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.

Feasibility and Utility of a Smartphone Application-Based Longitudinal Cough Monitoring in Chronic Cough Patients in a Real-World Setting.

PURPOSE: This study evaluated the feasibility and utility of longitudinal cough frequency monitoring with the Hyfe Cough Tracker, a mobile application equipped with cough-counting artificial intelligence algorithms, in real-world patients with chronic cough. METHODS: Patients with chronic cough (> 8-week duration) were monitored continuously for cough frequency with the Hyfe app for at least one week. Cough was also evaluated using the Leicester Cough Questionnaire (LCQ) and daily cough severity scoring (0-10). The study analyzed adherence rate, the correlation between objective cough frequency and subjective scores, day-to-day variability, and patient experience. RESULTS: Of 65 subjects consecutively recruited, 43 completed the study. The median cough monitoring duration was 13.9 days, with a median adherence of 91%. Study completion was associated with baseline cough severity, and the adherence rate was higher in younger subjects. Cross-sectional correlation analyses showed modest correlations between objective and subjective cough measures at the group level. However, in time series correlation analyses, correlations between objective and subjective measures widely varied across individuals. Cough frequency had greater day-to-day variability than daily cough severity scores in most subjects. A patient experience survey found that 70% of participants found the cough monitoring helpful, 86% considered it acceptable, and 84% felt it was easy to use. CONCLUSION: Monitoring cough frequency longitudinally for at least one week may be feasible. The substantial day-to-day variability in objective cough frequency highlights the need for continuous monitoring. Grasping the implications of daily cough variability is crucial in both clinical practice and clinical trials.

A social network analysis model approach to understand tuberculosis transmission in remote rural Madagascar.

BACKGROUND: Quality surveillance data used to build tuberculosis (TB) transmission models are frequently unavailable and may overlook community intrinsic dynamics that impact TB transmission. Social network analysis (SNA) generates data on hyperlocal social-demographic structures that contribute to disease transmission. METHODS: We collected social contact data in five villages and built SNA-informed village-specific stochastic TB transmission models in remote Madagascar. A name-generator approach was used to elicit individual contact networks. Recruitment included confirmed TB patients, followed by snowball sampling of named contacts. Egocentric network data were aggregated into village-level networks. Network- and individual-level characteristics determining contact formation and structure were identified by fitting an exponential random graph model (ERGM), which formed the basis of the contact structure and model dynamics. Models were calibrated and used to evaluate WHO-recommended interventions and community resiliency to foreign TB introduction. RESULTS: Inter- and intra-village SNA showed variable degrees of interconnectivity, with transitivity (individual clustering) values of 0.16, 0.29, and 0.43. Active case finding and treatment yielded 67%-79% reduction in active TB disease prevalence and a 75% reduction in TB mortality in all village networks. Following hypothetical TB elimination and without specific interventions, networks A and B showed resilience to both active and latent TB reintroduction, while Network C, the village network with the highest transitivity, lacked resiliency to reintroduction and generated a TB prevalence of 2% and a TB mortality rate of 7.3% after introduction of one new contagious infection post hypothetical elimination. CONCLUSION: In remote Madagascar, SNA-informed models suggest that WHO-recommended interventions reduce TB disease (active TB) prevalence and mortality while TB infection (latent TB) burden remains high. Communities' resiliency to TB introduction decreases as their interconnectivity increases. "Top down" population level TB models would most likely miss this difference between small communities. SNA bridges large-scale population-based and hyper focused community-level TB modeling.

Digital cough monitoring - A potential predictive acoustic biomarker of clinical outcomes in hospitalized COVID-19 patients.

PURPOSE: Recent developments in the field of artificial intelligence and acoustics have made it possible to objectively monitor cough in clinical and ambulatory settings. We hypothesized that time patterns of objectively measured cough in COVID-19 patients could predict clinical prognosis and help rapidly identify patients at high risk of intubation or death. METHODS: One hundred and twenty-three patients hospitalized with COVID-19 were enrolled at University of Florida Health Shands and the Centre Hospitalier de l'Université de Montréal. Patients' cough was continuously monitored digitally along with clinical severity of disease until hospital discharge, intubation, or death. The natural history of cough in hospitalized COVID-19 disease was described and logistic models fitted on cough time patterns were used to predict clinical outcomes. RESULTS: In both cohorts, higher early coughing rates were associated with more favorable clinical outcomes. The transitional cough rate, or maximum cough per hour rate predicting unfavorable outcomes, was 3·40 and the AUC for cough frequency as a predictor of unfavorable outcomes was 0·761. The initial 6 h (0·792) and 24 h (0·719) post-enrolment observation periods confirmed this association and showed similar predictive value. INTERPRETATION: Digital cough monitoring could be used as a prognosis biomarker to predict unfavorable clinical outcomes in COVID-19 disease. With early sampling periods showing good predictive value, this digital biomarker could be combined with clinical and paraclinical evaluation and is well adapted for triaging patients in overwhelmed or resources-limited health programs.

