Who Transmits Tuberculosis to Whom: A Cross-Sectional Analysis of a Cohort Study in Lima, Peru.

Rationale: The persistent burden of tuberculosis (TB) disease emphasizes the need to identify individuals with TB for treatment and those at a high risk of incident TB for prevention. Targeting interventions toward those at high risk of developing and transmitting TB is a public health priority. Objectives: We aimed to identify characteristics of individuals involved in TB transmission in a community setting, which may guide the prioritization of targeted interventions. Methods: We collected clinical and sociodemographic data from a cohort of patients with TB in Lima, Peru. We used whole-genome sequencing data to assess the genetic distance between all possible pairs of patients; we considered pairs to be the result of a direct transmission event if they differed by three or fewer SNPs, and we assumed that the first diagnosed patient in a pair was the transmitter and the second was the recipient. We used logistic regression to examine the association between host factors and the likelihood of direct TB transmission. Measurements and Main Results: Analyzing data from 2,518 index patients with TB, we identified 1,447 direct transmission pairs. Regardless of recipient attributes, individuals less than 34 years old, males, and those with a history of incarceration had a higher likelihood of being transmitters in direct transmission pairs. Direct transmission was more likely when both patients were drinkers or smokers. Conclusions: This study identifies men, young adults, former prisoners, alcohol consumers, and smokers as priority groups for targeted interventions. Innovative strategies are needed to extend TB screening to social groups such as young adults and prisoners with limited access to routine preventive care.

Sensitivity of Various Case Detection Algorithms for Community-based Tuberculosis Screening.

Using data from 388 people diagnosed with tuberculosis through a community-based screening program in Lima, Peru, we estimated that cough screening followed by sputum smear microscopy would have detected only 23% of cases found using an algorithm of radiographic screening followed by rapid nucleic acid amplification testing and clinical evaluation.

The impact of clinical placement site, community clinic versus tertiary hospital, on midwifery students' clinical learning experience in Sierra Leone: a cohort study.

BACKGROUND: In midwifery education, the clinical learning experience (CLE) is a critical component to gaining competency and should comprise greater than 50% of a student's education. Many studies have identified positive and negative factors affecting students' CLE. However, few studies have directly compared the difference in CLE based on placement at a community clinic versus a tertiary hospital. METHODS: The aim of this study was to examine how clinical placement site, clinic or hospital, impacts students' CLE in Sierra Leone. A once 34-question survey was given to midwifery students attending one of four public midwifery schools in Sierra Leone. Median scores were compared for survey items by placement site using Wilcoxon tests. The relationship between clinical placement and student's experience were assessed using multilevel logistic regression. RESULTS: Two-hundred students (hospitals students = 145 (72.5%); clinic students = 55 (27.5%) across Sierra Leone completed surveys. Most students (76%, n = 151) reported satisfaction with their clinical placement. Students placed at clinics were more satisfied with opportunities to practice/develop skills (p = 0.007) and more strongly agreed preceptors treated them with respect (p = 0.001), helped improve their skills (p = 0.001), provided a safe environment to ask questions (p = 0.002), and had stronger teaching/mentorship skills (p = 0.009) than hospital students. Students placed at hospitals had greater satisfaction in exposure to certain clinical opportunities including completing partographs (p < 0.001); perineal suturing (p < 0.001); drug calculations/administration (p < 0.001) and estimation of blood loss (p = 0.004) compared to clinic students. The odds of students spending more than 4 h per day in direct clinical care were 5.841 (95% CI: 2.187-15.602) times higher for clinic students versus hospital students. There was no difference between clinical placement sites in regards to number of births students attended (OR 0.903; 95% CI: 0.399, 2.047) or number of births students managed without a preceptor/clinician present (OR 0.729; 95% CI: 0.285, 1.867). CONCLUSION: The clinical placement site, hospital or clinic, impacts midwifery students' CLE. Clinics offered students significantly greater attributes of a supportive learning environment and access to direct, hands-on opportunities for patient care. These findings may be helpful for schools when using limited resources to improve the quality of midwifery education.

Concordance of Drug-resistance Profiles Between Persons With Drug-resistant Tuberculosis and Their Household Contacts: A Systematic Review and Meta-analysis.

