patients switched to other providers without a diagnosis. Our model estimates that immediate testing for TB by LTFQs at the first visit (at the current level of diagnostic accuracy) could reduce the average diagnostic delay from 35.53 days (95% CI: 34.60, 36.46) to 18.72 days (95% CI: 18.01, 19.43). In Patna, 61% of TB patients first approached fully qualified providers (FQs), who take 9.74 days on average for diagnosis. Similarly, immediate testing by FQs at the first visit (at the current level of diagnostic accuracy) could reduce the average diagnostic delay from 23.39 days (95% CI: 22.77, 24.02) to 11.16 days (95% CI: 10.52, 11.81). Improving the diagnostic accuracy of providers per se, without reducing the time to testing, was not predicted to lead to any reduction in diagnostic delay. Our study was limited because of its restricted geographic scope, small sample size, and possible recall bias, which are typically associated with studies of patient pathways using patient interviews.ConclusionsIn this study, we found that encouraging private providers to order definitive TB diagnostic tests earlier during patient consultation may have substantial impact on reducing diagnostic delay in these urban Indian settings. These results should be combined with disease transmission models to predict the impact of changes in provider behavior on TB incidence.

Detection of Mycobacterial CFP-10 (Rv3874) Protein in Tuberculosis Patients by Gold Nanoparticle-Based Real-Time Immuno-PCR

Aim: Timely and reliable diagnostic test for tuberculosis (TB) is immediately required. Attempts were made to improve the technology and diagnostic potential of real-time immuno-PCR (RT-I-PCR). Methods: We designed gold nanoparticle (GNP)-based RT-I-PCR (GNP-RT-I-PCR) assay for the detection of Mycobacterium tuberculosis CFP-10 (Rv3874) protein in clinical samples of TB patients. Results: A wide quantitative detection range of CFP-10 was found to be 0.5-5×104pg/ml in bodily fluids of TB patients, which can evaluate the progression of disease. Moreover, sensitivities of 83.7 and 76.2% were observed in pulmonary (n=49) and extrapulmonary TB (n=42) patients, respectively, with specificities of 93.5-93.8% (n=63). Conclusion: Conjugation of detection antibodies and oligonucleotides to functionalized GNPs of GNP-RT-I-PCR is relatively easier, compared with streptavidin-biotin/succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate system employed in RT-I-PCR. Our assay also showed better diagnostic performance than RT-I-PCR, which may provide a viable platform for the development of an efficient TB diagnostic test.

Accuracy and consequences of using trial-of-antibiotics for TB diagnosis (ACT-TB study): protocol for a randomised controlled clinical trial

IntroductionOver 40% of global tuberculosis case notifications are diagnosed clinically without mycobacteriological confirmation. Standard diagnostic algorithms include ‘trial-of-antibiotics’—empirical antibiotic treatment given to mycobacteriology-negative individuals to treat infectious causes of symptoms...

Risk factors of delayed isolation of patients with pulmonary tuberculosis

ObjectivesThe aim was to examine the rate of delayed or no isolation of hospitalized patients with pulmonary tuberculosis (TB) and the causes for isolation failure. MethodsThis retrospective study included patients with pulmonary TB at a university-affiliated hospital in South Korea between January 2015 and June 2018 after excluding those with a stay ≤2 days and those who only visited the emergency department. Patients who were not isolated for ≥3 days were classified as the delayed or no isolation group. We compared the clinical findings and diagnostic test results, between patients managed with delayed or no isolation (D-isolation) and timely isolation (T-isolation). ResultsOf 486 patients with pulmonary TB, 222 patients were included. In 106 cases (47.7%), isolation was delayed or not applied, while in 116 cases, isolation was applied in a timely manner. Typical findings of TB were seen on the chest X-rays of 87 (75.0%) patients in the T-isolation group versus 25 (23.6%) patients in the D-isolation group (p < 0.001). Other factors significantly associated with delayed or no isolation on univariate analyses were older age, admission route (emergency room vs. other), admitting department, negative acid-fast bacilli (AFB) stain, and negative MTB PCR. On multivariate analysis, admission through an outpatient clinic, admission to a department other than infectious diseases or pulmonology, an atypical chest X-ray finding and negative sputum AFB stains were risk factors for isolation failure. DiscussionDelayed or no isolation of patients with pulmonary TB was attributed mainly to atypical radiological findings and negative findings of direct TB diagnostic tests.

