Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method.

Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and estimated the effect of monitoring strategies on timing of failure detection.We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors. Frailty survival models were used to estimate pooled relative risk of failure detection in the last 12 months of treatment; hazard of failure using monthly culture was the reference.Data were obtained for 5410 patients across 12 observational studies. During the last 12 months of treatment, failure detection occurred in a median of 3 months by monthly culture; failure detection was delayed by 2, 7, and 9 months relying on bimonthly culture, monthly smear and bimonthly smear, respectively. Risk (95% CI) of failure detection delay resulting from monthly smear relative to culture is 0.38 (0.34-0.42) for all patients and 0.33 (0.25-0.42) for HIV-co-infected patients.Failure detection is delayed by reducing the sensitivity and frequency of the monitoring method. Monthly monitoring of sputum cultures from patients receiving MDR-TB treatment is recommended. Expanded laboratory capacity is needed for high-quality culture, and for smear microscopy and rapid molecular tests.

Tuberculosis progression rates in U.S. Immigrants following screening with interferon-gamma release assays.

BACKGROUND: Interferon-gamma release assays may be used as an alternative to the tuberculin skin test for detection of M. tuberculosis infection. However, the risk of active tuberculosis disease following screening using interferon-gamma release assays in immigrants is not well defined. To address these uncertainties, we determined the incidence rates of active tuberculosis disease in a cohort of high-risk immigrants with Class B TB screened with interferon-gamma release assays (IGRAs) upon arrival in the United States. METHODS: Using a retrospective cohort design, we enrolled recent U.S. immigrants with Class B TB who were screened with an IGRA (QuantiFERON ® Gold or Gold In-Tube Assay) at the San Francisco Department of Public Health Tuberculosis Control Clinic from January 2005 through December 2010. We reviewed records from the Tuberculosis Control Patient Management Database and from the California Department of Public Health Tuberculosis Case Registry to determine incident cases of active tuberculosis disease through February 2015. RESULTS: Of 1233 eligible immigrants with IGRA screening at baseline, 81 (6.6 %) were diagnosed with active tuberculosis disease as a result of their initial evaluation. Of the remaining 1152 participants without active tuberculosis disease at baseline, 513 tested IGRA-positive and 639 tested IGRA-negative. Seven participants developed incident active tuberculosis disease over 7730 person-years of follow-up, for an incidence rate of 91 per 100,000 person-years (95 % CI 43-190). Five IGRA-positive and two IGRA-negative participants developed active tuberculosis disease (incidence rates 139 per 100,000 person-years (95 % CI 58-335) and 48 per 100,000 person-years (95 % CI 12-193), respectively) for an unadjusted incidence rate ratio of 2.9 (95 % CI 0.5-30, p = 0.21). IGRA test results had a negative predictive value of 99.7 % but a positive predictive value of only 0.97 %. CONCLUSIONS: Among high-risk immigrants without active tuberculosis disease at the time of entry into the United States, risk of progression to active tuberculosis disease was higher in IGRA-positive participants compared with IGRA-negative participants. However, these findings did not reach statistical significance, and a positive IGRA at enrollment had a poor predictive value for progressing to active tuberculosis disease. Additional research is needed to identify biomarkers and develop clinical algorithms that can better predict progression to active tuberculosis disease among U.S. immigrants.

Interferon-Gamma Release Assays and Pediatric Public Health Tuberculosis Screening: The San Francisco Program Experience 2005 to 2008.

