Tuberculosis disease and infection among household contacts of bacteriologically confirmed and non-confirmed tuberculosis patients.

OBJECTIVE: To compare the prevalence of tuberculosis infection and disease in household contacts of patients with bacteriologically confirmed tuberculosis disease and contacts of non-bacteriologically confirmed disease in western Kenya. METHODS: We enrolled newly diagnosed index patients and their household contacts from March 2014 to June 2016. All contacts were evaluated with a symptom questionnaire, tuberculin skin test (TST) and HIV test. Clinical evaluation and sputum testing were performed for those with symptoms, positive TST result or HIV infection. RESULTS: We enrolled 1155 contacts of 330 index patients with bacteriologically confirmed tuberculosis and 192 contacts of 55 index patients with non-bacteriologically confirmed tuberculosis. 3.5% of contacts of patients with bacteriologically confirmed tuberculosis were diagnosed with tuberculosis, whereas no contacts of index patients with non-bacteriologically confirmed tuberculosis were. Of those diagnosed with tuberculosis disease, 58.5% reported symptoms, 34.1% reported no symptoms but had positive TST results, and 7.3% had neither symptoms nor positive TST but were HIV-positive. Among 872 contacts with a TST result, 50.9% of contacts of index patients with bacteriologically confirmed tuberculosis and 41.0% of contacts of index patients with non-bacteriologically confirmed tuberculosis had a positive result (prevalence ratio = 1.16, 95% confidence interval 0.92-1.48). CONCLUSION: In a high-burden setting, tuberculosis disease was more prevalent among contacts of patients with bacteriologically confirmed tuberculosis than contacts of patients with non-bacteriologically confirmed disease. TST was feasible to perform and helped to detect cases that would have been missed had only symptomatic contacts been evaluated.

OBJECTIF: Comparer la prévalence de l'infection et de la maladie tuberculeuses chez les contacts familiaux des patients atteints de tuberculose confirmée bactériologiquement et les contacts de maladies non bactériologiquement confirmées dans l'ouest du Kenya. MÉTHODES: Nous avons recruté des patients indice nouvellement diagnostiqués et leurs contacts familiaux de mars 2014 à juin 2016. Tous les contacts ont été évalués à l'aide d'un questionnaire sur les symptômes, le test cutané à la tuberculine (TCT) et le test VIH. Une évaluation clinique et des tests d'expectoration ont été effectués pour les personnes présentant des symptômes, un résultat positif au TCT ou une infection par le VIH. RÉSULTATS: Nous avons recruté 1.155 contacts de 330 patients index avec une tuberculose confirmée bactériologiquement et 192 contacts de 55 patients indice avec une tuberculose non confirmée bactériologiquement. 3,5% des contacts des patients atteints de tuberculose confirmée bactériologiquement ont été diagnostiqués avec la tuberculose, alors qu'aucun contact des patients indice avec une tuberculose non bactériologiquement confirmée ne l'a été. Parmi les personnes diagnostiquées avec une tuberculose, 58,5% ont signalé des symptômes, 34,1% n'ont signalé aucun symptôme mais avaient des résultats positifs au TCT, et 7,3% n'avaient ni symptômes ni TCT positifs mais étaient VIH positifs. Parmi 872 contacts avec un résultat TCT, 50,9% des contacts des patients indice avec une tuberculose confirmée bactériologiquement et 41,0% des contacts des patients indice avec une tuberculose non bactériologiquement confirmée avaient un résultat positif (rapport de prévalence = 1,16, intervalle de confiance à 95%: 0,92-1,48 ). CONCLUSION: Dans un contexte de charge élevée, la maladie tuberculose était plus fréquente chez les contacts des patients atteints de tuberculose confirmée bactériologiquement que chez les contacts des patients atteints de la maladie non bactériologiquement confirmée. Le TCT était réalisable et a aidé à détecter les cas qui auraient été ratés si seuls les contacts symptomatiques avaient été évalués.