Improving the design of studies evaluating the impact of diagnostic tests for tuberculosis on health outcomes: a qualitative study of perspectives of diverse stakeholders

Background: Studies evaluating the impact of Xpert MTB/RIF testing for tuberculosis (TB) have demonstrated varied effects on health outcomes with many studies showing inconclusive results. We explored perceptions among diverse stakeholders about studies evaluating the impact of TB diagnostic tests, and identified suggestions for improving these studies. Methods: We used purposive sampling with consideration for differing expertise and geographical balance and conducted in depth semi-structured interviews. We interviewed English-speaking participants, including TB patients, and others involved in research, care or decision-making about TB diagnostics. We used the thematic approach to code and analyse the interview transcripts. Results: We interviewed 31 participants. Our study showed that stakeholders had different expectations with regard to test impact and how it is measured. TB test impact studies were perceived to be important for supporting implementation of tests but there were concerns about the unrealistic expectations placed on tests to improve outcomes in health systems with many influencing factors. To improve TB test impact studies, respondents suggested conducting health system assessments prior to the study; developing clear guidance on the study methodology and interpretation; improving study design by describing questions and interventions that consider the influences of the health-care ecosystem on the diagnostic test; selecting the target population at the health-care level most likely to benefit from the test; setting realistic targets for effect sizes in the sample size calculations; and interpreting study results carefully and avoiding categorisation and interpretation of results based on statistical significance alone. Researchers should involve multiple stakeholders in the design of studies. Advocating for more funding to support robust studies is essential. Conclusion: TB test impact studies were perceived to be important to support implementation of tests but there were concerns about their complexity. Process evaluations of their health system context and guidance for their design and interpretation are recommended.

Evaluation of pulmonary tuberculosis diagnostic tests in children and adolescents at a pediatric reference center

IntroductionThis study evaluates the performance of individual and combinations tests used for pediatric tuberculosis diagnosis at a reference center. Materials and MethodsDiagnostic test outcomes from children with presumed pulmonary tuberculosis evaluated from January 2005 - July 2010 were compared to a standard diagnosis made by an expert panel of physicians. ResultsPresence of at least one sign/symptom, history of contact, or abnormal chest X-ray (aCXR) individually showed the highest sensitivity (85.7%). While the combination of history of contact, at least one sign/symptom, positive tuberculin skin test, and aCXR had low sensitivity of 20%, but the specificity and a positive predictive value were 100%, respectively. The combination of tests used in the International Union Against Tuberculosis and Lung Disease and the Brazilian Ministry of Health systems showed sensitivity of 28.6% and 71.4% and specificity of 95.8% and 97.0%, respectively. ConclusionsIn the absence of a gold standard, the combination of clinical history, tuberculin skin test, and aCXR, as well as the Brazilian scoring system serve as simple, low-cost approach that can be used for pediatric TB diagnosis by first-contact care providers.

Tapping private health sector for public health program? Findings of a novel intervention to tackle TB in Mumbai, India

