Solicited Cough Sound Analysis for Tuberculosis Triage Testing: The CODA TB DREAM Challenge Dataset.

Cough is a common and commonly ignored symptom of lung disease. Cough is often perceived as difficult to quantify, frequently self-limiting, and non-specific. However, cough has a central role in the clinical detection of many lung diseases including tuberculosis (TB), which remains the leading infectious disease killer worldwide. TB screening currently relies on self-reported cough which fails to meet the World Health Organization (WHO) accuracy targets for a TB triage test. Artificial intelligence (AI) models based on cough sound have been developed for several respiratory conditions, with limited work being done in TB. To support the development of an accurate, point-of-care cough-based triage tool for TB, we have compiled a large multi-country database of cough sounds from individuals being evaluated for TB. The dataset includes more than 700,000 cough sounds from 2,143 individuals with detailed demographic, clinical and microbiologic diagnostic information. We aim to empower researchers in the development of cough sound analysis models to improve TB diagnosis, where innovative approaches are critically needed to end this long-standing pandemic.

Epidemiology and Treatment Outcomes of Tuberculosis with Chronic Hepatitis B Infection-California, 2016-2020.

BACKGROUND: Improved epidemiologic and treatment data for active tuberculosis (TB) with chronic hepatitis B virus (cHBV) infection might inform and encourage screening and vaccination programs focused on persons at risk of having both conditions. METHODS: We matched the California Department of Public Health TB registry during 2016-2020 to the cHBV registry using probabilistic matching algorithms. We used chi-square analysis to compare the characteristics of persons with TB and cHBV with those with TB only. We compared TB treatment outcomes between these groups using modified Poisson regression models. We calculated the time between reporting of TB and cHBV diagnoses for those with both conditions. RESULTS: We identified 8,435 persons with TB, including 316 (3.7%) with cHBV.- Among persons with TB and cHBV, 256 (81.0%) were non-U.S.-born Asian vs 4,186 (51.6%) with TB only (P <0.0001). End-stage renal disease (26 [8.2%] vs 322 [4.0%]; P <0.001) and HIV (21 [6.7%] vs 247 [3.0%]; P value = 0.02) were more frequent among those with TB and cHBV compared with those with TB only. Among those with both conditions, 35 (11.1%) had TB diagnosed >60 days before cHBV (median 363 days) and 220 (69.6%) had TB diagnosed >60 days after cHBV (median 3,411 days). CONCLUSION: Persons with TB and cHBV were found more frequently in certain groups compared with TB only, and infrequently had their conditions diagnosed together. This highlights an opportunity to improve screening and treatment of TB and cHBV in those at high risk for coinfection.

The socioeconomic burden of pediatric tuberculosis and role of child-sensitive social protection.

BACKGROUND: Households of children with tuberculosis (TB) experience financial and social hardships, but TB-specific social protection initiatives primarily focus on adults. METHODS: We conducted a single-arm, pilot study of multi-component supportive benefits for children with pulmonary TB in Kampala, Uganda. At diagnosis, participants received in-kind coverage of direct medical costs, a cash transfer, and patient navigation. Caregivers were surveyed before diagnosis and 2 months into TB treatment on social and financial challenges related to their child's illness, including estimated costs, loss of income and dissaving practices. RESULTS: We included 368 children from 321 households. Pre-diagnosis, 80.1% of caregivers reported that their child's illness negatively impacted household finances, 44.1% of caregivers missed work, and 24% engaged in dissaving practices. Catastrophic costs (> 20% annual income) were experienced by 18.4% (95% CI 13.7-24.0) of households. School disruption was common (25.6%), and 28% of caregivers were concerned their child was falling behind in development. Two months post-diagnosis, 12 households (4.8%) reported being negatively affected by their child's TB disease (difference -75.2%, 95% CI -81.2 to -69.2, p < 0.001), with limited ongoing loss of income (1.6%) or dissavings practices (0.8%). Catastrophic costs occurred in one household (0.4%) at 2 months post-diagnosis. CONCLUSIONS: Households face financial and social challenges prior to a child's TB diagnosis, and child-sensitive social protection support may mitigate ongoing burden.