Long-COVID severe refractory cough: discussion of a case with 6-week longitudinal cough characterization.

Long coronavirus disease (COVID) refers to an array of variable and fluctuating symptoms experienced after acute illness, with signs and symptoms that persist for 8-12 weeks and are not otherwise explicable. Cough is the most common symptom of acute COVID-19, but cough may persist in some individuals for weeks or months after recovery from acute phase. Long-COVID cough patients may get stigmatised because of the public fear of contagion and reinfection. However, clinical characteristics and longitudinal course of long-COVID cough have not been reported in detail, and evidence-based treatment is also lacking. In this paper, we describe a case of long-COVID severe refractory cough with features of laryngeal hypersensitivity and dysfunction. We characterized cough using patient-reported outcomes and engaged in continuous cough frequency monitoring. Through the case study, we discuss potential mechanisms, managements, and clinical implications of long-COVID refractory cough problems.

Prevalence and factors associated with human Taenia solium taeniosis and cysticercosis in twelve remote villages of Ranomafana rainforest, Madagascar.

BACKGROUND: Infections with the tapeworm Taenia solium (taeniosis and cysticercosis) are Neglected Tropical Diseases (NTD) highly endemic in Madagascar. These infections are however underdiagnosed, underreported and their burden at the community level remains unknown especially in rural remote settings. This study aims at assessing the prevalence of T. solium infections and associated risk factors in twelve remote villages surrounding Ranomafana National Park (RNP), Ifanadiana District, Madagascar. METHODOLOGY: A community based cross-sectional survey was conducted in June 2016. Stool and serum samples were collected from participants. Tapeworm carriers were identified by stool examination. Taenia species and T. solium genotypes were characterised by PCR and sequencing of the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene. Detection of specific anti-cysticercal antibodies (IgG) or circulating cysticercal antigens was performed by ELISA or EITB/Western blot assays. PRINCIPAL FINDINGS: Of the 459 participants with paired stool and blood samples included ten participants from seven distinct villages harbored Taenia spp. eggs in their stools samples DNA sequencing of the cox1 gene revealed a majority of T. solium Asian genotype (9/10) carriage. The overall seroprevalences of anti-cysticercal IgGs detected by ELISA and EITB were quite similar (27.5% and 29.8% respectively). A prevalence rate of 12.4% of circulating cysticercal antigens was observed reflecting cysticercosis with viable cysts. Open defecation (Odds Ratio, OR = 1.5, 95% CI: 1.0-2.3) and promiscuity with households of more than 4 people (OR = 1.9, 95% CI: 1.1-3.1) seem to be the main risk factors associated with anticysticercal antibodies detection. Being over 15 years of age would be a risk factor associated with an active cysticercosis (OR = 1.6, 95% CI: 1.0-2.7). Females (OR = 0.5, 95% CI: 0.3-0.9) and use of river as house water source (OR = 0.3, 95% CI: 0.1-1.5) were less likely to have cysticercosis with viable cysts. CONCLUSIONS/SIGNIFICANCE: This study indicates a high exposure of the investigated population to T. solium infections with a high prevalence of cysticercosis with viable cysts. These data can be useful to strengthen public health interventions in these remote settings.

Diagnostic accuracy of point-of-care ultrasound for pulmonary tuberculosis: A systematic review.

The advent of affordable, portable ultrasound devices has led to increasing interest in the use of point-of-care ultrasound (POCUS) for the detection of pulmonary TB (PTB). We undertook a systematic review of the diagnostic accuracy of POCUS for PTB. Five databases were searched for articles published between January 2010 and June 2020. Risk of bias was assessed using QUADAS-2. Data on sensitivity and specificity of individual lung ultrasound findings were collected, with variable reference standards including PCR and sputum smear microscopy. Six of 3,919 reviewed articles were included: five in adults and one in children, with a total sample size of 564. Studies had high risk of bias in many domains. In adults, subpleural nodule and lung consolidation were the lung ultrasound findings with the highest sensitivities, ranging from 72.5% to 100.0% and 46.7% to 80.4%, respectively. Only one study reported specificity data. Variability in sensitivity may be due to variable reference standards or may imply operator dependence. There is insufficient evidence to judge the diagnostic accuracy of POCUS for PTB. There is also no consensus on the optimal protocols for acquiring and analysing POCUS images for PTB. New studies which minimise potential sources of bias are required to further assess the diagnostic accuracy of POCUS for PTB.