BackgroundIndia carries one-fourth of the global tuberculosis (TB) burden. Hence the country has drafted the ambitious National Strategic Plan to eliminate tuberculosis by 2025. To realise this goal, India's Revised National Tuberculosis Control Programme (RNTCP) and partners piloted a novel strategy to engage private-providers for tuberculosis care via a “Private-provider Interface Agency” (PPIA) in Mumbai and other locations. InterventionThe program mapped and engaged private-providers, chemists, and laboratories; facilitated TB notification via call centers and field staff; provided free tuberculosis diagnostic tests and anti-TB drugs using novel electronic vouchers; monitored quality of care; and supported patients to ensure anti-TB treatment adherence and completion. This report summarises the descriptive analysis of PPIA implementation data piloted in Mumbai from 2014 to 2017. FindingsThe program mapped 8789 private doctors, 3438 chemists, and 985 laboratories. Of these, 3836 (44%) doctors, 285 (29%) laboratories, and 353 (10%) chemists were prioritized and engaged in the program. Over three and a half years, the program recorded 60,366 privately-notified tuberculosis patients, of which, 24,146 (40%) were microbiologically-confirmed, 5203 (9%) were rifampicin-resistant, and 4401 (7%) were paediatric TB patients. Mumbai's annual total TB case notification rate increased from a pre-program baseline of 272 per 100,000/year in 2013 to 416 per 100,000/year in 2017. Overall, 42,300 (78%) patients completed the TB treatment, and 4979 (9%) could not be evaluated. InterpretationThe PPIA program in Mumbai demonstrated that private-providers can be effectively engaged for TB control in urban India. This program has influenced national policy and has been adapted and funded for a country-wide scale up. The model may also be considered in conditions where private-provider engagement is needed to improve access and quality of care for any area of public health.

Two-stage classification of tuberculosis culture diagnosis using convolutional neural network with transfer learning

Tuberculosis (TB) has been one of top 10 leading causes of death. A computer-aided diagnosis system to accelerate TB diagnosis is crucial. In this paper, we apply convolutional neural network and deep learning to classify the images of TB culture test—the gold standard of TB diagnostic test. Since the dataset is small and imbalanced, a transfer learning approach is applied. Moreover, as the recall of non-negative class is an important metric for this application, we propose a two-stage classification method to boost the results. The experiment results on a real dataset of TB culture test (1727 samples with 16,503 images from Tao-Yuan General Hospital, Taiwan) show that the proposed method can achieve 99% precision and 98% recall on the non-negative class.

Molecular Epidemiology of &amp;lt;i&amp;gt;Mycobacterium tuberculosis&amp;lt;/i&amp;gt; among Pulmonary Tuberculosis Patients in Ilorin, Nigeria

Background: Tuberculosis (TB) is an infectious disease and it is a public health concern due to the endemic nature of the disease. Nigeria’s health systems still rely heavily on out-dated tuberculosis diagnostic tests; including sputum smear microscopy and chest radiography. This necessitated the urgent need to explore a more reliable, effective method that can rapidly enhance simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance. Aims: We evaluated the prevalence of MTB and rifampicin resistance and the influence of socio-demographic factors. Methods: A longitudinal, descriptive study that employs the Xpert MTB/RIF automated molecular method for rapid detection of rifampicin resistance. Secondary data were collected from the medical record from March 2017 to December 2018. Primary data were collected by direct clinical observations and analysis with gene expert machine from January 2019-March 2019. Results: Study populations were 1893 subjects pooled as secondary data at the Gene Expert laboratory, with a mean age of 44.92 years and were categorized based on sex, 1125 (59.4%) males and 768 (40.6%) females respectively. The MTB detected were 117 (15.7%) for males while 76 (9.9%) were positive for females. 948 (84.3%) were negative for males and 692 (90.1%) negative for females. Also, the categories for age were grouped into three but the older age groups (29 - 54) and (55 - 80) were more vulnerable to MTB having a p = 0.506 which is statistically non-significant; only 14 (5.5%) have RIF while 239 (94.5%) do not have RIF resistance strains. Logistic regression analysis of MTB detected showed a significant association (p 0.05) for age. The prevalence rate for RIF Resistance is 5.53%, there is a statistical difference p = 0.001 between RIF Resistance and MTB in Ilorin. Conclusion: The utilization of validated molecular technique for MTB strain identification has shown stronger epidemiological impetus for an improved care management outcome specifically in resources limited areas.