Epidemiology of Culture-Negative Pulmonary Tuberculosis-Alameda County, 2010-2019.

CONTEXT: Patients with culture-negative pulmonary TB (PTB) can face delays in diagnosis that worsen outcomes and lead to ongoing transmission. An understanding of current trends and characteristics of culture-negative PTB can support earlier detection and access to care. OBJECTIVE: Describe epidemiology of culture-negative PTB. DESIGN, SETTING, PARTICIPANTS: We utilized Alameda County TB surveillance data from 2010 to 2019. Culture-negative PTB cases met clinical but not laboratory criteria for PTB per US National Tuberculosis Surveillance System definitions. We calculated trends in annual incidence and proportion of culture-negative PTB using Poisson and weighted linear regression, respectively. We further compared demographic and clinical characteristics among culture-negative versus culture-positive PTB cases. RESULTS: During 2010-2019, there were 870 cases of PTB, of which 152 (17%) were culture-negative. The incidence of culture-negative PTB declined by 76%, from 1.9/100 000 to 0.46/100 000 ( P for trend <.01), while the incidence of culture-positive PTB reduced by 37% (6.5/100 000 to 4.1/100 000, P for trend =.1). Culture-negative PTB case-patients were more likely than culture-positive PTB case-patients to be younger (7.9% were children <15 years old vs 1.1%; P < .01), recent immigrants within 5 years of arrival (38.2% vs 25.5%; P < .01), and have a TB contact (11.2% vs 2.9%; P < .01). Culture-negative PTB case-patients were less likely than culture-positive PTB case-patients to be evaluated because of TB symptoms (57.2% vs 74.7%; P < .01) or have cavitation on chest imaging (13.1% vs 38.8%; P < .01). At the same time culture-negative PTB case-patients were less likely to die during TB treatment (2.0% vs 9.6%; P < .01). CONCLUSIONS: The incidence of culture-negative PTB disproportionately declined compared with culture-positive TB and raises concern for gaps in detection. Expansion of screening programs for recent immigrants and TB contacts and greater recognition of risk factors may increase detection of culture-negative PTB.

Tuberculosis Disease Among Adults Aged 65 Years and Older: Alameda County, California, 2016-2019.

Background: Older adults aged ≥65 years old represent an increasing proportion of tuberculosis (TB) cases in the United States, but limited evidence exists on the characteristics and treatment outcomes that differentiate them from younger adults. Methods: We evaluated Alameda County TB surveillance data from 2016 to 2019 and abstracted public health charts for older adult TB cases. Clinical presentation and treatment outcomes were compared in older and younger adults (15-64 years), and multivariable logistic regression was conducted to assess risk factors for TB treatment noncompletion among older adults. Results: Of 517 TB cases, 172 (33.2%) were older adults and 101 were ≥75 years old. Compared to younger adults, older TB cases were more likely to be non-US-born, and have diabetes. For diagnosis, older adults were more likely to have negative interferon-gamma release assays (24.6% vs 16.0%; P = .01) and were less likely to have cavitary disease (18.6% vs 26.7%; P < .001). One third of older adults experienced an adverse event; older adults were less likely to complete TB treatment (77.7% vs 88.4%; P = .002) and were more likely to die during TB treatment (16.3% vs 2.9%; P < .01), especially among those ≥75 years old, who had a mortality rate of 22.9%. In multivariable analysis, dementia was significantly associated with treatment noncompletion (adjusted odds ratio, 5.05; 95% confidence interval, 1.33-20.32; P = .02). Conclusions: Diabetes, negative diagnostic tests, and poor treatment outcomes were more prevalent in older adult TB cases. A greater understanding of their TB presentation and comorbidities will inform interventions to improve outcomes among older adults.

Social Determinants of Adherence to Treatment for Tuberculosis Infection and Disease Among Children, Adolescents, and Young Adults: A Narrative Review.

