Tuberculosis Mortality in the United States: Epidemiology and Prevention Opportunities.

Rationale: More information on risk factors for death from tuberculosis in the United States could help reduce the tuberculosis mortality rate, which has remained steady for more than a decade.Objective: To identify risk factors for tuberculosis-related death in adults.Methods: We performed a retrospective study of 1,304 adults with tuberculosis who died before treatment completion and 1,039 frequency-matched control subjects who completed tuberculosis treatment in 2005 to 2006 in 13 states reporting 65% of U.S. tuberculosis cases. We used in-depth record abstractions and a standard algorithm to classify deaths in persons with tuberculosis as tuberculosis-related or not. We then compared these classifications to causes of death as coded in death certificates. We used multivariable logistic regression to calculate adjusted odds ratios for predictors of tuberculosis-related death among adults compared with those who completed tuberculosis treatment.Results: Of 1,304 adult deaths, 942 (72%) were tuberculosis related, 272 (21%) were not, and 90 (7%) could not be classified. Of 847 tuberculosis-related deaths with death certificates available, 378 (45%) did not list tuberculosis as a cause of death. Adjusting for known risks, we identified new risks for tuberculosis-related death during treatment: absence of pyrazinamide in the initial regimen (adjusted odds ratio, 3.4; 95% confidence interval, 1.9-6.0); immunosuppressive medications (adjusted odds ratio, 2.5; 95% confidence interval, 1.1-5.6); incomplete tuberculosis diagnostic evaluation (adjusted odds ratio, 2.2; 95% confidence interval, 1.5-3.3), and an alternative nontuberculosis diagnosis before tuberculosis diagnosis (adjusted odds ratio, 1.6; 95% confidence interval, 1.2-2.2).Conclusions: Most persons who died with tuberculosis had a tuberculosis-related death. Intensive record review revealed tuberculosis as a cause of death more often than did death certificate diagnoses. New tools, such as a tuberculosis mortality risk score based on our study findings, may identify patients with tuberculosis for in-hospital interventions to prevent death.

A systematic synthesis of direct costs to treat and manage tuberculosis disease applied to California, 2015.

BACKGROUND: The cost of treating and managing cases of active tuberculosis (TB) disease-from diagnosis to treatment completion-is needed by agencies working on public health budgets, resource allocation and cost-effectiveness analysis. Although components of TB costs have been published in the United States (US), no recent study has assessed overall costs for TB care and potential gaps. To systematically review the US literature for costs of treating and managing cases of active TB disease, adjust these costs to current (2015) values, and assess gaps. We quantified total direct costs-from the perspective of the health care payer-of the treatment and case management of active TB disease. Estimates were based on published figures in the US, and operational data of the California Department of Public Health. RESULT: The average direct cost of treating and managing a TB case was $34,600 in 2015. The average cost of a multidrug-resistant TB case was $110,900. Health care spending for treating and case managing TB patients in California amounted to approximately $75.6 million for the 2133 new cases reported in 2015. Most published cost estimates were based on data from the 1990s. CONCLUSION: TB is resource-intensive to treat and manage. Our synthesis provides inputs for budgets and economic analyses. New studies to provide original cost data are needed to better reflect current clinical and public health practices.

Getting to Zero: Tuberculosis Elimination in California.

This review of tuberculosis epidemiology is intended to provide a historical perspective on the public health approach to tuberculosis (TB) control in California. This historical context offers a lens through which to view current epidemiologic trends and insight into how new therapeutic tools can be applied. Since 1993, the year detailed case reporting was instituted, California has had a decrease in recent TB transmission as evidenced by a reduction in pediatric cases and an increased percentage of cases attributable to progression of latent infection to TB disease in the foreign-born population. Overall, there has been a dramatic decline in the annual TB case count, but the speed of the decline has slowed over the last several years. At the current pace and case count of 2137 in 2015, California will not achieve TB elimination (<1 TB case per one million population) for at least 100 years. There are an estimated 2.1 million persons in California with latent TB infection. Modeling suggests that LTBI detection and treatment are important in reaching TB elimination. For this reason, a coalition of stakeholders in California is exploring novel approaches to accelerate the case decline in order to prevent unnecessary disease and death.

Review of nucleic acid amplification tests and clinical prediction rules for diagnosis of tuberculosis in acute care facilities.

