Parallels and Mutual Lessons in Tuberculosis and COVID-19 Transmission, Prevention, and Control.

The coronavirus disease (COVID-19) pandemic has had unprecedented negative effects on global health and economies, drawing attention and resources from many other public health services. To minimize negative effects, the parallels, lessons, and resources from existing public health programs need to be identified and used. Often underappreciated synergies relating to COVID-19 are with tuberculosis (TB). COVID-19 and TB share commonalities in transmission and public health response: case finding, contact identification, and evaluation. Data supporting interventions for either disease are, understandably, vastly different, given the diseases' different histories. However, many of the evolving issues affecting these diseases are increasingly similar. As previously done for TB, all aspects of congregate investigations and preventive and therapeutic measures for COVID-19 must be prospectively studied for optimal evidence-based interventions. New attention garnered by the pandemic can ensure that knowledge and investment can benefit both COVID-19 response and traditional public health programs such as TB programs.

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

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

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

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

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.

Drug-resistant tuberculosis in high-risk groups, Zimbabwe.

To estimate prevalence of multidrug-resistant tuberculosis (MDR TB) in Harare, Zimbabwe, in 2012, we performed microbiologic testing on acid-fast bacilli smear-positive sputum samples from patients previously treated for TB. Twenty (24%) of 84 specimens were consistent with MDR TB. A national drug-resistance survey is needed to determine MDR TB prevalence in Zimbabwe.

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.

Tuberculosis and HIV co-infection, California, USA, 1993­2008.

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 1993­2008 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 1993­2008; rates were highest for Hispanics (225/100,000) and Blacks (148/100,000). Patients co-infected with TB­HIV during 2001­2008 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.

Evolution and revolution: the formation of Today's American Thoracic Society, Part 2.

The major event in the recent history of the American Thoracic Society (ATS) is its separation from the American Lung Association (ALA), resulting in the Society's independence. The seeds of the separation were sown over the course of many years. The fundamental reason driving the separation was the organizational structure of the ALA, with the ATS being a division within the larger organization and having neither the standing to make independent decisions nor the ability to respond effectively to the expectations of a growing and diverse membership. Additional important factors included continual organizational conflicts; ongoing struggles over finances; reluctance by the ALA to provide what the ATS considered to be appropriate support for research; divergence of areas of interest as the Society became more broad based to include critical care and sleep medicine, as well as concerns with medical practice issues; and internationalization of the Society, with an increasing proportion of members residing outside the United States. Once it was decided that the ATS could only exist as an independent organization, the separation agreement was negotiated in less than 3 years. Although there were substantial unknowns immediately after the separation, a unified leadership, a strongly supportive membership, and a skilled and dedicated staff guided the organization through this difficult period, from which the Society emerged as a strong independent professional organization that remains true to the public-minded spirit that guided its formation 107 years ago.

Evolution and revolution: the formation of today's American Thoracic Society, part 1.

The American Thoracic Society (ATS), the preeminent professional organization in the field of respiratory, critical care, and sleep medicine, is now 107 years old. For the most part, the Society's administrative and medical-scientific interests evolved in an orderly fashion, but two "revolutions" took place that should be remembered. What ultimately metamorphosed into the ATS in 1960 began in 1905 as the 34-member American Sanatorium Association, which in 1915 became the medical section of the National Association for the Study and Prevention of Tuberculosis (NASPT). In 1918, the NASPT became the National Tuberculosis Association and in 1939, the ASA became the American Trudeau Society, cosmetic revisions having no effect on either the medical section-parent relationship or the one-disease orientation of both organizations. After World War II, the narrow focus of the ATS on tuberculosis was progressively enlarged through coalescence of several factors that transformed the practice of pulmonary medicine: the growth of intensive care units and pulmonary function laboratories and the advent of fiberoptic bronchoscopy; the rise of asthma, chronic obstructive pulmonary disease, and lung cancer coincident with the withering of tuberculosis; and the arrival of pulmonary physician-scientists who sought enrichment through a professional society. The newcomers found a home in the ATS, but it was slow to fulfill their needs for scientific communication and administrative responsibility. The first revolution, the formation of Scientific Assemblies, got the job done quickly and well, as described in Part 1 of this perspective. The second revolution, separation from the American Lung Association, is described in Part 2.

Integrated strategies to optimize sputum smear microscopy: a prospective observational study.

