OBJECTIVES:Aspergillosis is a fungal infection known to contribute to post-tuberculosis lung disease, but its prevalence and impact during tuberculosis (TB) treatment are not well understood. We aimed to estimate the prevalence of Aspergillus infection among newly diagnosed TB patients and its association with treatment response and outcomes. METHODS:We conducted a prospective cohort study of pulmonary TB patients in Lima, Peru. We screened for Aspergillus infection by measuring anti-Aspergillus antibodies in serum at TB treatment initiation and after two months of treatment. We assessed patient disease status at baseline and two months with chest x-ray, the St. George's Respiratory Questionnaire (SGRQ), and 6-minute walking test. We used modified Poisson regression to identify risk factors for baseline Aspergillus seropositivity and study the association of Aspergillus seropositivity with clinical non-improvement at 2 months and with final treatment outcomes. RESULTS:At baseline, 5.4% of 1998 participants were seropositive for anti-Aspergillus antibodies. Older age and a history of prior TB were associated with baseline Aspergillus seropositivity. Cavitary lesions were not a significant risk factor for the presence of Aspergillus antibodies. The presence of baseline Aspergillus antibodies was found to be independently associated with non-improvement on chest x-ray (adjusted RR = 1.76, 95% CI: 1.07, 2.89) and non-improvement in SGRQ score (adjusted RR = 1.44, 95% CI: 1.02, 2.03) after 2 months. CONCLUSIONS:Aspergillus seropositivity was associated with poorer clinical response during TB treatment, including among patients with no prior history of TB. These findings raise the possibility that aspergillosis may emerge during TB treatment itself and underscore the importance of careful end-of-treatment and post-treatment monitoring to improve longer-term outcomes.

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.

RATIONALE:Recent empirical research suggests that isoniazid may lead to a risk reduction of incident tuberculosis (TB) among close TB contacts of someone with multidrug-resistant TB (MDR-TB). OBJECTIVES:To evaluate the association between isoniazid TB preventive treatment (TPT), compared to no treatment, upon incident TB in household contacts of MDR-TB cases using a large global consortium of TB contact tracing studies. METHODS:We conducted a systematic review and individual-participant meta-analysis among observational studies of household contact tracing studies. Participants were included if they were exposed to someone with MDR-TB and were given either 6 months of isoniazid TPT or no TPT. Our primary outcome was incident TB in contacts exposed to TB. We derived adjusted hazard ratios (aHRs) using mixed-effects, multivariable survival regression models with study-level random effects. The effectiveness of isoniazid TPT against incident TB was estimated through propensity score matching. MEASUREMENTS AND MAIN RESULTS:We included participant-level data from 6668 contacts exposed to MDR-TB from 17 countries. The effectiveness of isoniazid TPT against incident TB in contacts of MDR-TB was 57% (aHR, 0.43 [95% CI, 0.26-0.71]) and did not appreciably change with adjustment for additional potential confounders. The reduction in incident TB was marginally greater among child (<20 years old) contacts (aHR, 0.51 [95% CI, 0.28-0.92) compared to adult contacts (aHR, 0.69 [95% CI, 0.22-2.20]). The reduction in incidence was 73% (aHR, 0.27 [95% CI, 0.11-0.70]) in the first year of follow-up; effectiveness dropped to 60% (aHR, 0.40 [95% CI, 0.15-1.06]) from 12 to 23 months of follow-up and was nonsignificant after 2 years (28% effectiveness; aHR, 0.72 [95% CI, 0.33-1.54]). CONCLUSIONS:Among >6500 contacts of MDR-TB, isoniazid TPT was highly effective in preventing incident TB. The reduction was greatest in high-burden countries and waned after 2 years of follow-up.

Identifying transmission events is important in understanding infectious disease dynamics. Such events are typically unobservable, particularly in respiratory diseases such as tuberculosis (TB). We apply network techniques to identify transmission clusters and features shared within clusters. We estimate directed pairwise transmission probabilities via an existing iterative algorithm that employs a modified Naïve Bayes classifier and use these probabilities to create a network. We explore noise reduction techniques to trim low-probability edges. We group individuals with TB based on edges informed by transmission probabilities via network clustering algorithms. We apply our framework to simulated data and assess clustering algorithm performance. We then apply this approach to data from a cohort study in Lima, Peru, and examine homogeneity of the clusters using a binary entropy measure. We find cluster performance to be consistent across all edge-trimming scenarios and clustering methods. We find high levels of entropy, implying heterogeneity for age, sex, socioeconomic status, individuals who work outside the home, and people using public transit. We analyze estimated directed pairwise transmission probabilities with network techniques. The approach is consistent across network construction and clustering methods and can be applied to any disease outbreak to understand its dynamics. This article is part of a Special Collection on Latino Health.