Tuberculosis (TB) remains an important cause of hospitalization and mortality in the United States. Prevention of TB transmission in acute care facilities relies on prompt identification and implementation of airborne isolation, rapid diagnosis, and treatment of presumptive pulmonary TB patients. In areas with low TB burden, this strategy may result in inefficient utilization of airborne infection isolation rooms (AIIRs). We reviewed TB epidemiology and diagnostic approaches to inform optimal TB detection in low-burden settings. Published clinical prediction rules for individual studies have a sensitivity ranging from 81% to 100% and specificity ranging from 14% to 63% for detection of culture-positive pulmonary TB patients admitted to acute care facilities. Nucleic acid amplification tests (NAATs) have a specificity of >98%, and the sensitivity of NAATs varies by acid-fast bacilli sputum smear status (positive smear, ≥95%; negative smear, 50%-70%). We propose an infection prevention strategy using a clinical prediction rule to identify patients who warrant diagnostic evaluation for TB in an AIIR with an NAAT. Future studies are needed to evaluate whether use of clinical prediction rules and NAATs results in optimized utilization of AIIRs and improved detection and treatment of presumptive pulmonary TB patients.

Epidemiology of tuberculosis cases with end-stage renal disease, California, 2010.

BACKGROUND/AIMS: Few studies have compared population-based tuberculosis (TB) incidence rates by end-stage renal disease (ESRD) status. No studies have compared TB genotypes by ESRD status to determine whether TB disease resulted from recent transmission or reactivation of latent TB infection (LTBI). We calculated TB incidence rates and compared demographic and clinical characteristics and genotypes among TB cases by ESRD status. METHODS: This analysis was based on prospective surveillance for TB cases during 2010 in California. Clustered genotype was defined as ≥2 culture-positive TB cases with matching genotypes in the same county. The χ(2) or Wilcoxon rank-sum test was used to compare variables. RESULTS: During 2010, 83 TB cases with ESRD and 2,244 cases without ESRD were reported in California; TB incidence rates were 110.3/100,000 and 6.0/100,000, respectively. ESRD case patients versus patients without ESRD were more likely to be older (median age 66 vs. 49 years; p < 0.001), foreign-born persons who had arrived in the USA >5 years before TB diagnosis (97 vs. 75%; p < 0.001) and dead at TB diagnosis (7 vs. 2%; p = 0.01). ESRD patients were less likely to have a positive tuberculin skin test (50 vs. 80%; p < 0.001), positive acid-fast bacilli sputum smears (33 vs. 53%; p = 0.01) and cavities on chest radiography (6 vs. 21%; p = 0.01). No differences in proportions of clustered TB genotypes were detected (20 vs. 23%; p = 0.54). CONCLUSIONS: Rates of TB are 18 times higher in California's ESRD population, and TB disease likely occurred due to LTBI reactivation because few patients had clustered genotypes. Efforts to prevent TB among ESRD patients may require the use of newer diagnostic tests and promotion of LTBI treatment.

Timely HIV diagnosis and HIV/TB comanagement among California patients in 2008.

OBJECTIVE: National guidelines highlight the roles of early HIV diagnosis and effective comanagement for HIV and tuberculosis (TB) to prevent mortality and morbidity from HIV-related TB. We assessed HIV diagnosis timing and HIV/TB comanagement for California HIV/TB patients. METHODS: We reviewed and analyzed public health charts for California HIV/TB patients reported during 2008. HIV diagnoses fewer than three months before TB diagnosis were considered new HIV diagnoses. We determined the proportion of patients with new HIV diagnoses, risk factors for new HIV diagnoses, and proportion of patients receiving recommended CD4 cell count measurements, supervised TB therapy, and antiretroviral therapy (ART). RESULTS: Of 130 HIV/TB patients, 51% had new HIV diagnoses. Foreign-born patients were more likely than U.S.-born patients to have new HIV diagnoses. Supervised TB therapy and CD4 cell count measurements followed national recommendations for 91% and 74% of patients, respectively. At least 73% of patients started ART before completing TB therapy. Compared with patients who had previous HIV diagnoses, patients with new HIV diagnoses started ART later and had lower CD4 cell counts and higher viral loads at TB diagnosis. CONCLUSIONS: Although most HIV/TB patients received the recommended treatment, half had new HIV diagnoses. Compared with patients who had previous HIV diagnoses, patients with new HIV diagnoses had greater immunosuppression at TB diagnosis. A new diagnosis indicates that HIV could have been diagnosed earlier and ART or treatment for latent TB infection could have been initiated to prevent TB development.