RATIONALE: Smear-positive tuberculosis (TB) case detection rates are far below targets in most low-income countries. The standard approach to smear microscopy involves sputum collection over multiple days and examination of sputum smears by light microscopy (LM), an insensitive and time-consuming technique. OBJECTIVE: To determine whether two alternative approaches can increase smear-positive case detection by increasing the efficiency (single-specimen microscopy) or sensitivity (light-emitting diode [LED] fluorescence microscopy [FM]) of TB suspect evaluation. METHODS: We enrolled patients with cough of 2 weeks or more admitted to Mulago Hospital in Kampala, Uganda and collected spot and early morning sputum specimens. We compared the diagnostic accuracy of four prespecified strategies based on the number of sputum specimens collected (one specimen versus two specimens) and the type of microscopy (LM versus LED FM) using mycobacterial culture as a reference standard. MEASUREMENTS AND MAIN RESULTS: Two hundred thirty-three of 464 (50%) patients had culture-positive TB. There was no difference in sensitivity between single-specimen and two-specimen strategies when smears were examined with LM (55 vs. 56%; difference, -1%; 95% confidence interval [CI], -5 to +2%) or LED FM (61 vs. 64%; difference, -3%; 95% CI, -7 to +1%). LED FM was more sensitive than LM with both the single-specimen (61 vs. 55%; difference, 6%; 95% CI, 2-10%) and two-specimen strategies (64 vs. 56%; difference, 8%; 95% CI, 3-12%). Findings were similar among the HIV-infected patient subset (n = 321 patients). CONCLUSIONS: In low-income, high TB burden settings, single-specimen microscopy and LED FM, either alone or in combination, could considerably increase identification of smear-positive TB cases.

Evaluating tuberculosis case detection via real-time monitoring of tuberculosis diagnostic services.

RATIONALE: Tuberculosis case-detection rates are below internationally established targets in high-burden countries. Real-time monitoring and evaluation of adherence to widely endorsed standards of tuberculosis care might facilitate improved case finding. OBJECTIVES: To monitor and evaluate the quality of tuberculosis case-detection and management services in a low-income country with a high incidence of tuberculosis. METHODS: We prospectively evaluated tuberculosis diagnostic services at five primary health-care facilities in Uganda for 1 year, after introducing a real-time, electronic performance-monitoring system. We collected data on every clinical encounter, and measured quality using indicators derived from the International Standards of Tuberculosis Care. MEASUREMENTS AND MAIN RESULTS: In 2009, there were 62,909 adult primary-care visits. During the first quarter of 2009, clinicians referred only 21% of patients with cough greater than or equal to 2 weeks for sputum smear microscopy and only 71% of patients with a positive sputum examination for tuberculosis treatment. These proportions increased to 53% and 84%, respectively, in the fourth quarter of 2009. The cumulative probability that a smear-positive patient with cough greater than or equal to 2 weeks would be appropriately evaluated and referred for treatment rose from 11% to 34% (P = 0.005). The quarterly number of tuberculosis cases identified and prescribed treatment also increased four-fold, from 5 to 21. CONCLUSIONS: Poor adherence to internationally accepted standards of tuberculosis care improved after introduction of real-time performance monitoring and was associated with increased tuberculosis case detection. Real-time monitoring and evaluation can strengthen health systems in low-income countries and facilitate operational research on the effectiveness and sustainability of interventions to improve tuberculosis case detection.

Interferon-γ release assays for active pulmonary tuberculosis diagnosis in adults in low- and middle-income countries: systematic review and meta-analysis.

BACKGROUND: The diagnostic value of interferon-γ release assays (IGRAs) for active tuberculosis in low- and middle-income countries is unclear. METHODS: We searched multiple databases for studies published through May 2010 that evaluated the diagnostic performance of QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB (T-SPOT) among adults with suspected active pulmonary tuberculosis or patients with confirmed cases in low- and middle-income countries. We summarized test performance characteristics with use of forest plots, hierarchical summary receiver operating characteristic (HSROC) curves, and bivariate random effects models. RESULTS: Our search identified 789 citations, of which 27 observational studies (17 QFT-GIT and 10 T-SPOT) evaluating 590 human immunodeficiency virus (HIV)-uninfected and 844 HIV-infected individuals met inclusion criteria. Among HIV-infected patients, HSROC/bivariate pooled sensitivity estimates (highest quality data) were 76% (95% confidence interval [CI], 45%-92%) for T-SPOT and 60% (95% CI, 34%-82%) for QFT-GIT. HSROC/bivariate pooled specificity estimates were low for both IGRA platforms among all participants (T-SPOT, 61% [95% CI, 40%-79%]; QFT-GIT, 52% [95% CI, 41%-62%]) and among HIV-infected persons (T-SPOT, 52% [95% CI, 40%-63%]; QFT-GIT, 50% [95% CI, 35%-65%]). There was no consistent evidence that either IGRA was more sensitive than the tuberculin skin test for active tuberculosis diagnosis. CONCLUSIONS: In low- and middle-income countries, neither the tuberculin skin test nor IGRAs have value for active tuberculosis diagnosis in adults, especially in the context of HIV coinfection.

