Abstract Background Understanding tuberculosis (TB) transmission dynamics is necessary to interrupt disease spread. We developed a model to estimate adjusted odds ratios (ORs) for factors associated with genetic relatedness, as proxy for transmission. Methods We build upon an existing iterative model that modifies genetically linked tuberculosis case data to better represent true transmission links. We incorporate bootstrapped logistic regression to calculate adjusted ORs with confidence intervals that account for correlation from individuals present across multiple transmission pairs. We assess model performance with simulation studies and apply the method to cohort data from Lima, Peru. Results Iterative algorithm estimates resembled those from logistic regression but had larger confidence intervals, reflecting the data correlation adjustment. Transmission pairs where at least one member was >34 years had decreased transmission odds. Pairs with at least one incarcerated or male member had increased adjusted transmission odds. Conclusions We produce adjusted ORs accounting for the correlation of pairwise genetic relatedness data. These ORs are an accurate proxy for the association between covariates and transmission and further our understanding of factors associated with tuberculosis transmission.

BACKGROUND:Tuberculosis (TB) causes major morbidity and mortality among children worldwide. Isoniazid preventive therapy (IPT) protects against progression to TB disease, but its effect on preventing new TB infection remains uncertain. METHODS:We conducted a longitudinal cohort study in Lima, Peru, enrolling adults with microbiologically confirmed pulmonary TB and their household contacts (HHCs). We assessed HHCs at baseline and 6 months for TB infection using tuberculin skin testing (TST) and for TB disease through clinical evaluation. We assessed two outcomes in relation to IPT initiation: TB infection among HHCs under 5 years of age, indicated by an increase in TST induration of ≥6 mm from baseline to 6 months, and progression to TB disease among HHCs of all ages, diagnosed between 15 days and 12 months after enrollment. RESULTS:Among 666 under-5-year-olds included assessed for TST conversion, 361 (54.2%) had initiated IPT. Overall, 103 (15.5%) converted at 6 months; IPT initiation was not associated with conversion (adjusted OR 1.01; 95% CI, 0.64-1.59). Index-participant cavitary disease was associated with an increased risk of conversion. In contrast, IPT initiation was associated with reduced risk of progression to TB disease among 14,032 HHCs of all ages (adjusted HR 0.45; 95% CI, 0.32-0.64) with more pronounced efficacy among under-5s (adjusted HR 0.19; 95% CI, 0.10-0.36). CONCLUSION:IPT was not associated with reduced TST conversion among children under 5 years, but it was strongly associated with reduced progression to TB disease among HHCs of all ages.

People who experience incarceration face a markedly elevated risk of tuberculosis (TB), yet the extent to which this vulnerability persists after release remains incompletely characterized. We analyze data from a prospective cohort study conducted in Lima, Peru, including 3,658 adults with newly diagnosed pulmonary TB and 6,335 household contacts aged 15-60. Recent incarceration (within the preceding five years) is reported by 187 (5%) index patients and 112 household contacts (1.7%). Compared with those without incarceration history, formerly incarcerated individuals are more likely to present with more severe TB disease at diagnosis and experience a higher likelihood of adverse treatment outcomes. Among individuals with available incarceration timing data, TB diagnoses cluster after release, with nearly three-quarters occurring within two years. At the household level, TB infection prevalence at enrollment is higher among contacts with a history of incarceration and among those exposed to an index patient with prior incarceration, including among those with relatively short incarceration histories. These associations persist after adjustment for demographic, clinical, and socioeconomic factors. Together, these findings indicate that TB-related vulnerability extends beyond incarceration and into the post-release period, underscoring the importance of timely diagnosis and continuity of care post release.