BACKGROUND: Interferon-gamma release assay utilization in pediatric tuberculosis (TB) screening is limited by a paucity of longitudinal experience, particularly in low-TB burden populations. METHODS: We conducted a retrospective review of QuantiFERON (QFT)-TB Gold results in San Francisco children from 2005 to 2008. Concordance with the tuberculin skin test (TST) was analyzed for a subset of children. Progression to active disease was determined through San Francisco and California TB registry matches. RESULTS: Of 1092 children <15 years of age, 853 (78%) were foreign-born, and 136 (12%) were exposed to active TB cases (contacts). QuantiFERON tests were positive in 72 of 1092 (7%) children; 15 of 136 (11%) recent contacts; 53 of 807 (7%) foreign-born noncontacts; and 4 of 149 (3%) US-born noncontacts. QuantiFERON-negative/TST-positive discordance was seen more often in foreign-born/bacille Calmette-Guerin (BCG)-vaccinated children <5 years of age (52 of 56, 93%) compared to those ≥ 5 years of age (90 of 123, 73%; P = .003). Foreign-born, BCG-vaccinated children were more than twice as likely to have a discordant (79%) result as US-born, non-BCG-vaccinated children (37%; P < .0001). During 5587 person-years of follow-up of untreated children, including 146 TST-positive/QFT-negative children, no cases of active TB were identified, consistent with a negative predictive value of 100%. CONCLUSIONS: Our experience supports the use of QFT to evaluate latent TB infection in children, particularly young BCG-vaccinated children. The proportion of QFT-positive results correlated with risk of exposure, and none of the untreated QFT-negative children developed TB. The low QFT-positive rate highlights the need for more selective testing based on current epidemiology and TB exposure risk.

Association between diabetes mellitus and tuberculosis in United States-born and foreign-born populations in San Francisco.

SETTING: The impact of diabetes on tuberculosis in United States and foreign-born populations in San Francisco has not been studied. OBJECTIVE: To determine the characteristics, prevalence and temporal trends of diabetes in US and foreign-born persons attending the San Francisco Tuberculosis Clinic. DESIGN: We analyzed data from individuals seeking medical attention at the San Francisco Tuberculosis Clinic. We included patients with diagnosis of tuberculosis, latent infection, or not infected with Mycobacterium tuberculosis. We assessed the temporal trend and the characteristics of individuals with and without diabetes. RESULT: Between 2005 and 2012, there were 4371 (19.0%) individuals without evidence of tuberculosis infection, 17,856 (77.6%) with latent tuberculosis, and 791 (3.4%) with tuberculosis. 66% were born in the United States, China, Mexico, and the Philippines. The prevalence of diabetes was the highest among individuals with tuberculosis and increased during the study period. Patients with tuberculosis and diabetes were more likely to be male, older than 45 years and born in the Philippines. There was a disproportionate association of TB and DM relative to LTBI and DM among Filipinos in individuals older than 45 years old. CONCLUSIONS: Our data suggest that Filipinos older than 45 years old are more likely to have tuberculosis probably due to a higher prevalence of diabetes. In San Francisco, tuberculosis-screening programs in individuals with diabetes and latent tuberculosis may be beneficial in patients older than 45 years old especially from the Philippines.

Impact of GeneXpert MTB/RIF on patients and tuberculosis programs in a low-burden setting. a hypothetical trial.

RATIONALE: Guidelines recommend routine nucleic-acid amplification testing in patients with presumed tuberculosis (TB), but these tests have not been widely adopted. GeneXpert MTB/RIF (Xpert), a novel, semiautomated TB nucleic-acid amplification test, has renewed interest in this technology, but data from low-burden countries are limited. OBJECTIVES: We sought to estimate Xpert's potential clinical and public health impact on empiric treatment, contact investigation, and housing in patients undergoing TB evaluation. METHODS: We performed a prospective, cross-sectional study with 2-month follow-up comparing Xpert with standard strategies for evaluating outpatients for active pulmonary TB at the San Francisco Department of Public Health TB Clinic between May 2010 and June 2011. We calculated the diagnostic accuracy of standard algorithms for initial empiric TB treatment, contact investigation, and housing in reference to three Mycobacterium tuberculosis sputum cultures, as compared with that of a single sputum Xpert test. We estimated the incremental diagnostic value of Xpert, and the hypothetical reductions in unnecessary treatment, contact investigation, and housing if Xpert were adopted to guide management decisions. MEASUREMENTS AND MAIN RESULTS: A total of 156 patients underwent Xpert testing. Fifty-nine (38%) received empiric TB treatment. Thirteen (8%) had culture-positive TB. Xpert-guided management would have hypothetically decreased overtreatment by 94%, eliminating a median of 44 overtreatment days (interquartile range, 43-47) per patient and 2,169 total overtreatment days (95% confidence interval, 1,938-2,400) annually, without reducing early detection of TB patients. We projected similar benefits for contact investigation and housing. CONCLUSIONS: Xpert could greatly reduce the frequency and impact of unnecessary empiric treatment, contact investigation, and housing, providing substantial patient and programmatic benefits if used in management decisions.