Global efforts to eliminate tuberculosis (TB) must address the unique barriers that children (ages 0 through 9 years) and adolescents/young adults (AYA; ages 10 through 24 years) face in adhering to treatment for TB infection and disease. We conducted a narrative review to summarize current knowledge on the social determinants of treatment adherence among these age groups to guide efforts and policy to address their unique needs. Our findings revealed that research on TB treatment adherence among children and AYA is still in its nascent stage. The current literature revealed structural/community-, health system-, household-, and individual-level factors that influence treatment adherence and varied with developmental stage. There is a need to develop multilevel interventions to address the unique challenges that children and AYA face in adhering to TB treatment.

Engineered Electroactive Solutions for Electrochemical Detection of Tuberculosis-Associated Volatile Organic Biomarkers.

Rapid screening of tuberculosis by evaluation of associated volatile organic biomarkers in breath is a promising technology that is significantly faster and more convenient than traditional sputum culture tests. Methyl nicotinate (MN) and methyl p-anisate (MPA) have been isolated as potential biomarkers for mycobacterium tuberculosis and have been found in the breath of patients with active pulmonary tuberculosis. A novel approach to detection of these biomarkers in liquid droplets (e.g. from breath condensate) using inexpensive screen-printed electrodes is presented. Previous modelling studies suggest that these biomarkers complex with certain transition metals of particular valence state. This interaction can be exploited by mixing the biomarker sample into an electroactive solution (EAS) containing the functional metal ion and observing the change electrochemically. The study focuses on low biomarker concentrations, determined to be clinically relevant based on preliminary GC-MS studies of the levels found in patient breath. It was found that both the cyclic voltammogram and square wave voltammogram of copper(II) change significantly when as little as 0.1 mM MN is added to the solution, with analysis times of less than 2 min. Copper(II) exhibits three separate peaks during square wave voltammetry. The location and area of each peak are affected differently as the concentration of MN increases, suggesting a reaction with specific oxidation states of the metal. In this way, a "fingerprint" method can be used to identify biomarkers once their known interaction is established.

Making cough count in tuberculosis care.

Cough assessment is central to the clinical management of respiratory diseases, including tuberculosis (TB), but strategies to objectively and unobtrusively measure cough are lacking. Acoustic epidemiology is an emerging field that uses technology to detect cough sounds and analyze cough patterns to improve health outcomes among people with respiratory conditions linked to cough. This field is increasingly exploring the potential of artificial intelligence (AI) for more advanced applications, such as analyzing cough sounds as a biomarker for disease screening. While much of the data are preliminary, objective cough assessment could potentially transform disease control programs, including TB, and support individual patient management. Here, we present an overview of recent advances in this field and describe how cough assessment, if validated, could support public health programs at various stages of the TB care cascade.

A narrative review of tuberculosis in the United States among persons aged 65 years and older.

Tuberculosis (TB) is a preventable infectious disease that confers significant morbidity, mortality, and psychosocial challenges. As TB incidence in the United States (U.S.) decreased from 9.7/100,000 to 2.2/100,000 from 1993 to 2020, the proportion of cases occurring among adults aged 65 and older increased. We conducted a review of published literature in the U.S. and other similar low-TB-burden settings to characterize the epidemiology and unique diagnostic challenges of TB in older adults. This narrative review also provides an overview of treatment characteristics, outcomes, and research gaps in this patient population. Older adults had a 30% higher likelihood of delayed TB diagnosis, with contributing factors such as acid-fast bacilli sputum smear-negative disease (56%) and non-classical clinical presentation. At least 90% of TB cases among older adults resulted from reactivation of latent TB infection (LTBI), but guidance around when to screen and treat LTBI in these patients is lacking. In addition, routine TB testing methods such as interferon-gamma release assays were two times more likely to have false-negative results among older adults. Advanced age was also often accompanied by complex comorbidities and impaired drug metabolism, increasing the risk of treatment failure (23%) and death (19%). A greater understanding of the unique factors of TB among older adults will inform clinical and public health efforts to improve outcomes in this complex patient population and TB control in the U.S.

The Role of C-Reactive Protein as a Triage Tool for Pulmonary Tuberculosis in Children.

