Diagnostic accuracy, feasibility and acceptability of stool-based testing for childhood tuberculosis.

Background: Childhood tuberculosis (TB) diagnosis remains challenging, partly because children cannot provide sputum. This study evaluated the diagnostic accuracy of the Simple One-Step (SOS) stool method with Xpert MTB/RIF Ultra (Xpert-Ultra) for childhood TB compared to culture and Xpert-Ultra on a respiratory sample (RS) and clinical diagnosis. It also assessed the feasibility and acceptability of stool testing according to laboratory staff, and caregivers' sample preference. Methods: We enrolled children (≤10 years) with presumptive pulmonary tuberculosis in Ethiopia. RS was tested using Xpert-Ultra and culture; stool samples were tested using the SOS stool method with Xpert-Ultra. Laboratory staff and caregivers' opinions were assessed using standardised questionnaires. Results: Of the 898 children enrolled, 792, 832 and 794 were included for assessing the diagnostic accuracy of SOS stool with Xpert-Ultra against culture, RS Xpert-Ultra and clinical diagnosis, respectively, yielding sensitivity estimates for SOS stool with Xpert-Ultra of 69.1% (95% confidence interval (CI) 56.0-79.7%), 76.8% (95% CI 64.2-85.9%) and 59.0% (95% CI 47.9-69.2%), respectively. The specificity was ≥98.8% for all comparisons. The rate of non-determinate test results was 2.8% after one repeat test. According to laboratory staff, stool collection was feasible and acceptable and the SOS stool method was easy to perform. Most caregivers (75%) preferred stool for TB diagnosis over RS. Conclusion: This study shows that SOS stool Xpert-Ultra testing offers a good alternative to RS testing for TB in children who cannot spontaneously produce a sputum sample and would otherwise need to undergo invasive procedures to obtain RS for diagnosis.

Prevalence of subclinical pulmonary tuberculosis in adults in community settings: an individual participant data meta-analysis.

BACKGROUND: Subclinical pulmonary tuberculosis, which presents without recognisable symptoms, is frequently detected in community screening. However, the disease category is poorly clinically defined. We explored the prevalence of subclinical pulmonary tuberculosis according to different case definitions. METHODS: We did a one-stage individual participant data meta-analysis of nationally representative surveys that were conducted in countries with high incidence of tuberculosis between 2007 and 2020, that reported the prevalence of pulmonary tuberculosis based on chest x-ray and symptom screening in participants aged 15 years and older. Screening and diagnostic criteria were standardised across the surveys, and tuberculosis was defined by positive Mycobacterium tuberculosis sputum culture. We estimated proportions of subclinical tuberculosis for three case definitions: no persistent cough (ie, duration ≥2 weeks), no cough at all, and no symptoms (ie, absence of cough, fever, chest pain, night sweats, and weight loss), both unadjusted and adjusted for false-negative chest x-rays and uninterpretable culture results. FINDINGS: We identified 34 surveys, of which 31 were eligible. Individual participant data were obtained and included for 12 surveys (620 682 participants) across eight countries in Africa and four in Asia. Data on 602 863 participants were analysed, of whom 1944 had tuberculosis. The unadjusted proportion of subclinical tuberculosis was 59·1% (n=1149/1944; 95% CI 55·8-62·3) for no persistent cough and 39·8% (773/1944; 36·6-43·0) for no cough of any duration. The adjusted proportions were 82·8% (95% CI 78·6-86·6) for no persistent cough and 62·5% (56·6-68·7) for no cough at all. In a subset of four surveys, the proportion of participants with tuberculosis but without any symptoms was 20·3% (n=111/547; 95% CI 15·5-25·1) before adjustment and 27·7% (95% CI 21·0-36·4) after adjustment. Tuberculosis without cough, irrespective of its duration, was more frequent among women (no persistent cough: adjusted odds ratio 0·79, 95% CI 0·63-0·97; no cough: adjusted odds ratio 0·76, 95% CI 0·62-0·93). Among participants with tuberculosis, 29·1% (95% CI 25·2-33·3) of those without persistent cough and 23·1% (18·8-27·4) of those without any cough had positive smear examinations. INTERPRETATION: The majority of people in the community who have pulmonary tuberculosis do not report cough, a quarter report no tuberculosis-suggestive symptoms at all, and a quarter of those not reporting any cough have positive sputum smears, suggesting infectiousness. In high-incidence settings, subclinical tuberculosis could contribute considerably to the tuberculosis burden and to Mycobacterium tuberculosis transmission. FUNDING: Mr Willem Bakhuys Roozeboom Foundation.