Point-Of-Care Urine LAM Tests for Tuberculosis Diagnosis: A Status Update.

Most diagnostic tests for tuberculosis (TB) rely on sputum samples, which are difficult to obtain and have low sensitivity in immunocompromised patients, patients with disseminated TB, and children, delaying treatment initiation. The World Health Organization (WHO) calls for the development of a rapid, biomarker-based, non-sputum test capable of detecting all forms of TB at the point-of-care to enable immediate treatment initiation. Lipoarabinomannan (LAM) is the only WHO-endorsed TB biomarker that can be detected in urine, an easily collected sample. This status update discusses the characteristics of LAM as a biomarker, describes the performance of first-generation urine LAM tests and reasons for slow uptake, and presents considerations for developing the next generation of more sensitive and impactful tests. Next-generation urine LAM tests have the potential to reach adult and pediatric patients regardless of HIV status or site of infection and facilitate global TB control. Implementation and scale-up of existing LAM tests and development of next-generation assays should be prioritized.

Drones Optimized Therapy System (DrOTS): Use of Drones for Tuberculosis Diagnosis in Nepal

Over 50% of the total Nepalese population lives in hilly and mountainous areas with extremely poor transportation and access to health care facilities. With advanced health centers concentrated only in urban areas, and diagnostic laboratories not being present in most primary healthcare facilities, majority of people are forced to have to walk by foot, in an average 6-8 hours, to access proper healthcare facilities. Drone Optimized Therapy System, (DrOTS) aims to improve access to healthcare access in rural villages of Nepal. The pilot phase currently involved improving the accessibility of Tuberculosis diagnostic tests by linking communit y health workers (CHWs) with state-of-the-art diagnostic tools (GeneXpert) via drones in two municipalities of Pyuthan district, Nepal. The drones fly from central Hospitals to remote healthcare centers and bring back sputum samples for diagnosis. The purpose of this project is to assist the Ministry of Health and Population (MoHP) and National Tuberculosis Center (NTC) by generating the data necessary to assess the suitability of the drones-based services for nationwide expansion. The aerial distance between any two points being lesser than the actual road distance, drone technology has come out as a very popular tool in transporting medical samples/medicines between health centers. Drones can be used as crucial tools to connect primary healthcare facilities to hospitals by delivering patient information such as blood, urine, sputum, stool etc. samples required for diagnosis from primary facilities to hospitals, and medicines from hospitals to patients in nearby rural locations for treatment. The project team consists of multisector experts; Public Health- Birat Nepal Medical Trust (BNMT), Drones &amp; Tech - WeRobotics, Nepal Flying Labs &amp; DroNepal, Research: The Liverpool School of Tropical Medicine, Govt. stakeholders: MoHP Nepal, the National TB Center and the District Public Health Office (DPHO Pyuthan) is supported by Stony Brook University and the Simons Foundation.International Journal of Human and Health Sciences Supplementary Issue: 2019 Page: 14

Swpermute: Permutation tests for Stepped-Wedge Cluster-Randomised Trials.

Permutation tests are useful in stepped-wedge trials to provide robust statistical tests of intervention-effect estimates. However, the Stata command permute does not produce valid tests in this setting because individual observations are not exchangeable. We introduce the swpermute command that permutes clusters to sequences to maintain exchangeability. The command provides additional functionality to aid users in performing analyses of stepped-wedge trials. In particular, we include the option "withinperiod" that performs the specified analysis separately in each period of the study with the resulting period-specific intervention-effect estimates combined as a weighted average. We also include functionality to test non-zero null hypotheses to aid the construction of confidence intervals. Examples of the application of swpermute are given using data from a trial testing the impact of a new tuberculosis diagnostic test on bacterial confirmation of a tuberculosis diagnosis.

