A Cluster-based Method to Quantify Individual Heterogeneity in Tuberculosis Transmission.

BACKGROUND: Recent evidence suggests transmission of Mycobacterium tuberculosis (Mtb) may be characterized by extreme individual heterogeneity in secondary cases (i.e., few cases account for the majority of transmission). Such heterogeneity implies outbreaks are rarer but more extensive and has profound implications in infectious disease control. However, discrete person-to-person transmission events in tuberculosis (TB) are often unobserved, precluding our ability to directly quantify individual heterogeneity in TB epidemiology. METHODS: We used a modified negative binomial branching process model to quantify the extent of individual heterogeneity using only observed transmission cluster size distribution data (i.e., the simple sum of all cases in a transmission chain) without knowledge of individual-level transmission events. The negative binomial parameter k quantifies the extent of individual heterogeneity (generally, indicates extensive heterogeneity, and as transmission becomes more homogenous). We validated the robustness of the inference procedure considering common limitations affecting cluster size data. Finally, we demonstrate the epidemiologic utility of this method by applying it to aggregate US molecular surveillance data from the US Centers for Disease Control and Prevention. RESULTS: The cluster-based method reliably inferred k using TB transmission cluster data despite a high degree of bias introduced into the model. We found that the TB transmission in the United States was characterized by a high propensity for extensive outbreaks (; 95% confidence interval = 0.09, 0.10). CONCLUSIONS: The proposed method can accurately quantify critical parameters that govern TB transmission using simple, more easily obtainable cluster data to improve our understanding of TB epidemiology.

Logically Inferred Tuberculosis Transmission (LITT): A Data Integration Algorithm to Rank Potential Source Cases.

Understanding tuberculosis (TB) transmission chains can help public health staff target their resources to prevent further transmission, but currently there are few tools to automate this process. We have developed the Logically Inferred Tuberculosis Transmission (LITT) algorithm to systematize the integration and analysis of whole-genome sequencing, clinical, and epidemiological data. Based on the work typically performed by hand during a cluster investigation, LITT identifies and ranks potential source cases for each case in a TB cluster. We evaluated LITT using a diverse dataset of 534 cases in 56 clusters (size range: 2-69 cases), which were investigated locally in three different U.S. jurisdictions. Investigators and LITT agreed on the most likely source case for 145 (80%) of 181 cases. By reviewing discrepancies, we found that many of the remaining differences resulted from errors in the dataset used for the LITT algorithm. In addition, we developed a graphical user interface, user's manual, and training resources to improve LITT accessibility for frontline staff. While LITT cannot replace thorough field investigation, the algorithm can help investigators systematically analyze and interpret complex data over the course of a TB cluster investigation. Code available at: https://github.com/CDCgov/TB_molecular_epidemiology/tree/1.0; https://zenodo.org/badge/latestdoi/166261171.

Tuberculosis Genotype Clusters and Transmission in the U.S., 2009-2018.

INTRODUCTION: In the U.S., universal genotyping of culture-confirmed tuberculosis cases facilitates cluster detection. Early recognition of the small clusters more likely to become outbreaks can help prioritize public health resources for immediate interventions. METHODS: This study used national surveillance data reported during 2009-2018 to describe incident clusters (≥3 tuberculosis cases with matching genotypes not previously reported in the same county); data were analyzed during 2020. Cox proportional hazards regression models were used to examine the patient characteristics associated with clusters doubling in size to ≥6 cases. RESULTS: During 2009-2018, a total of 1,516 incident clusters (comprising 6,577 cases) occurred in 47 U.S. states; 231 clusters had ≥6 cases. Clusters of ≥6 cases disproportionately included patients who used substances, who had recently experienced homelessness, who were incarcerated, who were U.S. born, or who self-identified as being of American Indian or Alaska Native race or of Black race. A median of 54 months elapsed between the first and the third cases in clusters that remained at 3-5 cases compared with a median of 9.5 months in clusters that grew to ≥6 cases. The longer time between the first and third cases and the presence of ≥1 patient aged ≥65 years among the first 3 cases predicted a lower hazard for accumulating ≥6 cases. CONCLUSIONS: Clusters accumulating ≥3 cases within a year should be prioritized for intervention. Effective response strategies should include plans for targeted outreach to U.S.-born individuals, incarcerated people, those experiencing homelessness, people using substances, and individuals self-identifying as being of American Indian or Alaska Native race or of Black race.

Tuberculosis genotyping information management system: enhancing tuberculosis surveillance in the United States.

Molecular characterization of Mycobacterium tuberculosis complex isolates (genotyping) can be used by public health programs to more readily identify tuberculosis (TB) transmission. The Centers for Disease Control and Prevention's National Tuberculosis Genotyping Service has offered M. tuberculosis genotyping for every culture-confirmed case in the United States since 2004. The TB Genotyping Information Management System (TB GIMS), launched in March 2010, is a secure online database containing genotype results linked with case characteristics from the national TB registry for state and local TB programs to access, manage and analyze these data. As of September 2011, TB GIMS contains genotype results for 89% of all culture-positive TB cases for 2010. Over 400 users can generate local and national reports and maps using TB GIMS. Automated alerts on geospatially concentrated cases with matching genotypes that may represent outbreaks are also generated by TB GIMS. TB genotyping results are available to enhance national TB surveillance and apply genotyping results to conduct TB control activities in the United States.

