Transmission of Mycobacterium tuberculosis From Patients Who Are Nucleic Acid Amplification Test Negative.

Background: Among adults with signs and symptoms of pulmonary tuberculosis (TB), recognition of transmissible TB has implications for airborne infection isolation and public health activities. Sputum smear-negative TB patients account for around one-fifth of tuberculosis transmission. The tuberculosis transmission risk of TB patients with negative results on nucleic acid amplification test (NAAT) of respiratory specimens has not been established. We sought to estimate the tuberculosis transmission risk of NAAT-negative TB patients. Methods: We retrospectively reviewed Maryland TB program data collected from 2004 to 2009, during which time NAAT using the Mycobacterium Tuberculosis Direct Test (MTD) was performed routinely. Patients with sputum Mycobacterium tuberculosis (M.tb) isolates having matching genotypes were assigned to clusters. Transmission sequence was approximated by collection order of individuals' first culture-positive specimens. Minimum transmission risks of NAAT (MTD)-negative TB patients and of smear-negative TB patients were estimated based on individuals' positions within clusters. Results: Among 809 patients with culture-confirmed TB, M.tb genotypes were available for 782 (96.7%). For NAA-negative TB patients, the minimum transmission risk estimate was 5.1% (95% CI 0-11.4). For smear-negative TB patients, the minimum transmission risk estimate was 11.2% (95% CI 7.2-15.3). Conclusions: Minimum transmission risk of NAAT-negative TB patients was lower than that of smear-negative TB patients. However, transmission risk of NAA-negative TB patients appears to not be negligible.

Improved Detection of Tuberculosis and Multidrug-Resistant Tuberculosis among Tibetan Refugees, India.

The incidence of tuberculosis (TB) among Tibetan refugees in India is 431 cases/100,000 persons, compared with 181 cases/100,000 persons overall in India in 2010. More than half of TB cases in these refugees occur among students, monks, and nuns in congregate settings. We sought to increase TB case detection rates for this population through active case finding and rapid molecular diagnostics. We screened 27,714 persons for symptoms of TB and tested 3,830 symptomatic persons by using an algorithm incorporating chest radiography, sputum smear microscopy, culture, and a rapid diagnostic test; 96 (2.5%) cases of TB were detected (prevalence 346 cases/100,000 persons). Of these cases, 5% were multidrug-resistant TB. Use of the rapid diagnostic test and active case finding enabled rapid detection of undiagnosed TB cases in congregate living settings, which would not have otherwise been identified. The burden of TB in the Tibetan exile population in India is extremely high and requires urgent attention.

Validation of genotype cluster investigations for Mycobacterium tuberculosis: application results for 44 clusters from four heterogeneous United States jurisdictions.

BACKGROUND: Tracking the dissemination of specific Mycobacterium tuberculosis (Mtb) strains using genotyped Mtb isolates from tuberculosis patients is a routine public health practice in the United States. The present study proposes a standardized cluster investigation method to identify epidemiologic-linked patients in Mtb genotype clusters. The study also attempts to determine the proportion of epidemiologic-linked patients the proposed method would identify beyond the outcome of the conventional contact investigation. METHODS: The study population included Mtb culture positive patients from Georgia, Maryland, Massachusetts and Houston, Texas. Mtb isolates were genotyped by CDC's National TB Genotyping Service (NTGS) from January 2006 to October 2010. Mtb cluster investigations (CLIs) were conducted for patients whose isolates matched exactly by spoligotyping and 12-locus MIRU-VNTR. CLIs were carried out in four sequential steps: (1) Public Health Worker (PHW) Interview, (2) Contact Investigation (CI) Evaluation, (3) Public Health Records Review, and (4) CLI TB Patient Interviews. Comparison between patients whose links were identified through the study's CLI interviews (Step 4) and patients whose links were identified earlier in CLI (Steps 1-3) was conducted using logistic regression. RESULTS: Forty-four clusters were randomly selected from the four study sites (401 patients in total). Epidemiologic links were identified for 189/401 (47 %) study patients in a total of 201 linked patient-pairs. The numbers of linked patients identified in each CLI steps were: Step 1 - 105/401 (26.2 %), Step 2 - 15/388 (3.9 %), Step 3 - 41/281 (14.6 %), and Step 4 - 28/119 (30 %). Among the 189 linked patients, 28 (14.8 %) were not identified in previous CI. No epidemiologic links were identified in 13/44 (30 %) clusters. CONCLUSIONS: We validated a standardized and practical method to systematically identify epidemiologic links among patients in Mtb genotype clusters, which can be integrated into the TB control and prevention programs in public health settings. The CLI interview identified additional epidemiologic links that were not identified in previous CI. One-third of the clusters showed no epidemiologic links despite being extensively investigated, suggesting that some improvement in the interviewing methods is still needed.