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.

INTRODUCTION:Despite numerous randomized controlled trials, lung protective ventilation and prone positioning remain the only therapies shown to have a survival benefit in acute respiratory distress syndrome (ARDS). A National Heart, Lung, and Blood Institute workshop on the future of clinical research in ARDS suggested that identification of at-risk patients earlier in their clinical course would allow implementation of prevention strategies and facilitate study of these interventions. To this end, the Lung Injury Prevention Score (LIPS) was derived and validated to identify patients at risk of developing ARDS upon hospital admission, and the Emergency Department Lung Injury Prevention Score (EDLIPS) was subsequently derived and internally validated. For this study, we sought to externally validate EDLIPS. METHODS:We performed a validation study of EDLIPS, using data from a large, multicenter trial- the Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial. After identifying patients who met VIOLET inclusion criteria while in the ED, variables comprising EDLIPS were extracted for each patient. We calculated area under the receiver operating characteristic curves (AUC) of EDLIPS for the VIOLET dataset. RESULTS:We identified a total of 1,270 patients. The mean age was 56, and 55% were male. The incidence of ARDS was 8.1%. EDLIPS discriminated patients who developed ARDS from those who did not with an AUC of 0.786 (95% CI, 0.740-0.832), nearly identical to its performance in the original study, which yielded an AUC of 0.784 (95% CI, 0.748-0.820). CONCLUSION:We successfully validated a risk-prediction model for the identification of ED patients at risk for ARDS in a large cohort of critically ill patients. The development of ARDS prevention trials will involve collaboration with other clinical groups, such as emergency physicians, to enroll patients as early as possible in their clinical course. EDLIPS is the first tool of its kind to undergo external validation, and it can aid in the identification of ED patients at risk for the development of ARDS.

Incarcerated populations face an extremely high risk of tuberculosis (TB), yet little is known about whether this elevated risk persists after release into the community. Among 3,666 TB patients aged ≤ 60 years enrolled in a prospective cohort study in Lima, Peru, 188 (5%) reported a history of incarceration. These individuals presented with more severe disease (mean score difference = 0.25) and had a higher risk of a poor treatment outcome compared to those who had not been incarcerated (risk ratio [RR] = 2.17). Among 138 with known incarceration dates, nearly three-quarters (73%) were diagnosed within two years of release, suggesting that infections were acquired while in prison. Among 7,101 household contacts aged 15-60 years, 121 (1.7%) had a history of incarceration and these had a higher prevalence of TB infection (prevalence risk ratio [PRR] = 1.33). The prevalence risk was similarly elevated in the subset who were incarcerated for only ≤ 3 months (PRR = 1.37). Incarceration leaves a lasting imprint on TB dynamics, driving more severe disease, poorer outcomes, and elevated household infection risk after release. Prisons act as reservoirs that amplify TB epidemics, underscoring the urgent need for control strategies that bridge prison and community health systems.

INTRODUCTION:Food insecurity, defined as a lack of access to adequate nutrition, impacts approximately 30% of the global population. Despite clear evidence regarding the benefit of proper nutrition on clinical outcomes, the burden of incident food insecurity after surgical intervention in previously food secure patients is unknown. The goal of the study was to quantify incident food insecurity post operatively and to identify associated risk factors. METHODS:A multicenter, prospective, longitudinal study was conducted among adult surgical trauma patients at tertiary care public and private hospitals in India. The primary outcome was new food insecurity from initial admission for traumatic injury to 6 mo post operatively. Cox proportional hazards models were used to evaluate associations between clinical and sociodemographic variables and incident food insecurity. RESULTS:Of 774 patients enrolled, 20% were food insecure at baseline. During the follow-up period, 21% of patients who were food secure at baseline experienced new food insecurity. Incident food insecurity was associated with longer length of stay (hazard ratio (HR): 3.76, 95% confidence interval (CI): 1.62-8.74; P = 0.002), intensive care unit admission (HR: 1.87, 95% CI: 1.05-3.31; P = 0.032), receiving welfare support (HR: 2.00, 95% CI: 1.00-3.98; P = 0.049) and daily wage, rather than salaried, employment (HR: 2.95, 95% CI: 1.24-7.06; P = 0.015). Higher total household income was associated with maintaining food security (HR: 0.24, 95% CI: 0.13-0.44; P < 0.001). Hospitalization-related financial toxicity was significantly associated with incident food insecurity (HR: 3.07, 95% CI: 2.09-4.50; P < 0.001). CONCLUSIONS:High levels of incident food insecurity were observed among surgical trauma patients. This highlights the need for serial food insecurity assessment post discharge. In lieu of serial follow-up, risk factors associated with incident food insecurity can be used to identify high-risk patients prior to discharge to facilitate connection to food insecurity interventions such as food prescription programs, monetary support, and nutritional welfare policies.