Latent tuberculosis infection prevalence in rural Madagascar.

BACKGROUND: Understanding latent Mycobacterium tuberculosis infection (LTBI) prevalence is crucial for the design of TB control strategies. There are no data on LTBI in rural Madagascar. METHODS: Tuberculin skin tests were performed in 98 adults aged >15 y in five rural villages in the Ifanadiana district, Madagascar. RESULTS: Of adults, 78.6% were positive for LTBI, ranging between 28.6% and 95.0% among villages. The majority (65.3%) showed an induration reaction of >15 mm. CONCLUSIONS: LTBI prevalence is high in rural Madagascar. Long-term TB control strategies including LTBI testing and treatment must account for high and heterogeneous prevalence in remote, underdeveloped areas.

Drones and digital adherence monitoring for community-based tuberculosis control in remote Madagascar: A cost-effectiveness analysis.

BACKGROUND: Continuing tuberculosis control with current approaches is unlikely to reach the World Health Organization's objective to eliminate TB by 2035. Innovative interventions such as unmanned aerial vehicles (or drones) and digital adherence monitoring technologies have the potential to enhance patient-centric quality tuberculosis care and help challenged National Tuberculosis Programs leapfrog over the impediments of conventional Directly Observed Therapy (DOTS) implementation. A bundle of innovative interventions referred to for its delivery technology as the Drone Observed Therapy System (DrOTS) was implemented in remote Madagascar. Given the potentially increased cost these interventions represent for health systems, a cost-effectiveness analysis was indicated. METHODS: A decision analysis model was created to calculate the incremental cost-effectiveness of the DrOTS strategy compared to DOTS, the standard of care, in a study population of 200,000 inhabitants in rural Madagascar with tuberculosis disease prevalence of 250/100,000. A mixed top-down and bottom-up costing approach was used to identify costs associated with both models, and net costs were calculated accounting for resulting TB treatment costs. Net cost per disability-adjusted life years averted was calculated. Sensitivity analyses were performed for key input variables to identify main drivers of health and cost outcomes, and cost-effectiveness. FINDINGS: Net cost per TB patient identified within DOTS and DrOTS were, respectively, $282 and $1,172. The incremental cost per additional TB patient diagnosed in DrOTS was $2,631 and the incremental cost-effectiveness ratio of DrOTS compared to DOTS was $177 per DALY averted. Analyses suggest that integrating drones with interventions ensuring highly sensitive laboratory testing and high treatment adherence optimizes cost-effectiveness. CONCLUSION: Innovative technology packages including drones, digital adherence monitoring technologies, and molecular diagnostics for TB case finding and retention within the cascade of care can be cost effective. Their integration with other interventions within health systems may further lower costs and support access to universal health coverage.

Bi-directional drones to strengthen healthcare provision: experiences and lessons from Madagascar, Malawi and Senegal.

Drones are increasingly being used globally for the support of healthcare programmes. Madagascar, Malawi and Senegal are among a group of early adopters piloting the use of bi-directional transport drones for health systems in sub-Saharan Africa. This article presents the experiences as well as the strengths, weaknesses, opportunities and threats (SWOT analysis) of these country projects. Methods for addressing regulatory, feasibility, acceptability, and monitoring and evaluation issues are presented to guide future implementations. Main recommendations for governments, implementers, drone providers and funders include (1) developing more reliable technologies, (2) thorough vetting of drone providers' capabilities during the selection process, (3) using and strengthening local capacity, (4) building in-country markets and businesses to maintain drone operations locally, (5) coordinating efforts among all stakeholders under government leadership, (6) implementing and identifying funding for long-term projects beyond pilots, and (7) evaluating impacts via standardised indicators. Sharing experiences and evidence from ongoing projects is needed to advance the use of drones for healthcare.

Perceptions of drones, digital adherence monitoring technologies and educational videos for tuberculosis control in remote Madagascar: a mixed-method study protocol.