Improved Alere Determine Lipoarabinomannan Antigen Detection Test for the Diagnosis of Human and Bovine Tuberculosis by Manipulating Urine and Milk

Tuberculosis (TB) disease still kills 1-person every 21-seconds. Few TB diagnostic tests are considered truly appropriate for point of care settings. The WHO-endorsed immunodiagnostic Alere Determine Lipoarabinomannan Ag-test (LAM-test) detects Mycobacterium tuberculosis complex LAM in urine, and its use is recommended for TB diagnosis among HIV co-infected individuals with low CD4 T-cell counts. Here we found that a simple 15-minute enzymatic treatment at room temperature of LAM-spiked urine with α-mannosidase (for human TB), and LAM-spiked milk with combined lactase and caseinase (for bovine TB), enhanced 10-fold the detection levels of the LAM-test and thus, improved the detection of LAM by the LAM-test in urine and milk that otherwise could be missed in the field. Future separate clinical research studies specifically designed to address the potential of these findings are required.

Improving the design of studies evaluating the impact of diagnostic tests for tuberculosis on health outcomes: a qualitative study of perspectives of diverse stakeholders.

Background: Studies evaluating the impact of Xpert MTB/RIF testing for tuberculosis (TB) have demonstrated varied effects on health outcomes with many studies showing inconclusive results. We explored perceptions among diverse stakeholders about studies evaluating the impact of TB diagnostic tests, and identified suggestions for improving these studies. Methods: We used purposive sampling with consideration for differing expertise and geographical balance and conducted in depth semi-structured interviews. We interviewed English-speaking participants, including TB patients, and others involved in research, care or decision-making about TB diagnostics. We used the thematic approach to code and analyse the interview transcripts. Results: We interviewed 31 participants. Our study showed that stakeholders had different expectations with regard to test impact and how it is measured. TB test impact studies were perceived to be important for supporting implementation of tests but there were concerns about the unrealistic expectations placed on tests to improve outcomes in health systems with many influencing factors. To improve TB test impact studies, respondents suggested conducting health system assessments prior to the study; developing clear guidance on the study methodology and interpretation; improving study design by describing questions and interventions that consider the influences of the health-care ecosystem on the diagnostic test; selecting the target population at the health-care level most likely to benefit from the test; setting realistic targets for effect sizes in the sample size calculations; and interpreting study results carefully and avoiding categorisation and interpretation of results based on statistical significance alone. Researchers should involve multiple stakeholders in the design of studies. Advocating for more funding to support robust studies is essential. Conclusion: TB test impact studies were perceived to be important to support implementation of tests but there were concerns about their complexity. Process evaluations of their health system context and guidance for their design and interpretation are recommended.

Bacillus Calmette–Guérin strains with defined resistance mutations: a new tool for tuberculosis laboratory quality control

ObjectiveLaboratory quality control (QC) is essential to assess the reliability of tuberculosis diagnostic testing. To provide safe QC reagents for the detection of drug-resistant Mycobacterium tuberculosis, we generated antibiotic-resistant mycobacterial strains of attenuated virulence (M. bovis bacillus Calmette–Guérin (BCG)). MethodsSeven mono-resistant BCG strains were developed by introducing resistance-conferring mutations into wild-type BCG strains. Mutations were confirmed by dideoxynucleotide sequencing. Phenotypic resistance was quantified by microbroth dilution to determine the MIC90. The capacity of two commercial tests (GeneXpert TB/RIF and Genotype MTBDRplus) to detect resistance-conferring mutations was evaluated independently. ResultsOur panel included BCG strains with mutations in rpoB (S450L, I491F), katG (deletion at AA428), gyrA (D94G), rpsL (K43R) and Rv0678c (S63R). These mutations translated respectively into phenotypic resistance to rifampin (MIC ≥8 mg/L), isoniazid (MIC ≥8 mg/L), moxifloxacin (MIC 4 mg/L) and streptomycin (MIC ≥8 mg/L); the Rv0678c mutant showed decreased susceptibility to both clofazimine (MIC 4 mg/L) and bedaqualine (MIC 1 mg/L). GeneXpert (Cepheid) and Genotype MTBDRplus (Hain Lifesciences) both called the rpoB S450L strain rifampin-resistant and the I491F mutant rifampin-susceptible, as expected based on single nucleotide polymorphism positions. Likewise, MTBDRplus called the novel katG deletion mutant isoniazid susceptible despite phenotypic resistance. ConclusionBCG strains engineered to be mono-resistant to anti-tuberculosis drugs can be used as safe QC reagents for tuberculosis diagnostics and drug susceptibility testing.

