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.

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.

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.

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.

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.

Tuberculosis among Newly Arrived Immigrants and Refugees in the United States.

Rationale: U.S. health departments routinely conduct post-arrival evaluation of immigrants and refugees at risk for tuberculosis (TB), but this important intervention has not been thoroughly studied.Objectives: To assess outcomes of the post-arrival evaluation intervention.Methods: We categorized at-risk immigrants and refugees as having had recent completion of treatment for pulmonary TB disease overseas (including in Mexico and Canada); as having suspected TB disease (chest radiograph/clinical symptoms suggestive of TB) but negative culture results overseas; or as having latent TB infection (LTBI) diagnosed overseas. Among 2.1 million U.S.-bound immigrants and refugees screened for TB overseas during 2013-2016, 90,737 were identified as at risk for TB. We analyzed a national data set of these at-risk immigrants and refugees and calculated rates of TB disease for those who completed post-arrival evaluation.Results: Among 4,225 persons with recent completion of treatment for pulmonary TB disease overseas, 3,005 (71.1%) completed post-arrival evaluation within 1 year of arrival; of these, TB disease was diagnosed in 22 (732 cases/100,000 persons), including 4 sputum culture-positive cases (133 cases/100,000 persons), 13 sputum culture-negative cases (433 cases/100,000 persons), and 5 cases with no reported sputum-culture results (166 cases/100,000 persons). Among 55,938 with suspected TB disease but negative culture results overseas, 37,089 (66.3%) completed post-arrival evaluation; of these, TB disease was diagnosed in 597 (1,610 cases/100,000 persons), including 262 sputum culture-positive cases (706 cases/100,000 persons), 281 sputum culture-negative cases (758 cases/100,000 persons), and 54 cases with no reported sputum-culture results (146 cases/100,000 persons). Among 30,574 with LTBI diagnosed overseas, 18,466 (60.4%) completed post-arrival evaluation; of these, TB disease was diagnosed in 48 (260 cases/100,000 persons), including 11 sputum culture-positive cases (60 cases/100,000 persons), 22 sputum culture-negative cases (119 cases/100,000 persons), and 15 cases with no reported sputum-culture results (81 cases/100,000 persons). Of 21,714 persons for whom treatment for LTBI was recommended at post-arrival evaluation, 14,977 (69.0%) initiated treatment and 8,695 (40.0%) completed treatment.Conclusions: Post-arrival evaluation of at-risk immigrants and refugees can be highly effective. To optimize the yield and impact of this intervention, strategies are needed to improve completion rates of post-arrival evaluation and treatment for LTBI.

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.

High yield of new HIV diagnoses during active case-finding for tuberculosis.

OBJECTIVE: To evaluate the utility of a broad and nonspecific symptom screen for identifying people with undiagnosed HIV infection. DESIGN: Secondary analysis of operational data collected during implementation of a cluster-randomized trial for tuberculosis case detection. METHODS: As part of the trial, adults reporting cough, fever, night sweats, weight loss, or difficulty breathing for any duration in the past month were identified in health facilities and community-based mobile screening units in western Kenya. Adults reporting any symptom were offered HIV testing. We analysed the HIV testing data from this study, using modified Poisson regression, to identify predictors of new HIV diagnoses among adults with symptoms and initially unknown HIV status. RESULTS: We identified 3818 symptomatic adults, referred 1424 (37%) for testing, of whom 1065 (75%) accepted, and 107 (10%) were newly diagnosed with HIV. The prevalence of new HIV diagnoses was 21% [95% confidence interval (CI) 17-25%] among those tested in health facilities and 5% (95% CI 4-7%) among those tested in mobile units. More men were diagnosed with HIV than women, despite fewer men being screened. People who reported 4-5 symptoms were over twice as likely to be diagnosed with HIV compared to those reporting 1-3 symptoms (adjusted prevalence ratio in health facilities = 2.58, 95% CI 1.65-4.05; adjusted prevalence ratio in mobile units = 2.63, 95% CI 1.37-5.03). CONCLUSION: We observed a high yield of new HIV diagnoses among adults identified by active application of a broad symptom screen. Use of integrated tuberculosis and HIV screening could help close the detection gap for both conditions.