BACKGROUND: Household contacts of patients with drug-resistant tuberculosis (TB) are at high risk for being infected with Mycobacterium tuberculosis and for developing TB disease. To guide regimen composition for the empirical treatment of TB infection and disease in these household contacts, we estimated drug-resistance profile concordance between index patients with drug-resistant TB and their household contacts. METHODS: We performed a systematic review and meta-analysis of studies published through 24 July 2018 that reported resistance profiles of drug-resistant TB index cases and secondary cases within their households. Using a random-effects meta-analysis, we estimated resistance profile concordance, defined as the percentage of secondary cases whose M. tuberculosis strains were resistant to the same drugs as strains from their index cases. We also estimated isoniazid/rifampin concordance, defined as whether index and secondary cases had identical susceptibilities for isoniazid and rifampin only. RESULTS: We identified 33 eligible studies that evaluated resistance profile concordance between 484 secondary cases and their household index cases. Pooled resistance profile concordance was 54.3% (95% confidence interval [CI], 40.7-67.6%; I2 = 85%). Pooled isoniazid/rifampin concordance was 82.6% (95% CI, 72.3-90.9%; I2 = 73%). Concordance estimates were similar in a subanalysis of 16 studies from high-TB-burden countries. There were insufficient data to perform a subanalysis among pediatric secondary cases. CONCLUSIONS: Household contacts of patients with drug-resistant TB should receive treatment for TB infection and disease that assumes that they, too, are infected with a drug-resistant M. tuberculosis strain. Whenever possible, drug susceptibility testing should be performed for secondary cases to optimize regimen composition.

Tuberculosis clinical presentation and treatment outcomes in pregnancy: a prospective cohort study.

BACKGROUND: There is limited research to guide TB treatment specifically in pregnant women and few studies have described the presentation of TB in pregnant women. We aimed to understand TB presentation and treatment outcomes in pregnant women in a low HIV burden setting. We describe a cohort of women of childbearing age treated for TB disease in Lima, Peru, and compare clinical presentation and treatment outcomes among pregnant and non-pregnant women between 2009 and 2012, including 36 pregnant women. METHODS: This is a prospective cohort study. Subjects were recruited from across 106 public health centers in Lima, Peru. Baseline demographic, medical history, and drug-susceptibility test results were collected. We used descriptive statistics to describe demographic and clinical characteristics of the women using Pearson chi-squared, Fisher's exact tests, or Kruskal-Wallis. RESULTS: Among 4500 individuals with pulmonary TB disease, 1334 women were included in analysis with 36 (2.69%) pregnant women. Pregnant women had similar demographics, past medical histories, and clinical presentation to non-pregnant women, except being more likely to be married (p = 0.01) and have cardiac disease (p = 0.04) and less likely to have weight loss (p = 0.05). Twenty (71.4%) pregnant women had pan-susceptible TB compared with 616 (63.1%) non-pregnant women; four (14.3%) pregnant women had mono-resistant TB compared with 154 (15.8%) non-pregnant women; and four (14.3%) pregnant women had multi-drug-resistant TB compared with 140 (14.3%) of non-pregnant women (p = 0.53). Twenty-eight (96.6%) pregnant women had a successful outcome (cure, completed treatment, treatment ended early by clinical team) while one (3.4%) had an unsuccessful outcome (treatment failed) and 1074 (97.3%) non-pregnant women had a successful outcome while 30 (2.7%) had an unsuccessful outcome (p = 0.56). CONCLUSION: In this cohort with low HIV co-infection, we found high TB treatment success rates in both pregnant and non-pregnant women, irrespective of drug-susceptibility profiles. If treated appropriately, pregnant women with TB disease can have successful outcomes.

Pharmacokinetics of Levofloxacin in Children Treated for Exposure to Drug-Resistant Tuberculosis.

Levofloxacin is used to treat and prevent drug-resistant tuberculosis in children. We assessed levofloxacin serum drug concentrations in 24 children aged 2 to 10 years who received levofloxacin-based tuberculosis preventive therapy in Karachi, Pakistan. Only 9 children (37.5%) achieved adequate drug exposure. Target serum drug concentration was met in 4 (26.7%) of 15 children dosed consistently with World Health Organization recommendations and 4 (80.0%) of 5 who received higher-than-recommended doses. Levofloxacin dosing recommendations may require reevaluation.

Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial.

RATIONALE: We examined whether increased rifampin doses could shorten standard therapy for tuberculosis without increased toxicity. OBJECTIVES: To assess the differences across three daily oral doses of rifampin in change in elimination rate of Mycobacterium tuberculosis in sputum and frequency of rifampin-related adverse events. METHODS: We conducted a blinded, randomized, controlled phase 2 clinical trial of 180 adults with new smear-positive pulmonary tuberculosis, susceptible to isoniazid and rifampin. We randomized 1:1:1 to rifampin at 10, 15, and 20 mg/kg/d during the intensive phase. We report the primary efficacy and safety endpoints: change in elimination rate of M. tuberculosis log10 colony-forming units and frequency of grade 2 or higher rifampin-related adverse events. We report efficacy by treatment arm and by primary (area under the plasma concentration-time curve [AUC]/minimum inhibitory concentration [MIC]) and secondary (AUC) pharmacokinetic exposure. MEASUREMENTS AND MAIN RESULTS: Each 5-mg/kg/d increase in rifampin dose resulted in differences of -0.011 (95% confidence interval, -0.025 to +0.002; P = 0.230) and -0.022 (95% confidence interval, -0.046 to -0.002; P = 0.022) log10 cfu/ml/d in the modified intention-to-treat and per-protocol analyses, respectively. The elimination rate in the per-protocol population increased significantly with rifampin AUC0-6 (P = 0.011) but not with AUC0-6/MIC99.9 (P = 0.053). Grade 2 or higher rifampin-related adverse events occurred with similar frequency across the three treatment arms: 26, 31, and 23 participants (43.3%, 51.7%, and 38.3%, respectively) had at least one event (P = 0.7092) up to 4 weeks after the intensive phase. Treatment failed or disease recurred in 11 participants (6.1%). CONCLUSIONS: Our findings of more rapid sputum sterilization and similar toxicity with higher rifampin doses support investigation of increased rifampin doses to shorten tuberculosis treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01408914) .

Use of predicted vital status to improve survival analysis of multidrug-resistant tuberculosis cohorts.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) cohorts often lack long-term survival data, and are summarized instead by initial treatment outcomes. When using Cox proportional hazards models to analyze these cohorts, this leads to censoring subjects at the time of the initial treatment outcome, instead of them providing full survival data. This may violate the non-informative censoring assumption of the model and may produce biased effect estimates. To address this problem, we develop a tool to predict vital status at the end of a cohort period using the initial treatment outcome and assess its ability to reduce bias in treatment effect estimates. METHODS: We derive and apply a logistic regression model to predict vital status at the end of the cohort period and modify the unobserved survival outcomes to better match the predicted survival experience of study subjects. We compare hazard ratio estimates for effect of an aggressive treatment regimen from Cox proportional hazards models using time to initial treatment outcome, predicted vital status, and true vital status at the end of the cohort period. RESULTS: Models fit from initial treatment outcomes underestimate treatment effects by up to 22.1%, while using predicted vital status reduced this bias by 5.4%. Models utilizing the predicted vital status produce effect estimates consistently stronger and closer to the true treatment effect than estimates produced by models using the initial treatment outcome. CONCLUSIONS: Although studies often use initial treatment outcomes to estimate treatment effects, this may violate the non-informative censoring assumption of the Cox proportional hazards model and result in biased treatment effect estimates. Using predicted vital status at the end of the cohort period may reduce this bias in the analyses of MDR-TB treatment cohorts, yielding more accurate, and likely larger, treatment effect estimates. Further, these larger effect sizes can have downstream impacts on future study design by increasing power and reducing sample size needs.

Evaluation of the Tuberculosis Infection Care Cascade Among Pregnant Individuals in a Low-Tuberculosis-Burden Setting.

In the United States, tuberculosis (TB) screening is recommended for pregnant individuals with TB risk factors. We conducted a retrospective study of perinatal TB infection testing and treatment in a tertiary health system. Of 165 pregnant individuals with positive TB infection tests, only 9% completed treatment within 4.6 years of follow-up.