A High Throughput Whole Blood Assay for Analysis of Multiple Antigen-Specific T Cell Responses in Human Mycobacterium tuberculosis Infection.

Antigen-specific CD4 and CD8 T cells are important components of the immune response to Mycobacterium tuberculosis, yet little information is currently known regarding how the breadth, specificity, phenotype, and function of M. tuberculosis-specific T cells correlate with M. tuberculosis infection outcome in humans. To facilitate evaluation of human M. tuberculosis-specific T cell responses targeting multiple different Ags, we sought to develop a high throughput and reproducible T cell response spectrum assay requiring low blood sample volumes. We describe here the optimization and standardization of a microtiter plate-based, diluted whole blood stimulation assay utilizing overlapping peptide pools corresponding to a functionally diverse panel of 60 M. tuberculosis Ags. Using IFN-γ production as a readout of Ag specificity, the assay can be conducted using 50 µl of blood per test condition and can be expanded to accommodate additional Ags. We evaluated the intra- and interassay variability, and implemented testing of the assay in diverse cohorts of M. tuberculosis-unexposed healthy adults, foreign-born adults with latent M. tuberculosis infection residing in the United States, and tuberculosis household contacts with latent M. tuberculosis infection in a tuberculosis-endemic setting in Kenya. The M. tuberculosis-specific T cell response spectrum assay further enhances the immunological toolkit available for evaluating M. tuberculosis-specific T cell responses across different states of M. tuberculosis infection, and can be readily implemented in resource-limited settings. Moreover, application of the assay to longitudinal cohorts will facilitate evaluation of treatment- or vaccine-induced changes in the breadth and specificity of Ag-specific T cell responses, as well as identification of M. tuberculosis-specific T cell responses associated with M. tuberculosis infection outcomes.

Mortality Surveillance Methods to Identify and Characterize Deaths in Child Health and Mortality Prevention Surveillance Network Sites.

Despite reductions over the past 2 decades, childhood mortality remains high in low- and middle-income countries in sub-Saharan Africa and South Asia. In these settings, children often die at home, without contact with the health system, and are neither accounted for, nor attributed with a cause of death. In addition, when cause of death determinations occur, they often use nonspecific methods. Consequently, findings from models currently utilized to build national and global estimates of causes of death are associated with substantial uncertainty. Higher-quality data would enable stakeholders to effectively target interventions for the leading causes of childhood mortality, a critical component to achieving the Sustainable Development Goals by eliminating preventable perinatal and childhood deaths. The Child Health and Mortality Prevention Surveillance (CHAMPS) Network tracks the causes of under-5 mortality and stillbirths at sites in sub-Saharan Africa and South Asia through comprehensive mortality surveillance, utilizing minimally invasive tissue sampling (MITS), postmortem laboratory and pathology testing, verbal autopsy, and clinical and demographic data. CHAMPS sites have established facility- and community-based mortality notification systems, which aim to report potentially eligible deaths, defined as under-5 deaths and stillbirths within a defined catchment area, within 24-36 hours so that MITS can be conducted quickly after death. Where MITS has been conducted, a final cause of death is determined by an expert review panel. Data on cause of death will be provided to local, national, and global stakeholders to inform strategies to reduce perinatal and childhood mortality in sub-Saharan Africa and South Asia.

Assessing the impact of antiretroviral therapy on tuberculosis notification rates among people with HIV: a descriptive analysis of 23 countries in sub-Saharan Africa, 2010-2015.