Pyrazinamide resistance, Mycobacterium tuberculosis lineage and treatment outcomes in San Francisco, California.

BACKGROUND: Pyrazinamide (PZA) is a first line agent for the treatment of active tuberculosis. PZA is also considered a potent companion drug for newer regimens under development. There are limited data on the demographic, clinical, and pathogen characteristics of PZA resistant tuberculosis. METHODS: Using a retrospective cohort study design, we evaluated all PZA resistant M. tuberculosis (M.tb) and M. bovis cases reported in San Francisco from 1991 to 2011. Demographic, clinical, and molecular data were analyzed. M.tb lineage was determined for all PZA resistant strains and compared to PZA susceptible strains. RESULTS: PZA resistance was identified in 1.8% (50 of 2,842) of mycobacterial isolates tested, corresponding to a case rate of 0.3 per 100,000 in the population. Monoresistant PZA infection was associated with the Hispanic population ([OR], 6.3; 95% [CI], 1.97-20.16) and 48% of cases were due to M. bovis. Infection with monoresistant PZA was also associated with extrapulmonary disease ([OR], 6.0; 95% [CI], 2.70-13.26). There was no statistically significant difference between treatment failure and mortality rates in patients infected with PZA monoresistance compared to pansusceptible controls (4% vs. 8%, p = 0.51), or those with PZA and MDR resistance (PZA-MDR) compared to MDR controls (18% vs. 29%, p = 0.40). PZA resistance was not associated with M.tb lineage. CONCLUSIONS: Across two decades of comprehensive epidemiologic data on tuberculosis in San Francisco County, PZA resistance was uncommon. PZA resistance caused predominantly extrapulmonary disease and was more common in Hispanics compared to other ethnicities, with nearly half the cases attributed to M. bovis. No association was found between PZA monoresistance and M.tb lineage. Treatment outcomes were not adversely influenced by the presence of PZA resistance.

A public health framework for developing local preventive services guidelines.

In this article, we describe the San Francisco Department of Public Health's (SFDPH's) framework for developing evidence-based screening and vaccination recommendations. We first reviewed our local data using surveillance and syndemic data. We then compiled and compared existing federal, state, and local recommendations. Then we identified differences as compared with our local evidence; where more evidence was required to make a recommendation, we culled from additional data sources and conducted additional analyses. Lastly, we developed our guidelines by confirming existing recommendations or making new recommendations based on this process. In the end, we successfully developed evidence-based clinical screening and prevention guidelines that have been adopted by the SFDPH Health Commission. We encourage the use of this framework in other public health settings at the local level.

Use of whole genome sequencing to determine the microevolution of Mycobacterium tuberculosis during an outbreak.

RATIONALE: Current tools available to study the molecular epidemiology of tuberculosis do not provide information about the directionality and sequence of transmission for tuberculosis cases occurring over a short period of time, such as during an outbreak. Recently, whole genome sequencing has been used to study molecular epidemiology of Mycobacterium tuberculosis over short time periods. OBJECTIVE: To describe the microevolution of M. tuberculosis during an outbreak caused by one drug-susceptible strain. METHOD AND MEASUREMENTS: We included 9 patients with tuberculosis diagnosed during a period of 22 months, from a population-based study of the molecular epidemiology in San Francisco. Whole genome sequencing was performed using Illumina's sequencing by synthesis technology. A custom program written in Python was used to determine single nucleotide polymorphisms which were confirmed by PCR product Sanger sequencing. MAIN RESULTS: We obtained an average of 95.7% (94.1-96.9%) coverage for each isolate and an average fold read depth of 73 (1 to 250). We found 7 single nucleotide polymorphisms among the 9 isolates. The single nucleotide polymorphisms data confirmed all except one known epidemiological link. The outbreak strain resulted in 5 bacterial variants originating from the index case A1 with 0-2 mutations per transmission event that resulted in a secondary case. CONCLUSIONS: Whole genome sequencing analysis from a recent outbreak of tuberculosis enabled us to identify microevolutionary events observable during transmission, to determine 0-2 single nucleotide polymorphisms per transmission event that resulted in a secondary case, and to identify new epidemiologic links in the chain of transmission.

Molecular epidemiology of tuberculosis in foreign-born persons living in San Francisco.