Estimating the contribution of subclinical tuberculosis disease to transmission: An individual patient data analysis from prevalence surveys.

Background: Individuals with bacteriologically confirmed pulmonary tuberculosis (TB) disease who do not report symptoms (subclinical TB) represent around half of all prevalent cases of TB, yet their contribution to Mycobacterium tuberculosis (Mtb) transmission is unknown, especially compared to individuals who report symptoms at the time of diagnosis (clinical TB). Relative infectiousness can be approximated by cumulative infections in household contacts, but such data are rare. Methods: We reviewed the literature to identify studies where surveys of Mtb infection were linked to population surveys of TB disease. We collated individual-level data on representative populations for analysis and used literature on the relative durations of subclinical and clinical TB to estimate relative infectiousness through a cumulative hazard model, accounting for sputum-smear status. Relative prevalence of subclinical and clinical disease in high-burden settings was used to estimate the contribution of subclinical TB to global Mtb transmission. Results: We collated data on 414 index cases and 789 household contacts from three prevalence surveys (Bangladesh, the Philippines, and Viet Nam) and one case-finding trial in Viet Nam. The odds ratio for infection in a household with a clinical versus subclinical index case (irrespective of sputum smear status) was 1.2 (0.6-2.3, 95% confidence interval). Adjusting for duration of disease, we found a per-unit-time infectiousness of subclinical TB relative to clinical TB of 1.93 (0.62-6.18, 95% prediction interval [PrI]). Fourteen countries across Asia and Africa provided data on relative prevalence of subclinical and clinical TB, suggesting an estimated 68% (27-92%, 95% PrI) of global transmission is from subclinical TB. Conclusions: Our results suggest that subclinical TB contributes substantially to transmission and needs to be diagnosed and treated for effective progress towards TB elimination. Funding: JCE, KCH, ASR, NS, and RH have received funding from the European Research Council (ERC) under the Horizon 2020 research and innovation programme (ERC Starting Grant No. 757699) KCH is also supported by UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). This research has been partially funded by UK aid from the UK government (to KCH); however, the views expressed do not necessarily reflect the UK government's official policies. PJD was supported by a fellowship from the UK Medical Research Council (MR/P022081/1); this UK-funded award is part of the EDCTP2 programme supported by the European Union. RGW is funded by the Wellcome Trust (218261/Z/19/Z), NIH (1R01AI147321-01), EDTCP (RIA208D-2505B), UK MRC (CCF17-7779 via SET Bloomsbury), ESRC (ES/P008011/1), BMGF (OPP1084276, OPP1135288 and INV-001754), and the WHO (2020/985800-0).

Funding and financial sustainability of pharmacovigilance: suggested models for funding pharmacovigilance in resource-limited African countries.

Background: An important factor hindering the growth of pharmacovigilance (PV) in resource-limited settings is the lack of adequate funds to establish a functional National Pharmacovigilance System. Consequently, the crucial function of monitoring and ensuring the availability of safe medicines in these settings cannot be guaranteed considering the peculiarities of diseases and medicines used. Objectives: The objective of this paper is to provide an overview as to the availability of potential sources of funds, which could be explored to ensure Medicine Safety and to proffer a potential framework likely to ensure sustainable funding of PV in Africa. Methods/processes: The process of developing this framework entailed a review of PV financing in some developed economies, a landscape study of funding of PV in some African countries, an in-depth understanding of the PV system and the organisational structure and nexus between the regulatory agencies and National Pharmacovigilance Centre. Critical points for consideration included the sources of funds, revenue pool, the disbursement of funds, budgeting and expenditure profile and the legal framework. Consultative meetings, webinars and interviews with experts were carried out. Results: The findings showed that most of the PV systems were mainly integrated into the regulatory agencies regarding operational and fiscal governance with few facilities being independent of the regulatory agencies. The main source of funding was from the government with significant donor funding which is ad hoc and non-sustainable. Several potential sources were identified but yet to be exploited. There were no legal provisions for PV financing. A framework likely to ensure sustainable PV financing is suggested to capture all available sources of funding, mine the potential sources providing a sizeable pool of revenue to address its activities and enabling legal framework which will engender autonomy. Furthermore, it will address the nexus between the regulatory agencies and the PV outfits, thus enabling appropriate share of resources and blockage of diversions. Conclusion: In all, addressing the various elements identified in this study and providing the legal provisions which guarantees some degree of autonomy will provide a sustainable mechanism for PV funding in the resource-limited setting of Africa.

