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Objective: Rifampin monoresistant tuberculosis (RMR-TB) is increasingly identified because of scale-up of rapid molecular tests. The longitudinal association of RMR-TB, multidrug-resistant TB (MDR-TB), and HIV/AIDS is incompletely described., Methods: We examined clinical characteristics and treatment outcomes of patients with RMR-TB, isoniazid monoresistant TB (IMR-TB), MDR-TB, and drug-susceptible TB during a 16-year period (1993-2008) in California. TB cases were cross-matched with the state HIV/AIDS registry, and HIV prevalence denominators modeled using nonparametric backcalculation., Results: Of 42,582 TB cases, 178 (0.4%), 3469 (8.1%), and 635 (1.5%) were RMR-TB, IMR-TB, and MDR-TB, respectively. From the pre-HAART (1993-1996) to HAART (2005-2008) era, RMR-TB rates declined rapidly (12.0 vs. 0.5 per 100,000) among patients with HIV infection. The proportion of patients for whom rifampin resistance indicated RMR-TB (rather than MDR-TB) decreased from 31% [95% confidence interval (CI) 26-38%] to 11% (95% CI 5-19%). In multivariate analysis controlling for HIV coinfection and other covariates, patients with RMR-TB were twice as likely to die as patients with drug-sensitive TB (relative risk 1.94, 95% CI 1.40-2.69)., Conclusion: RMR-TB/HIV rates declined substantially over time in association with improved TB control and HIV control in California. Mortality among patients with RMR-TB was high, even after adjusting for HIV status.

To understand the epidemiology of tuberculosis (TB) and HIV co-infection in California, we cross-matched incident TB cases reported to state surveillance systems during 1993–2008 with cases in the state HIV/AIDS registry. Of 57,527 TB case-patients, 3,904 (7%) had known HIV infection. TB rates for persons with HIV declined from 437 to 126 cases/100,000 persons during 1993–2008; rates were highest for Hispanics (225/100,000) and Blacks (148/100,000). Patients co-infected with TB–HIV during 2001–2008 were significantly more likely than those infected before highly active antiretroviral therapy became available to be foreign born, Hispanic, or Asian/Pacific Islander and to have pyrazinamide-monoresistant TB. Death rates decreased after highly active antiretroviral therapy became available but remained twice that for TB patients without HIV infection and higher for women. In California, HIV-associated TB has concentrated among persons from low- and middle-income countries who often acquire HIV infection in the peri-immigration period.

Objective: To determine whether interferon-gamma release assays (IGRAs) improve the identification of HIV-infected individuals who could benefit from latent tuberculosis infection therapy., Design: Systematic review and meta-analysis., Methods: We searched multiple databases through May 2010 for studies evaluating the performance of the newest commercial IGRAs (QuantiFERON-TB Gold In-Tube [QFT-GIT] and T-SPOT.TB [TSPOT]) in HIV-infected individuals. We assessed the quality of all studies included in the review, summarized results in prespecified subgroups using forest plots, and where appropriate, calculated pooled estimates using random effects models., Results: The search identified 37 studies that included 5736 HIV-infected individuals. In three longitudinal studies, the risk of active tuberculosis was higher in HIV-infected individuals with positive versus negative IGRA results. However, the risk difference was not statistically significant in the two studies that reported IGRA results according to manufacturer-recommended criteria. In persons with active tuberculosis (a surrogate reference standard for latent tuberculosis infection), pooled sensitivity estimates were heterogeneous but higher for TSPOT (72%; 95% confidence interval [CI], 62-81%) than for QFT-GIT (61%; 95% CI, 47-75%) in low-/middle-income countries. However, neither IGRA was consistently more sensitive than the tuberculin skin test in head-to-head comparisons. Although TSPOT appeared to be less affected by immunosuppression than QFT-GIT and the tuberculin skin test, overall, differences among the three tests were small or inconclusive., Conclusions: Current evidence suggests that IGRAs perform similarly to the tuberculin skin test at identifying HIV-infected individuals with latent tuberculosis infection. Given that both tests have modest predictive value and suboptimal sensitivity, the decision to use either test should be based on country guidelines and resource and logistic considerations.

