The yield of tuberculosis contact investigation in low- and middle-income settings: a systematic review and meta-analysis.

BACKGROUND: Contact investigation, the systematic evaluation of individuals in close contact with an infectious tuberculosis (TB) patient, is a key active case-finding strategy for global TB control. Better estimates of the yield of contact investigation can guide strategies to reduce the number of underreported and underdiagnosed TB cases, approximately three million cases per year globally. A systematic review (Prospero ID # CRD42019133380) and meta-analysis was conducted to update and enhance the estimates of the yield of TB contact investigation in low- and middle-income countries (LMIC). Pubmed, Web of Science, Embase and the WHO Global Index Medicus were searched for peer-reviewed studies (published between January 2006-April 2019); studies reporting the number of active TB or latent tuberculosis infection (LTBI) found through contact investigation were included. Pooled data were meta-analyzed using a random effects model and risk of bias was assessed. RESULTS: Of 1,644 unique citations obtained from database searches, 110 studies met eligibility criteria for descriptive data synthesis and 95 for meta-analysis. The pooled yields of contact investigation activities for different outcomes were: secondary cases of all active TB (defined as those bacteriologically confirmed or clinically diagnosed) 2.87% (2.61-3.14, I2 97.79%), bacteriologically confirmed active TB 2.04% (1.77-2.31, I2 98.06%), and LTBI 43.83% (38.11-49.55, I2 99.36%). Yields are interpreted as the percent of contacts screened who are diagnosed with active TB as a result of TB contact investigation activities. Pooled estimates were substantially heterogenous (I2 ≥ 75%). CONCLUSIONS: This study provides methodologically rigorous and up-to-date estimates for the yield of TB contact investigation activities in low- and middle-income countries (LMIC). While the data are heterogenous, these findings can inform strategic and programmatic planning for scale up of TB contact investigation activities.

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.

Identifying barriers to and facilitators of tuberculosis contact investigation in Kampala, Uganda: a behavioral approach.

BACKGROUND: The World Health Organization recommends routine household tuberculosis contact investigation in high-burden countries but adoption has been limited. We sought to identify barriers to and facilitators of TB contact investigation during its introduction in Kampala, Uganda. METHODS: We collected cross-sectional qualitative data through focus group discussions and interviews with stakeholders, addressing three core activities of contact investigation: arranging household screening visits through index TB patients, visiting households to screen contacts and refer them to clinics, and evaluating at-risk contacts coming to clinics. We analyzed the data using a validated theory of behavior change, the Capability, Opportunity, and Motivation determine Behavior (COM-B) model, and sought to identify targeted interventions using the related Behavior Change Wheel implementation framework. RESULTS: We led seven focus-group discussions with 61 health-care workers, two with 21 lay health workers (LHWs), and one with four household contacts of newly diagnosed TB patients. We, in addition, performed 32 interviews with household contacts from 14 households of newly diagnosed TB patients. Commonly noted barriers included stigma, limited knowledge about TB among contacts, insufficient time and space in clinics for counselling, mistrust of health-center staff among index patients and contacts, and high travel costs for LHWs and contacts. The most important facilitators identified were the personalized and enabling services provided by LHWs. We identified education, persuasion, enablement, modeling of health-positive behaviors, incentivization, and restructuring of the service environment as relevant intervention functions with potential to alleviate barriers to and enhance facilitators of TB contact investigation. CONCLUSIONS: The use of a behavioral theory and a validated implementation framework provided a comprehensive approach for systematically identifying barriers to and facilitators of TB contact investigation. The behavioral determinants identified here may be useful in tailoring interventions to improve implementation of contact investigation in Kampala and other similar urban settings.

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.

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.

Treatment of Tuberculosis. A Historical Perspective.