Funding models for pharmacovigilance in resource-limited African countries An important factor hindering the growth of pharmacovigilance (PV) in resource-limited settings following their entry into the WHO Programme of International Drug Monitoring is the lack of adequate funds to establish a functional National Pharmacovigilance System. This article provides an overview of various potential sources of funds in these settings and how they can be harnessed to fund PV. We undertook a review of PV financing in developed settings and carried out a landscape study of funding of PV in some African countries, as well as having an in-depth understanding of the PV system and the organisational structure. The nexus between the regulatory agencies and National Pharmacovigilance Centre was noted. We took into account the sources of funds, revenue pool, the disbursement of funds, budgeting and expenditure profile and the legal framework for the different African countries. We also identified the prevalent and potential sources of funds for PV. Consultative meetings, webinars and interviews with experts in PV were carried out as well. We discovered that most of the PV facilities were mainly integrated into the regulatory agencies regarding operational and fiscal governance with few facilities being independent of the regulatory agencies. The main source of funding was from the government with significant donor funding which is ad hoc and non-sustainable. Several potential sources were identified but yet to be exploited. There were no legal provisions for PV financing. We have now proposed funding models that may lead to increased revenue for PV in these countries as well as suggesting that a legal framework be provided to guarantee sustainability and address the nexus between the regulatory agencies and the PV outfits to ensure an appropriate share of resources and blocking diversions.

Comparison of Xpert MTB/RIF Ultra Results of Stool and Sputum in Children with Presumptive Tuberculosis in Southern Ethiopia.

The introduction of stool as a readily obtainable sample and the recently developed simple one-step (SOS) stool processing method on Xpert MTB/RIF Ultra (Xpert Ultra) offer an opportunity for TB diagnosis in children. We conducted this study in secondary health facilities in Ethiopia, which are the first-level referral facilities for childhood TB diagnosis and treatment, with the aim to determine if stool-based TB diagnosis can be performed with a reasonable level of concordance with sputum tests using Xpert MTB/RIF Ultra. Eligible children 0-14 years old with presumptive pulmonary TB were asked to provide stools in addition to routinely requested sputum samples. We determined the level of agreement between the stool and sputum test results. Of the 373 children included in the study, 61% were <5 years of age and 56% were male. Thirty-six children (9.7%) were diagnosed with TB, and all started treatment. The rate of concordance between stool and sputum was high, with a kappa value of 0.83 (p < 0.001). There were more Xpert Ultra positive results on stool (n = 27 (7.2%)) than on sputum/NGA (n = 23 (6.2%)). Laboratories in secondary hospitals can perform stool-based TB diagnosis in children, with high concordance between stool and sputum test results reaffirming the applicability of the SOS stool method.

Optimization of the Simple One-Step Stool Processing Method to Diagnose Tuberculosis: Evaluation of Robustness and Stool Transport Conditions for Global Implementation.

Stool is recommended as an alternative specimen for the diagnosis of tuberculosis (TB) in young children, as they cannot easily produce sputum. The Simple One-Step (SOS) stool processing method is a new and simple stool processing method for the detection of Mycobacterium tuberculosis (MTB) using Xpert MTB/RIF Ultra (Xpert-Ultra). We determined the robustness of the SOS stool processing method and stool specimen transport conditions in participants with confirmed TB. We processed stool using the standard protocol after simulated "transport," varying time, and temperature, and experimented with slightly modified processing steps. We included 2,963 Xpert-Ultra test results from 132 stool specimens of 47 TB participants, including 11 children aged <10 years. We compared Xpert-Ultra processing errors and MTB positivity rates between standard and modified procedures. Minor deviations from the standard SOS protocol did not significantly impact the Xpert-Ultra test outcomes. The rate of Xpert-Ultra processing errors significantly increased with noncold-chain transport, exposure of stool to sample reagent at room temperature or beyond 12 h, and adding >0.8 g of stool. We found that almost all steps in the current SOS stool processing method provide optimal Xpert-Ultra results but recommend an adjustment to use a wider range of stool amounts (0.3 to 0.8 g) than advised previously (0.8 g). With this adaptation, stool-based diagnosis of TB using the SOS stool processing method can be scaled-up. IMPORTANCE The manuscript will support the global implementation and scale-up of the SOS stool method in routine settings. It also provides important insights on the optimal stool transport conditions and robustness of the SOS method, which can be used for bacteriological diagnosis of TB in children at the lowest levels of the healthcare system, avoiding lengthy healthcare-seeking pathways and additional costs.