Background: T-cell interferon-gamma release assays (IGRAs) may have a role in the diagnosis of active tuberculosis when evaluating patients for whom standard microbiology has limited sensitivity. Our objective was to examine the accuracy of a commercial IGRA for diagnosis of active tuberculosis in HIV-infected persons., Methods: We enrolled HIV-infected patients admitted to Mulago Hospital in Kampala, Uganda with cough > or = 2 weeks. All patients underwent standard medical evaluation. We collected peripheral blood specimens at enrollment and performed a commercial, ELISPOT-based IGRA according to the manufacturer's recommendations. IGRA sensitivity and specificity were determined using mycobacterial culture results as the reference standard., Results: Overall, 236 patients were enrolled. The median CD4+ T-lymphocyte count was 49 cells/microl and 126 (53%) patients were diagnosed with active pulmonary tuberculosis. IGRAs were not performed in 24 (10%) patients due to insufficient mononuclear cell counts. In the remaining 212 patients, results were indeterminate in 54 (25%). IGRAs were positive in 95 of 158 (60%) patients with interpretable results. The proportion of positive test results was similar across CD4+ count strata. IGRA sensitivity was 73% and specificity 54%. IGRA results did not meaningfully alter the probability of active tuberculosis in patients with negative sputum smears., Conclusions: An ELISPOT-based IGRA detected a high prevalence of latent tuberculosis infection in a hospitalized population of tuberculosis suspects with advanced HIV/AIDS but had limited utility for diagnosis of active tuberculosis in a high prevalence setting. Further research is needed to identify stronger and more specific immune responses in patients with active tuberculosis.

Background: Sputum concentration increases the sensitivity of smear microscopy for the diagnosis of tuberculosis (TB), but few studies have investigated this method in human immunodeficiency virus (HIV)-infected individuals., Methods: We performed a prospective, blinded evaluation of direct and concentrated Ziehl-Neelsen smear microscopy on a single early-morning sputum sample in HIV-infected patients with > 2 weeks of cough hospitalized in Kampala, Uganda. Direct and concentrated smear results were compared with results of Lowenstein-Jensen culture., Results: Of 279 participants, 170 (61%) had culture-confirmed TB. The sensitivity of direct and concentrated smear microscopy was not significantly different (51% vs. 52%, difference 1%, 95% confidence interval (CI): [-7%, 10%], p = 0.88). However, when results of both direct and concentrated smears were considered together, sensitivity was significantly increased compared with either method alone (64%, 95% CI: [56%, 72%], p < 0.01 for both comparisons) and was similar to that of direct smear results from consecutive (spot and early-morning) specimens (64% vs. 63%, difference 1%, 95% CI: [-6%, 8%], p = 0.85). Among 109 patients with negative cultures, one had a positive direct smear and 12 had positive concentrated smears (specificity 99% vs. 89%, difference 10%, 95% CI: [2%, 18%], p = 0.003). Of these 13 patients, 5 (38%) had improved on TB therapy after two months., Conclusion: Sputum concentration did not increase the sensitivity of light microscopy for TB diagnosis in this HIV-infected population. Given the resource requirements for sputum concentration, additional studies using maximal blinding, high-quality direct microscopy, and a rigorous gold standard should be conducted before universally recommending this technique.

Rationale: Human immunodeficiency virus (HIV) infection has a major but unquantified impact on the risk of tuberculosis., Objectives: To quantify the impact of HIV infection on the number of tuberculosis cases in San Francisco., Methods: We studied all patients reported with tuberculosis in San Francisco from 1991 to 2002. The initial isolates of Mycobacterium tuberculosis were genotyped using IS6110 restriction fragment-length polymorphism genotyping as the primary method, and clustered cases (identical genotype patterns) were identified., Measurements and Main Results: We determined the case number, case rate, and the fraction of tuberculosis attributable to HIV infection. Of 2,991 reported tuberculosis cases, 2,193 (73.3%) had a genotype pattern of M. tuberculosis available. Genotypic clusters with at least one HIV-positive person were larger, lasted longer, and had a shorter time between successive cases relative to clusters with only HIV-uninfected persons (P < 0.00005, P = 0.0009, P = 0.018, respectively). Overall, 13.7% of the tuberculosis cases were attributable to HIV infection and an estimated 405 excess tuberculosis cases occurred., Conclusions: During a period encompassing the resurgence and decline of tuberculosis in San Francisco, a substantial number of the tuberculosis cases were attributable to HIV infection. Coinfection with HIV amplified the local tuberculosis epidemic.