Racial differences in tuberculosis infection in United States communities: the coronary artery risk development in young adults study.

Previously reported associations between race/ethnicity and tuberculosis infection have lacked sufficient adjustment for socioeconomic factors. We analyzed race/ethnicity and self-reported tuberculosis infection data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a well-characterized cohort of 5115 black and white participants, and found that after adjusting for sociodemographic and clinical factors, black participants were more likely to report tuberculosis infection and/or disease (odds ratio, 2.0; 95% confidence interval, 1.5-2.9).

Commercial serological tests for the diagnosis of active pulmonary and extrapulmonary tuberculosis: an updated systematic review and meta-analysis.

BACKGROUND: Serological (antibody detection) tests for tuberculosis (TB) are widely used in developing countries. As part of a World Health Organization policy process, we performed an updated systematic review to assess the diagnostic accuracy of commercial serological tests for pulmonary and extrapulmonary TB with a focus on the relevance of these tests in low- and middle-income countries. METHODS AND FINDINGS: We used methods recommended by the Cochrane Collaboration and GRADE approach for rating quality of evidence. In a previous review, we searched multiple databases for papers published from 1 January 1990 to 30 May 2006, and in this update, we add additional papers published from that period until 29 June 2010. We prespecified subgroups to address heterogeneity and summarized test performance using bivariate random effects meta-analysis. For pulmonary TB, we included 67 studies (48% from low- and middle-income countries) with 5,147 participants. For all tests, estimates were variable for sensitivity (0% to 100%) and specificity (31% to 100%). For anda-TB IgG, the only test with enough studies for meta-analysis, pooled sensitivity was 76% (95% CI 63%-87%) in smear-positive (seven studies) and 59% (95% CI 10%-96%) in smear-negative (four studies) patients; pooled specificities were 92% (95% CI 74%-98%) and 91% (95% CI 79%-96%), respectively. Compared with ELISA (pooled sensitivity 60% [95% CI 6%-65%]; pooled specificity 98% [95% CI 96%-99%]), immunochromatographic tests yielded lower pooled sensitivity (53%, 95% CI 42%-64%) and comparable pooled specificity (98%, 95% CI 94%-99%). For extrapulmonary TB, we included 25 studies (40% from low- and middle-income countries) with 1,809 participants. For all tests, estimates were variable for sensitivity (0% to 100%) and specificity (59% to 100%). Overall, quality of evidence was graded very low for studies of pulmonary and extrapulmonary TB. CONCLUSIONS: Despite expansion of the literature since 2006, commercial serological tests continue to produce inconsistent and imprecise estimates of sensitivity and specificity. Quality of evidence remains very low. These data informed a recently published World Health Organization policy statement against serological tests. Please see later in the article for the Editors' Summary.

Factors associated with mortality in patients with drug-susceptible pulmonary tuberculosis.

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.

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.

Determinants of multidrug-resistant tuberculosis clusters, California, USA, 2004-2007.

Laboratory and epidemiologic evidence suggests that pathogen-specific factors may affect multidrug-resistant (MDR) tuberculosis (TB) transmission and pathogenesis. To identify demographic and clinical characteristics of MDR TB case clustering and to estimate the effect of specific isoniazid resistance-conferring mutations and strain lineage on genotypic clustering, we conducted a population-based cohort study of all MDR TB cases reported in California from January 1, 2004, through December 31, 2007. Of 8,899 incident culture-positive cases for which drug susceptibility information was available, 141 (2%) were MDR. Of 123 (87%) strains with genotype data, 25 (20%) were aggregated in 8 clusters; 113 (92%) of all MDR TB cases and 21 (84%) of clustered MDR TB cases occurred among foreign-born patients. In multivariate analysis, the katG S315T mutation (odds ratio 11.2, 95% confidence interval 2.2-Yen; p = 0.004), but not strain lineage, was independently associated with case clustering.