BACKGROUND:Youth aged 15-24 years are significantly impacted by tuberculosis globally. Their expanding social networks heighten exposure risks, potentially amplifying tuberculosis transmission, but their role in within-household transmission remains poorly understood. METHODS:A household contact cohort study in Lima, Peru (2009-2012) enrolled individuals (>15 years) with incident tuberculosis (index patients) and their household contacts (HHCs), following them for 12 months. We evaluated whether the age of index patients and HHCs modified the risk of tuberculosis infection among HHCs. Study outcomes included: (1) prevalent tuberculosis infection among child contacts (<15 years) at enrollment and (2) incident tuberculosis infection among HHCs. Whole-genome sequencing of Mycobacterium tuberculosis (Mtb) isolates from index-HHC pairs assessed whether index patient age modified the likelihood of within-household transmission, defined as ≤12 single-nucleotide polymorphism differences. RESULTS:Child contacts of youth index patients had a lower risk of prevalent tuberculosis infection than those with adult index patients (aRR = 0.77; 95% CI: .67-.87). Among index-secondary patient pairs, 62% (26/42) of pairs with a youth index patient were genetically linked, compared to 72% (48/67) of pairs with an adult index patient (P = .3). Child and youth contacts had lower incident tuberculosis infection risk at 12-month follow-up compared to adult contacts (child vs adult: HR = 0.33; 95% CI: .28-.38; youth vs adult: HR = 0.61; 95% CI: .52-.71). CONCLUSIONS:Youth play a limited role in household tuberculosis transmission. Compared to adults, youth transmitted less TB as index patients and were less likely to be infected as HHCs. Research should explore youth social interactions and community-based transmission to inform targeted prevention strategies.

Estimating the transmissibility of asymptomatic Mycobacterium tuberculosis infection can clarify its contribution to tuberculosis (TB) spread. We conducted a prospective cohort study in Lima, Peru, enrolling index TB patients and their household contacts (HHCs) and classifying patients by the presence of symptoms including cough, night sweats, weight loss, or fever. We followed HHCs with serial tuberculin skin testing and clinical evaluations. Among 4,296 child HHCs, adjusted estimates for baseline infection (prevalence ratio 0.62 [95%CI 0.37-1.03]), incident infection at 6 months (hazard ratio (aHR) 0.63 [95% CI 0.27-1.49]), and TB disease during 1 year of follow-up (aHR 0.74 [95% CI 0.35-1.56]) were all consistent with lower risk for infection and disease progression among HHCs of asymptomatic compared with symptomatic index patients. Although asymptomatic infections may be less transmissible than symptomatic infections, the high prevalence of asymptomatic patients in national surveys suggest that they may contribute substantially to transmission.

BACKGROUND:Household-based studies are commonly used to investigate tuberculosis (TB) transmission and evaluate preventive interventions. These studies typically assume that household contacts (HHCs) who develop TB disease were infected by the identified index patient. However, community-acquired infections may challenge this assumption, potentially biasing findings. Here, we evaluated the proportion of genetically linked index-HHC pairs and examined whether this proportion varied based on the TB burden in the community. METHODS:We conducted a prospective cohort study in Lima, Peru, enrolling microbiologically confirmed pulmonary TB index patients and their HHCs who were followed for 1 year. Mycobacterium tuberculosis (Mtb) isolates from culture-positive index patients and HHCs underwent whole-genome sequencing (WGS). We defined index-HHC patient pairs as resulting from within-household transmission when the genetic distance between their Mtb isolates was ≤12 single nucleotide polymorphisms. To contextualize our findings, we conducted a systematic review of Mtb genotyping studies that used spoligotyping, restriction fragment length polymorphisms , mycobacterial interspersed repetitive units-variable number tandem repeats, or WGS to assess within-household TB infection transmission among index-HHC patient pairs. RESULTS:In our Lima study, among 175 index-HHC patient pairs, 109 (62%) were classified as within-household transmission. The systematic review identified 22 qualifying studies from settings with TB burdens ranging from 6.7 to 845 cases per 100 000 person-years. Studies in settings with TB incidence of ≤250 per 100 000 person-years consistently reported linkage proportions of ≥61%, whereas high-burden settings exhibited greater variability. CONCLUSIONS:Our findings suggest that, among individuals exposed to TB at home, within-household transmission predominates in moderate- or low-TB-burden settings. However, its relative contribution in high-incidence settings remains unclear.

