Adverse events among persons with TB using in-person vs. electronic directly observed therapy.

BACKGROUND: We evaluated patient safety within a randomized crossover trial comparing electronic directly observed therapy (eDOT) to in-person DOT (ipDOT) in persons undergoing TB treatment in New York City, NY, USA.METHODS: Participant symptoms, symptom severity, and clinical management were documented. We assessed adverse event reports (AERs) by DOT method during the two-period crossover. Using Cox proportional-hazards mixed-effects models, we estimated the adjusted hazard ratio (aHR) of participants reporting an adverse event (AE) vs. not reporting an AE.RESULTS: Of 211 participants, 57 (27.0%) reported AEs during the two-period crossover; of these, 54.4% (31/57) were reported while using eDOT vs. 45.6% (26/57) while using ipDOT. Controlling for study group and period, the aHR for eDOT vs. ipDOT was 0.98 (95% CI 0.49-1.93). Although statistically not significant, the wide confidence intervals suggest that a significant association cannot be entirely ruled out. Gastrointestinal symptoms were most frequently reported (42.1%, 24/57). AER types and severity did not differ significantly by DOT method. Days from symptom onset to medical attention was similar across DOT methods (median: 1.0 day, IQR 0.0-2.0). No participants switched DOT methods due to AERs or monitoring concerns.CONCLUSION: Further evaluation to ascertain whether AERs differ when patients use eDOT vs. ipDOT is warranted.

Strategic response to COVID-19 in Ethiopia.

COVID-19, the novel coronavirus, has posed a major threat to low- and middle-income countries (LMICs) due to inadequate health infrastructure and human resources. Ethiopia, a low-income country with the second largest population in Africa, has coordinated a strategic response, leveraging existing infrastructure and health systems and mobilizing public health professionals and specialist expert physicians for a multifaceted, unified government approach and adaptive response. Resource limitations, particularly in critical care, have still posed challenges, but the public health and clinical interventions thus far have prevented the catastrophic toll that many predicted. As the pandemic continues, Ethiopia expects to use a triple care model integrated at all levels, consisting of COVID-19 care, isolation care for suspected cases, and essential health services, and urges intensified non-pharmaceutical interventions alongside equitable global vaccine distribution as the ultimate answers to pandemic control. This paper draws on existing data, national planning and guidelines, and expertise from health leadership to describe this response in hopes of providing an example of how future large-scale health challenges might be faced in LMICs, using Ethiopia's successes and challenges in facing the pandemic.

COVID-19, le nouveau coronavirus, a représenté une menace majeure pour les pays à revenu faible et intermédiaire (LMIC) en raison de l'insuffisance des infrastructures de santé et des ressources humaines. L'Éthiopie, un pays à faible revenu dont la population est la deuxième plus importante d'Afrique, a coordonné une réponse stratégique, en tirant parti des infrastructures et des systèmes de santé existants et en mobilisant des professionnels de la santé publique et des médecins experts spécialisés pour une approche gouvernementale unifiée à multiples facettes et une réponse adaptative. Les ressources limitées, notamment en matière de soins intensifs, ont encore posé des problèmes, mais les interventions cliniques et de santé publique menées jusqu'à présent ont permis d'éviter le bilan catastrophique que beaucoup prédisaient. Alors que la pandémie se poursuit, l'Éthiopie prévoit d'utiliser un modèle de soins triple intégré à tous les niveaux, composé de soins COVID-19, de soins d'isolement pour les cas suspects et de services de santé essentiels, et préconise l'intensification des interventions non pharmaceutiques parallèlement à une distribution équitable des vaccins à l'échelle mondiale comme réponses ultimes au contrôle de la pandémie. Cet article s'appuie sur les données existantes, la planification et les directives nationales, et l'expertise des responsables de la santé pour décrire cette réponse dans l'espoir de fournir un exemple de la manière dont les futurs défis sanitaires à grande échelle pourraient être relevés dans les LMIC, en utilisant les succès et les défis de l'Éthiopie face à la pandémie.

Risks for tuberculosis in Kazakhstan: implications for prevention.