Objectives: Streptococcus pneumoniae is the leading cause of bacterial pneumonia and associated bacteremia during HIV infection. Rapid diagnostic assays may limit inappropriate therapy., Methods: Clinical signs and symptoms and sera and urine were collected prospectively from 70 adults with pneumococcal pneumonia, including 47 with HIV co-infection. Pneumococcal C-polysaccharide antigen was detected in urine using the Binax immunochromatographic test (ICT). A systematic review of 24 published studies was conducted., Results: Clinical symptoms, signs, and laboratory parameters except leukocytosis, were similar in HIV-infected and HIV-seronegative pneumonia. The performance of the urine antigen ICT was independent of HIV-status (sensitivity 81%, specificity 98%, positive (PPV) and negative predictive values (NPV) 98%, and 82%, respectively). The sensitivity of sputum Gram's stain was 58% (34/59) with sputum unable to be provided by 16%. The CRP response was identical in HIV-infected (mean+/-SD) 133+/-88 vs. seronegative 135+/-104 mg/L (p=0.9). In the systematic review, the ICT performance revealed 74% sensitivity (95% CI 72-77%) and 94% specificity (95% CI 93-95%). Urine antigen testing increases etiologic diagnosis by 23% (range: 10-59%) when testing adults with community acquired pneumonia of unknown etiology., Conclusions: Urinary antigen detection provides a credible rapid diagnostic test for pneumococcal pneumonia regardless of HIV-status. CRP response to acute infection is similar in HIV co-infection and increases diagnostic certainty.

Rationale: The optimal length of tuberculosis treatment in patients coinfected with HIV is unknown., Objectives: To evaluate treatment outcomes for HIV-infected patients stratified by duration of rifamycin-based tuberculosis therapy., Methods: We retrospectively reviewed data on all patients with tuberculosis reported to the San Francisco Tuberculosis Control Program from 1990 through 2001. Patients were followed for up to 12 months after treatment completion., Measurements and Main Results: Of 700 patients, 264 (38%) were HIV infected, 315 (45%) were not infected, and 121 (17%) were not tested. Mean duration of treatment was extended to 10.2 months for HIV-infected patients versus 8.4 months for uninfected/unknown patients (p < 0.001). Seventeen percent of the HIV-infected and 37% of the HIV uninfected/unknown patients received 6 months of rifamycin-based therapy. The relapse rate among HIV-infected was 9.3 per 100 person-years versus 1.0 in HIV-uninfected/unknown patients (p < 0.001). HIV-infected individuals who received a standard 6-month rifamycin-based regimen were more likely to relapse than those treated longer (adjusted hazard ratio, 4.33; p = 0.02). HIV-infected individuals who received intermittent therapy were also more likely to relapse than those treated on daily basis (adjusted hazard ratio, 4.12; p = 0.04). The use of highly active antiretroviral therapy was associated with more rapid conversion of smears and cultures and with improved survival., Conclusions: HIV-infected patients who received a 6-month rifamycin-based course of tuberculosis treatment or who received intermittent therapy had a higher relapse rate than HIV-infected subjects who received longer therapy or daily therapy, respectively. Standard 6-month therapy may be insufficient to prevent relapse in patients with HIV.

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.

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.