Systems analysis and improvement approach to optimize tuberculosis (SAIA-TB) screening, treatment, and prevention in South Africa: a stepped-wedge cluster randomized trial.

BACKGROUND: The use of systems engineering tools, including the development and use of care cascades using routinely collected data, process mapping, and continuous quality improvement, is used for frontline healthcare workers to devise systems level change. South Africa experiences high rates of tuberculosis (TB) infection and disease as well as HIV co-infection. The Department of Health has made significant gains in HIV services over the last two decades, reaching their set "90-90-90" targets for HIV. However, TB services, although robust, have lagged in comparison for both disease and infection. The Systems Analysis and Improvement Approach (SAIA) is a five-step implementation science method, drawn from systems engineering, to identify, define, and implement workflow modifications using cascade analysis, process mapping, and repeated quality improvement cycles within healthcare facilities. METHODS: This stepped-wedge cluster randomized trial will evaluate the effectiveness of SAIA on TB (SAIA-TB) cascade optimization for patients with TB and high-risk contacts across 16 clinics in four local municipalities in the Sarah Baartman district, Eastern Cape, South Africa. We hypothesize that SAIA-TB implementation will lead to a 20% increase in each of: TB screening, TB preventive treatment initiation, and TB disease treatment initiation during the 18-month intervention period. Focus group discussions and key informant interviews with clinic staff will also be conducted to determine drivers of implementation variability across clinics. DISCUSSION: This study has the potential to improve TB screening, treatment initiation, and completion for both active disease and preventive measures among individuals with and without HIV in a high burden setting. SAIA-TB provides frontline health care workers with a systems-level view of their care delivery system with the aim of sustainable systems-level improvements. TRIAL REGISTRATION: Clinicaltrials.gov, NCT06314386. Registered 18 March 2024, https://clinicaltrials.gov/study/NCT06314386 . NCT06314386.

Tuberculosis treatment loss to follow-up in children exposed at home: A prospective cohort study.

Background: Loss to follow-up (LTFU) from tuberculosis (TB) treatment and care is a significant public health problem. It is important to understand what drives LTFU in children - a population whose treatment and management depend on an adult caregiver - to better provide support services to families affected by TB. Methods: We conducted a prospective cohort study of household contacts in Lima, Peru (2009-12). Using multilevel logistic regression analysis, we explored individual-level characteristics of children and their adult household members with TB disease to identify risk factors for LTFU among children initiated on treatment for TB. Results: A total of 154 child (0-14 years) household contacts were diagnosed with TB and initiated on treatment. While most (n = 133, 86.4%) had a successful outcome, 20 (13.0%) children were LTFU. Six (30.0%) children were LTFU within three months, nine (45.0%) between five to seven months, and three (15.0%) after seven months of treatment being initiated. In univariable analysis, children with index patients above 25 years of age had decreased odds of being LTFU (odds ratio = 0.26; 95% confidence interval = 0.08-0.84) compared to children with index patients 25 years or younger. Conclusions: In this cohort, more than 10% of children sick with TB who were exposed to the disease at home were LTFU. An integrated, family-centred TB prevention and management approach may reduce barriers to a child completing their course of TB treatment.

Task-sharing spinal anaesthesia care in three rural Indian hospitals: a non-inferiority randomised controlled clinical trial.

BACKGROUND: Task-sharing of spinal anaesthesia care by non-specialist graduate physicians, termed medical officers (MOs), is commonly practised in rural Indian healthcare facilities to mitigate workforce constraints. We sought to assess whether spinal anaesthesia failure rates of MOs were non-inferior to those of consultant anaesthesiologists (CA) following a standardised educational curriculum. METHODS: We performed a randomised, non-inferiority trial in three rural hospitals in Tamil Nadu and Chhattisgarh, India. Patients aged over 18 years with low perioperative risk (ASA I & II) were randomised to receive MO or CA care. Prior to the trial, MOs underwent task-based anaesthesia training, inclusive of remotely accessed lectures, simulation-based training and directly observed anaesthetic procedures and intraoperative care. The primary outcome measure was spinal anaesthesia failure with a non-inferiority margin of 5%. Secondary outcome measures consisted of incidence of perioperative and postoperative complications. FINDINGS: Between 12 July 2019 and 8 June 2020, a total of 422 patients undergoing surgical procedures amenable to spinal anaesthesia care were randomised to receive either MO (231, 54.7%) or CA care (191, 45.2%). Spinal anaesthesia failure rate for MOs (7, 3.0%) was non-inferior to those of CA (5, 2.6%); difference in success rate of 0.4% (95% CI=0.36-0.43%; p=0.80). Additionally, there were no statistically significant differences observed between the two groups for intraoperative or postoperative complications, or patients' experience of pain during the procedure. INTERPRETATION: This study demonstrates that failure rates of spinal anaesthesia care provided by trained MOs are non-inferior to care provided by CAs in low-risk surgical patients. This may support policy measures that use task-sharing as a means of expanding anaesthesia care capacity in rural Indian hospitals. TRIAL REGISTRATION NUMBER: NCT04438811.