BACKGROUND: C-reactive protein (CRP) has shown promise as a triage tool for pulmonary tuberculosis (TB) in adults living with the human immunodeficiency virus. We performed the first assessment of CRP for TB triage in children. METHODS: Symptomatic children less than 15 years old were prospectively enrolled in Kampala, Uganda. We completed a standard TB evaluation and measured CRP using a point-of-care assay. We determined the sensitivity and specificity of CRP to identify pulmonary TB in children using 10 mg/L and 5 mg/L cut-off points and generated a receiver operating characteristic (ROC) curve to determine alternative cut-offs that could approach the target accuracy for a triage test (≥90% sensitivity and ≥70% specificity). RESULTS: We included 332 children (median age 3 years old, interquartile range [IQR]: 1-6). The median CRP level was low at 3.0 mg/L (IQR: 2.5-26.6) but was higher in children with Confirmed TB than in children with Unlikely TB (9.5 mg/L vs. 2.9 mg/L, P-value = .03). At a 10 mg/L cut-off, CRP sensitivity was 50.0% (95% confidence interval [CI], 37.0-63.0) among Confirmed TB cases and specificity was 63.3% (95% CI, 54.7-71.3) among children with Unlikely TB. Sensitivity increased to 56.5% (95% CI, 43.3-69.0) at the 5 mg/L cut-off, but specificity decreased to 54.0% (95% CI, 45.3-62.4). The area under the ROC curve was 0.59 (95% CI, 0.51-0.67), and the highest sensitivity achieved was 66.1% at a specificity of 46.8%. CONCLUSIONS: CRP levels were low in children with pulmonary TB, and CRP was unable to achieve the accuracy targets for a TB triage test.

Tuberculosis in Children.

Tuberculosis (TB) is one of the leading causes of mortality in children worldwide, but there remain significant challenges in diagnosing and treating TB infection and disease. Treatment of TB infection in children and adolescents is critical to prevent progression to TB disease and to prevent them from becoming the future reservoir for TB transmission. This article reviews the clinical approach to diagnosing and treating latent TB infection and pulmonary and extrapulmonary TB disease in children. Also discussed are emerging diagnostics and therapeutic regimens that aim to improve pediatric TB detection and outcomes.

Toward Comprehensive Plasma Proteomics by Orthogonal Protease Digestion.

Rapid and consistent protein identification across large clinical cohorts is an important goal for clinical proteomics. With the development of data-independent technologies (DIA/SWATH-MS), it is now possible to analyze hundreds of samples with great reproducibility and quantitative accuracy. However, this technology benefits from empirically derived spectral libraries that define the detectable set of peptides and proteins. Here, we apply a simple and accessible tip-based workflow for the generation of spectral libraries to provide a comprehensive overview on the plasma proteome in individuals with and without active tuberculosis (TB). To boost protein coverage, we utilized nonconventional proteases such as GluC and AspN together with the gold standard trypsin, identifying more than 30,000 peptides mapping to 3309 proteins. Application of this library to quantify plasma proteome differences in TB infection recovered more than 400 proteins in 50 min of MS acquisition, including diagnostic Mycobacterium tuberculosis (Mtb) proteins that have previously been detectable primarily by antibody-based assays and intracellular proteins not previously described to be in plasma.

A Prospective Evaluation of Xpert MTB/RIF Ultra for Childhood Pulmonary Tuberculosis in Uganda.

BACKGROUND: Xpert MTB/RIF Ultra (Xpert Ultra) has improved the sensitivity to detect pulmonary tuberculosis (TB) in adults. However, there have been limited prospective evaluations of its diagnostic accuracy in children. METHODS: We enrolled children undergoing assessment for pulmonary TB in Kampala, Uganda, over a 12-month period. Children received a complete TB evaluation and were classified as Confirmed, Unconfirmed, or Unlikely TB. We calculated the sensitivity and specificity of Xpert Ultra among children with Confirmed vs Unlikely TB. We also determined the diagnostic accuracy with clinical, microbiological, and extended microbiological reference standards (MRSs). RESULTS: Of the 213 children included, 23 (10.8%) had Confirmed TB, 88 (41.3%) had Unconfirmed TB, and 102 (47.9%) had Unlikely TB. The median age was 3.9 years, 13% were HIV-positive, and 61.5% were underweight. Xpert Ultra sensitivity was 69.6% (95% confidence interval [CI]: 47.1-86.8) among children with Confirmed TB and decreased to 23.4% (95% CI: 15.9-32.4) with the clinical reference standard. Specificity was 100% (95% CI: 96.4-100) among children with Unlikely TB and decreased to 94.7% (95% CI: 90.5-97.4) with a MRS. Sensitivity was 52.9% (95% CI: 35.1-70.2) and specificity 95.5% (95% CI: 91.4-98.1) with the extended MRS. Of the 26 positive Xpert Ultra results, 6 (23.1%) were "Trace-positive," with most (5/6) occurring in children with Unconfirmed TB. CONCLUSIONS: Xpert Ultra is a useful tool for diagnosing pulmonary TB in children, but there remains a need for more sensitive tests to detect culture-negative TB.