Tuberculosis among persons born in the Philippines and living in the United States, 2000-2007.

OBJECTIVES: We examined demographic, clinical, and treatment outcome characteristics of Filipinos with tuberculosis (TB) in the United States. METHODS: We calculated TB case rates from US Census Bureau population estimates and National Tuberculosis Surveillance System data for US-born non-Hispanic Whites and for US residents born in the Philippines, India, China, Cambodia, Vietnam, Pakistan, and Korea--countries that are major contributors to the TB burden in the United States. We compared Filipinos with the other groups through univariate and multivariate analyses. RESULTS: Of 45,504 TB patients, 15.5% were Filipinos; 43.0% were other Asian/Pacific Islander groups; and 41.6% were Whites. Per 100 000 persons in 2007, the TB rate was 73.5 among Cambodians, 54.0 among Vietnamese, 52.1 among Filipinos, and 0.9 among Whites. Filipinos were more likely than other groups to be employed as health care workers and to have used private health care providers but less likely to be HIV positive and to be offered HIV testing. CONCLUSIONS: The relatively high TB rate among Filipinos indicates that TB control strategies should target this population. Providers should be encouraged to offer HIV testing to all TB patients.

Time to sputum culture conversion in multidrug-resistant tuberculosis: predictors and relationship to treatment outcome.

BACKGROUND: Conversion of sputum mycobacterial cultures from positive growth to negative growth of Mycobacterium tuberculosis in patients with pulmonary tuberculosis (TB) is considered the most important interim indicator of the efficacy of anti-TB pharmacologic treatment for multidrug-resistant disease. OBJECTIVE: To evaluate and compare time to and predictors of initial sputum culture conversion with predictors of treatment outcome for patients with multidrug-resistant TB. DESIGN: Retrospective cohort study. SETTING: Latvia. PATIENTS: All civilian patients with multidrug-resistant TB treated with the DOTS-Plus strategy between 1 January and 31 December 2000. INTERVENTION: Individualized treatment for confirmed sputum culture-positive pulmonary multidrug-resistant TB. MEASUREMENTS: Time to initial sputum culture conversion and treatment outcome. RESULTS: Among 167 patients who were sputum culture-positive at initiation of second-line therapy, 129 (77%) converted in a median time of 60 days (range, 4 to 462 days) and 38 (23%) did not convert. Independent predictors of a longer sputum culture conversion time, using an accelerated failure time regression model, included previous treatment for multidrug-resistant TB, high initial sputum culture colony count, bilateral cavitations on chest radiography, and the number of drugs the initial isolate was resistant to at treatment initiation. Treatment outcomes were statistically significantly worse for patients who did not convert their sputum culture within 2 months. LIMITATIONS: Twenty-five percent of patients missed 5 or more monthly sputum collections. CONCLUSIONS: Under program conditions in Latvia, most patients with multidrug-resistant TB achieved sputum culture conversion within 12 weeks of starting treatment. Chest radiography and sputum culture drug susceptibility testing can assist physicians in predicting which patients will convert more slowly. Sputum culture conversion is a useful and appropriate interim indicator of treatment outcome in patients with multidrug-resistant TB.

Molecular epidemiology of tuberculosis in a sentinel surveillance population.

We conducted a population-based study to assess demographic and risk-factor correlates for the most frequently occurring Mycobacterium tuberculosis genotypes from tuberculosis (TB) patients. The study included all incident, culture-positive TB patients from seven sentinel surveillance sites in the United States from 1996 to 2000. M. tuberculosis isolates were genotyped by IS6110-based restriction fragment length polymorphism and spoligotyping. Genotyping was available for 90% of 11923 TB patients. Overall, 48% of cases had isolates that matched those from another patient, including 64% of U.S.-born and 35% of foreign-born patients. By logistic regression analysis, risk factors for clustering of genotypes were being male, U.S.-born, black, homeless, and infected with HIV; having pulmonary disease with cavitations on chest radiograph and a sputum smear with acid-fast bacilli; and excessive drug or alcohol use. Molecular characterization of TB isolates permitted risk correlates for clusters and specific genotypes to be described and provided information regarding cluster dynamics over time.

Identifying the sources of tuberculosis in young children: a multistate investigation.

To better understand the molecular epidemiology of tuberculosis (TB) transmission for culture-confirmed patients <5 years of age, data were analyzed from a population-based study conducted in seven U.S. sites from 1996 to 2000. Mycobacterium tuberculosis isolates were genotyped with IS6110-based restriction fragment length polymorphism analysis and spoligotyping. Case-patient data were obtained from the Centers for Disease Control and Prevention s national tuberculosis registry and health department records. Routine public health investigations conducted by local health departments identified suspected source patients for 57 (51%) of 111 culture-confirmed patients <5 years of age. For 8 (15%) of 52 culture-confirmed patients <5 years of age and their suspected source patients with complete genotyping results, genotypes suggested infection with different TB strains. Potential differences between sources for patients <5 years of age and source patients that transmitted TB to adolescent and adult patients were identified.