Epidemiology and Treatment Outcomes of Tuberculosis with Chronic Hepatitis B Infection-California, 2016-2020.

BACKGROUND: Improved epidemiologic and treatment data for active tuberculosis (TB) with chronic hepatitis B virus (cHBV) infection might inform and encourage screening and vaccination programs focused on persons at risk of having both conditions. METHODS: We matched the California Department of Public Health TB registry during 2016-2020 to the cHBV registry using probabilistic matching algorithms. We used chi-square analysis to compare the characteristics of persons with TB and cHBV with those with TB only. We compared TB treatment outcomes between these groups using modified Poisson regression models. We calculated the time between reporting of TB and cHBV diagnoses for those with both conditions. RESULTS: We identified 8,435 persons with TB, including 316 (3.7%) with cHBV.- Among persons with TB and cHBV, 256 (81.0%) were non-U.S.-born Asian vs 4,186 (51.6%) with TB only (P <0.0001). End-stage renal disease (26 [8.2%] vs 322 [4.0%]; P <0.001) and HIV (21 [6.7%] vs 247 [3.0%]; P value = 0.02) were more frequent among those with TB and cHBV compared with those with TB only. Among those with both conditions, 35 (11.1%) had TB diagnosed >60 days before cHBV (median 363 days) and 220 (69.6%) had TB diagnosed >60 days after cHBV (median 3,411 days). CONCLUSION: Persons with TB and cHBV were found more frequently in certain groups compared with TB only, and infrequently had their conditions diagnosed together. This highlights an opportunity to improve screening and treatment of TB and cHBV in those at high risk for coinfection.

Tuberculosis Diagnostic Delays and Treatment Outcomes among Patients with COVID-19, California, USA, 2020.

We assessed tuberculosis (TB) diagnostic delays among patients with TB and COVID-19 in California, USA. Among 58 persons, 43% experienced TB diagnostic delays, and a high proportion (83%) required hospitalization for TB. Even when viral respiratory pathogens circulate widely, timely TB diagnostic workup for at-risk persons remains critical for reducing TB-related illness.

Association of indicators of extensive disease and rifampin-resistant tuberculosis treatment outcomes: an individual participant data meta-analysis.

BACKGROUND: Indicators of extensive disease-acid fast bacilli (AFB) smear positivity and lung cavitation-have been inconsistently associated with clinical rifampin-resistant/multidrug-resistant tuberculosis (RR/MDR-TB) outcomes. We evaluated the association of these indicators with end-of-treatment outcomes. METHODS: We did an individual participant data meta-analysis of people treated for RR/MDR-TB with longer regimens with documented AFB smear and chest radiography findings. We compared people AFB smear-negative without cavities to people: (1) smear-negative with lung cavities; (2) smear-positive without lung cavities and (3) AFB smear-positive with lung cavities. Using multivariable logistic regression accounting for demographic, treatment and clinical factors, we calculated adjusted ORs (aOR) for any unfavourable outcome (death, lost to follow-up, failure/recurrence), and mortality and treatment failure/recurrence alone. RESULTS: We included 5596 participants; included participants significantly differed from excluded participants. Overall, 774 (13.8%) were AFB smear-negative without cavities, 647 (11.6%) only had cavities, 1424 (25.4%) were AFB smear-positive alone and 2751 (49.2%) were AFB smear-positive with cavities. The median age was 37 years (IQR: 28-47), 3580 (64%) were male and 686 (12.5%) had HIV. Compared with participants AFB smear-negative without cavities, aOR (95% CI) for any unfavourable outcome was 1.0 (0.8 to 1.4) for participants smear-negative with lung cavities, 1.2 (0.9 to 1.5) if smear-positive without cavities and 1.6 (1.3 to 2.0) if AFB smear-positive with lung cavities. Odds were only significantly increased for mortality (1.5, 95% CI 1.1 to 2.1) and failure/recurrence (2.2, 95% CI 1.5 to 3.3) among participants AFB smear-positive with lung cavities. CONCLUSION: Only the combination of AFB smear-positivity and lung cavitation was associated with unfavourable outcomes, suggesting they may benefit from stronger regimens.

Tuberculosis Diagnoses Following Wildfire Smoke Exposure in California.