BACKGROUND:Diabetes mellitus (DM) increases the risk of tuberculosis (TB) progression and poor treatment outcomes. Rising global DM prevalence presents an emerging threat to TB control. We sought to determine whether DM affects TB transmissibility. METHODS:From 2009 to 2012, we enrolled 3109 microbiologically confirmed pulmonary TB patients and their 12 767 household contacts (HHCs) whom we followed for 1 year for the occurrence of TB infection as measured by a tuberculin skin test and for TB disease. We assessed the association between index patient DM and TB infection and disease occurrence in HHCs. RESULTS:The DM status of index patients was not associated with TB infection among child HHCs (adjusted prevalence rate ratio [aPRR], 1.05; 95% CI: 0.78-1.42) or with incident TB infection at 6 months among HHCs uninfected at baseline (adjusted cumulative rate ratio [aCRR], 0.85; 95% CI: 0.66-1.09). Among the 12 442 HHCs without TB disease at baseline, 368 (3.0%) developed TB during the 12-month follow-up. HHCs exposed to an index TB patient with DM had a reduced incidence of TB disease (aCRR = 0.33, 95% CI: 0.13-0.85). CONCLUSIONS:In this cohort study, diabetes mellitus in index patients did not increase the risk of TB infection among HHCs and was instead associated with a substantially lower risk of incident TB disease. These findings challenge the prevailing assumption that DM uniformly amplifies transmission due to its association with smear positivity and cavitary disease, suggesting that its influence on TB dynamics may be more complex than previously understood.

Community-based tuberculosis screening using mobile X-ray units can effectively increase case detection rates by reducing barriers to accessing services. This study evaluated the multi-armed bandit (MAB) framework, a machine learning approach, for optimizing mobile screening locations. Using simulations, we compared two MAB algorithms-Exp3 and LinUCB-with strategies based on historical case rates and random placement. The MAB algorithms continually updated site selection based on observed screening yields, and LinUCB additionally incorporated local socioeconomic indicators associated with tuberculosis rates. Over three years, assuming two mobile units serving 95 sites in Lima, Peru, 1,000 simulations demonstrated the MAB algorithms significantly reduced the average number of screenings needed to detect one individual with tuberculosis: 112 (standard deviation [SD]: 10) for Exp3 and 79 (SD: 12) for LinUCB, versus 152 (SD: 11) for random placement and 143 (SD: 11) for historic case-rate-driven placement. LinUCB performed best, achieving a 20% increase in detection efficiency by week 16 and 50% by week 40 compared to case-rate-driven placement. Overall, both MAB algorithms improved tuberculosis screening yields, emphasizing the value of data-driven approaches for optimizing mobile screening interventions. Incorporating adaptive models into screening programs may enhance targeting efficiency and offers a promising direction for policymakers and implementers seeking to optimize resource allocation in high-burden setting.

Household-based studies are widely used to assess tuberculosis (TB) transmission and evaluate preventive strategies. These studies typically assume that household contacts (HHCs) who develop TB are infected by their index patient, but community-acquired infections may introduce misclassification, potentially biasing results. We aimed to quantify the extent of within-household TB transmission using genetic linkage data. We first analyzed a prospective cohort study conducted in Lima, Peru, where we enrolled microbiologically confirmed TB index patients and their HHCs, following them for one year. We applied whole-genome sequencing (WGS) and 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) genotyping to determine genetic relatedness between index-HHC pairs. We then conducted a systematic review of household TB transmission studies that applied genotyping methods to assess the proportion of genetically linked index-HHC pairs across diverse settings. In Lima, we analyzed 175 index-HHC pairs with high-quality WGS data. We classified 62% as genetically linked, suggesting household transmission. Matching proportions were higher for secondary HHC cases (68%) than co-prevalent cases (52%). Our systematic review identified 13 studies across various epidemiological settings. Among statistically robust studies, household transmission predominated in moderate TB incidence settings (<250 cases per 100,000 person-years), with genetic linkage exceeding 68%. However, in high-burden settings, within-household transmission varied widely, likely due to community-acquired infections and methodological differences. In summary, our findings suggest that in settings with ≤250 TB cases per 100,000 person-years, 20–35% of household TB cases may be misclassified due to community transmission, with lower misclassification among child and female contacts. The extent of this issue in high-burden settings remains unclear.

