Jennifer Grinsdale

Low Sensitivity of a Whole-Blood Interferon-γ 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.

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.

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

BackgroundThe 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.MethodsPatients 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.ResultsBetween 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

Use of Whole Genome Sequencing to Determine the Microevolution of Mycobacterium tuberculosis during an Outbreak

33.67 per patient tested.ConclusionIGRA 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.

Evaluation of Quantitative IFN-γ Response for Risk Stratification of Active Tuberculosis Suspects

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.

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

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.

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

BackgroundImmigrants 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.MethodsUsing 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.ResultsDomestic 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.ConclusionWhile 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.

Early Detection of Tuberculosis Outbreaks among the San Francisco Homeless: Trade-Offs Between Spatial Resolution and Temporal Scale

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 ≥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.

Programmatic impact of using QuantiFERON®-TB Gold in routine contact investigation activities.

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 patients 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.

Impact of GeneXpert MTB/RIF on Patients and Tuberculosis Programs in a Low-Burden Setting. A Hypothetical Trial

OBJECTIVES To retrospectively assess the proportion of contacts tested with QuantiFERON ® -TB Gold (QFT-G) compared to the tuberculin skin test (TST) who were successfully evaluated and treated for latent tuberculosis infection (LTBI), and to assess the correlation of positive test results with measures of TB exposure. METHODS Contacts of culture-confirmed pulmonary TB cases reported to the San Francisco Department of Public Health between 1 March 2005 and 31 December 2007 were included. RESULTS Of 1291 contacts meeting the eligibility criteria, 641 (50%) were tested with QFT-G and 650 (50%) with TST. Contacts tested with QFT-G were more likely to complete evaluation (64% vs. 56%, OR(adj ) = 1.52, 95%CI 1.12-2.06). Infected contacts started (89% vs. 72%, OR(adj) = 5.18, 95%CI 2.10-14.18) and completed (70% vs. 53%, OR(adj) = 3.37, 95%CI 1.78-6.56) LTBI treatment more often in the group tested with QFT-G. Positive QFT-G results, but not positive TST results, correlated with the intensity, proximity and duration of TB exposure in foreign-born subjects. CONCLUSION More contacts were successfully evaluated and treated for LTBI when screened with QFT-G compared to TST. Measures of exposure correlated better with QFT-G-positive results and, therefore, appropriately identified high-risk contacts for TB prevention.