BACKGROUND: HIV is a major driver of the tuberculosis epidemic in sub-Saharan Africa. The population-level impact of antiretroviral therapy (ART) scale-up on tuberculosis rates in this region has not been well studied. We conducted a descriptive analysis to examine evidence of population-level effect of ART on tuberculosis by comparing trends in estimated tuberculosis notification rates, by HIV status, for countries in sub-Saharan Africa. METHODS: We estimated annual tuberculosis notification rates, stratified by HIV status during 2010-2015 using data from WHO, the Joint United Nations Programme on HIV/AIDS, and the United Nations Population Division. Countries were included in this analysis if they had ≥4 years of HIV prevalence estimates and ≥ 75% of tuberculosis patients with known HIV status. We compared tuberculosis notification rates among people living with HIV (PLHIV) and people without HIV via Wilcoxon rank sum test. RESULTS: Among 23 included countries, the median annual average change in tuberculosis notification rates among PLHIV during 2010-2015 was -5.7% (IQR -6.9 to -1.7%), compared to a median change of -2.3% (IQR -4.2 to -0.1%) among people without HIV (p-value = 0.0099). Among 11 countries with higher ART coverage, the median annual average change in TB notification rates among PLHIV was -6.8% (IQR -7.6 to -5.7%) compared to a median change of -2.1% (IQR -6.0 to 0.7%) for PLHIV in 12 countries with lower ART coverage (p = 0.0106). CONCLUSION: Tuberculosis notification rates declined more among PLHIV than people without HIV, and have declined more in countries with higher ART coverage. These results are consistent with a population-level effect of ART on decreasing TB incidence among PLHIV. To further reduce TB incidence among PLHIV, additional scale-up of ART as well as greater use of isoniazid preventive therapy and active case-finding will be necessary.

The movement of multidrug-resistant tuberculosis across borders in East Africa needs a regional and global solution.

Kevin Cain and colleagues reflect on the cross border movement of people from Somalia with MDR-TB and the implications for MDR-TB programs in East Africa.

A review of data quality of an electronic tuberculosis surveillance system for case-based reporting in Kenya.

BACKGROUND: Kenya recently transitioned from a paper to an electronic system for recording and reporting of tuberculosis (TB) data. METHODS: During September-October 2013, the data quality of the new system was evaluated through an audit of data in paper source documents and in the national electronic system, and an analysis of all 99 281 cases reported in 2012. RESULTS: While the new electronic system overall is robust, this assessment demonstrated limitations in the concordance and completeness of data reaching the national level. CONCLUSIONS: Additional oversight and training in data entry are needed to strengthen TB surveillance data quality in Kenya.

An algorithm for tuberculosis screening and diagnosis in people with HIV.

BACKGROUND: Tuberculosis screening is recommended for people with human immunodeficiency virus (HIV) infection to facilitate early diagnosis and safe initiation of antiretroviral therapy and isoniazid preventive therapy. No internationally accepted, evidence-based guideline addresses the optimal means of conducting such screening, although screening for chronic cough is common. METHODS: We consecutively enrolled people with HIV infection from eight outpatient clinics in Cambodia, Thailand, and Vietnam. For each patient, three samples of sputum and one each of urine, stool, blood, and lymph-node aspirate (for patients with lymphadenopathy) were obtained for mycobacterial culture. We compared the characteristics of patients who received a diagnosis of tuberculosis (on the basis of having one or more specimens that were culture-positive) with those of patients who did not have tuberculosis to derive an algorithm for screening and diagnosis. RESULTS: Tuberculosis was diagnosed in 267 (15%) of 1748 patients (median CD4+ T-lymphocyte count, 242 per cubic millimeter; interquartile range, 82 to 396). The presence of a cough for 2 or 3 weeks or more during the preceding 4 weeks had a sensitivity of 22 to 33% for detecting tuberculosis. The presence of cough of any duration, fever of any duration, or night sweats lasting 3 or more weeks in the preceding 4 weeks was 93% sensitive and 36% specific for tuberculosis. In the 1199 patients with any of these symptoms, a combination of two negative sputum smears, a normal chest radiograph, and a CD4+ cell count of 350 or more per cubic millimeter helped to rule out a diagnosis of tuberculosis, whereas a positive diagnosis could be made only for the 113 patients (9%) with one or more positive sputum smears; mycobacterial culture was required for most other patients. CONCLUSIONS: In persons with HIV infection, screening for tuberculosis should include asking questions about a combination of symptoms rather than only about chronic cough. It is likely that antiretroviral therapy and isoniazid preventive therapy can be started safely in people whose screening for all three symptoms is negative, whereas diagnosis in most others will require mycobacterial culture.