OBJECTIVE:To investigate the prevalence of non-communicable diseases among household contacts of people with tuberculosis. METHODS:We conducted a systematic review and individual participant data meta-analysis. We searched Medline, Embase and the Global Index Medicus from inception to 16 May 2023. We included studies that assessed for at least one non-communicable disease among household contacts of people with clinical tuberculosis. We estimated the non-communicable disease prevalence through mixed effects logistic regression for studies providing individual participant data, and compared it with estimates from aggregated data meta-analyses. Furthermore, we compared age and sex-standardised non-communicable disease prevalence with national-level estimates standardised for age and sex. RESULTS:We identified 39 eligible studies, of which 14 provided individual participant data (29,194 contacts). Of the remaining 25 studies, 18 studies reported aggregated data suitable for aggregated data meta-analysis. In individual participant data analysis, the pooled prevalence of diabetes in studies that undertook biochemical testing was 8.8% (95% confidence interval [CI], 5.1%-14.9%, four studies). Age-and sex-standardised prevalence was higher in two studies (10.4% vs. 6.9% and 11.5% vs. 8.4%) than the corresponding national estimates and similar in two studies. Prevalence of diabetes mellitus based on self-report or medical records was 3.4% (95% CI 2.6%-4.6%, 14 studies). Prevalence did not significantly differ compared to estimates from aggregated data meta-analysis. There were limited data for other non-communicable diseases. CONCLUSION:The prevalence of diabetes mellitus among household contacts was high while that of known diabetes was substantially lower, suggesting the underdiagnosis. tuberculosis household contact investigation offers opportunities to deliver multifaceted interventions to identify tuberculosis infection and disease, screen for non-communicable diseases and address shared risk factors.

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 wholegenome 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.

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.

The World Health Organization's end TB strategy promotes the use of symptom and chest radiograph screening for tuberculosis (TB) disease. However, asymptomatic early states of TB beyond latent TB infection and active disease can go unrecognized using current screening criteria. We conducted a longitudinal cohort study enrolling household contacts initially free of TB disease and followed them for the occurrence of incident TB over 1 year. Among 1,747 screened contacts, 27 (52%) of the 52 persons in whom TB subsequently developed during follow-up had a baseline abnormal radiograph. Of contacts without TB symptoms, persons with an abnormal radiograph were at higher risk for subsequent TB than persons with an unremarkable radiograph (adjusted hazard ratio 15.62 [95% CI 7.74-31.54]). In young adults, we found a strong linear relationship between radiograph severity and time to TB diagnosis. Our findings suggest chest radiograph screening can extend to detecting early TB states, thereby enabling timely intervention.

We explored the utility of brief Mycobacterium tuberculosis whole-genome sequencing (WGS) "snapshots" at a sentinel site within Lima, Peru, for evaluating local transmission dynamics over time. Within a 17-km2 area, 15 of 70 (21%) isolates with WGS collected during 2011-2012 and 22 of 81 (27%) collected during 2020-2021 were clustered (P = .414), and additional isolates clustered with those from outside the area. Isolates from the later period were disproportionately related to large historic clusters in Lima from the earlier period. WGS snapshots at a sentinel site may not be useful for monitoring transmission, but monitoring the persistence of large transmission clusters might be.

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.