Influence of Sex and Sex-Based Disparities on Prevalent Tuberculosis, Vietnam, 2017-2018.

To assess sex disparities in tuberculosis in Vietnam, we conducted a nested, case-control study based on a 2017 tuberculosis prevalence survey. We defined the case group as all survey participants with laboratory-confirmed tuberculosis and the control group as a randomly selected group of participants with no tuberculosis. We used structural equation modeling to describe pathways from sex to tuberculosis according to an a priori conceptual framework. Our analysis included 1,319 participants, of whom 250 were case-patients. We found that sex was directly associated with tuberculosis prevalence (adjusted odds ratio for men compared with women 3.0 [95% CI 1.7-5.0]) and indirectly associated through other domains. The strong sex difference in tuberculosis prevalence is explained by a complex interplay of factors relating to behavioral and environmental risks, access to healthcare, and clinical manifestations. However, after controlling for all those factors, a direct sex effect remains that might be caused by biological factors.

Disease Transmission by Patients With Subclinical Tuberculosis.

BACKGROUND: Subclinical tuberculosis has been increasingly recognized as a separate state in the spectrum of the disease. However, evidence on the transmissibility of subclinical tuberculosis is still inconclusive. METHODS: We re-analyzed the data from the 2007 combined tuberculosis prevalence and tuberculin surveys in Vietnam. Poisson regression with robust standard errors was conducted to assess the effect of clinical presentation of individuals with tuberculosis in the household on tuberculin skin test (TST) positivity among children aged 6-14 years who participated in the tuberculin survey, adjusting for child's age, smear status of the index patient, and other covariates. RESULTS: In the multivariate analysis, we found significantly increased risks for TST positivity in children living with patients with clinical, smear-positive tuberculosis, compared with those living with individuals without tuberculosis (adjusted risk ratio [aRR]: 3.04; 95% confidence interval [CI]: 2.00-4.63) and with those living with patients with subclinical tuberculosis, adjusting for index smear status (aRR: 2.26; 95% CI: 1.03-4.96). Among children aged 6-10 years, those living with patients with clinical, smear-positive tuberculosis and those living with patients with subclinical, smear-positive tuberculosis had similarly increased risks of TST positivity compared with those living with individuals without tuberculosis (aRRs [95% CI] of 3.56 [1.91-6.62] and 3.11 [1.44-6.72], respectively). CONCLUSIONS: Our findings support the hypothesis that smear-positive subclinical tuberculosis contributes to Mycobacterium tuberculosis transmission. To eliminate tuberculosis in 2035, control strategies need to address subclinical presentations of the disease.

The Simple One-step stool processing method for detection of Pulmonary tuberculosis: A study protocol to assess the robustness, stool storage conditions and sampling strategy for global implementation and scale-up.

