Genomic Epidemiology of Multidrug-Resistant Mycobacterium tuberculosis During Transcontinental Spread

The transcontinental spread of multidrug-resistant (MDR) tuberculosis is poorly characterized in molecular epidemiologic studies. We used genomic sequencing to understand the establishment and dispersion of MDR Mycobacterium tuberculosis within a group of immigrants to the United States. We used a genomic epidemiology approach to study a genotypically matched (by spoligotype, IS6110 restriction fragment length polymorphism, and mycobacterial interspersed repetitive units-variable number of tandem repeat signature) lineage 2/Beijing MDR strain implicated in an outbreak of tuberculosis among refugees in Thailand and consecutive cases within California. All 46 MDR M. tuberculosis genomes from both Thailand and California were highly related, with a median difference of 10 single-nucleotide polymorphisms (SNPs). The Wat Tham Krabok (WTK) strain is a new sequence type distinguished from all known Beijing strains by 55 SNPs and a genomic deletion (Rv1267c) associated with increased fitness. Sequence data revealed a highly prevalent MDR strain that included several closely related but distinct allelic variants within Thailand, rather than the occurrence of a single outbreak. In California, sequencing data supported multiple independent introductions of WTK with subsequent transmission and reactivation within the state, as well as a potential super spreader with a prolonged infectious period. Twenty-seven drug resistance-conferring mutations and 4 putative compensatory mutations were found within WTK strains. Genomic sequencing has substantial epidemiologic value in both low- and high-burden settings in understanding transmission chains of highly prevalent MDR strain

Sputum Smear Microscopy at Two Months into Continuation-Phase: Should It Be Done in All Patients with Sputum Smear-Positive Tuberculosis?

BACKGROUND: The Revised National Tuberculosis Control Program (RNTCP) of India recommends follow-up sputum smear examination at two months into the continuation phase of treatment. The main intent of this (mid-CP) follow-up is to detect patients not responding to treatment around two-three months earlier than at the end of the treatment. However, the utility of mid-CP follow-up under programmatic conditions has been questioned. We undertook a multi-district study to determine if mid-CP follow-up is able to detect cases of treatment failures early among all types of patients with sputum smear-positive TB. METHODOLOGY: We reviewed existing records of patients with sputum smear-positive TB registered under the RNTCP in 43 districts across three states of India during a three month period in 2009. We estimated proportions of patients that could be detected as a case of treatment failure early, and assessed the impact of various policy options on laboratory workload and number needed to test to detect one case of treatment failure early. RESULTS: Of 10055 cases, mid-CP follow-up was done in 6944 (69%) cases. Mid-CP follow-up could benefit 117/8015 (1.5%) new and 206/2040 (10%) previously-treated sputum smear-positive cases by detecting their treatment failure early. Under the current policy, 31 patients had to be tested to detect one case of treatment failure early. All cases of treatment failure would still be detected early if mid-CP follow-up were discontinued for new sputum smear-positive cases who become sputum smear-negative after the intensive-phase of treatment. This would reduce the related laboratory workload by 69% and only 10 patients would need to be tested to detect one case of treatment failure early. CONCLUSION: Discontinuation of mid-CP follow-up among new sputum smear-positive cases who become sputum smear-negative after completing the intensive-phase of treatment will reduce the laboratory workload without impacting overall early detection of cases of treatment failure

Tuberculosis Outbreak Investigations in the United States, 2002–2008

To understand circumstances of tuberculosis transmission that strain public health resources, we systematically reviewed Centers for Disease Control and Prevention (CDC) staff reports of US outbreaks in which CDC participated during 2002–2008 that involved >3 culture-confirmed tuberculosis cases linked by genotype and epidemiology. Twenty-seven outbreaks, representing 398 patients, were reviewed. Twenty-four of the 27 outbreaks involved primarily US-born patients; substance abuse was another predominant feature of outbreaks. Prolonged infectiousness because of provider- and patient-related factors was common. In 17 outbreaks, a drug house was a notable contributing factor. The most frequently documented intervention to control the outbreak was prioritizing contacts according to risk for infection and disease progression to ensure that the highest risk contacts were completely evaluated. US-born persons with reported substance abuse most strongly characterized the tuberculosis outbreaks in this review. Substance abuse remains one of the greatest challenges to controlling tuberculosis transmission in the United States

Multidrug-Resistant Tuberculosis Outbreak among US-bound Hmong Refugees, Thailand, 2005

Enhanced pre-immigration screening and program expansion decreased TB importation

Overseas Treatment of Latent Tuberculosis Infection in US-Bound Immigrants.

Seventy percent of tuberculosis (TB) cases in the United States occur among non-US-born persons; cases usually result from reactivation of latent TB infection (LTBI) likely acquired before the person's US arrival. We conducted a prospective study among US immigrant visa applicants undergoing the required overseas medical examination in Vietnam. Consenting applicants >15 years of age were offered an interferon-γ release assay (IGRA); those 12-14 years of age received an IGRA as part of the required examination. Eligible participants were offered LTBI treatment with 12 doses of weekly isoniazid and rifapentine. Of 5,311 immigrant visa applicants recruited, 2,438 (46%) consented to participate; 2,276 had an IGRA processed, and 484 (21%) tested positive. Among 452 participants eligible for treatment, 304 (67%) initiated treatment, and 268 (88%) completed treatment. We demonstrated that using the overseas medical examination to provide voluntary LTBI testing and treatment should be considered to advance US TB elimination efforts

Characteristics of Tuberculosis Cases that Started Outbreaks in the United States, 2002–2011

A review of 26 tuberculosis outbreaks in the United States (2002–2011) showed that initial source case-patients had long infectious periods (median 10 months) and were characterized by substance abuse, incarceration, and homelessness. Improved timeliness of diagnosis and thorough contact investigations for such cases may reduce the risk for outbreaks

Estimating the burden of tuberculosis among foreign-born persons acquired prior to entering the U.S., 2005-2009.

BACKGROUND: The true burden of reactivation of remote latent tuberculosis infection (reactivation TB) among foreign-born persons with tuberculosis (TB) within the United States is not known. Our study objectives were to estimate the proportion of foreign-born persons with TB due reactivation TB and to describe characteristics of foreign-born persons with reactivation TB. METHODS: We conducted a cross-sectional study of patients with an M. tuberculosis isolate genotyped by the U.S. National TB Genotyping Service, 2005-2009. TB cases were attributed to reactivation TB if they were not a member of a localized cluster of cases. Localized clusters were determined by a spatial scan statistic of cases with isolates with matching TB genotype results. Crude odds ratios and 95% confidence intervals were used to assess relations between reactivation TB and select factors among foreign-born persons. MAIN RESULTS: Among the 36,860 cases with genotyping and surveillance data reported, 22,151 (60%) were foreign-born. Among foreign-born persons with TB, 18,540 (83.7%) were attributed to reactivation TB. Reactivation TB among foreign-born persons was associated with increasing age at arrival, incidence of TB in the country of origin, and decreased time in the U.S. at the time of TB diagnosis. CONCLUSIONS: Four out of five TB cases among foreign-born persons can be attributed to reactivation TB and present the largest challenge to TB elimination in the U.S. TB control strategies among foreign-born persons should focus on finding and treating latent tuberculosis infection prior to or shortly after arrival to the United States and on reducing the burden of LTBI through improvements in global TB control