Association between tuberculin skin test result and clinical presentation of tuberculosis disease.

BACKGROUND: The tuberculin skin test (TST) is used to test for latent tuberculosis (TB) infection and support the diagnosis of active TB. However, little is known about the relationship between the TST result and the clinical presentation of TB disease. METHODS: We analyzed US TB surveillance data, 1993-2010, and used multinomial logistic regression to calculate the association between TST result (0-4 mm [negative], 5-9 mm, 10-14 mm, and ≥ 15 mm) and clinical presentation of disease (miliary, combined pulmonary and extrapulmonary, extrapulmonary only, non-cavitary pulmonary, and cavitary pulmonary). For persons with pulmonary disease, multivariate logistic regression was used to calculate the odds of having acid-fast bacilli (AFB) positive sputum. RESULTS: There were 64,238 persons with culture-confirmed TB included in the analysis, which was stratified by HIV status and birthplace (US- vs. foreign-born). Persons with a TST ≥ 15 mm were less likely to have miliary or combined pulmonary and extrapulmonary disease, but more likely to have cavitary pulmonary disease than non-cavitary pulmonary disease. Persons with non-cavitary pulmonary disease with a negative TST were significantly more likely to have AFB positive sputum. CONCLUSIONS: Clinical presentation of TB disease differed according to TST result and persons with a negative TST were more likely to have disseminated disease (i.e., miliary or combined pulmonary and extrapulmonary). Further study of the TST result may improve our understanding of the host-pathogen relationship in TB disease.

The value of effective public tuberculosis treatment: an analysis of opportunity costs associated with multidrug resistant tuberculosis in Latvia.

BACKGROUND: A challenge to effective protection against tuberculosis is to sustain expensive and complex treatment public programs. Potential consequences of program failure include acquired drug resistance, poor patient outcomes, and potentially much higher system costs, however. In contrast, effective efforts have value illustrated by impacts they prevent. We compared the healthcare costs and treatment outcomes among multidrug-resistant tuberculosis (MDR-TB) and non MDR-TB patients in Latvia to identify benefits or costs associated with both. METHODS: We measured and compared costs, healthcare utilization, and outcomes for patients who began treatment through Latvia's TB control program in 2002 using multivariate regression analysis and negative binomial regression. RESULTS: We analyzed data for 92 MDR-TB and 54 non MDR-TB patients. Most (67%) MDR-TB patients had history of prior tuberculosis treatment. MDR-TB was associated with lower cure rates (71% vs. 91%) and greater resource utilization. MDR-TB treatment cost almost $20,000 more than non MDR-TB. CONCLUSION: Up to 2/3 of MDR-TB treated in our sample was preventable at a potential savings of over $1.3 million in healthcare resources as well as substantial individual health.

Moving toward tuberculosis elimination: implementation of statewide targeted tuberculin testing in Tennessee.

RATIONALE: From 1993 to 2010, annual U.S. tuberculosis (TB) rates declined by 58%. However, this decline has slowed and disproportionately occurred among U.S.-born (78%) versus foreign-born persons (47%). Addressing the high burden of latent TB infection (LTBI) must be prioritized. OBJECTIVES: Only Tennessee has implemented a statewide program for finding and treating people with LTBI. The program was designed to address high statewide TB rates and growing burden among the foreign-born. We sought to assess the feasibility and yield of Tennessee's program. METHODS: Analyzing data from the 4.8-year period from program inception in March 2002 through December 2006, we quantified patients screened using a TB risk assessment tool, tuberculin skin tests (TST) placed and read, TST results, and patients initiating and completing LTBI treatment. We then estimated the number needed to screen to find and treat one person with LTBI and to prevent one case of TB. MEASUREMENTS AND MAIN RESULTS: Of 168,517 persons screened, 102,709 had a TST placed and read. Among 9,090 (9%) with a positive TST result, 53% initiated treatment, 54% of whom completed treatment. An estimated 195 TB cases were prevented over the 4.8 years analyzed, and program performance measures improved annually. The number of TSTs placed to prevent one TB case ranged from 150 for foreign-born persons to 9,834 for persons without TB risk. CONCLUSIONS: Targeted tuberculin testing and LTBI treatment is feasible and likely to reduce TB rates over time. Yield and cost-effectiveness are maximized by prioritizing foreign-born persons, a large population with high TB risk.