Antituberculosis drug resistance acquired during treatment: an analysis of cases reported in California, 1994-2006.

BACKGROUND: To inform efforts to prevent antituberculosis drug resistance acquired during treatment, particularly multidrug-resistant (MDR) tuberculosis, we analyzed surveillance records from the US state with the highest morbidity. METHODS: Surveillance data from the California tuberculosis registry of cases reported between 1994 and 2006 were examined retrospectively. Crude risks of acquired resistance were estimated. Multivariate logistic regression was used to estimate odds ratios of demographic, clinical, and case management characteristics associated with acquired drug resistance (ADR), and secular trends in the incidence of ADR were assessed. RESULTS: One in 688 patients acquired MDR tuberculosis, with crude risks varying greatly by initial drug susceptibility test results: 1 in 1909 if initially susceptible to isoniazid and rifampin, 1 in 113 if initially isoniazid resistant, and 1 in 23 if initially rifampicin resistant. Acquired isoniazid and rifampicin monoresistance occurred in 1 in 1018 and 1 in 1455 patients, respectively. Independent predictors of acquired MDR tuberculosis were initial isoniazid resistance (odds ratio [OR], 19.2; 95% confidence interval [CI], 8.25-44.7; P < .001), initial rifampicin resistance (OR, 35.9; 95% CI, 8.61-150; P < .001), human immunodeficiency virus (HIV) infection (OR, 5.07; 95% CI, 1.73-14.9; P = .003), and cavitary disease in the absence of directly observed therapy throughout therapy (OR, 2.65; 95% CI, 1.05-6.69; P = .04). The annual incidence of ADR declined over the study period. CONCLUSIONS: Although ADR is rare and declining in California, its costly consequences warrant improvements in treatment practices. Our findings suggest that we ensure DOT throughout the course of therapy for patients with baseline drug resistance, cavitary disease, or HIV infection.

When tuberculosis comes back: who develops recurrent tuberculosis in california?

BACKGROUND: Recurrent tuberculosis suggests potentially modifiable gaps in tuberculosis treatment and control activities. The frequency of late recurrences following treatment completion has not been well-studied. We determined the frequency of, and risk factors associated with, tuberculosis that recurs at least one year after completion of anti-tuberculosis therapy in California. METHODS: The study population included culture-positive, pulmonary tuberculosis patients reported to the California tuberculosis case registry from 1993 to 2007 who completed anti-tuberculosis therapy. A person with late recurrent tuberculosis was defined as an individual that appeared in the registry more than once, determined by match on name and date-of-birth, with at least one year between treatment completion of the first episode and treatment initiation of the second episode. RESULTS: Among 23,517 tuberculosis patients, 148 (0.63%) had a late recurrence. Independent risk factors for recurrence included: infection with a pyrazinamide mono-resistant isolate (adjusted hazard ratio, 2.93; p = 0.019); initiation of an isoniazid- and rifampin-only treatment regimen (adjusted hazard ratio, 2.55; p = 0.0412); sputum smear-positive disease (adjusted hazard ratio, 1.96; p = 0.0003); human immunodeficiency virus infection (adjusted hazard ratio, 1.81; p = 0.0149); and birth in the United States (adjusted hazard ratio, 1.88; p = 0.0002). Infection with an isoniazid mono-resistant isolate was protective (adjusted hazard ratio, 0.25; p = 0.0171). CONCLUSIONS: The low frequency of late recurrent tuberculosis in California suggests that local TB control programs are largely successful at preventing this adverse outcome. Nonetheless, we identified subpopulations at increased risk of late tuberculosis recurrence that may benefit from additional medical or public health interventions.

Matching AIDS and tuberculosis registry data to identify AIDS/tuberculosis comorbidity cases in California.

The purpose of this study was to evaluate the sensitivity and positive predictive value (PPV) of a registry data linkage procedure used in the California AIDS and Tuberculosis (TB) Registry Data Linkage Study to identify AIDS/TB comorbidity cases in California. The California AIDS registry data from 1981 to 2006 were linked to the California TB registry data from 1996 to 2006 using LinkPlus, a probabilistic record linkage program developed by the Centers for Disease Control and Prevention, and matched results were manually reviewed to determine true or false matches. We estimated the sensitivity of this procedure to range from 98.0 per cent (95% confidence interval, CI: 97.3%, 98.7%) to 98.8 per cent (95% CI: 98.1%, 99.2%), and the PPV to be 100 per cent (95% CI: 96.8%, 100.0%). Our study demonstrated the feasibility of using this linkage procedure to match AIDS and TB registry data with a very high degree of accuracy.