Rationale: Wildfires are a significant cause of exposure to ambient air pollution in the United States and other settings. Although indoor air pollution is a known contributor to tuberculosis reactivation and progression, it is unclear whether ambient pollution exposures, including wildfire smoke, similarly increase risk. Objectives: To determine whether tuberculosis diagnosis was associated with recent exposure to acute outdoor air pollution events, including those caused by wildfire smoke. Methods: We conducted a case-crossover analysis of 6,238 patients aged ⩾15 years diagnosed with active tuberculosis disease between 2014 and 2019 in 8 California counties. Using geocoded address data, we characterized individuals' daily exposure to <2.5 µm-diameter particulate matter (PM2.5) during counterfactual risk periods 3-6 months before tuberculosis diagnosis (hazard period) and the same time 1 year previously (control period). We compared the frequency of residential PM2.5 exposures exceeding 35 µg/m3 (PM2.5 events) overall and for wildfire-associated and nonwildfire events during individuals' hazard and control periods. Measurements and Main Results: In total, 3,139 patients experienced 1 or more PM2.5 events during the hazard period, including 671 experiencing 1 or more wildfire-associated events. Adjusted odds of tuberculosis diagnosis increased by 5% (95% confidence interval, 3-6%) with each PM2.5 event experienced over the 6-month observation period. Each wildfire-associated PM2.5 event was associated with 23% (19-28%) higher odds of tuberculosis diagnosis in this time window, whereas no association was apparent for nonwildfire-associated events. Conclusions: Residential exposure to wildfire-associated ambient air pollution is associated with an increased risk of active tuberculosis diagnosis.

Expected vs Reported Chronic Hepatitis B Infection Cases in Persons with Active Tuberculosis - California, 2016-2020.

Epidemiologic data regarding persons with active tuberculosis (TB) and chronic hepatitis B virus (cHBV) infection are limited because of lack of routine surveillance of cHBV in persons with TB. Potential underdiagnosis of cHBV in California among those with TB is concerning. We matched TB and cHBV registries to identify cHBV infections among persons diagnosed with TB during 2016-2020 and described their demographic characteristics. We calculated expected cHBV cases among persons with TB for each demographic characteristic using published cHBV prevalence estimates for the locations of birth for persons with TB. Estimates were from general or emigrant adult and teen populations. Reported cHBV infection among persons with TB were 23% lower than expected, particularly among Asian persons, persons living in the two healthiest Healthy Places Index quartiles, and residents of less populated jurisdictions in California. Results show the possibility exists for underdiagnosis of cHBV in persons with TB in California.

Solid organ transplant recipients with tuberculosis disease in California, 2010 to 2020.

Using California Tuberculosis (TB) Registry data from 2010-2020, we compared the presentation and outcomes of patients with TB aged >15 years with and without solid organ transplantation (SOT). We matched to the United Network for Organ Sharing registry for 1987-2020 and the estimated time from transplantation to the diagnosis of TB, the incidence of posttransplant TB, and the probability of death and graft failure in SOT recipients with TB, compared to those without TB. From 2010-2020, there were 148 posttransplant TB cases. Patients with posttransplant TB were more likely to have extrapulmonary disease and more than twice as likely to die as TB patients without SOT (relative risk [RR], 2.2; 95% confidence interval [CI], 1.6-2.9). The median time from transplantation to TB diagnosis was 1.2 years, with the shortest time among lung transplant recipients. The incidence of TB disease among Californians with SOT was 56.0 per 100 000 person-years. The risk of death was higher among SOT recipients with posttransplant TB than those without (adjusted hazard ratio, 2.8; 95% CI, 2.0-4.1); the risk of graft failure was higher among kidney transplant recipients with posttransplant TB than those without (adjusted hazard ratio, 3.4; 95% CI, 1.7-6.9). An increased risk of death and graft failure in SOT recipients with posttransplant TB highlights the need for enhanced pretransplant TB prevention.

A Cross-sectional Study of Patients With Extrapulmonary Tuberculosis and Normal Chest Radiographs - What Characteristics Were Associated With Sputum Culture Positivity?

BACKGROUND: Recognizing pulmonary involvement in tuberculosis (TB) patients is necessary to prevent TB transmission. We describe frequency and characteristics of patients with extrapulmonary TB (EPTB), normal chest radiographs, and positive sputum culture. METHODS: We analyzed data of patients ≥15 years of age with EPTB reported to the California TB registry during 2011-2017 with cultured sputum and normal chest radiographs using generalized linear modeling to estimate prevalence ratios associated with positive sputum culture. Demographic, behavioral, clinical characteristics, and testing were compared for patients with positive and negative sputum culture. RESULTS: Of 1635 patients with EPTB and normal chest radiographs, 937 (57%) had sputum culture performed, and 127 (13%) patients had positive results for Mycobacterium tuberculosis complex. Patients with positive results were more likely to: be male, experience homelessness, use substances, have HIV, and have >1 disease site. Among 85 patients with HIV co-infection, 54% had positive culture results compared with 9.5% among 852 patients without HIV co-infection. Patients with EPTB in more than 1 site were also more likely to have a positive sputum culture. CONCLUSIONS: Culturing sputum from patients with EPTB identified pulmonary cases not detected by chest radiograph, particularly among patients with HIV or >1 disease site.