Background:Hepatitis C virus (HCV) disproportionately affects racial minorities and socially disadvantaged groups in the United States. Despite highly effective direct-acting antiviral (DAA) therapies, treatment disparities persist. Methods:We conducted a retrospective cohort study using electronic medical record data from both inpatient and outpatient settings in an urban academic medical center between 1 October 2018 and 1 October 2023. Multivariable logistic regression identified sociodemographic and clinical predictors of HCV treatment initiation, defined as a documented direct-acting antiviral prescription, among individuals with positive HCV RNA between 2018 and 2023. Results:Among 4345 individuals, 1150 (26.5%) were prescribed HCV treatment. Black individuals were less likely to be prescribed HCV treatment compared to White individuals (adjusted odds ratio [aOR], 0.68 [95% confidence interval {CI}, .53-.88]). Individuals experiencing homelessness (aOR, 0.57 [95% CI, .46-.69]) and those with Medicaid (aOR, 0.82 [95% CI, .68-.98]) or no insurance (aOR, 0.49 [95% CI, .37-.65]) were also less likely to be prescribed HCV treatment. Individuals with mental health diagnoses (aOR, 1.34 [95% CI, 1.11-1.61]) were more likely to receive HCV treatment. Untreated individuals had a higher percentage of inpatient (12.3%) and emergency department visits (17.7%) than those who received treatment (3.4% and 4.8%, respectively). Conclusions:Significant disparities in HCV treatment initiation were observed, with lower rates among Black individuals, those experiencing homelessness, and individuals with Medicaid or no insurance. These inequities perpetuate a disproportionate burden of liver disease and preventable mortality in already marginalized populations.

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.

Importance:Tuberculosis (TB) is now understood to exist on a spectrum from TB infection to active TB disease. While World Health Organization guidelines target TB infection and TB disease, they overlook individuals with early TB in the middle of this spectrum. Objective:To evaluate chest radiograph (CR)-guided screening strategies among household contacts (HHCs) of patients with TB in a high-burden setting. Design, Setting, and Participants:This decision analytical model was constructed from June 1 to November 31, 2024. Community-based care in an environment with high TB burden and limited resources was used as the setting in Lima, Peru. Participants included a hypothetical cohort of 1000 HHCs with positive results of a tuberculin skin test and negative results of a sputum culture who were cleared of TB disease based on a clinician's evaluation. The hypothetical cohort was based on the clinical and demographic features of a cohort studied between September 1, 2009, and August 29, 2012. Interventions:Strategy 1 included CR screening to rule out TB disease followed by TB preventive therapy for all; strategy 2, CR screening with treatment for TB disease for those with abnormal CR findings and TB preventive therapy for those without; and strategy 3, observation without pharmacological intervention. We modeled 6 intervention scenarios by applying strategies 1 and 2 to the entire HHC population, to HHCs younger than 35 years, and to HHCs younger than 19 years (Peru's national TB policy). Main Outcomes and Measures:TB cases averted, serious adverse events (SAEs), and drug resistance. Results:A simulated cohort of 1000 HHCs with age and clinical status distributions was based on a previously published cohort of 12 767 TB HHCs in Lima, Peru. Of these, 7661 (60.0%) were male, 4212 (33.0%) were younger than 15 years, and 444 (3.4%) developed TB during 1 year of follow-up. Strategy 2 applied to all HHCs reduced TB cases by 71% to 81%, outperforming strategy 1 applied to all HHCs, which reduced cases by 49% to 69%. Strategy 2 reduced acquired isoniazid resistance but increased SAEs. When both strategies were restricted to HHCs younger than 19 years, strategy 2 reduced TB cases by 42% to 50%. Expanding treatment to older adults further reduced cases but also increased SAEs (19-22 additional SAEs). Conclusions and Relevance:In this model of TB HHC management, CR-guided identification and treatment of early TB was more effective than universal isoniazid preventive therapy, especially in children and young adults. Trade-offs between benefit and harm must be carefully considered in older adults.