Lipoarabinomannan antigenic epitope differences in tuberculosis disease subtypes.

An accurate urine test for diverse populations with active tuberculosis could be transformative for preventing TB deaths. Urinary liporabinomannan (LAM) testing has been previously restricted to HIV co-infected TB patients. In this study we evaluate urinary LAM in HIV negative, pediatric and adult, pulmonary and extrapulmonary tuberculosis patients. We measured 430 microbiologically confirmed pretreatment tuberculosis patients and controls from Peru, Guinea Bissau, Venezuela, Uganda and the United States using three monoclonal antibodies, MoAb1, CS35, and A194, which recognize distinct LAM epitopes, a one-sided immunoassay, and blinded cohorts. We evaluated sources of assay variability and comorbidities (HIV and diabetes). All antibodies successfully discriminated TB positive from TB negative patients. ROAUC from the average of three antibodies' responses was 0.90; 95% CI 0.87-0.93, 90% sensitivity, 73.5% specificity (80 pg/mL). MoAb1, recognizing the 5-methylthio-D-xylofuranose(MTX)-mannose(Man) cap epitope, performed the best, was less influenced by glycosuria and identified culture positive pediatric (N = 19) and extrapulmonary (N = 24) patients with high accuracy (ROAUC 0.87, 95% CI 0.77-0.98, 0.90 sensitivity 0.80 specificity at 80 pg/mL; ROAUC = 0.96, 95% CI 0.92-0.99, 96% sensitivity, 80% specificity at 82 pg/mL, respectively). The MoAb1 antibody, recognizing the MTX-Man cap epitope, is a novel analyte for active TB detection in pediatric and extrapulmonary disease.

Evaluation of multi-antigen serological screening for active tuberculosis among people living with HIV.

Better triage tests for screening tuberculosis (TB) disease are needed for people living with HIV (PLHIV). We performed the first evaluation of a previously-validated 8-antigen serological panel to screen PLHIV for pulmonary TB in Kampala, Uganda. We selected a random 1:1 sample with and without TB (defined by sputum culture) from a cohort of PLHIV initiating antiretroviral therapy. We used a multiplex microbead immunoassay and an ensemble machine learning classifier to determine the area under the receiver operating characteristic curve (AUC) for Ag85A, Ag85B, Ag85C, Rv0934-P38, Rv3881, Rv3841-BfrB, Rv3873, and Rv2878c. We then assessed the performance with the addition of four TB-specific antigens ESAT-6, CFP-10, Rv1980-MPT64, and Rv2031-HSPX, and every antigen combination. Of 262 participants (median CD4 cell-count 152 cells/µL [IQR 65-279]), 138 (53%) had culture-confirmed TB. The 8-antigen panel had an AUC of 0.53 (95% CI 0.40-0.66), and the additional 4 antigens did not improve performance (AUC 0.51, 95% CI 0.39-0.64). When sensitivity was restricted to ≥90% for the 8- and 12-antigen panel, specificity was 2.2% (95% CI 0-17.7%) and 8.1% (95% CI 0-23.9%), respectively. A three-antigen combination (Rv0934-P38, Ag85A, and Rv2031-HSPX) outperformed both panels, with an AUC of 0.60 (95% CI 0.48-0.73), 90% sensitivity (95% CI 78.2-96.7%) and 29.7% specificity (95% CI 15.9-47%). The multi-antigen panels did not achieve the target accuracy for a TB triage test among PLHIV. We identified a new combination that improved performance for TB screening in an HIV-positive sample compared to an existing serological panel in Uganda, and suggests an approach to identify novel antigen combinations specifically for screening TB in PLHIV.