Guidance for the Evaluation of Tuberculosis Diagnostics That Meet the World Health Organization (WHO) Target Product Profiles: An Introduction to WHO Process and Study Design Principles.

Existing high-priority target product profiles (TPPs) of the World Health Organization (WHO) establish important needs for tuberculosis (TB) diagnostic development. Building on this earlier work, this guidance series aims to provide study guidance for performing accuracy studies of novel diagnostic products that may meet the 4 high-priority WHO TPPs and thus enable adequate evidence generation to inform a WHO evidence review process. Diagnostic accuracy studies represent a fundamental step in the validation of all tests. Unfortunately, such studies often have limitations in design, execution, and reporting, leading to low certainty of the evidence about true test performance, which can delay or impede policy and scale-up decisions. This introductory paper outlines the following: (1) the purpose of this series of papers on study guidance; (2) WHO evidence needs and process for the development of policy guidelines for new TB diagnostic tests; and (3) study design considerations, ie, general diagnostic study considerations, intended use of test and role in the clinical pathway, choice of population and setting, index-test specific issues, suitable reference standard and comparators, study flow and specimen issues, and finally key issues beyond accuracy that should be considered. The other 4 papers in this series will provide more detailed guidance for each of the 4 WHO high-priority TPPs. By increasing the clarity around the clinical evaluation needs for tests that have the potential to meet the TPP specifications, we hope to support harmonized evidence generation and enable the WHO review process towards meeting the WHO End TB Strategy targets for reducing the incidence and mortality associated with TB.

Clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with HIV-associated tuberculosis: A prospective cohort study.

BackgroundIn high-burden settings, case fatality rates are reported to be between 11% and 32% in hospitalized patients with HIV-associated tuberculosis, yet the underlying causes of mortality remain poorly characterized. Understanding causes of mortality could inform the development of novel management strategies to improve survival. We aimed to assess clinical and microbiologic determinants of mortality and to characterize the pathophysiological processes underlying death by evaluating host soluble inflammatory mediators and determined the relationship between these mediators and death as well as biomarkers of disseminated tuberculosis.Methods and findingsAdult patients with HIV hospitalized with a new diagnosis of HIV-associated tuberculosis were enrolled in Cape Town between 2014 and 2016. Detailed tuberculosis diagnostic testing was performed. Biomarkers of tuberculosis dissemination and host soluble inflammatory mediators at baseline were assessed. Of 682 enrolled participants, 576 with tuberculosis (487/576, 84.5% microbiologically confirmed) were included in analyses. The median age was 37 years (IQR = 31–43), 51.2% were female, and the patients had advanced HIV with a median cluster of differentiation 4 (CD4) count of 58 cells/L (IQR = 21–120) and a median HIV viral load of 5.1 log10 copies/mL (IQR = 3.3–5.7). Antituberculosis therapy was initiated in 566/576 (98.3%) and 487/576 (84.5%) started therapy within 48 hours of enrolment. Twelve-week mortality was 124/576 (21.5%), with 46/124 (37.1%) deaths occurring within 7 days of enrolment. Clinical and microbiologic determinants of mortality included disseminated tuberculosis (positive urine lipoarabinomannan [LAM], urine Xpert MTB/RIF, or tuberculosis blood culture in 79.6% of deaths versus 60.7% of survivors, p = 0.001), sepsis syndrome (high lactate in 50.8% of deaths versus 28.9% of survivors, p < 0.001), and rifampicin-resistant tuberculosis (16.9% of deaths versus 7.2% of survivors, p = 0.002). Using non-supervised two-way hierarchical cluster and principal components analyses, we describe an immune profile dominated by mediators of the innate immune system and chemotactic signaling (interleukin-1 receptor antagonist [IL-1Ra], IL-6, IL-8, macrophage inflammatory protein-1 beta [MIP-1β]/C-C motif chemokine ligand 4 [CCL4], interferon gamma-induced protein-10 [IP-10]/C-X-C motif chemokine ligand 10 [CXCL10], MIP-1 alpha [MIP-1α]/CCL3), which segregated participants who died from those who survived. This immune profile was associated with mortality in a Cox proportional hazards model (adjusted hazard ratio [aHR] = 2.2, 95%CI = 1.9–2.7, p < 0.001) and with detection of biomarkers of disseminated tuberculosis. Clinicians attributing causes of death identified tuberculosis as a cause or one of the major causes of death in 89.5% of cases. We did not perform longitudinal sampling and did not have autopsy-confirmed causes of death.ConclusionsIn this study, we did not identify a major contribution from coinfections to these deaths. Disseminated tuberculosis, sepsis syndrome, and rifampicin resistance were associated with mortality. An immune profile dominated by mediators of the innate immune system and chemotactic signaling was associated with both tuberculosis dissemination and mortality. These findings provide pathophysiologic insights into underlying causes of mortality and could be used to inform the development of novel treatment strategies and to develop methods to risk stratify patients to appropriately target novel interventions. Causal relationships cannot be established from this study.