BACKGROUND: The Xpert MTB/RIF Ultra (Xpert-Ultra) assay provides timely results with good sensitivity and acceptable specificity with stool specimens in children for bacteriological confirmation of tuberculosis (TB). This study aims to optimize the Simple One-Step (SOS) stool processing method for testing stool specimens using the Xpert-Ultra in children and adults in selected health facilities in Addis Ababa, Ethiopia. The study is designed to assess the robustness of the SOS stool method, to help fine-tune the practical aspects of performing the test and to provide insights in stool storage conditions and sampling strategies before the method can be implemented and scaled in routine settings in Ethiopia as well as globally. METHODS AND DESIGN: The project "painless optimized diagnosis of TB in Ethiopian children" (PODTEC) will be a cross sectional study where three key experiments will be carried out focusing on 1) sampling strategy to investigate if the Xpert-Ultra M. tuberculosis (MTB) -positivity rate depends on stool consistency, and if sensitivity can be increased by taking more than one stool specimen from the same participant, or doing multiple tests from the same stool specimen, 2) storage conditions to determine how long and at what temperature stool can be stored without losing sensitivity, and 3) optimization of sensitivity and robustness of the SOS stool processing method by varying stool processing steps, stool volume, and storage time and conditions of the stool-sample reagent mixture. Stool specimens will be collected from participants (children and adults) who are either sputum or naso-gastric aspiration (NGA) and/or stool Xpert-Ultra MTB positive depending on the experiment. Stool specimens from these participants, recruited from 22 sites for an ongoing related study, will be utilized for the PODTEC experiments. The sample size is estimated to be 50 participants. We will use EpiData for data entry and Stata for data analysis purposes. The main analyses will include computing the loss or gain in the Xpert-Ultra MTB positivity rate and rates of non-determinate Xpert-Ultra test results per experiment compared to the Xpert-Ultra MTB result of stool processed according to the published standard operating procedures for SOS stool processing. The differences in the MTB positivity rate by regarding testing more than one sample per child, and using different storage, and processing conditions, will be also compared to the baseline (on-site) Xpert-Ultra result.

Xpert Ultra stool testing to diagnose tuberculosis in children in Ethiopia and Indonesia: a model-based cost-effectiveness analysis.

OBJECTIVES: The WHO currently recommends stool testing using GeneXpert MTB/Rif (Xpert) for the diagnosis of paediatric tuberculosis (TB). The simple one-step (SOS) stool method enables processing for Xpert testing at the primary healthcare (PHC) level. We modelled the impact and cost-effectiveness of implementing the SOS stool method at PHC for the diagnosis of paediatric TB in Ethiopia and Indonesia, compared with the standard of care. SETTING: All children (age <15 years) presenting with presumptive TB at primary healthcare or hospital level in Ethiopia and Indonesia. PRIMARY OUTCOME: Cost-effectiveness estimated as incremental costs compared with incremental disability-adjusted life-years (DALYs) saved. METHODS: Decision tree modelling was used to represent pathways of patient care and referral. We based model parameters on ongoing studies and surveillance, systematic literature review, and expert opinion. We estimated costs using data available publicly and obtained through in-country expert consultations. Health outcomes were based on modelled mortality and discounted life-years lost. RESULTS: The intervention increased the sensitivity of TB diagnosis by 19-25% in both countries leading to a 14-20% relative reduction in mortality. Under the intervention, fewer children seeking care at PHC were referred (or self-referred) to higher levels of care; the number of children initiating anti-TB treatment (ATT) increased by 18-25%; and more children (85%) initiated ATT at PHC level. Costs increased under the intervention compared with a base case using smear microscopy in the standard of care resulting in incremental cost-effectiveness ratios of US$132 and US$94 per DALY averted in Ethiopia and Indonesia, respectively. At a cost-effectiveness threshold of 0.5×gross domestic product per capita, the projected probability of the intervention being cost-effective in Ethiopia and Indonesia was 87% and 96%, respectively. The intervention remained cost-effective under sensitivity analyses. CONCLUSIONS: The addition of the SOS stool method to national algorithms for diagnosing TB in children is likely to be cost-effective in both Ethiopia and Indonesia.

Discordant results of Xpert MTB/Rif assay and BACTEC MGIT 960 liquid culture to detect Mycobacterium tuberculosis in community screening in Vietnam.

BACKGROUND: Xpert MTB/Rif, a molecular test to detect tuberculosis (TB), has been proven to have high sensitivity and specificity when compared with liquid culture in clinical settings. However, little is known about its performance in community TB screening. METHODS: In Vietnam, a national TB prevalence survey was conducted in 2017. Survey participants who screened positive by chest X-ray, cough symptoms and/or recent history of tuberculosis were requested to provide at least two sputum samples that were tested for Mycobacterium tuberculosis by Xpert MTB/Rif G4 (Xpert) and BACTEC MGIT960 culture (MGIT). RESULTS: There were 4,649 eligible participants provided both samples for testing. Among them, 236 (5.1%) participants tested positive for TB by Xpert, 244 (5.3%) tested positive by MGIT and 317 tested positive by at least one test; 163 (51.4%) had discordant test results. Of the positive Xpert, 162 (68.6%) showed a low or very low bacterial load. In multivariate logistic regression comparing discordant with Xpert-MGIT concordant positive results, discordant Xpert-positive results occurred more often among participants who had low sputum bacterial load, male sex, a history of TB treatment, or night sweats. The associated factors were male sex, abnormal chest X-ray and having night sweats when the logistic model was against those with both Xpert and MGIT negative. CONCLUSIONS: We found high rates of discordance in the performance of Xpert and MGIT for community-based TB case finding. In situations where the majority of TB cases are expected to have a low bacterial load, multiple diagnostic tests and/or multiple samples are required to reach sufficient sensitivity.