SETTING: Four regions in Kazakhstan where participants were recruited from June 2012 to May 2014. OBJECTIVE: To examine associations between incarceration history and tobacco, alcohol, and drug consumption, and human immunodeficiency virus (HIV) infection and diabetes mellitus (DM) with TB. DESIGN: This matched case-control study included 1600 participants who completed a survey on sociodemographics, history of incarceration, tobacco, alcohol and drug use, and HIV and DM diagnosis. Conditional logistic regression analysis was used to examine associations between a TB diagnosis and risk factors. RESULTS: Participants who had ever smoked tobacco (aOR 1.73, 95%CI 1.23-2.43, P  0.01), ever drank alcohol (aOR 1.41, 95%CI 1.03-1.93, P  0.05), were HIV-positive (aOR 36.37, 95%CI 2.05-646.13, P  0.05) or had DM (aOR 13.96, 95%CI 6.37-30.56, P  0.01) were more likely to have TB. CONCLUSIONS: The association between TB and tobacco use, alcohol use, HIV and DM in Kazakhstan suggests a need for comprehensive intervention and prevention approaches that also address tobacco and alcohol use, DM and HIV.

Successfully treated but not fit for purpose: paying attention to chronic lung impairment after TB treatment.

In 2013, 86% of patients with newly diagnosed tuberculosis (TB) successfully completed treatment and were discharged from care. However, long-term studies in industrialised and resource-poor countries all point to a higher risk of death in TB survivors than in the general population. The likely explanation is chronic restrictive and obstructive lung disease consequent to TB. We call for better linkages between TB control programmes and respiratory medicine services, a better understanding of the burden of respiratory disability at the end of anti-tuberculosis treatment, and political, programmatic, clinical and research action to improve the quality of life of affected patients.

Tuberculosis report among injection drug users and their partners in Kazakhstan.

OBJECTIVES: Tuberculosis (TB) is a major threat to global public health. Kazakhstan has the second highest percentage of multidrug-resistant tuberculosis (MDR-TB) cases among incident tuberculosis cases in the world (WHO 2013). A high burden of MDR-TB suggests TB prevention, control, and treatment programs are failing. This study provides an epidemiologic profile of TB among injection drug users (IDUs), a high-risk and chronically underserved population, in Kazakhstan. STUDY DESIGN: Cross-sectional study. METHODS: The authors studied the characteristics and risk environment of IDUs with self-reported previous active TB and their primary sexual partners in Almaty, Kazakhstan. 728 individuals (364 couples) participated in a couple-based study in 2009. RESULTS: 16.75% of participants reported at least one positive TB test (x-ray) in their lifetime. In a multivariable logistic regression adjusting for couple-based sampling, persons with positive TB test were significantly more likely to be older (odds ratio (OR) 7.26, 95% confidence interval (CI): 1.73, 30.43), male (OR 5.53, 95% CI: 2.74, 11.16), have a shorter duration of injection drug use (OR 0.17, 95% CI: 0.04, 0.65), have received high social support from their significant other (OR 2.13, 95% CI: 1.03, 4.40) and more likely (non-significantly) to have been incarcerated (OR 7.03, 95% CI: 0.64, 77.30). CONCLUSIONS: Older men with a history of incarceration and recent injection drug use were more likely to have positive TB test in Kazakhstan. Social network support, while potentially positive for many aspects of population health, may increase risk of TB among IDUs in this context. Public health policies that target high-risk populations and their at-risk networks may be necessary to stem the rise of MDR-TB in Central Asia.

Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report.

Mycobacterium tuberculosis is a ubiquitous organism that infects one-third of the world's population. In previous decades, access to organ transplantation was restricted to academic medical centers in more developed, low tuberculosis (TB) incidence countries. Globalization, changing immigration patterns, and the expansion of sophisticated medical procedures to medium and high TB incidence countries have made tuberculosis an increasingly important posttransplant infectious disease. Tuberculosis is now one of the most common bacterial causes of solid-organ transplant donor-derived infection reported in transplant recipients in the United States. Recognition of latent or undiagnosed active TB in the potential organ donor is critical to prevent emergence of disease in the recipient posttransplant. Donor-derived tuberculosis after transplantation is associated with significant morbidity and mortality, which can best be prevented through careful screening and targeted treatment. To address this growing challenge and provide recommendations, an expert international working group was assembled including specialists in transplant infectious diseases, transplant surgery, organ procurement and TB epidemiology, diagnostics and management. This working group reviewed the currently available data to formulate consensus recommendations for screening and management of TB in organ donors.