Noninvasive Detection of Tuberculosis by Oral Swab Analysis.

Diagnostic tests for tuberculosis (TB) usually require collection of sputum, a viscous material derived from human airways. Sputum can be difficult and hazardous to collect and challenging to process in the laboratory. Oral swabs have been proposed as alternative sample types that are noninvasive and easy to collect. This study evaluated the biological feasibility of oral swab analysis (OSA) for the diagnosis of TB. Swabs were tested from South African adult subjects, including sputum GeneXpert MTB/RIF (GeneXpert)-confirmed TB patients (n = 138), sputum GeneXpert-negative but culture-positive TB patients (n = 10), ill non-TB patients (n = 37), and QuantiFERON-negative controls (n = 34). Swabs were analyzed by using a manual, nonnested quantitative PCR (qPCR) targeting IS6110 Two swab brands and three sites within the oral cavity were compared. Tongue swabbing yielded significantly stronger signals than cheek or gum swabbing. A flocked swab performed better than a more expensive paper swab. In a two-phase study, tongue swabs (two per subject) exhibited a combined sensitivity of 92.8% relative to sputum GeneXpert. Relative to all laboratory-diagnosed TB, the diagnostic yields of sputum GeneXpert (1 sample per subject) and OSA (2 samples per subject) were identical at 49/59 (83.1%) each. The specificity of the OSA was 91.5%. An analysis of "air swabs" suggested that most false-positive results were due to contamination of manual PCRs. With the development of appropriate automated methods, oral swabs could facilitate TB diagnosis in clinical settings and patient populations that are limited by the physical or logistical challenges of sputum collection.

Constructing care cascades for active tuberculosis: A strategy for program monitoring and identifying gaps in quality of care.

The cascade of care is a model for evaluating patient retention across sequential stages of care required to achieve a successful treatment outcome. This approach was first used to evaluate HIV care and has since been applied to other diseases. The tuberculosis (TB) community has only recently started using care cascade analyses to quantify gaps in quality of care. In this article, we describe methods for estimating gaps (patient losses) and steps (patients retained) in the care cascade for active TB disease. We highlight approaches for overcoming challenges in constructing the TB care cascade, which include difficulties in estimating the population-level burden of disease and the diagnostic gap due to the limited sensitivity of TB diagnostic tests. We also describe potential uses of this model for evaluating the impact of interventions to improve case finding, diagnosis, linkage to care, retention in care, and post-treatment monitoring of TB patients.