BackgroundThe global tuberculosis epidemic results in nearly 2 million deaths and 9 million new cases of the disease a year. The vast majority of tuberculosis patients live in developing countries, where the diagnosis of tuberculosis relies on the identification of acid-fast bacilli on unprocessed sputum smears using conventional light microscopy. Microscopy has high specificity in tuberculosis-endemic countries, but modest sensitivity which varies among laboratories (range 20% to 80%). Moreover, the sensitivity is poor for paucibacillary disease (e.g., pediatric and HIV-associated tuberculosis). Thus, the development of rapid and accurate new diagnostic tools is imperative. Immune-based tests are potentially suitable for use in low-income countries as some test formats can be performed at the point of care without laboratory equipment. Currently, dozens of distinct commercial antibody detection tests are sold in developing countries. The question is "do they work?"Methods and findingsWe conducted a systematic review to assess the accuracy of commercial antibody detection tests for the diagnosis of pulmonary tuberculosis. Studies from all countries using culture and/or microscopy smear for confirmation of pulmonary tuberculosis were eligible. Studies with fewer than 50 participants (25 patients and 25 control participants) were excluded. In a comprehensive search, we identified 68 studies. The results demonstrate that (1) overall, commercial tests vary widely in performance; (2) sensitivity is higher in smear-positive than smear-negative samples; (3) in studies of smear-positive patients, Anda-TB IgG by enzyme-linked immunosorbent assay shows limited sensitivity (range 63% to 85%) and inconsistent specificity (range 73% to 100%); (4) specificity is higher in healthy volunteers than in patients in whom tuberculosis disease is initially suspected and subsequently ruled out; and (5) there are insufficient data to determine the accuracy of most commercial tests in smear microscopy-negative patients, as well as their performance in children or persons with HIV infection.ConclusionsNone of the commercial tests evaluated perform well enough to replace sputum smear microscopy. Thus, these tests have little or no role in the diagnosis of pulmonary tuberculosis. Lack of methodological rigor in these studies was identified as a concern. It will be important to review the basic science literature evaluating serological tests for the diagnosis of pulmonary tuberculosis to determine whether useful antigens have been described but their potential has not been fully exploited. Activities leading to the discovery of new antigens with immunodiagnostic potential need to be intensified.

Objective: Poverty is both a cause and consequence of tuberculosis. The objective of this study is to quantify patient/household costs for an episode of tuberculosis (TB), its relationships with household impoverishment, and the strategies used to cope with the costs by TB patients in a resource-limited high TB/HIV setting. Methods: A cross-sectional study was conducted in three rural hospitals in southeast Nigeria. Consecutive adults with newly diagnosed pulmonary TB were interviewed to determine the costs each incurred in their care-seeking pathway using a standardised questionnaire. We defined direct costs as out-of-pocket payments, and indirect costs as lost income. Results: Of 452 patients enrolled, majority were male 55% (249), and rural residents 79% (356), with a mean age of 34 (±11.6) years. Median direct pre-diagnosis/diagnosis cost was $49 per patient. Median direct treatment cost was $36 per patient. Indirect pre-diagnostic and treatment costs were $416, or 79% of total patient costs, $528. The median total cost of TB care per household was $592; corresponding to 37% of median annual household income pre-TB. Most patients reported having to borrow money 212(47%), sell assets 42(9%), or both 144(32%) to cope with the cost of care. Following an episode of TB, household income reduced increasing the proportion of households classified as poor from 54% to 79%. Before TB illness, independent predictors of household poverty were; rural residence (adjusted odds ratio [aOR] 2.8), HIV-positive status (aOR 4.8), and care-seeking at a private facility (aOR 5.1). After TB care, independent determinants of household poverty were; younger age (≤35 years; aOR 2.4), male gender (aOR 2.1), and HIV-positive status (aOR 2.5). Conclusion: Patient and household costs for TB care are potentially catastrophic even where services are provided free-of-charge. There is an urgent need to implement strategies for TB care that are affordable for the poor. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis is a leading cause of death worldwide, yet the determinants of death are not well understood. We sought to determine risk factors for mortality during treatment of drug-susceptible pulmonary tuberculosis under program settings. Methods: Retrospective chart review of patients with drug-susceptible tuberculosis reported to the San Francisco Tuberculosis Control Program from 1990-2001. Results: Of 565 patients meeting eligibility criteria, 37 (6.6%) died during the study period. Of 37 deaths, 12 (32.4%) had tuberculosis listed as a contributing factor. In multivariate analysis controlling for follow-up time, four characteristics were independently associated with mortality: HIV co-infection (HR = 2.57, p = 0.02), older age at tuberculosis diagnosis (HR = 1.52 per 10 years, p = 0.001); initial sputum smear positive for acid fast bacilli (HR = 3.07, p = 0.004); and experiencing an interruption in tuberculosis therapy (HR = 3.15, p = 0.002). The association between treatment interruption and risk of death was due to non-adherence during the intensive phase of treatment (HR = 3.20, p = 0.001). The median duration of treatment interruption did not differ significantly in either intensive or continuation phases between those who died and survived (23 versus 18 days, and 37 versus 29 days, respectively). No deaths were directly attributed to adverse drug reactions. Conclusions: In addition to advanced age, HIV and characteristics of advanced tuberculosis, experiencing an interruption in anti-tuberculosis therapy, primarily due to non-adherence, was also independently associated with increased risk of death. Improving adherence early during treatment for tuberculosis may both improve tuberculosis outcomes as well as decrease mortality. [ABSTRACT FROM AUTHOR]