Improved adherence and less toxicity with rifampin vs isoniazid for treatment of latent tuberculosis: a retrospective study.

BACKGROUND: Treatment of latent tuberculosis infection (LTBI) is an important aspect of tuberculosis control in the United States, but the effectiveness of this strategy is compromised by poor adherence to the recommended 9-month isoniazid regimen. In this study, we compared treatment completion and clinically recognized adverse drug reactions in patients prescribed 9 months of isoniazid therapy or 4 months of rifampin therapy for LTBI. METHODS: Retrospective chart review of patients who received LTBI treatment at a public health clinic. RESULTS: A total of 770 patients were prescribed 9 months of isoniazid therapy, and 1379 patients were prescribed 4 months of rifampin therapy. The percentages of patients who completed 80% or more of their prescribed treatment were 52.6% and 71.6% in the isoniazid and rifampin groups, respectively (P<.001). In multivariate logistic regression analysis, treatment regimen was independently associated with treatment completion (adjusted odds ratio for treatment completion, 2.88 for rifampin group vs isoniazid group; 95% confidence interval, 2.27-3.66). Clinically recognized adverse reactions resulting in permanent treatment discontinuation occurred in 4.6% and 1.9% of patients in the isoniazid and rifampin groups, respectively (P<.001). Clinically recognized hepatotoxicity was more common in the isoniazid group (1.8%) than in the rifampin group (0.08%, P<.001). CONCLUSIONS: Compared with a 9-month isoniazid regimen, a 4-month rifampin regimen was associated with a higher percentage of patients completing treatment and a lower percentage of patients with clinically recognized adverse reactions. Additional studies are warranted to determine efficacy and effectiveness of rifampin therapy for LTBI.

Evaluation of 24-locus MIRU-VNTR genotyping in Mycobacterium tuberculosis cluster investigations in four jurisdictions in the United States, 2006-2010.

The U.S. Centers for Disease Control and Prevention (CDC) uses a combination of spacer oligonucleotide typing (spoligotyping) and mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) analyses as part of the National TB Genotyping Service (NTGS). The NTGS expansion from 12-locus MIRU-VNTR (MIRU12) to 24-locus MIRU-VNTR (MIRU24) in 2009 enhanced the ability to discriminate Mycobacterium tuberculosis strains. In the current study, we investigated the MIRU24 concordance among epidemiologic-linked tuberculosis (TB) patients in four U.S. health jurisdictions. We also evaluated the programmatic benefits of combining MIRU24 and spoligotyping with epidemiologic evidence in identifying potential recent TB transmission. We examined 342 TB patients in 42 spoligotype/MIRU12 (PCRType) clusters (equivalent to 46 spoligotype/MIRU24 [GENType] clusters) to identify epidemiologic links among cases. GENType clusters, when compared to PCRType clusters, had 12 times higher odds of epidemiologic links being identified if patients were younger than 25 years and 3 times higher odds if patients resided in the same zip code, or had HIV infection. Sixty (18%) fewer PCRType-clustered patients would need investigations if clusters are defined using GENType instead of PCRType. An important advantage of defining clusters by MIRU24 is resource savings related to the reduced number of clustered cases needing investigation.

Geo-epidemiologic and molecular characterization to identify social, cultural, and economic factors where targeted tuberculosis control activities can reduce incidence in Maryland, 2004-2010.

OBJECTIVES: Tuberculosis (TB) disproportionately affects members of socioeconomically disadvantaged and minority populations in the U.S. We describe the geospatial distribution of TB cases in Maryland, identify areas at high risk for TB, and compare the geospatial clustering of cases with genotype clustering and demographic, socioeconomic, and TB risk-factor information. METHODS: Addresses of culture-positive, genotyped TB cases reported to the Maryland Department of Health and Mental Hygiene from January 1, 2004, to December 31, 2010, were geocoded and aggregated to census tracts. Geospatial clusters with higher-than-expected case numbers were identified using Poisson spatial cluster analysis. Case distribution and geospatial clustering information were compared with (1) genotype clustering (spoligotypes and 12-locus MIRU-VNTR), (2) individual-level risk and demographic data, and (3) census tract-level demographic and socioeconomic data. RESULTS: We genotoyped 1,384 (98%) isolates from 1,409 culture-positive TB cases. Two geospatial clusters were found: one in Baltimore City and one in Montgomery and Prince George's counties. Cases in these geospatial clusters were equally or less likely to share genotypes than cases outside the geospatial clusters. The two geospatial clusters had poverty and crowding in common but differed significantly by risk populations and behaviors. CONCLUSIONS: Genotyping results indicated that recent transmission did not explain most geospatial clustering, suggesting that geospatial clustering is largely mitigated by social determinants. Analyses combining geospatial, genotyping, and epidemiologic data can help characterize populations most at risk for TB and inform the design of targeted interventions.