Background. Scaling up a shorter preventive regimen such as weekly isoniazid and rifapentine (3HP) for 3 months is a priority for tuberculosis (TB) preventive treatment (TPT). However, there are limited data on 3HP acceptability and completion from high-burden-TB countries. Methods. We scaled up 3HP from 2018 to 2021 in 2 cities in Pakistan. Eligible participants were household contacts of persons diagnosed with TB disease. Participants were prescribed 3HP after ruling out TB disease. Treatment was self-administered. We analyzed the proportion who completed 3HP. Results. In Karachi, we verbally screened 22 054 household contacts of all ages. Of these, 83% were clinically evaluated and 3% were diagnosed with TB. Of household contacts without TB disease, 59% initiated the 3HP regimen, of which 69% completed treatment. In Peshawar, we verbally screened 6389 household contacts of all ages. We evaluated 95% of household contacts, of whom 2% were diagnosed with TB disease. Among those without TB disease, 65% initiated 3HP, of which 93% completed. Factors associated with higher 3HP completion included residence in Peshawar (risk ratio [RR], 1.35 [95% confidence interval {CI}: 1.32-1.37]), index patient being a male (RR, 1.03 [95% CI: 1.01-1.05]), and index patient with extrapulmonary TB compared to bacteriologically positive pulmonary TB (RR, 1.10 [95% CI: 1.06-1.14]). The age of the index patient was inversely associated with completion. Conclusions. We observed a high level of acceptance and completion of 3HP in programs implemented in 2 cities in Pakistan, with differences observed across the cities. These findings suggest that 3HP can be effectively scaled up in urban settings to improve the reach and impact of TPT. [GRAPHICS] .

Mathematical models have suggested that spatially-targeted screening interventions for tuberculosis may efficiently accelerate disease control, but empirical data supporting these findings are limited. Previous models demonstrating substantial impacts of these interventions have typically simulated large-scale screening efforts and have not attempted to capture the spatial distribution of tuberculosis in households and communities at a high resolution. Here, we calibrate an individual-based model to the locations of case notifications in one district of Lima, Peru. We estimate the incremental efficiency and impact of a spatially-targeted interventions used in combination with household contact tracing (HHCT). Our analysis reveals that HHCT is relatively efficient with a median of 40 (Interquartile Range: 31.7 to 49.9) household contacts required to be screened to detect a single case of active tuberculosis. However, HHCT has limited population impact, producing a median incidence reduction of only 3.7% (Interquartile Range: 5.8% to 1.9%) over 5 years. In comparison, spatially targeted screening (which we modeled as active case finding within high tuberculosis prevalence areas 100 m2 grid cell) is far less efficient, requiring evaluation of ≈12 times the number of individuals as HHCT to find a single individual with active tuberculosis. Furthermore, the addition of the spatially targeted screening effort produced only modest additional reductions in tuberculosis incidence over the 5 year period (≈1.3%) in tuberculosis incidence. In summary, we found that HHCT is an efficient approach for tuberculosis case finding, but has limited population impact. Other screening approaches which target areas of high tuberculosis prevalence are less efficient, and may have limited impact unless very large numbers of individuals can be screened.

OBJECTIVE.:To evaluate the association between overweight/obesity and multidrug resistance in patients with and without a history of tuberculosis treatment. MATERIALS AND METHODS.:Cross-sectional study of secondary data from a tuberculosis cohort, which included anthropometric and drug-sensitivity testing data at the baseline visit of patients with and without previous tuberculosis treatment. RESULTS.:We evaluated 3,734 new cases and 766 with a history of having received treatment for tuberculosis. Overweight/obesity was not associated with multidrug resistance in patients with a history of tuberculosis treatment, with a prevalence ratio of 0.97 and a 95% confidence interval of 0.68-1.38. CONCLUSIONS.:Overweight/obesity is not associated with multidrug resistance in tuberculosis. Overweight/obesity is a dynamic process that may influence the relationship between the immune system and the metabolic system.

OBJECTIVE.To evaluate the association between overweight/obesity and multidrug resistance in patients with and without a history of tuberculosis treatment.MATERIALS AND METHODS.Cross-sectional study of secondary data from a tuberculosis cohort, which included anthropometric and drug-sensitivity testing data at the baseline visit of patients with and without previous tuberculosis treatment.RESULTS.We evaluated 3,734 new cases and 766 with a history of having received treatment for tuberculosis. Overweight/obesity was not associated with multidrug resistance in patients with a history of tuberculosis treatment, with a prevalence ratio of 0.97 and a 95% confidence interval of 0.68-1.38.CONCLUSIONS.Overweight/obesity is not associated with multidrug resistance in tuberculosis. Overweight/obesity is a dynamic process that may influence the relationship between the immune system and the metabolic system.

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.