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.

Development of colorimetric sensor array for diagnosis of tuberculosis through detection of urinary volatile organic compounds.

BACKGROUND: Top priorities for tuberculosis control and elimination include a simple, low-cost screening test using sputum and a non-sputum-based test in patients that do not produce sputum. The aim of this study was to evaluate the performance of a colorimetric sensor array (CSA) test, for analysis of volatile organic compounds in urine, in the diagnosis of pulmonary TB. MATERIAL AND METHODS: Urine samples were collected from individuals suspected of having pulmonary TB in Western Kenya. Reference methods included MGIT culture and/or Xpert MTB/RIF nucleic acid amplification test on sputa. Fresh urine samples were tested with the CSA, with acid and base and without an additive. The CSA were digitally imaged, and the resulting colorimetric response patterns were used for chemometric analysis. Sensitivity, specificity, and negative (NPV) and positive predictive (PPV) values were determined for HIV-positive and HIV-negative patients. RESULTS: In HIV-negative patients, the highest accuracy was obtained in urine samples pre-treated with a base, yielding a sensitivity, specificity, PPV, and NPV of 78.3% (65/83), 69.2% (54/78), 73.0% (n/89) and 75.0% (n/72). The highest sensitivity of 79.5% was achieved using sensor data from all three test conditions at a specificity of 65.4%. In HIV-positive subjects, the sensor performance was substantially lower with sensitivity, specificity, PPV, and NPV ranging from 48.3% to 62.3%, 54.1% to 74.0%, 55.9% to 64.2%, and 60.6% to 64.9%, respectively. CONCLUSION: The CSA fingerprint of urine headspace volatiles showed moderate accuracy in diagnosing TB in HIV-negative patients, but the sensor performance dropped substantially in HIV-coinfected patients. Further development of TB-responsive CSA indicators may improve the accuracy of CSA urine assay.

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.

Reduction of HIV-associated excess mortality by antiretroviral treatment among tuberculosis patients in Kenya.

BACKGROUND: Mortality from TB continues to be a global public health challenge. TB ranks alongside Human Immunodeficiency Virus (HIV) as the leading infectious causes of death globally. HIV is a major driver of TB related morbidity and mortality while TB is the leading cause of mortality among people living with HIV/AIDS. We sought to determine excess mortality associated with HIV and the effect of antiretroviral therapy on reducing mortality among tuberculosis patients in Kenya. METHODS: We conducted a retrospective analysis of Kenya national tuberculosis program data of patients enrolled from 2013 through 2014. We used direct standardization to obtain standardized mortality ratios for tuberculosis patients compared with the general population. We calculated the population attributable fraction of tuberculosis deaths due to HIV based on the standardized mortality ratio for deaths among TB patients with HIV compared to TB patients without HIV. We used Cox proportional hazards regression for assessing risk factors for mortality. RESULTS: Of 162,014 patients included in the analysis, 6% died. Mortality was 10.6 (95% CI: 10.4-10.8) times higher among TB patients than the general population; 42% of deaths were attributable to HIV infection. Patients with HIV who were not receiving ART had an over four-fold risk of death compared to patients without HIV (aHR = 4.2, 95% CI 3.9-4.6). In contrast, patients with HIV who were receiving ART had only 2.6 times the risk of death (aHR = 2.6, 95% CI 2.5-2.7). CONCLUSION: HIV was a significant contributor to TB-associated deaths in Kenya. Mortality among HIV-infected individuals was higher among those not on ART than those on ART. Early initiation of ART among HIV infected people (a "test and treat" approach) should further reduce TB-associated deaths.