Evaluation of large genotypic Mycobacterium tuberculosis clusters: contributions from remote and recent transmission.

Tuberculosis genotypic clustering is used as a proxy for recent transmission. The association between clustering and recent transmission becomes problematic when the genotyping method lacks specificity in defining a cluster, as well as for clusters with extensive jurisdictional histories and/or common genotypes. We investigated the four largest spoligotype/12 loci MIRU-VNTR-defined clusters in Harris County, Texas from 2006-2012 to determine their historical contribution to tuberculosis morbidity, estimate the contributions from recent and remote transmission, and determine the impact of secondary genotyping on cluster definition. The clusters contained 189, 64, 51 and 38 cases. Each cluster was linked to cluster(s) previously identified by Houston Tuberculosis Initiative; 3 since 1995 and the fourth in 2002. Among cases for which timing of Mycobacterium tuberculosis transmission relative to tuberculosis disease could be ascertained, nearly equal proportions were associated with recent and remote transmission. The extent to which genotyping with an additional 12 MIRU-VNTR loci modified the cluster definition varied from little or no impact for the two smaller clusters to moderate impact for the larger clusters. Tuberculosis control measures to reduce morbidity associated with large clusters must involve strategies to identify and treat individuals who recently acquired infection, as well as persons infected for years.

Cross-jurisdictional transmission of Mycobacterium tuberculosis in Maryland and Washington, D C, 1996-2000, linked to the homeless.

From 1996 to 2000, 23 Maryland and Washington, D.C., tuberculosis cases were identified in one six-band DNA cluster. Cases were clustered on the basis of their Mycobacterium tuberculosis isolates. Medical record reviews and interviews were conducted to identify epidemiologic linkages. Eighteen (78%) of the 23 case-patients with identical restriction fragment length polymorphism patterns were linked to another member; half the patients were associated with a Washington, D.C., homeless shelter. Molecular epidemiology defined the extent of this large, cross-jurisdictional outbreak.

Use of DNA fingerprinting to investigate a multiyear, multistate tuberculosis outbreak.

In 1998-1999, the Baltimore TB control program detected a cluster of 21 tuberculosis (TB) cases. Patients reported frequent travel to various East Coast cities. An investigation was conducted to determine whether transmission of the same Mycobacterium tuberculosis strain was occurring in these other localities. A collaborative investigation among federal, state, and local TB controllers included TB record reviews, interviews of patients, and restriction fragment length polymorphism (RFLP) analysis of selected M. tuberculosis isolates from diagnosed TB patients in several cities in 1996-2001. A national TB genotyping database was searched for RFLP patterns that matched the outbreak pattern. Eighteen additional outbreak-related cases were detected outside of Baltimore-the earliest diagnosed in New Jersey in 1996, and the most recent in New York City in late 2001. The outbreak demonstrates the need for strategies to detect links among patients diagnosed with TB across multiple TB control jurisdictions.

Molecular epidemiology of tuberculosis in a low- to moderate-incidence state: are contact investigations enough?

To assess the circumstances of recent transmission of tuberculosis (TB) (progression to active disease <2 years after infection), we obtained DNA fingerprints for 1172 (99%) of 1179 Mycobacterium tuberculosis isolates collected from Maryland TB patients from 1996 to 2000. We also reviewed medical records and interviewed patients with genetically matching M. tuberculosis strains to identify epidemiologic links (cluster investigation). Traditional settings for transmission were defined as households or close relatives and friends; all other settings were considered nontraditional. Of 436 clustered patients, 115 had recently acquired TB. Cluster investigations were significantly more likely than contact investigations to identify patients who recently acquired TB in nontraditional settings (33/42 vs. 23/72, respectively; p<0.001). Transmission from a foreign-born person to a U.S.-born person was rare and occurred mainly in public settings. The time from symptom onset to diagnosis was twice as long for transmitters as for nontransmitters (16.8 vs. 8.5 weeks, respectively; p<0.01). Molecular epidemiologic studies showed that reducing diagnostic delays can prevent TB transmission in nontraditional settings, which elude contact investigations.