Comparative Modeling of Tuberculosis Epidemiology and Policy Outcomes in California.

Rationale: Mathematical modeling is used to understand disease dynamics, forecast trends, and inform public health prioritization. We conducted a comparative analysis of tuberculosis (TB) epidemiology and potential intervention effects in California, using three previously developed epidemiologic models of TB.Objectives: To compare the influence of various modeling methods and assumptions on epidemiologic projections of domestic latent TB infection (LTBI) control interventions in California.Methods: We compared model results between 2005 and 2050 under a base-case scenario representing current TB services and alternative scenarios including: 1) sustained interruption of Mycobacterium tuberculosis (Mtb) transmission, 2) sustained resolution of LTBI and TB prior to entry of new residents, and 3) one-time targeted testing and treatment of LTBI among 25% of non-U.S.-born individuals residing in California.Measurements and Main Results: Model estimates of TB cases and deaths in California were in close agreement over the historical period but diverged for LTBI prevalence and new Mtb infections-outcomes for which definitive data are unavailable. Between 2018 and 2050, models projected average annual declines of 0.58-1.42% in TB cases, without additional interventions. A one-time LTBI testing and treatment intervention among non-U.S.-born residents was projected to produce sustained reductions in TB incidence. Models found prevalent Mtb infection and migration to be more significant drivers of future TB incidence than local transmission.Conclusions: All models projected a stagnation in the decline of TB incidence, highlighting the need for additional interventions including greater access to LTBI diagnosis and treatment for non-U.S.-born individuals. Differences in model results reflect gaps in historical data and uncertainty in the trends of key parameters, demonstrating the need for high-quality, up-to-date data on TB determinants and outcomes.

Bedaquiline for the Treatment of Multidrug-resistant Tuberculosis in the United States.

BACKGROUND: In 2012, the Food and Drug Administration approved use of bedaquiline fumarate as part of combination therapy for multidrug-resistant tuberculosis (MDR TB). We describe treatment outcomes, safety, and tolerability of bedaquiline in our case series. METHODS: Data on patients started on bedaquiline for MDR TB between September 2012 and August 2016 were collected retrospectively through 4 TB programs using a standardized abstraction tool. Data were analyzed using univariate methods. Adverse events were graded using the Common Terminology Criteria for Adverse Events. RESULTS: Of 14 patients, 7 (50%) had MDR, 4 (29%) had pre-extensively drug-resistant (XDR), and 3 (21%) had XDR TB. All had pulmonary TB, 5 (36%) had pulmonary and extrapulmonary TB, and 9/13 (69%) were smear positive. One patient (7%) had HIV coinfection, 5 (36%) had diabetes mellitus, and 5/14 (36%) had previous treatment TB. All patients were non-US-born and 5/14 (36%) had private insurance. All patients achieved sputum culture conversion within a mean of 71 days (26-116); 5 after starting bedaquiline. Twelve (86%) completed treatment and 1 (7%) moved out of the country. One patient (7%) had QTc prolongation >500 milliseconds and died 20 months after discontinuing bedaquiline of a cause not attributable to the drug. Common adverse events were peripheral neuropathy 7/14 (50%), not customarily associated with bedaquiline use, and QTc prolongation 6/14 (43%). CONCLUSIONS: Of 14 patients, 1 (7%) had an adverse event necessitating bedaquiline discontinuation. Safety, culture conversion, and treatment completion in this series (7%) support use of bedaquiline for the treatment of MDR/XDR TB.

Evaluation of the Impact of a Sequencing Assay for Detection of Drug Resistance on the Clinical Management of Tuberculosis.