Performance of Clinical Screening Algorithms for Tuberculosis Intensified Case Finding among People Living with HIV in Western Kenya.

OBJECTIVE: To assess the performance of symptom-based screening for tuberculosis (TB), alone and with chest radiography among people living with HIV (PLHIV), including pregnant women, in Western Kenya. DESIGN: Prospective cohort study. METHODS: PLHIV from 15 randomly-selected HIV clinics were screened with three clinical algorithms [World Health Organization (WHO), Ministry of Health (MOH), and "Improving Diagnosis of TB in HIV-infected persons" (ID-TB/HIV) study], underwent chest radiography (unless pregnant), and provided two or more sputum specimens for smear microscopy, liquid culture, and Xpert MTB/RIF. Performance of clinical screening was compared to laboratory results, controlling for the complex design of the survey. RESULTS: Overall, 738 (85.6%) of 862 PLHIV enrolled were included in the analysis. Estimated TB prevalence was 11.2% (95% CI, 9.9-12.7). Sensitivity of the three screening algorithms was similar [WHO, 74.1% (95% CI, 64.1-82.2); MOH, 77.5% (95% CI, 68.6-84.5); and ID-TB/HIV, 72.5% (95% CI, 60.9-81.7)]. Sensitivity of the WHO algorithm was significantly lower among HIV-infected pregnant women [28.2% (95% CI, 14.9-46.7)] compared to non-pregnant women [78.3% (95% CI, 67.3-86.4)] and men [77.2% (95% CI, 68.3-84.2)]. Chest radiography increased WHO algorithm sensitivity and negative predictive value to 90.9% (95% CI, 86.4-93.9) and 96.1% (95% CI, 94.4-97.3), respectively, among asymptomatic men and non-pregnant women. CONCLUSIONS: Clinical screening missed approximately 25% of laboratory-confirmed TB cases among all PLHIV and more than 70% among HIV-infected pregnant women. National HIV programs should evaluate the feasibility of laboratory-based screening for TB, such as a single Xpert MTB/RIF test for all PLHIV, especially pregnant women, at enrollment in HIV services.

Abrupt Decline in Tuberculosis among Foreign-Born Persons in the United States.

While the number of reported tuberculosis (TB) cases in the United States has declined over the past two decades, TB morbidity among foreign-born persons has remained persistently elevated. A recent unexpected decline in reported TB cases among foreign-born persons beginning in 2007 provided an opportunity to examine contributing factors and inform future TB control strategies. We investigated the relative influence of three factors on the decline: 1) changes in the size of the foreign-born population through immigration and emigration, 2) changes in distribution of country of origin among foreign-born persons, and 3) changes in the TB case rates among foreign-born subpopulations. Using data from the U.S. National Tuberculosis Surveillance System and the American Community Survey, we examined TB case counts, TB case rates, and population estimates, stratified by years since U.S. entry and country of origin. Regression modeling was used to assess statistically significant changes in trend. Among foreign-born recent entrants (<3 years since U.S. entry), we found a 39.5% decline (-1,013 cases) beginning in 2007 (P<0.05 compared to 2000-2007) and ending in 2011 (P<0.05 compared to 2011-2014). Among recent entrants from Mexico, 80.7% of the decline was attributable to a decrease in population, while the declines among recent entrants from the Philippines, India, Vietnam, and China were almost exclusively (95.5%-100%) the result of decreases in TB case rates. Among foreign-born non-recent entrants (≥3 years since U.S. entry), we found an 8.9% decline (-443 cases) that resulted entirely (100%) from a decrease in the TB case rate. Both recent and non-recent entrants contributed to the decline in TB cases; factors contributing to the decline among recent entrants varied by country of origin. Strategies that impact both recent and non-recent entrants (e.g., investment in overseas TB control) as well as those that focus on non-recent entrants (e.g., expanded targeted testing of high-risk subgroups among non-recent entrants) will be necessary to achieve further declines in TB morbidity among foreign-born persons.

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.