Diagnostic challenges of central nervous system tuberculosis.

Central nervous system tuberculosis (TB) was identified in 20 cases of unexplained encephalitis referred to the California Encephalitis Project. Atypical features (encephalitic symptoms, rapid onset, age) and diagnostic challenges (insensitive cerebrospinal fluid [CSF] TB PCR result, elevated CSF glucose levels in patients with diabetes, negative result for tuberculin skin test) complicated diagnosis.

Assessing the validity of tuberculosis surveillance data in California.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) convened a workgroup to revise the tuberculosis (TB) case report in the United States of America (U.S.). The group proposed substantial revisions. Study objectives were to systematically assess the validity and completeness of reported TB case surveillance data in California and to inform TB case report revision process. METHODS: A sample of 594 cases was retrospectively selected from the cohort of all TB cases reported during 6/1/96-5/31/97 to the State TB Registry. Cases, stratified by treatment outcome, were randomly sampled within each outcome category. Data for 53 variables were abstracted from each case's public health medical record and compared to data recorded on the TB case report. Using the medical record as the "gold standard," estimates were developed for 1) concordance, sensitivity, and positive predictive value of reported data for categorical variables; 2) the absolute mean difference between the two information source for date variables; and 3) the completeness of data on the case report and in medical record. RESULTS: At least 90% of the values for 35 (79.5%) categorical variables submitted on the TB case report form were identical to values in the medical record. Concordance between data on the case report and medical record was lower for the remaining nine (20.5%) categorical variables: status of abnormal chest x-ray (46.8%); directly observed therapy (48.6%); smear result for tissue or body fluid other than sputum (49.2%); type(s) of tissue or body fluid for smears and cultures other than sputum (76.4% and 73.9% respectively); provider type (73.4%); occupation (84.4%); sputum culture conversion (85.4%); and sputum smear result (89.6%). Case report data were more complete than data in the medical record; 2.9% versus 9.8% of data were missing/unknown, respectively. CONCLUSION: For most variables examined on the TB case report, data validity was excellent, indicating a robust surveillance system. However, lower data quality was noted for a small number of variables primarily impacting treatment adherence, including assessment and planning; advocacy; allocation and garnering of resources; and research. The study provides compelling evidence supporting the CDC workgroup's proposed revisions to the TB case report.

Cost-effectiveness of tuberculosis evaluation and treatment of newly-arrived immigrants.

BACKGROUND: Immigrants to the U.S. are required to undergo overseas screening for tuberculosis (TB), but the value of evaluation and treatment following entry to the U.S. is not well understood. We determined the cost-effectiveness of domestic follow-up of immigrants identified as tuberculosis suspects through overseas screening. METHODS: Using a stochastic simulation for tuberculosis reactivation, transmission, and follow-up for a hypothetical cohort of 1000 individuals, we calculated the incremental cost-effectiveness of follow-up and evaluation interventions. We utilized published literature, California Reports of Verified Cases of Tuberculosis (RVCTs), demographic estimates from the California Department of Finance, Medicare reimbursement, and Medi-Cal reimbursement rates. Our target population was legal immigrants to the United States, our time horizon is twenty years, and our perspective was that of all domestic health-care payers. We examined the intervention to offer latent tuberculosis therapy to infected individuals, to increase the yield of domestic evaluation, and to increase the starting and completion rates of LTBI therapy with INH (isoniazid). Our outcome measures were the number of cases averted, the number of deaths averted, the incremental dollar cost (year 2004), and the number of quality-adjusted life-years saved. RESULTS: Domestic follow-up of B-notification patients, including LTBI treatment for latently infected individuals, is highly cost-effective, and at times, cost-saving. B-notification follow-up in California would reduce the number of new tuberculosis cases by about 6-26 per year (out of a total of approximately 3000). Sensitivity analysis revealed that domestic follow-up remains cost-effective when the hepatitis rates due to INH therapy are over fifteen times our best estimates, when at least 0.4 percent of patients have active disease and when hospitalization of cases detected through domestic follow-up is no less likely than hospitalization of passively detected cases. CONCLUSION: While the current immigration screening program is unlikely to result in a large change in case rates, domestic follow-up of B-notification patients, including LTBI treatment, is highly cost-effective. If as many as three percent of screened individuals have active TB, and early detection reduces the rate of hospitalization, net savings may be expected.