Social determinants of the changing tuberculosis prevalence in Viet Nam: Analysis of population-level cross-sectional studies.

BACKGROUND: An ecological relationship between economic development and reduction in tuberculosis prevalence has been observed. Between 2007 and 2017, Viet Nam experienced rapid economic development with equitable distribution of resources and a 37% reduction in tuberculosis prevalence. Analysing consecutive prevalence surveys, we examined how the reduction in tuberculosis (and subclinical tuberculosis) prevalence was concentrated between socioeconomic groups. METHODS AND FINDINGS: We combined data from 2 nationally representative Viet Nam tuberculosis prevalence surveys with provincial-level measures of poverty. Data from 94,156 (2007) and 61,763 (2017) individuals were included. Of people with microbiologically confirmed tuberculosis, 21.6% (47/218) in 2007 and 29.0% (36/124) in 2017 had subclinical disease. We constructed an asset index using principal component analysis of consumption data. An illness concentration index was estimated to measure socioeconomic position inequality in tuberculosis prevalence. The illness concentration index changed from -0.10 (95% CI -0.08, -0.16; p = 0.003) in 2007 to 0.07 (95% CI 0.06, 0.18; p = 0.158) in 2017, indicating that tuberculosis was concentrated among the poorest households in 2007, with a shift towards more equal distribution between rich and poor households in 2017. This finding was similar for subclinical tuberculosis. We fitted multilevel models to investigate relationships between change in tuberculosis prevalence, individual risks, household socioeconomic position, and neighbourhood poverty. Controlling for provincial poverty level reduced the difference in prevalence, suggesting that changes in neighbourhood poverty contribute to the explanation of change in tuberculosis prevalence. A limitation of our study is that while tuberculosis prevalence surveys are valuable for understanding socioeconomic differences in tuberculosis prevalence in countries, given that tuberculosis is a relatively rare disease in the population studied, there is limited power to explore socioeconomic drivers. However, combining repeated cross-sectional surveys with provincial deprivation estimates during a period of remarkable economic growth provides valuable insights into the dynamics of the relationship between tuberculosis and economic development in Viet Nam. CONCLUSIONS: We found that with equitable economic growth and a reduction in tuberculosis burden, tuberculosis became less concentrated among the poor in Viet Nam.

Active surveillance for adverse events in patients on longer treatment regimens for multidrug-resistant tuberculosis in Viet Nam.

OBJECTIVE: Management of multidrug-resistant tuberculosis (MDR-TB) is a significant challenge to the global healthcare system due to the complexity and long duration of the MDR-TB treatment. This study analyzed the safety of patients on longer injectable-based MDR-TB treatment regimens using active pharmacovigilance data. METHOD: We conducted an observational, prospective study based on active pharmacovigilance within the national TB program. A total of 659 MDR-TB patients were enrolled and followed up at 9 TB- hospitals in 9 provinces of all 3 regions in Vietnam between 2014 and 2016. Patients received a treatment regimen (standardized or individualized) based on their drug susceptibility test result and their treatment history. Baseline and follow-up information was collected at the start and during treatment. Adverse events (AE) were defined and classified as serious adverse events (SAEs) or otherwise. Multivariate Cox regression following the Iterative Bayesian Model Averaging algorithm was performed to identify factors associated with AE occurrence. RESULTS: Out of 659 patients assessed, 71.3% experienced at least one AE, and 17.5% suffered at least one SAE. The most common AEs were gastrointestinal disorders (38.5%), arthralgia (34.7%), and psychiatric disorders (30.0%). The proportion of patients with nephrotoxicity and hearing loss or vestibular disorders were 7.4% and 15.2%, respectively. 13.1% of patients required modifications or interruption of one or more drugs. In 77.7% of patients, treatment was completed successfully, while 9.3% lost to follow-up, in 3.0% treatment failed, and 7.4% died. Some significant risk factors for nephrotoxicity included diabetes mellitus (HR = 8.46 [1.91-37.42]), renal dysfunction (HR = 8.46 [1.91-37.42]), alcoholism (HR = 13.28 [5.04-34.99]), and a higher average daily dose of injectable drugs (HR = 1.28 [1.14-1.43]). CONCLUSION: While a majority of patients on the longer injectable-based regimens experienced non-serious AEs during MDR-TB treatment, one in six patients experienced at least an SAE. Active TB drug-safety monitoring is useful to understand the safety of MDR-TB treatment and explore the risk factors for toxicity. All-oral, shorter MDR-TB regimens might be able to reduce the inconvenience, discomfort, and toxicity of such regimens and increase adherence and likelihood of successful completion.