Treatment of patients with multidrug-resistant tuberculosis requires prolonged therapy, often involving long hospital stays. Despite intensive and costly therapy, cure rates are relatively low. We reviewed the outcomes for all patients with multidrug-resistant tuberculosis treated in San Francisco, California, during 1982-2000 and identified billing charges for patients treated during 1995-2000. Mycobacterium tuberculosis isolates were genotyped by 1S6110-based restriction fragment-length polymorphism analysis. Forty-eight cases were identified with resistance to a median of 3 drugs (range, 2-9 drugs). The median age of the patients was 49.5 years (range, 22-78 years); 36 (75%) of 48 patients were foreign born, 11 (23%) were human immunodeficiency virus (HIV) seropositive, and 45 (94%) had pulmonary tuberculosis. Thirty- two (97%) of the 33 HIV-seronegative patients were cured, with only 1 relapse occurring 5 years after treatment. All 11 HIV-seropositive patients died during observation. Twenty-one patients (44%) required hospitalization, with a median duration of stay of 14 days (range, 3-74 days). The estimated inpatient and outpatient aggregate cost for the 11 patients treated after 1994 was $519,928, with a median cost of $27,752 per patient. No secondary cases of multidrug-resistant tuberculosis were identified through population-based genotyping. Treatment of multidrug-resistant tuberculosis in HIV-seronegative patients largely on an outpatient basis was feasible and was associated with high cure rates and lower cost than in other published studies. Patients with underlying HIV infection had very poor outcomes. [ABSTRACT FROM AUTHOR]

The article discusses the contributions of Doctor John F. Murray to modern pulmonary medicine. Topics discussed include Murray's publications that center on the principles of chest medicine and his role in the creation of the Division of Lung Disease in the National Heart, Lung and Blood Institute. His leadership in the American Thoracic Society and his efforts in studying pulmonary disease in people with HIV infection are also mentioned. [ABSTRACT FROM AUTHOR]

Background: In the United States there have been recent outbreaks of multidrug-resistant tuberculosis. These outbreaks have primarily involved persons infected with the human immunodeficiency virus (HIV). Methods: We collected clinical information on 17 patients seen at a New York City hospital who had repeatedly positive cultures for Mycobacterium tuberculosis. Analysis of restriction-fragment-length polymorphisms (RFLPs) was performed on serial isolates of M. tuberculosis obtained from these patients. Results: Six patients had isolates that remained drug-susceptible, and the RFLP patterns of these isolates did not change over time. Eleven patients had isolates that became resistant to antimicrobial agents. The RFLP patterns of the isolates from six of these patients remained essentially unchanged (two strains showed one additional band) despite the development of drug resistance. In five other patients, however, the RFLP patterns of the isolates changed dramatically at the time that drug resistance was detected. The change in the RFLP pattern of the isolate from one patient appeared to be the result of contamination during processing in the laboratory. In the remaining four patients, all of whom had advanced HIV disease, the clinical and microbiologic evidence was consistent with the presence of active tuberculosis caused by a new strain of M. tuberculosis. Conclusions: Resistance to antituberculous drugs can develop not only in the strain that caused the initial disease, but also as a result of reinfection with a new strain of M. tuberculosis that is drug-resistant. Exogenous reinfection with multidrug-resistant M. tuberculosis can occur either during therapy for the original infection or after therapy has been completed. (N Engl J Med 1993;328:1137-44.) [ABSTRACT FROM AUTHOR]