Outcomes of empiric treatment for pediatric tuberculosis, Kampala, Uganda, 2010-2015.

BACKGROUND: Childhood tuberculosis (TB) diagnoses often lack microbiologic confirmation and require empiric treatment. Barriers to empiric treatment include concern for poor outcomes and adverse effects. We thus determined the outcomes of empiric TB treatment from a retrospective cohort of children at a national referral hospital in Kampala, Uganda from 2010 to 2015. METHODS: Children were diagnosed clinically and followed through treatment. Demographics, clinical data, outcome and any adverse events were extracted from patient charts. A favorable outcome was defined as a child completing treatment with clinical improvement. We performed logistic regression to assess factors associated with loss to follow up and death. RESULTS: Of 516 children, median age was 36 months (IQR 15-73), 55% (95% CI 51-60%) were male, and HIV prevalence was 6% (95% CI 4-9%). The majority (n = 422, 82, 95% CI 78-85%) had a favorable outcome, with no adverse events that required treatment discontinuation. The most common unfavorable outcomes were loss to follow-up (57/94, 61%) and death (35/94, 37%; overall mortality 7%). In regression analysis, loss to follow up was associated with age 10-14 years (OR 2.38, 95% CI 1.15-4.93, p = 0.02), HIV positivity (OR 3.35, 95% CI 1.41-7.92, p = 0.01), hospitalization (OR 4.14, 95% CI 2.08-8.25, p < 0.001), and living outside of Kampala (OR 2.64, 95% CI 1.47-4.71, p = 0.001). Death was associated with hospitalization (OR 4.57, 95% CI 2.0-10.46, p < 0.001), severe malnutrition (OR 2.98, 95% CI 1.07-8.27, p = 0.04), baseline hepatomegaly (OR 4.11, 95% CI 2.09-8.09, p < 0.001), and living outside of Kampala (OR 2.41, 95% CI 1.17-4.96, p = 0.02). CONCLUSIONS: Empiric treatment of child TB was effective and safe, but treatment success remained below the 90% target. Addressing co-morbidities and improving retention in care may reduce unfavorable outcomes.

Seasonality of childhood tuberculosis cases in Kampala, Uganda, 2010-2015.

BACKGROUND: Seasonality in tuberculosis (TB) has been described, especially in children. However, few studies have assessed seasonality of TB in the equatorial region, and none in children. OBJECTIVES: To assess for seasonality of childhood TB cases in Kampala, Uganda, and determine the role of temperature, rainfall patterns, and influenza cases on TB diagnoses. METHODS: We retrospectively analyzed demographic and clinical data of children (under 15 years) diagnosed with TB at a pediatric TB clinic in Kampala, Uganda from 2010 to 2015. We performed decomposition analysis of the monthly case time series to assess seasonality. We compared monthly mean plots and performed Poisson regression to assess any association between TB diagnoses and temperature, rainfall, and influenza. RESULTS: Of the 713 childhood TB cases diagnosed at the clinic, 609 (85%) were clinically diagnosed and 492 (69%) were pulmonary cases. There were minimal monthly variations in TB cases, with a trough in December and peaks in July and October, but there was no significant seasonality. Temperature variations did not show a clear pattern with TB diagnoses. Rainfall alternated with TB diagnoses in the first half of the year, but then overlapped in the second half and was significantly associated with TB diagnoses. Influenza cases were significantly related to TB diagnoses with (ß = 0.05, 95% CI 0.01 to 0.09, p = 0.01) or without (ß = 0.06, 95% CI 0.01 to 0.1, p = 0.01) rainfall, and had particular overlap with pulmonary TB cases. CONCLUSIONS: Seasonal variations in childhood TB diagnoses were non-significant. Temperature did not have a clear pattern with TB diagnoses, but rainfall and influenza cases correlated with the primarily clinically diagnosed childhood TB cases.