BACKGROUND: In 2012, the California Department of Public Health began using pyrosequencing (PSQ) to detect mutations associated with resistance to isoniazid, rifampin, quinolones and injectable drugs in Mycobacterium tuberculosis complex. We evaluated the impact of the PSQ assay on the clinical management of tuberculosis (TB) in California. METHODS: TB surveillance and laboratory data for specimens submitted 1 August 2012 through 31 December 2016 were analyzed to determine time to effective treatment initiation. A survey of clinicians was used to assess how PSQ results influenced clinical decision making. RESULTS: Of 1957 specimens tested with PSQ, 52% were sediments and 46% were culture isolates, submitted a median of 8 and 35 days, respectively, after collection. Among 36 patients with multidrug-resistant (MDR) TB who had a sediment specimen submitted for PSQ, median time from specimen collection to MDR-TB treatment initiation was 12 days vs 51 days when PSQ was not used. Completed surveys were returned for 303 patients, 177 of whom reported a treatment change; 75 (42%) of clinicians reported PSQ as a reason for change. Twenty-one patients either had an MDR-TB risk factor and a smear-positive sputum specimen, but had PSQ performed on a culture isolate (9/36 [25%]); or did not have PSQ used for MDR-TB diagnosis (12/38 [32%]) and thus had an opportunity for earlier MDR-TB diagnosis with PSQ on sediment. CONCLUSIONS: Patients with MDR-TB initiated effective treatment 5 weeks earlier when PSQ was used compared to those without PSQ. Survey data suggest clinicians use PSQ to devise effective TB drug regimens. To maximize the benefit of PSQ, earlier submission of specimens should be prioritized.

Treatment Outcomes in Global Systematic Review and Patient Meta-Analysis of Children with Extensively Drug-Resistant Tuberculosis.

Extensively drug-resistant tuberculosis (XDR TB) has extremely poor treatment outcomes in adults. Limited data are available for children. We report on clinical manifestations, treatment, and outcomes for 37 children (<15 years of age) with bacteriologically confirmed XDR TB in 11 countries. These patients were managed during 1999-2013. For the 37 children, median age was 11 years, 32 (87%) had pulmonary TB, and 29 had a recorded HIV status; 7 (24%) were infected with HIV. Median treatment duration was 7.0 months for the intensive phase and 12.2 months for the continuation phase. Thirty (81%) children had favorable treatment outcomes. Four (11%) died, 1 (3%) failed treatment, and 2 (5%) did not complete treatment. We found a high proportion of favorable treatment outcomes among children, with mortality rates markedly lower than for adults. Regimens and duration of treatment varied considerably. Evaluation of new regimens in children is required.

Impact and Effectiveness of State-Level Tuberculosis Interventions in California, Florida, New York, and Texas: A Model-Based Analysis.

The incidence of tuberculosis (TB) in the United States has stabilized, and additional interventions are needed to make progress toward TB elimination. However, the impact of such interventions depends on local demography and the heterogeneity of populations at risk. Using state-level individual-based TB transmission models calibrated to California, Florida, New York, and Texas, we modeled 2 TB interventions: 1) increased targeted testing and treatment (TTT) of high-risk populations, including people who are non-US-born, diabetic, human immunodeficiency virus (HIV)-positive, homeless, or incarcerated; and 2) enhanced contact investigation (ECI) for contacts of TB patients, including higher completion of preventive therapy. For each intervention, we projected reductions in active TB incidence over 10 years (2016-2026) and numbers needed to screen and treat in order to avert 1 case. We estimated that TTT delivered to half of the non-US-born adult population could lower TB incidence by 19.8%-26.7% over a 10-year period. TTT delivered to smaller populations with higher TB risk (e.g., HIV-positive persons, homeless persons) and ECI were generally more efficient but had less overall impact on incidence. TTT targeted to smaller, highest-risk populations and ECI can be highly efficient; however, major reductions in incidence will only be achieved by also targeting larger, moderate-risk populations. Ultimately, to eliminate TB in the United States, a combination of these approaches will be necessary.

Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis.

BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Treatment and outcomes in children with multidrug-resistant tuberculosis: A systematic review and individual patient data meta-analysis.

BACKGROUND: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. METHODS AND FINDINGS: To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome. In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%-19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%-48%, p = 0.006). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15-20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95% CI 1.0-8.3, p = 0.041 and aOR 5.9, 95% CI 1.7-20.5, p = 0.007, respectively). These findings for high-dose isoniazid may have been affected by site effect, as the majority of patients came from Cape Town. Limitations of this study include the difficulty of estimating the treatment effects of individual drugs within multidrug regimens, only observational cohort studies were available for inclusion, and treatment decisions were based on the clinician's perception of illness, with resulting potential for bias. CONCLUSIONS: This study suggests that children respond favorably to MDR-TB treatment. The low success rate in children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children. Our findings of individual drug effects on treatment outcome should be further evaluated.