RATIONALE: In San Francisco, 70% of the tuberculosis cases occur among foreign-born persons, mainly from China, the Philippines, and Mexico. We postulate that there are differences in the characteristics and risk factors for tuberculosis among these populations. OBJECTIVES: To determine the clinical, epidemiological and microbiological characteristics of tuberculosis caused by recent infection and rapid evolution in the major groups of foreign-born and the U.S.-born populations. METHODS: We analyzed data from a 20-year prospective community-based study of the molecular epidemiology of tuberculosis in San Francisco. We included all culture-positive tuberculosis cases in the City during the study period. MEASUREMENTS AND MAIN RESULTS: We calculated and compared incidence rates, clinical and microbiological characteristics, and risk factors for being a secondary case between the various foreign-born and U.S.-born tuberculosis populations. Between 1991 and 2010, there were 4,058 new cases of tuberculosis, of which 1,226 (30%) were U.S.-born and 2,832 (70%) were foreign-born. A total of 3,278 (81%) were culture positive, of which 2,419 (74%) had complete data for analysis. The incidence rate, including the incidence rate of tuberculosis due to recent infection and rapid evolution, decreased significantly in the U.S.-born and the major foreign-born populations. The clinical and microbiological characteristics and the risk factors for tuberculosis due to recent infection differed among the groups. CONCLUSIONS: There are differences in the characteristics and the risk factors for tuberculosis due to recent transmission among the major foreign-born and U.S.-born populations in San Francisco. These differences should be considered for the design of targeted tuberculosis control interventions.

Evaluation of quantitative IFN-gamma response for risk stratification of active tuberculosis suspects.

RATIONALE: The contribution of interferon-gamma release assays (IGRAs) to appropriate risk stratification of active tuberculosis suspects has not been studied. OBJECTIVES: To determine whether the addition of quantitative IGRA results to a prediction model incorporating clinical criteria improves risk stratification of smear-negative-tuberculosis suspects. METHODS: Clinical data from tuberculosis suspects evaluated by the San Francisco Department of Public Health Tuberculosis Control Clinic from March 2005 to February 2008 were reviewed. We excluded tuberculosis suspects who were acid fast-bacilli smear-positive, HIV-infected, or under 10 years of age. We developed a clinical prediction model for culture-positive disease and examined the benefit of adding quantitative interferon (IFN)-gamma results measured by QuantiFERON-TB Gold (Cellestis, Carnegie, Australia). MEASUREMENTS AND MAIN RESULTS: Of 660 patients meeting eligibility criteria, 65 (10%) had culture-proven tuberculosis. The odds of active tuberculosis increased by 7% (95% confidence interval [CI], 3-11%) for each doubling of IFN-gamma level. The addition of quantitative IFN-gamma results to objective clinical data significantly improved model performance (c-statistic 0.71 vs. 0.78; P < 0.001) and correctly reclassified 32% of tuberculosis suspects (95% CI,11-52%; P < 0.001) into higher-risk or lower-risk categories. However, quantitative IFN-gamma results did not significantly improve appropriate risk reclassification beyond that provided by clinician assessment of risk (4%; 95% CI, -7 to +22%; P = 0.14). CONCLUSIONS: Higher quantitative IFN-gamma results were associated with active tuberculosis, and added clinical value to a prediction model incorporating conventional risk factors. Although this benefit may be attenuated within highly experienced centers, the predictive accuracy of quantitative IFN-gamma levels should be evaluated in other settings.

Comparison of restriction fragment length polymorphism with the polymorphic guanine-cytosine-rich sequence and spoligotyping for differentiation of Mycobacterium tuberculosis isolates with five or fewer copies of IS6110.

The use of IS6110 as a marker for molecular epidemiological studies is limited when a Mycobacterium tuberculosis isolate has five or fewer copies of IS6110. Restriction fragment length polymorphism analysis with a highly polymorphic GC-rich repetitive sequence located in the plasmid pTBN12 (PGRS RFLP) and spoligotyping (based on the polymorphism of the DR region) are two frequently used secondary typing methods. The aim of this study was to compare the performance of these two methods in a population-based study in San Francisco. We included all patients with culture-positive tuberculosis from 1999 to 2007 with IS6110 RFLP results presenting five or fewer bands. PGRS RFLP and spoligotyping were performed using standardized methods. We determined the concordance between the two methods regarding cluster status and the risk factors for an isolate to be in a cluster with each of the methods. Our data indicate that both methods had similar discriminatory power and that the risk factors associated with clustering by either method were the same. Although the cluster/unique status was concordant in 84% of the isolates, patients were clustered differently depending on the method. Therefore, the methods are not interchangeable, and the same method should be used for longitudinal studies.