Preventing the next generation of extensively drug-resistant tuberculosis.

Multidrug-resistant and extremely drug-resistant tuberculosis strains threaten to become an intractable problem. Misuse of antibiotics and inadequacy of diagnostic tools have fostered drug resistance. Effective diagnostic technology would eliminate this problem, but it remains unavailable in high-burden areas. New drugs with novel targets may help combat drug resistance. However, if added singly to existing combination regimens, resistance will increase. To protect the efficacy of a new drug, it should first be used only as a second-line drug, in cases that have undergone drug susceptibility testing. Widespread use of new drugs as first-line agents would follow with the dawn of a new rapid diagnostic era.

Tuberculosis following solid organ transplantation.

BACKGROUND: Organ transplantation places patients at risk for tuberculosis (TB), which constitutes a challenge to physicians due to its atypical and extrapulmonary presentations, complicated treatment issues, and high morbidity and mortality. METHODS: We identified all patients with TB following solid organ transplantation at a large university medical center in New York. Demographic data, transplant characteristics (type of organ and donor), underlying medical conditions, immunosuppressive drugs, rejection and opportunistic infections were analyzed, and a nested case-control study was performed to identify factors associated with the development of TB. RESULTS: From 1988 to 2007, 4925 transplants were performed at Columbia University Medical Center: 1858 kidney, 857 liver, 1714 heart, 460 lung, and 36 heart/lung. Thirteen patients developed TB, for a cumulative incidence of 264/100,000. Of the 13 patients who developed TB, 10 had a kidney transplant, 2 had a lung transplant, and 1 had a heart transplant. The median time to develop TB was 11.2 (interquartile ratio: 4.4-23.0) months following transplantation. These cases were compared with 52 randomly selected control patients who had transplants not complicated by TB. Patients with TB were more likely to be renal transplant recipients (adjusted odds ratio [OR]: 4.59; 95% confidence interval [CI]: 1.07-19.67) and to be non-Caucasians (adjusted OR: 3.94; 95% CI: 0.99-15.56) than controls. CONCLUSIONS: The incidence of TB in post-transplant patients is much higher than the overall background incidence in the United States. Non-Caucasian and kidney transplant recipients appear to be at increased risk of developing TB. This may be associated with prior exposure to TB before transplant in these populations.

The value of end-of-treatment chest radiograph in predicting pulmonary tuberculosis relapse.

SETTING: Patients with cavitary pulmonary tuberculosis (TB) on baseline chest radiograph (CXR) who remain culture-positive after 8 weeks of treatment are at high risk of relapse. The role of end-of-treatment (EOT) CXR in predicting relapse is unclear. OBJECTIVE: To determine whether EOT CXR independently predicts TB relapse. DESIGN: We conducted a secondary analysis of a randomized trial of intermittent treatment using rifapentine in the continuation phase of TB treatment among 1004 human immunodeficiency virus seronegative adults with culture-proven pulmonary TB. RESULTS: Relapse occurred in 17.3% of subjects with persistent cavity on EOT CXR, in 7.6% of subjects with a cavity that resolved by EOT, and 2.5% (P=0.002 for trend) of subjects who never had a cavity. In multivariable analysis, patients with persistent cavity on EOT CXR were significantly more likely to relapse than patients with no cavity on baseline or 2-month CXR (hazard ratio [HR] 4.22, 95%CI 2.00-8.91), and were more likely to relapse than subjects whose early cavity had resolved by EOT CXR (HR 1.92, 95%CI 1.09-3.39). CONCLUSION: A persistent cavity after 6 months of TB treatment was independently associated with disease relapse after controlling for other variables. EOT CXR may help predict those likely to relapse.

Mortality in a large tuberculosis treatment trial: modifiable and non-modifiable risk factors.