Nontuberculous mycobacterial disease in patients with HIV in Southeast Asia.

RATIONALE: Although nontuberculous mycobacteria (NTM) are widely documented as a cause of illness among HIV-infected people in the developed world, studies describing the prevalence of NTM disease among HIV-infected people in most resource-limited settings are rare. OBJECTIVES: To evaluate the prevalence of mycobacterial disease in HIV-infected patients in Southeast Asia. METHODS: We enrolled people with HIV from three countries in Southeast Asia and collected pulmonary and extrapulmonary specimens to evaluate the prevalence of mycobacterial disease. We adapted American Thoracic Society/Infectious Disease Society of America guidelines to classify patients into NTM pulmonary disease, NTM pulmonary disease suspects, NTM disseminated disease, and no NTM categories. MEASUREMENTS AND MAIN RESULTS: In Cambodia, where solid media alone was used, NTM was rare. Of 1,060 patients enrolled in Thailand and Vietnam, where liquid culture was performed, 124 (12%) had tuberculosis and 218 (21%) had NTM. Of 218 patients with NTM, 66 (30%) were classified as NTM pulmonary disease suspects, 9 (4%) with NTM pulmonary disease, and 10 (5%) with NTM disseminated disease. The prevalence of NTM disease was 2% (19 of 1,060). Of 51 patients receiving antiretroviral therapy (ART), none had NTM disease compared with 19 (2%) of 1,009 not receiving ART. CONCLUSIONS: Although people with HIV frequently have sputum cultures positive for NTM, few meet a strict case definition for NTM disease. Consistent with previous studies, ART was associated with lower odds of having NTM disease. Further studies of NTM in HIV-infected individuals in tuberculosis-endemic countries are needed to develop and validate case definitions.

Machine learning to predict bacteriologic confirmation of Mycobacterium tuberculosis in infants and very young children.

Diagnosis of tuberculosis (TB) among young children (<5 years) is challenging due to the paucibacillary nature of clinical disease and clinical similarities to other childhood diseases. We used machine learning to develop accurate prediction models of microbial confirmation with simply defined and easily obtainable clinical, demographic, and radiologic factors. We evaluated eleven supervised machine learning models (using stepwise regression, regularized regression, decision tree, and support vector machine approaches) to predict microbial confirmation in young children (<5 years) using samples from invasive (reference-standard) or noninvasive procedure. Models were trained and tested using data from a large prospective cohort of young children with symptoms suggestive of TB in Kenya. Model performance was evaluated using areas under the receiver operating curve (AUROC) and precision-recall curve (AUPRC), accuracy metrics. (i.e., sensitivity, specificity), F-beta scores, Cohen's Kappa, and Matthew's Correlation Coefficient. Among 262 included children, 29 (11%) were microbially confirmed using any sampling technique. Models were accurate at predicting microbial confirmation in samples obtained from invasive procedures (AUROC range: 0.84-0.90) and from noninvasive procedures (AUROC range: 0.83-0.89). History of household contact with a confirmed case of TB, immunological evidence of TB infection, and a chest x-ray consistent with TB disease were consistently influential across models. Our results suggest machine learning can accurately predict microbial confirmation of M. tuberculosis in young children using simply defined features and increase the bacteriologic yield in diagnostic cohorts. These findings may facilitate clinical decision making and guide clinical research into novel biomarkers of TB disease in young children.