Clinical characteristics and treatment outcomes of patients with isoniazid-monoresistant tuberculosis.

BACKGROUND: Risk factors and treatment outcomes under program conditions for isoniazid (INH)-monoresistant tuberculosis have not been well described. METHODS: Medical charts were retrospectively reviewed for all cases of culture-confirmed, INH-monoresistant tuberculosis ( n = 137) reported to the San Francisco Department of Public Health Tuberculosis Control Section from October 1992 through October 2005, and those cases were compared with a time-matched sample of drug-susceptible tuberculosis cases (n = 274) RESULTS: In multivariate analysis, only a history of treatment for latent tuberculosis (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.5-6.4; P = .003) or for active tuberculosis (OR, 2.7; 95% CI, 1.4-5.0; P = .002) were significantly associated with INH-monoresistant tuberculosis. Of the 119 patients who completed treatment, 49 (41%) completed a 6-month treatment regimen. Treatment was extended to 7-12 months for 53 (45%) of the patients and to >12 months for 17 (14%). Treatment was most commonly extended because pyrazinamide was not given for the recommended 6-month duration (35 patients [29%]). Despite variation in treatment regimens, the combined end point of treatment failure or relapse was uncommon among patients with INH-monoresistant tuberculosis and was not significantly different for patients with drug-susceptible tuberculosis (1.7% vs. 2.2%; P = .73). CONCLUSIONS: A history of treatment for latent or active tuberculosis was associated with subsequent INH monoresistance. Treatment outcomes for patients with INH-monoresistant tuberculosis were excellent and were no different from those for patients with drug-susceptible tuberculosis. However, new, short-course regimens are needed because a small proportion of patients completed the 6-month treatment regimen recommended by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America, primarily because of pyrazinamide intolerance.

Reaching the limits of tuberculosis prevention among foreign-born individuals: a tuberculosis-control program perspective.

Analysis of whether assiduous implementation of American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America guidelines for targeted testing and treatment of latent tuberculosis infection could have prevented any of 223 cases of active tuberculosis in foreign-born persons in San Francisco during the period 2002-2003. We report that 62% of these cases were not preventable and conclude that a further reduction in the incidence of tuberculosis among foreign-born persons will be modest without modification of current guidelines.

Early detection of tuberculosis outbreaks among the San Francisco homeless: trade-offs between spatial resolution and temporal scale.

BACKGROUND: San Francisco has the highest rate of tuberculosis (TB) in the U.S. with recurrent outbreaks among the homeless and marginally housed. It has been shown for syndromic data that when exact geographic coordinates of individual patients are used as the spatial base for outbreak detection, higher detection rates and accuracy are achieved compared to when data are aggregated into administrative regions such as zip codes and census tracts. We examine the effect of varying the spatial resolution in the TB data within the San Francisco homeless population on detection sensitivity, timeliness, and the amount of historical data needed to achieve better performance measures. METHODS AND FINDINGS: We apply a variation of space-time permutation scan statistic to the TB data in which a patient's location is either represented by its exact coordinates or by the centroid of its census tract. We show that the detection sensitivity and timeliness of the method generally improve when exact locations are used to identify real TB outbreaks. When outbreaks are simulated, while the detection timeliness is consistently improved when exact coordinates are used, the detection sensitivity varies depending on the size of the spatial scanning window and the number of tracts in which cases are simulated. Finally, we show that when exact locations are used, smaller amount of historical data is required for training the model. CONCLUSION: Systematic characterization of the spatio-temporal distribution of TB cases can widely benefit real time surveillance and guide public health investigations of TB outbreaks as to what level of spatial resolution results in improved detection sensitivity and timeliness. Trading higher spatial resolution for better performance is ultimately a tradeoff between maintaining patient confidentiality and improving public health when sharing data. Understanding such tradeoffs is critical to managing the complex interplay between public policy and public health. This study is a step forward in this direction.