INTRODUCTION:In high tuberculosis (TB)-burden countries, considerable transmission of Mycobacterium tuberculosis (M. tb) likely occurs outside of households. We aimed to estimate the TB prevalence and incidence in households and neighbourhoods around known TB cases and to understand transmission patterns. METHODS:Household and neighbourhood contacts of pulmonary TB index cases from contiguous areas in Bandung, Indonesia, were screened and followed up for 12 months. Sputum samples underwent smear microscopy, M. tb culture, Xpert MTB/RIF, DNA isolation and whole-genome sequencing (WGS). Pairwise single-nucleotide polymorphism (SNP) distance ≤12 defined transmission for pairs with known epidemiological links, or SNP≤3 for pairs without epidemiological link. An SNP=12 cut-off was used to characterise transmission clusters. RESULTS:From 213 index cases, 514 household and 4141 neighbourhood contacts underwent TB screening: 19 household (3.70%, 95% CI 2.24 to 5.71) and 45 neighbourhood (1.09%, 95% CI 0.79 to 1.45) contacts were identified with TB, of whom 18 (3.50%, 95% CI 2.20 to 5.48) and 38 (0.92%, 95% CI 0.65 to 1.13) respectively, were bacteriologically confirmed. During follow-up, 11 household and 13 neighbourhood contacts were identified with TB (incidence per 100 000 person-years: 2286 (95% CI 1286 to 4148) and 350 (95% CI 190 to 563)), of whom 6 and 8, respectively, were bacteriologically confirmed (incidence per 100 000 person-years: 1247 (95% CI 560 to 2776) and 201 (95% CI 101 to 402)). A total of 223 patient M. tb isolates underwent WGS. Of 15 intra-household pairs, 8 (53.3%) were transmission pairs. Of 24 neighbour to index case pairs, 1 (4.2%) was a transmission pair. 11 of 19 transmission pairs shared no epidemiological link. We identified 25 M. tb genetic clusters from 205 mono-TB isolates overall. CONCLUSION:Neighbours have lower prevalence and incidence of TB than household contacts, but twice as many cases. Very few received M. tb from their index case, suggesting uncontrolled community-wide transmission. Whole population active case finding may be necessary in high TB-burden settings.

OBJECTIVES:Approximately 40% of tuberculosis (TB) cases remain undiagnosed globally. Lower lung field TB (LLF TB) presents atypically and is often misidentified as other lung diseases, leading to diagnostic delays in resource-limited settings. It may contribute to increased TB transmission and mortality. We aimed to identify microbiological determinants of LLF TB and evaluate treatment responses to optimize care. METHODS:We conducted an observational cohort study in Lima, Peru, enrolling adults with microbiologically confirmed pulmonary TB (PTB) diagnosed by GeneXpert MTB/RIF assay or sputum culture. Mycobacterium tuberculosis (MTB) lineage was determined using whole-genome sequencing. Due to the delayed chest radiograph changes in LLF TB compared to non-LLF TB, we measured changes in the St. George's Respiratory Questionnaire (SGRQ) score at 2-month treatment mark and evaluated World Health Organization-specified final treatment outcomes. We used logistic regression to evaluate the associations between LLF TB and microbiological determinants and treatment outcomes. We used linear regression to assess whether the change in SGRQ scores over the first 2 months of treatment varied by LLF TB status. RESULTS:Among 1316 PTB patients, 84 (6%) had LLF TB. Compared to non-LLF TB patients, LLF TB patients were more likely to be smear-negative (adjusted odds ratio [aOR] [95% CI] = 2.04 [1.28-3.23], P = 0.002) and to be infected with Lineage 2 (aOR [95% CI] = 1.95 [95% CI: 1.07-3.41; P = 0.024]). People with LLF TB had less improvement in SGRQ scores after 2 months of treatment (adjusted score difference [95% CI] = -6.29 [-10.99 to -1.59], P = 0.009), while they experienced better final outcomes compared to non-LLF TB patients, though this difference did not reach statistical significance (aOR = 0.43 [95% CI: 0.13-1.05], P = 0.103). CONCLUSION:Patients with LLF TB are more likely than those with upper lung lesions to be sputum-negative on conventional tests, to be infected with Lineage 2, and to show less clinical improvement after treatment.