Development of treatment-decision algorithms for children evaluated for pulmonary tuberculosis: an individual participant data meta-analysis.

BACKGROUND: Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres. METHODS: For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings. FINDINGS: Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms. INTERPRETATION: We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance. FUNDING: WHO, US National Institutes of Health.

Seasonality of tuberculosis in the United States, 1993-2008.

BACKGROUND: Although seasonal variation in tuberculosis incidence has been described in several recent studies, the mechanism underlying this seasonality remains unknown. Seasonality of tuberculosis disease may indicate the presence of season-specific risk factors that could potentially be controlled if they were better understood. We conducted this study to determine whether tuberculosis is seasonal in the United States and to describe patterns of seasonality in specific populations. METHODS: We performed a time series decomposition analysis of tuberculosis cases reported to the Centers for Disease Control and Prevention from 1993 through 2008. Seasonal amplitude of tuberculosis disease (the difference between the months with the highest and lowest mean case counts), was calculated for the population as a whole and for populations with select demographic, clinical, and epidemiologic characteristics. RESULTS: A total of 243 432 laboratory-confirmed tuberculosis cases were reported over a period of 16 years. A mean of 21.4% more cases were diagnosed in March, the peak month, compared with November, the trough month. The magnitude of seasonality did not vary with latitude. The greatest seasonal amplitude was found among children aged <5 years and in cases associated with disease clusters. CONCLUSIONS: Tuberculosis is a seasonal disease in the United States, with a peak in spring and trough in late fall. The latitude independence of seasonality suggests that reduced winter sunlight exposure may not be a strong contributor to tuberculosis risk. Increased seasonality among young children and clustered cases suggests that disease that is the result of recent transmission is more influenced by season than disease resulting from activation of latent infection.

Clinical and Radiologic Factors Associated With Detection of Mycobacterium tuberculosis in Children Under 5†Years old Using Invasive and Noninvasive Sample Collection Techniques-Kenya.

Background: Pediatric tuberculosis (TB) remains a critical public health concern, yet bacteriologic confirmation of TB in children is challenging. Clinical, demographic, and radiological factors associated with a positive Mycobacterium tuberculosis specimen in young children (≤5 years) are poorly understood. Methods: We conducted a prospective cohort study of young children with presumptive TB and examined clinical, demographic, and radiologic factors associated with invasive and noninvasive specimen collection techniques (gastric aspirate, induced sputum, nasopharyngeal aspirate, stool, and string test); up to 2 samples were taken per child, per technique. We estimated associations between these factors and a positive specimen for each technique using generalized estimating equations (GEEs) and logistic regression. Results: A median (range) of 544 (507-566) samples were obtained for each specimen collection technique from 300 enrolled children; bacteriologic yield was low across all collection techniques (range, 1%-7% from Xpert MTB/RIF or culture), except for lymph node fine needle aspiration (29%) taken for children with cervical lymphadenopathy. Factors associated with positive M. tuberculosis samples across all techniques included prolonged lethargy (median [range] adjusted odds ratio [aOR], 8.1 [3.9-10.1]), history of exposure with a TB case (median [range] aOR, 6.1 [2.9-9.0]), immunologic evidence of M. tuberculosis infection (median [range] aOR, 4.6 [3.7-9.2]), large airway compression (median [range] aOR, 6.7 [4.7-9.5]), and hilar/mediastinal density (median [range] aOR, 2.9 [1.7-3.2]). Conclusions: Identifying factors that lead to a positive M. tuberculosis specimen in very young children can inform clinical management and increase the efficiency of diagnostic testing in children being assessed for TB.

Reaching 95-95-95 targets: The role of private sector health facilities in closing the HIV detection gap-Kisumu Kenya, 2018.