INTRODUCTION: Poor road and communication infrastructure pose major challenges to tuberculosis (TB) control in many regions of the world. TB surveillance and patient support often fall to community health workers (CHWs) who may lack the time or knowledge needed for this work. To meet the End TB Strategy goal of reducing TB incidence by 90% by 2035, the WHO calls for intensified research and innovation including the rapid uptake of new tools, interventions and strategies. Technologies that 'leapfrog' infrastructure challenges and support CHWs in TB control responsibilities have the potential to dramatically change TB outcomes in remote regions. Such technologies may strengthen TB control activities within challenged national tuberculosis treatment and control programmes (NTPs), and be adapted to address other public health challenges. The deployment of innovative technologies needs to be differentially adapted to context-specific factors. The Drone Observed Therapy System (DrOTS) project was launched in Madagascar in 2017 and integrates a bundle of innovative technologies including drones, digital adherence monitoring technology and mobile device-based educational videos to support TB control. METHODS AND ANALYSIS: This mixed-methods study gathers and analyses cultural perceptions of the DrOTS project among key stakeholders: patients, community members, CHWs, village chiefs and NTP-DrOTS mobile health teams. Data from questionnaires, semistructured interviews, focus group discussions (FGD) and ethnographic observation gathered from June 2018 to June 2019 are thematically analysed and compared to identify patterns and singularities in how DrOTS stakeholders perceive and interact with DrOTS technologies, its enrolment processes, objectives and team. ETHICS AND DISSEMINATION: Ethics approval was obtained from the National Bioethics Research Committee of Madagascar and Stony Brook University institutional review board. Study results will be submitted for peer-reviewed publication. In Madagascar, results will be presented in person to Ministry and other Malagasy decision-makers through the Institut Pasteur de Madagascar. PATIENT AND PUBLIC INVOLVEMENT: This study is designed to foreground the voices of patients and potential patients in the DrOTS programme. CHW participants in this study also supported the design of study information sessions and recruitment strategies. One member of the mobile health team provided detailed input on the wording and content of FGD and interview guides. Study findings will be presented via a report in French and Malagasy to CHW, mobile health team and other village-level participants who have email/internet access.

Tuberculosis in ageing: high rates, complex diagnosis and poor clinical outcomes.

BACKGROUND: worldwide, the frequency of tuberculosis among older people almost triples that observed among young adults. OBJECTIVE: to describe clinical and epidemiological consequences of pulmonary tuberculosis among older people. METHODS: we screened persons with a cough lasting more than 2 weeks in Southern Mexico from March 1995 to February 2007. We collected clinical and mycobacteriological information (isolation, identification, drug-susceptibility testing and IS6110-based genotyping and spoligotyping) from individuals with bacteriologically confirmed pulmonary tuberculosis. Patients were treated in accordance with official norms and followed to ascertain treatment outcomes, retreatment, and vital status. RESULTS: eight hundred ninety-three tuberculosis patients were older than 15 years of age; of these, 147 (16.5%) were 65 years of age or older. Individuals ≥ 65 years had significantly higher rates of recently transmitted and reactivated tuberculosis. Older age was associated with treatment failure (OR=5.37; 95% CI: 1.06-27.23; P=0.042), and death due to tuberculosis (HR=3.52; 95% CI: 1.78-6.96; P<0.001) adjusting for sociodemographic and clinical variables. CONCLUSIONS: community-dwelling older individuals participate in chains of transmission indicating that tuberculosis is not solely due to the reactivation of latent disease. Untimely and difficult diagnosis and a higher risk of poor outcomes even after treatment completion emphasise the need for specific strategies for this vulnerable group.

Methods to identify standard data elements in clinical and public health forms.

The fragmentation of clinical and public health systems results in divergent information collection practices, presenting challenges to standardization and EHR certification efforts. Data forms employed in public health jurisdictions nationwide reflect these differences in patient treatment, monitoring and evaluation, and follow-up, presenting challenges for data integration. To study these variations, we surveyed tuberculosis contact investigation forms from all fifty states, three municipalities and two countries. We apply statistics and cluster analysis to analyze the divergent content of contact investigation forms with the goal of characterizing normative practices and identifying a common core of data fields. We found widespread variation in data elements between states in the study, with the "Name" field being the only ubiquitous data element. Our method reveals distinct groupings of data fields employed in certain regions, allowing the simultaneous identification of core standard data fields as well as variations in practice.

Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved.

Mycobacterium tuberculosis is an obligate human pathogen capable of persisting in individual hosts for decades. We sequenced the genomes of 21 strains representative of the global diversity and six major lineages of the M. tuberculosis complex (MTBC) at 40- to 90-fold coverage using Illumina next-generation DNA sequencing. We constructed a genome-wide phylogeny based on these genome sequences. Comparative analyses of the sequences showed, as expected, that essential genes in MTBC were more evolutionarily conserved than nonessential genes. Notably, however, most of the 491 experimentally confirmed human T cell epitopes showed little sequence variation and had a lower ratio of nonsynonymous to synonymous changes than seen in essential and nonessential genes. We confirmed these findings in an additional data set consisting of 16 antigens in 99 MTBC strains. These findings are consistent with strong purifying selection acting on these epitopes, implying that MTBC might benefit from recognition by human T cells.