Epidemiology of Pediatric Multidrug-Resistant Tuberculosis in the United States, 1993-2014.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is an important global public health threat, but accurate estimates of MDR-TB burden among children are lacking. METHODS: We analyzed demographic, clinical, and laboratory data for newly diagnosed pediatric (age <15 years) TB cases reported to the US National TB Surveillance System during 1993-2014. MDR-TB was defined as culture-confirmed TB disease with resistance to at least isoniazid and rifampicin. To ascertain potential underestimation of pediatric MDR-TB, we surveyed high-burden states for clinically diagnosed cases treated for MDR-TB. RESULTS: Of 20789 pediatric TB cases, 5162 (24.8%) had bacteriologically confirmed TB. Among 4826 (93.5%) with drug susceptibility testing, 82 (1.7%) had MDR-TB. Most pediatric MDR-TB cases were female (n = 51 [62%]), median age was 5 years (interquartile range, 1-12 years), one-third were Hispanic (n = 28 [34%]), and two-thirds (n = 55 [67%]) were born in the United States. Most cases had additional resistance to ≥1 other first-line drug (n = 66 [81%]) and one-third had resistance to ≥1 second-line drug (24/73 tested). Of 77 who started treatment prior to 2013, 66 (86%) completed treatment and 4 (5%) died. Among the 4 high-TB-burden states/jurisdictions surveyed, there was 42%-55% underestimation of pediatric MDR-TB cases when using only culture-confirmed case definitions. CONCLUSIONS: Only one-quarter of pediatric TB cases had culture-confirmed TB, likely resulting in underestimation of true pediatric MDR-TB burden in the United States using strictly bacteriologic criteria. Better estimates of pediatric MDR-TB burden in the United States are needed and should include clinical diagnoses based on epidemiologic criteria.

Solid Organ Transplant-Transmitted Tuberculosis Linked to a Community Outbreak - California, 2015.

In the spring of 2015, a local health department (LHD) in county A notified the California Department of Public Health (CDPH) about three adults with close ties to one another and a congregate community site who had received diagnoses of tuberculosis (TB) disease within a 3-month period. Subsequent review revealed matching TB genotypes indicating that the cases were likely part of a chain of TB transmission. Only three TB cases in California in the preceding 2 years shared this same genotype. One of those three previous cases occurred in a lung-transplant recipient who had no identified epidemiologic links to the outbreak. CDPH, multiple LHDs, and CDC conducted an investigation and determined that the lung-transplant donor (patient 1) was epidemiologically linked to the three outbreak cases and had a tuberculin skin test (TST) conversion detected in 2012 upon reentry at a local jail. Three other solid organ recipients from this donor were identified; none had developed TB disease. This investigation suggests that review of organ donors' medical records from high-risk environments, such as jails, might reveal additional information about TB risk. The evaluation of TB in organ recipients could include genotyping analysis (1) and coordination among local, state, and national partners to evaluate the potential for donor-derived TB.

Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

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 strains.

Increased risk of tuberculosis among foreign-born persons with diabetes in California, 2010-2012.

BACKGROUND: Diabetes increases the risk of tuberculosis. We sought to identify populations of persons with diabetes in California at further increased risk for tuberculosis to target tuberculosis infection screening and treatment efforts. METHODS: We performed a retrospective population-based analysis of adult (aged ≥18 years) tuberculosis cases reported in California during 2010-2012. Tuberculosis cases with and without diabetes were grouped into regions of birth and stratified by age category. Population estimates were calculated using 2011-2012 California Health Interview Survey data. We calculated tuberculosis disease rate and relative risk of tuberculosis among persons with diabetes stratified by birth location and age group; and the number needed to screen and, if positive, treat for tuberculosis infection to prevent one case of active tuberculosis over 5 years (NNS). RESULTS: During 2010-2012, among 6,050 adults with active tuberculosis in California, 82% were foreign-born and 24% had diabetes. The overall relative risk for tuberculosis among persons with diabetes was 3.5 (95% confidence interval, 3.3-3.7) with a rate of 21 per 100,000 persons with diabetes. The rate among foreign-born persons with diabetes (141.5/100,000) was almost 12 times greater than among nonforeign-born persons with diabetes (12.0/100,000). The NNS was 7,930 among all adults, 2,740 among adults with diabetes, 1,526 among all foreign-born adults, and 596 among foreign-born adults with diabetes. CONCLUSIONS: In California, foreign-born persons with diabetes had significantly elevated rates of active tuberculosis. Focusing tuberculosis infection screening and treatment efforts on foreign-born persons with diabetes may be a feasible and efficient way to make progress toward tuberculosis elimination in California.