BACKGROUND: HIV testing efficiency could be improved by focusing on high yield populations and identifying types of health facilities where people with undiagnosed HIV infection are more likely to attend. METHODS: A retrospective cohort analysis of data collected during an integrated TB/HIV active case-finding intervention in Western Kenya. Data were analyzed from health facilities' registers on individuals who reported TB-suggestive symptoms between 1 July and 31 December 2018 and who had an HIV test result within one month following symptom screening. We used logistic regression with general estimating equations adjusting for sub-county level data to identify health facility-level predictors of new HIV diagnoses. RESULTS: Of 11,376 adults with presumptive TB identified in 143 health facilities, 1038 (9%) tested HIV positive. The median HIV positivity per health facility was 6% (IQR = 2-15%). Patients with TB symptoms were over three times as likely to have a new HIV diagnosis in private not-for-profit facilities compared to those in government facilities (adjusted odds ratio (aOR) 3.40; 95% CI = 1.96-5.90). Patients tested in hospitals were over two times as likely to have a new HIV diagnosis as those tested in smaller facilities (i.e., health centers and dispensaries) (aOR 2.26; 95% CI = 1.60-3.21). CONCLUSION: Individuals with presumptive TB who attended larger health facilities and private not-for-profit facilities had a higher likelihood of being newly diagnosed with HIV. Strengthening HIV services at these facilities and outreach to populations that use them could help to close the HIV diagnosis gap.

Performance of Xpert MTB/RIF and Mycobacterial Culture on Multiple Specimen Types for Diagnosis of Tuberculosis Disease in Young Children and Clinical Characterization According to Standardized Research Case Definitions.

BACKGROUND: Tuberculosis (TB) is a leading cause of illness and death in children globally. Improved bacteriologic and clinical diagnostic approaches in children are urgently needed. METHODS: In a prospective cohort study, a consecutive series of young (<5 years) children presenting with symptoms suggestive of TB and parenchymal abnormality on chest radiograph in inpatient and outpatient settings in Kisumu County, Kenya from October 2013 to August 2015 were evaluated at baseline and over 6 months. Up to 14 specimens per child were tested for the Mycobacterium tuberculosis complex by fluorescence microscopy, Xpert MTB/RIF and mycobacterial culture. Using detailed clinical characterization, cases were retrospectively classified according to standardized research case definitions and the sensitivity and specificity of microbiological tests on different specimen types were determined. RESULTS: Among 300 young children enrolled, 266 had sufficient information to be classified according to the research clinical case definition. Of these, 36% (96/266) had TB disease; 32% (31/96) with bacteriologically confirmed intrathoracic TB. Compared to culture, the sensitivity of a single Xpert test ranged from 60 to 67% and specificity from 97.5 to 100% for different specimen types. CONCLUSIONS: Despite extensive specimen collection and laboratory testing, TB could not be bacteriologically confirmed in almost two-thirds of children with intrathoracic TB classified by research clinical case definitions. Improved diagnostic tests are needed to identify children with TB and to exclude other potential causes of illness.

Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies.