Low sensitivity of a whole-blood interferon-gamma release assay for detection of active tuberculosis.

The sensitivity of an interferon-gamma assay (Quantiferon-TB Gold; Cellestis) was evaluated for the detection of tuberculosis among 242 persons with suspected tuberculosis in San Francisco, California. Thirty-seven subjects had culture-confirmed tuberculosis. Excluding 1 indeterminate result, 23 (64%; 95% confidence interval, 48%-78%) of 36 subjects had positive results using the QuantiFERON-TB Gold assay. The 64% sensitivity suggests that the QuantiFERON-TB Gold assay should not be used alone to exclude active tuberculosis.

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.

A tuberculosis outbreak in a private-home family child care center in San Francisco, 2002 to 2004.

BACKGROUND: Child care facilities are well known as sites of infectious disease transmission, and California child care facility licensure requirements include annual tuberculosis (TB) screening for on-site adults. In April 2004, we detected an adult with TB living in a private-home family child care center (child care center A). METHODS: We reviewed patient medical records and conducted a contact investigation. The investigation included all persons at the child care center, the workplace and leisure contacts of the adult patient with TB, and the household contacts of secondary case patients. Contact names were obtained through patient interviews. A positive tuberculin skin test result was defined as induration of > or =5 mm. DNA fingerprints of Mycobacterium tuberculosis isolates were analyzed. Outbreak cases were those that had matching DNA fingerprint patterns or were linked epidemiologically, if DNA fingerprint results were not available. RESULTS: Between August 2002 and July 2004, we detected 11 outbreak cases, including 9 (82%) among children (<18 years of age). All 11 outbreak patients lived or were cared for at child care center A. The 9 pediatric TB patients were young (<7 years of age), United States-born children of foreign-born parents, and 4 (44%) had positive cultures for M tuberculosis. Including isolates recovered from the 2 adult patients, all 6 M tuberculosis isolates shared identical, 7-band, DNA fingerprint patterns. The contact investigation identified 3 (33%) of the 9 pediatric cases; 2 (22%) presented with illness and 4 (44%) were detected by primary care providers during routine TB screening. Excluding case subjects, 36 (54%) of 67 named contacts had latent TB infection. CONCLUSIONS: Provider adherence to locally adapted pediatric TB screening recommendations proved critical to outbreak control. TB screening compliance by the child care center and more aggressive source-case investigation by the TB program might have prevented or abated this large pediatric TB outbreak.

Feasibility, acceptability, and cost of tuberculosis testing by whole-blood interferon-gamma assay.

BACKGROUND: The whole-blood interferon-gamma release assay (IGRA) is recommended in some settings as an alternative to the tuberculin skin test (TST). Outcomes from field implementation of the IGRA for routine tuberculosis (TB) testing have not been reported. We evaluated feasibility, acceptability, and costs after 1.5 years of IGRA use in San Francisco under routine program conditions. METHODS: Patients seen at six community clinics serving homeless, immigrant, or injection-drug user (IDU) populations were routinely offered IGRA (Quantiferon-TB). Per guidelines, we excluded patients who were <17 years old, HIV-infected, immunocompromised, or pregnant. We reviewed medical records for IGRA results and completion of medical evaluation for TB, and at two clinics reviewed TB screening logs for instances of IGRA refusal or phlebotomy failure. RESULTS: Between November 1, 2003 and February 28, 2005, 4143 persons were evaluated by IGRA. 225(5%) specimens were not tested, and 89 (2%) were IGRA-indeterminate. Positive or negative IGRA results were available for 3829 (92%). Of 819 patients with positive IGRA results, 524 (64%) completed diagnostic evaluation within 30 days of their IGRA test date. Among 503 patients eligible for IGRA testing at two clinics, phlebotomy was refused by 33 (7%) and failed in 40 (8%). Including phlebotomy, laboratory, and personnel costs, IGRA use cost $33.67 per patient tested. CONCLUSION: IGRA implementation in a routine TB control program setting was feasible and acceptable among homeless, IDU, and immigrant patients in San Francisco, with results more frequently available than the historically described performance of TST. Laboratory-based diagnosis and surveillance for M. tuberculosis infection is now possible.