The Simple One-Step (SOS) Stool Processing Method for Use with the Xpert MTB/RIF Assay for a Child-Friendly Diagnosis of Tuberculosis Closer to the Point of Care.

Young children cannot easily produce sputum for diagnosis of pulmonary tuberculosis (TB). Alternatively, Mycobacterium tuberculosis complex bacilli can be detected in stool by using the Xpert MTB/RIF (Ultra) assay (Xpert). Published stool processing methods contain somewhat complex procedures and require additional supplies. The aim of this study was to develop a simple one-step (SOS) stool processing method based on gravity sedimentation only, similar to Xpert testing of sputum samples, for the detection of M. tuberculosis in stool samples. We first assessed whether the SOS stool method could provide valid Xpert results without the need for bead-beating, dilution, and filtration steps. We concluded that this was the case, and we then validated the SOS stool method by testing spiked stool samples. By using the SOS stool method, 27 of the 29 spiked samples gave valid Xpert results, and M. tuberculosis was recovered from all 27 samples. The proof of principle of the SOS stool method was demonstrated in routine settings in Addis Ababa, Ethiopia. Nine of 123 children with presumptive TB had M. tuberculosis-positive results for nasogastric aspiration (NGA) samples, and 7 (77.8%) of those children also had M. tuberculosis-positive Xpert results for stool samples. Additionally, M. tuberculosis was detected in the stool samples but not the NGA samples from 2 children. The SOS stool processing method makes use of the standard Xpert assay kit, without the need for additional supplies or equipment. The method can potentially be rolled out to any Xpert site, bringing a bacteriologically confirmed diagnosis of TB in children closer to the point of care.

Decline of Tuberculosis Burden in Vietnam Measured by Consecutive National Surveys, 2007-2017.

Vietnam, a high tuberculosis (TB) burden country, conducted national TB prevalence surveys in 2007 and 2017. In both surveys participants were screened by using a questionnaire and chest radiograph; sputum samples were then collected to test for Mycobacterium tuberculosis by smear microscopy and Löwenstein-Jensen culture. Culture-positive, smear-positive, and smear-negative TB cases were defined by laboratory results, and the prevalence of tuberculosis was compared between the 2 surveys. The results showed prevalence of culture-positive TB decreased by 37% (95% CI 11.5%-55.4%), from 199 (95% CI 160-248) cases/100,000 adults in 2007 to 125 (95% CI 98-159) cases/100,000 adults in 2017. Prevalence of smear-positive TB dropped by 53% (95% CI 27.0%-69.7%), from 99 (95% CI 78-125) cases/100,000 adults to 46 (95% CI 32-68) cases/100,000 adults; smear-negative TB showed no substantial decrease. Replacing microscopy with molecular methods for primary diagnostics might enhance diagnosis of pulmonary TB cases and further lower TB burden.

Revisiting the Natural History of Pulmonary Tuberculosis: A Bayesian Estimation of Natural Recovery and Mortality Rates.