BACKGROUND: The World Health Organization recommends the screening of all people living with HIV for tuberculosis (TB) disease, followed by TB treatment, or isoniazid preventive therapy (IPT) when TB is excluded. However, the difficulty of reliably excluding TB disease has severely limited TB screening and IPT uptake in resource-limited settings. We conducted an individual participant data meta-analysis of primary studies, aiming to identify a sensitive TB screening rule. METHODS AND FINDINGS: We identified 12 studies that had systematically collected sputum specimens regardless of signs or symptoms, at least one mycobacterial culture, clinical symptoms, and HIV and TB disease status. Bivariate random-effects meta-analysis and the hierarchical summary relative operating characteristic curves were used to evaluate the screening performance of all combinations of variables of interest. TB disease was diagnosed in 557 (5.8%) of 9,626 people living with HIV. The primary analysis included 8,148 people living with HIV who could be evaluated on five symptoms from nine of the 12 studies. The median age was 34 years. The best performing rule was the presence of any one of: current cough (any duration), fever, night sweats, or weight loss. The overall sensitivity of this rule was 78.9% (95% confidence interval [CI] 58.3%-90.9%) and specificity was 49.6% (95% CI 29.2%-70.1%). Its sensitivity increased to 90.1% (95% CI 76.3%-96.2%) among participants selected from clinical settings and to 88.0% (95% CI 76.1%-94.4%) among those who were not previously screened for TB. Negative predictive value was 97.7% (95% CI 97.4%-98.0%) and 90.0% (95% CI 88.6%-91.3%) at 5% and 20% prevalence of TB among people living with HIV, respectively. Abnormal chest radiographic findings increased the sensitivity of the rule by 11.7% (90.6% versus 78.9%) with a reduction of specificity by 10.7% (49.6% versus 38.9%). CONCLUSIONS: Absence of all of current cough, fever, night sweats, and weight loss can identify a subset of people living with HIV who have a very low probability of having TB disease. A simplified screening rule using any one of these symptoms can be used in resource-constrained settings to identify people living with HIV in need of further diagnostic assessment for TB. Use of this algorithm should result in earlier TB diagnosis and treatment, and should allow for substantial scale-up of IPT.

Sensitive and Feasible Specimen Collection and Testing Strategies for Diagnosing Tuberculosis in Young Children.

Importance: Criterion-standard specimens for tuberculosis diagnosis in young children, gastric aspirate (GA) and induced sputum, are invasive and rarely collected in resource-limited settings. A far less invasive approach to tuberculosis diagnostic testing in children younger than 5 years as sensitive as current reference standards is important to identify. Objective: To characterize the sensitivity of preferably minimally invasive specimen and assay combinations relative to maximum observed yield from all specimens and assays combined. Design, Setting, and Participants: In this prospective cross-sectional diagnostic study, the reference standard was a panel of up to 2 samples of each of 6 specimen types tested for Mycobacterium tuberculosis complex by Xpert MTB/RIF assay and mycobacteria growth indicator tube culture. Multiple different combinations of specimens and tests were evaluated as index tests. A consecutive series of children was recruited from inpatient and outpatient settings in Kisumu County, Kenya, between October 2013 and August 2015. Participants were children younger than 5 years who had symptoms of tuberculosis (unexplained cough, fever, malnutrition) and parenchymal abnormality on chest radiography or who had cervical lymphadenopathy. Children with 1 or more evaluable specimen for 4 or more primary study specimen types were included in the analysis. Data were analyzed from February 2015 to October 2020. Main Outcomes and Measures: Cumulative and incremental diagnostic yield of combinations of specimen types and tests relative to the maximum observed yield. Results: Of the 300 enrolled children, the median (interquartile range) age was 2.0 (1.0-3.6) years, and 151 (50.3%) were female. A total of 294 met criteria for analysis. Of 31 participants with confirmed tuberculosis (maximum observed yield), 24 (sensitivity, 77%; interdecile range, 68%-87%) had positive results on up to 2 GA samples and 20 (sensitivity, 64%; interdecile range, 53%-76%) had positive test results on up to 2 induced sputum samples. The yields of 2 nasopharyngeal aspirate (NPA) samples (23 of 31 [sensitivity, 74%; interdecile range, 64%-84%]), of 1 NPA sample and 1 stool sample (22 of 31 [sensitivity, 71%; interdecile range, 60%-81%]), or of 1 NPA sample and 1 urine sample (21.5 of 31 [sensitivity, 69%; interdecile range, 58%-80%]) were similar to reference-standard specimens. Combining up to 2 each of GA and NPA samples had an average yield of 90% (28 of 31). Conclusions and Relevance: NPA, in duplicate or in combination with stool or urine specimens, was readily obtainable and had diagnostic yield comparable with reference-standard specimens. This combination could improve tuberculosis diagnosis among children in resource-limited settings. Combining GA and NPA had greater yield than that of the current reference standards and may be useful in certain clinical and research settings.