Of all achievements in medicine, the successful treatment of tuberculosis has had one of the greatest impacts on society. Tuberculosis was a leading cause of disease and a mortal enemy of humanity for millennia. The first step in finding a cure was the discovery of the cause of tuberculosis by Robert Koch in 1882. The sanatorium movement that began shortly afterward in Europe, and soon spread to the United States, brought attention to the plight of afflicted persons, and catalyzed public health action. The antituberculosis benefit of streptomycin was announced in 1945, although application was limited by the rapid development of resistance. para-Aminosalicylic acid, also discovered in 1945, when combined with streptomycin was found to greatly reduce the occurrence of drug resistance. In 1952, isoniazid opened the modern era of treatment; it was inexpensive, well tolerated, and safe. In the early 1960s, ethambutol was shown to be effective and better tolerated than para-aminosalicylic acid, which it replaced. In the 1970s, rifampin found its place as a keystone in the therapy of tuberculosis. The use of rifampin enabled the course of treatment to be reduced to nine months. Incorporation of pyrazinamide into the first-line regimen led to a further reduction of treatment duration to six months. Treatment of multiple drug-resistant tuberculosis remains a difficult problem requiring lengthy treatment with toxic drugs. However, shortened regimens show promise, and two new drugs, bedaquiline and delamanid, have demonstrated effectiveness in preliminary studies and are being used for extensively drug-resistant tuberculosis.

Pulmonary specialty training to improve respiratory health in low- and middle-income countries. Needs and challenges.

It is estimated that 85% of the world's population lives in low- and middle-income countries (LMICs). Although economic conditions are improving in these countries, health expenditures have not kept pace with the overall economic growth, and health systems remain weak. These already inadequate systems are being further stressed by the epidemiologic transition that is taking place, characterized by a slow decrease in communicable diseases and an increase in noninfectious chronic diseases, resulting in a "double burden" of infectious and noninfectious diseases. Respiratory diseases comprise the largest category of illness within this combined burden of disease. Although there are chronic respiratory disease programs of proven effectiveness appropriate for LMICs, implementation has been greatly hampered by the lack of physicians who have special knowledge and skills in addressing the full spectrum of lung diseases. Thus, there is an urgent need to create training programs for specialists in respiratory diseases. Such programs should be developed and conducted by institutions in LMICs and tailored to fit the prevailing circumstances of the country. Existing curriculum blueprints may be used to guide training program development with appropriate modifications. Academic institutions and professional societies in high-income countries may be called upon to provide technical assistance in developing and implementing training programs. In order to better define the burden of respiratory diseases and identify effective interventions, research, moved forward by persons committed and specialized in this area of health, will be essential.

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.

Updating the International Standards for Tuberculosis Care. Entering the era of molecular diagnostics.

The International Standards for Tuberculosis Care, first published in 2006 (Lancet Infect Dis 2006;6:710-725.) with a second edition in 2009 ( www.currytbcenter.ucsf.edu/international/istc_report ), was produced by an international coalition of organizations funded by the United States Agency for International Development. Development of the document was led jointly by the World Health Organization and the American Thoracic Society, with the aim of promoting engagement of all care providers, especially those in the private sector in low- and middle-income countries, in delivering high-quality services for tuberculosis. In keeping with World Health Organization recommendations regarding rapid molecular testing, as well as other pertinent new recommendations, the third edition of the Standards has been developed. After decades of dormancy, the technology available for tuberculosis care and control is now rapidly evolving. In particular, rapid molecular testing, using devices with excellent performance characteristics for detecting Mycobacterium tuberculosis and rifampin resistance, and that are practical and affordable for use in decentralized facilities in low-resource settings, is being widely deployed globally. Used appropriately, both within tuberculosis control programs and in private laboratories, these devices have the potential to revolutionize tuberculosis care and control, providing a confirmed diagnosis and a determination of rifampin resistance within a few hours, enabling appropriate treatment to be initiated promptly. Major changes have been made in the standards for diagnosis. Additional important changes include: emphasis on the recognition of groups at increased risk of tuberculosis; updating the standard on antiretroviral treatment in persons with tuberculosis and human immunodeficiency virus infection; and revising the standard on treating multiple drug-resistant tuberculosis.

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.

The high cost of free tuberculosis services: patient and household costs associated with tuberculosis care in Ebonyi State, Nigeria.

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.