Cost of inaction: a framework to estimate the economic cost of missing a patient with tuberculosis in the Indian context.

OBJECTIVES: To estimate the economic impact of failure to find and treat tuberculosis disease and prevent tuberculosis infection from progressing to active disease. DESIGN: Estimating the economic cost of not finding and treating a patient suffering from tuberculosis. SETTING: Estimation methodology is developed in the Indian context, as informed by local costs and reported tuberculosis epidemiology. PARTICIPANTS: No individual participants were included. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure is the total cost of patients with drug-susceptible and drug-resistant tuberculosis who are and are not found and treated by tuberculosis programmes, including costs for medications, lost productivity, healthcare services and furthered transmission. We calculate the economic burdens by varying the number of individuals a person sick with tuberculosis infects (10 or 15 people) and the risk of progression to tuberculosis disease if infected (5 or 8%). The secondary outcome measure is the amount saved by finding a patient early or who would not have otherwise been found. All costs are presented in US dollars (exchange rate: 72 Indian rupees/1 US$). RESULTS: By finding and treating a patient early before furthered transmission occurs-or stopping progression of tuberculosis infection to tuberculosis disease with preventive therapy-the Indian health system can save US$5502 to US$15 825 and US$5846 to US$25 575, for each individual with drug-susceptible and drug-resistant tuberculosis, respectively, across scenarios. CONCLUSIONS: These estimates provide crude, lower bounds for the potential costs of not appropriately diagnosing and treating a single patient with active tuberculosis in a timely manner, or preventing a patient with tuberculosis infection from progressing to active disease. The actual financial burden on society is far higher than estimated using this simple, short-term cost-effective analyses. Our results highlight the limitations of tuberculosis costing models to date, and demonstrate the importance of accounting for airborne transmission of tuberculosis.

Two Clinical Prediction Tools to Inform Rapid Tuberculosis Treatment Decision-making in Children.

Background: In the absence of bacteriologic confirmation to diagnose tuberculosis (TB) in children, it is suggested that treatment should be initiated when sufficient clinical evidence of disease is available. However, it is unclear what clinical evidence is sufficient to make this decision. To identify children who would benefit from rapid initiation of TB treatment, we developed 2 clinical prediction tools. Methods: We conducted a secondary analysis of a prospective intensified TB patient-finding intervention conducted in Pakistan in 2014-2016. TB disease was determined through either bacteriologic confirmation or a clinical diagnosis. We derived 2 tools: 1 uses classification and regression tree (CART) analysis to develop decision trees, while the second uses multivariable logistic regression to calculate a risk score. Results: Of the 5162 and 5074 children included in the CART and prediction score, respectively, 1417 (27.5%) and 1365 (26.9%) were eligible for TB treatment. CART identified abnormal chest radiographs and family history of TB as the most important predictors (area under the receiver operating characteristic curve [AUC], 0.949). The final prediction score model included age group (0-4, 5-9, 10-14), weight <5th percentile, cough, fever, weight loss, chest radiograph suggestive of TB disease, and family history of TB; the identified best cutoff score was 9 (AUC, 0.985%). Conclusions: Use of clinical evidence was sufficient to accurately identify children who would benefit from treatment initiation. Our tools performed well compared with existing algorithms, though these results need to be externally validated before operationalization.

Age-specific Clinical Presentation and Risk Factors for Extrapulmonary Tuberculosis Disease in Children.