BACKGROUND: Tuberculosis (TB) natural history remains poorly characterized, and new investigations are impossible as it would be unethical to follow up TB patients without treatment. METHODS: We considered the reports identified in a previous systematic review of studies from the prechemotherapy era, and extracted detailed data on mortality over time. We used a Bayesian framework to estimate the rates of TB-induced mortality and self-cure. A hierarchical model was employed to allow estimates to vary by cohort. Inference was performed separately for smear-positive TB (SP-TB) and smear-negative TB (SN-TB). RESULTS: We included 41 cohorts of SP-TB patients and 19 cohorts of pulmonary SN-TB patients in the analysis. The median estimates of the TB-specific mortality rates were 0.389 year-1 (95% credible interval [CrI], .335-.449) and 0.025 year-1 (95% CrI, .017-.035) for SP-TB and SN-TB patients, respectively. The estimates for self-recovery rates were 0.231 year-1 (95% CrI, .177-.288) and 0.130 year-1 (95% CrI, .073-.209) for SP-TB and SN-TB patients, respectively. These rates correspond to average durations of untreated TB of 1.57 years (95% CrI, 1.37-1.81) and 5.35 years (95% CrI, 3.42-8.23) for SP-TB and SN-TB, respectively, when assuming a non-TB-related mortality rate of 0.014 year-1 (ie, a 70-year life expectancy). CONCLUSIONS: TB-specific mortality rates are around 15 times higher for SP-TB than for SN-TB patients. This difference was underestimated dramatically in previous TB modeling studies, raising concerns about the accuracy of the associated predictions. Despite being less infectious, SN-TB may be responsible for equivalent numbers of secondary infections as SP-TB due to its much longer duration.

Correction: The second national tuberculosis prevalence survey in Vietnam.

[This corrects the article DOI: 10.1371/journal.pone.0232142.].

The second national tuberculosis prevalence survey in Vietnam.

INTRODUCTION: Tuberculosis (TB) remains a significant cause of morbidity and mortality in Vietnam. The current TB burden is unknown as not all individuals with TB are diagnosed, recorded and notified. The second national TB prevalence survey was conducted in 2017-2018 to assess the current burden of TB disease in the country. METHOD: Eighty-two clusters were selected using a multistage cluster sampling design. Adult (≥15 years of age) residents having lived for 2 weeks or more in the households of the selected clusters were invited to participate in the survey. The survey participants were screened for TB by a questionnaire and digital chest X-ray after providing written informed consent. Individuals with a positive symptom screen and/or chest X-ray suggestive of TB were asked to provide sputum samples to test for Mycobacterium tuberculosis by Ziehl-Neelsen direct light microscopy, Xpert MTB/RIF G4, BACTEC MGIT960 liquid culture and Löwenstein-Jensen solid culture. Bacteriologically confirmed TB cases were defined by an expert panel following a standard decision tree. RESULT: Of 87,207 eligible residents, 61,763 (70.8%) participated, and 4,738 (7.7%) screened positive for TB. Among these, 221 participants were defined as bacteriologically confirmed TB cases. The estimated prevalence of bacteriologically confirmed adult pulmonary TB was 322 (95% CI: 260-399) per 100,000, and the male-to-female ratio was 4.0 (2.8-5.8, p<0.001). In-depth interviews with the participants with TB disease showed that only 57.9% (95% CI: 51.3-64.3%) reported cough for 2 weeks or more and 32.1% (26.3-38.6%) did not report any symptom consistent with TB, while their chest X-ray results showed that 97.7% (95% CI: 94.6-99.1) had abnormal chest X-ray images suggesting TB. CONCLUSION: With highly sensitive diagnostics applied, this survey showed that the TB burden in Vietnam remains high. Half of the TB cases were not picked up by general symptom-based screening and were identified by chest X-ray only. Our results indicate that improving TB diagnostic capacity and access to care, along with reducing TB stigma, need to be top priorities for TB control and elimination in Vietnam.

Integration of drug safety monitoring in tuberculosis treatment programmes: country experiences.

New drugs and shorter treatments for drug-resistant tuberculosis (DR-TB) have become available in recent years and active pharmacovigilance (PV) is recommended by the World Health Organization (WHO) at least during the early phases of implementation, with active drug safety monitoring and management (aDSM) proposed for this. We conducted a literature review of papers reporting on aDSM. Up to 18 April, 2019, results have only been published from one national aDSM programme. Because aDSM is being introduced in many low- and middle-income countries, we also report experiences in introducing it into DR-TB treatment programmes, targeting the reporting of a restricted set of adverse events (AEs) as per WHO-recommended aDSM principles for the period 2014-2017. Early beneficial effects of active PV for TB patients include increased awareness about the occurrence, detection and management of AEs during TB treatment, and the increase of spontaneous reporting in some countries. However, because PV capacity is low in most countries and collaboration between national TB programmes and national PV centres remains weak, parallel and coordinated co-development of the capacities of both TB programmes and PV centres is needed.