BACKGROUND: Clinical presentation for extrapulmonary tuberculosis (EPTB) in children can be variable and nonspecific, leading to delayed diagnosis, disease and death. We describe the age-specific clinical presentation and identify risk factors for EPTB among children in Pakistan. METHODS: In 2015-2016 in 4 facilities in Sindh, Pakistan, children were diagnosed with TB either through bacteriologic confirmation or clinical-radiologic criteria. EPTB comprised any form of TB disease that did not involve the lungs. Among children with TB disease, we report demographics, clinical characteristics and symptoms, family medical history and diagnostic test results for children with and without EPTB. We conduct age-specific regression analyses to identify factors associated with an EPTB diagnosis among children age 0-4, 5-9 and 10-14 years. RESULTS: A total of 1163 children were diagnosed with TB disease, of which 157 (13.5%) had EPTB. Of those, 46 (29.3%) were 0-4, 53 (33.8%) were 5-9 and 58 (36.9%) were 10-14 years old. Of children with EPTB, the most frequently reported sites were lymph node (113, 72.4%) and abdominal (31, 19.9%). Weight loss was associated with an increased risk of EPTB in the 0-4-year-old (adjusted odds ratio: 2.80, 95% confidence interval: 1.05-7.47) and 10-14-year-old (adjusted odds ratio: 2.79, 95% confidence interval: 1.28-6.07) groups, and the presence of cough was associated with a decreased risk of EPTB. CONCLUSIONS: This study provides new knowledge about age-specific clinical presentation and risk factors of EPTB in children in Pakistan. Our results can help to optimize clinical algorithms designed to achieve a timely diagnosis in children with EPTB along with improved treatment outcomes.

A role for community-level socioeconomic indicators in targeting tuberculosis screening interventions.

Tuberculosis screening programs commonly target areas with high case notification rates. However, this may exacerbate disparities by excluding areas that already face barriers to accessing diagnostic services. We compared historic case notification rates, demographic, and socioeconomic indicators as predictors of neighborhood-level tuberculosis screening yield during a mobile screening program in 74 neighborhoods in Lima, Peru. We used logistic regression and Classification and Regression Tree (CART) analysis to identify predictors of screening yield. During February 7, 2019-February 6, 2020, the program screened 29,619 people and diagnosed 147 tuberculosis cases. Historic case notification rate was not associated with screening yield in any analysis. In regression analysis, screening yield decreased as the percent of vehicle ownership increased (odds ratio [OR]: 0.76 per 10% increase in vehicle ownership; 95% confidence interval [CI]: 0.58-0.99). CART analysis identified the percent of blender ownership (≤ 83.1% vs > 83.1%; OR: 1.7; 95% CI: 1.2-2.6) and the percent of TB patients with a prior tuberculosis episode (> 10.6% vs ≤ 10.6%; OR: 3.6; 95% CI: 1.0-12.7) as optimal predictors of screening yield. Overall, socioeconomic indicators were better predictors of tuberculosis screening yield than historic case notification rates. Considering community-level socioeconomic characteristics could help identify high-yield locations for screening interventions.

Geospatial analysis of reported activity locations to identify sites for tuberculosis screening.

Mobile screening units can help close tuberculosis case detection gaps. Placing screening units where people at high risk for undiagnosed tuberculosis preferentially spend time could make screening more resource-effective. We conducted a case-control study in Lima, Peru to identify locations where people with tuberculosis were more likely to spend time than community controls. We surveyed participants about activity locations over the past 6 months. We used density-based clustering to assess how patient and control activity locations differed, and logistic regression to compare location-based exposures. We included 109 tuberculosis patients and 79 controls. In density-based clustering analysis, the two groups had similar patterns of living locations, but their work locations clustered in distinct areas. Both groups were similarly likely to use public transit, but patients predominantly used buses and were less likely to use rapid transit (adjusted odds ratio [aOR] 0.31, 95% confidence interval [CI] 0.10-0.96) or taxis (aOR 0.42, 95% CI 0.21-0.85). Patients were more likely to have spent time in prison (aOR 11.55, 95% CI 1.48-90.13). Placing mobile screening units at bus terminals serving locations where tuberculosis patients have worked and within and around prisons could help reach people with undiagnosed tuberculosis.