SETTING: North America. OBJECTIVES: Tuberculosis (TB) patients in North America often have characteristics that may increase overall mortality. Identifying modifiable risk factors would allow for improvements in outcome. DESIGN: We evaluated mortality in a large TB treatment trial conducted in the United States and Canada. Persons with culture-positive pulmonary TB were enrolled after 2 months of treatment, treated for 4 more months under direct observation, and followed for 2 years (total observation: 28 months). Cause of death was determined by death certificate, autopsy, and/or clinical observation. RESULTS: Of 1075 participants, 71 (6.6%) died: 15/71 (21.1%) HIV-infected persons, and 56/1004 (5.6%) non-HIV-infected persons (P < 0.001). Only one death was attributed to TB. Cox multivariate regression analysis identified four independent risk factors for death after controlling for age: malignancy (hazard ratio [HR] 5.28, P < 0.0001), HIV (HR 3.89, P < 0.0001), daily alcohol (HR 2.94, P < 0.0001), and being unemployed (HR 1.99, P = 0.01). The risk of death increased with the number of independent risk factors present (P < 0.0001). Extent of disease and treatment failure/relapse were not associated with an increased risk of death. CONCLUSIONS: Death due to TB was rare. Interventions to treat malignancy, HIV, and alcohol use in TB patients are needed to reduce mortality in this patient population.

DOT and timely treatment completion among Asian-born immigrant tuberculosis patients.

SETTING: A large urban tuberculosis (TB) control program. OBJECTIVES: To identify factors associated with directly observed therapy (DOT) participation and to quantify how early use of DOT affected treatment duration. DESIGN: A retrospective study of 731 Asian-born patients with drug-susceptible Mycobacterium tuberculosis isolates who were verified in New York City between 1993 and 1997 and completed treatment. RESULTS: Overall, 297 (41%) of 731 patients in the study participated in DOT for some or all of their TB treatment. DOT participation was significantly associated with TB disease in a pulmonary site (adjusted odds ratio [aOR] 2.85, 95% CI 1.86-4.35), more recent year of diagnosis (aOR 1.70, 95% CI 1.50-1.94) and male sex (aOR 1.86, 95% CI 1.30-2.66). Patients who received > or = 70% of their TB treatment at a health department chest clinic were also significantly more likely to participate in DOT (aOR 3.83, 95% CI 2.55-5.74). Among 297 DOT patients, those who completed treatment by 9 months received a greater amount of treatment by DOT during the first 4 months of treatment than those who took longer to complete treatment. CONCLUSION: Earlier DOT participation can lead to overall shorter treatment duration. Health care providers should encourage TB patients to participate in DOT as early as possible in their TB treatment.

Transmission trends for human immunodeficiency virus associated tuberculosis in New York City.

SETTING: Since 1992, tuberculosis (TB) control measures have reduced incidence rates in New York City and elsewhere. Nevertheless, trends have not been uniform in all demographic groups. OBJECTIVE: To characterize the epidemiology of human immunodeficiency virus (HIV) associated TB in New York during the 1990s, we analyzed social, demographic and clinical characteristics and genetic data on Mycobacterium tuberculosis isolates among persons with known HIV-status. DESIGN: A retrospective case-control study to compare patients with HIV-associated TB and patients with TB alone. RESULTS: Of 546 patients (70.5%) in the Department of Health Tuberculosis Control Registry treated for TB, 385 also had documented HIV status; 198 were HIV-infected (51%) and 187 (49%) were not. Genotype analysis of the 385 M. tuberculosis isolates identified 200 (52%) clustered strains, representing recent transmission. Although the overall percentage of TB cases associated with restriction fragment length polymorphism (RFLP) clustering fell over the period studied, HIV-associated cases were still much more likely to be associated with clustering than non-HIV-associated cases. CONCLUSIONS: Continued attention is required to contain the spread of TB in this vulnerable population.

Recent advances in our understanding of human host responses to tuberculosis.

Tuberculosis remains one of the world's greatest public health challenges: 2 billion persons have latent infection, 8 million people develop active tuberculosis annually, and 2-3 million die. Recently, significant advances in our understanding of the human immune response against tuberculosis have occurred. The present review focuses on recent work in macrophage and T-cell biology that sheds light on the human immune response to tuberculosis. The role of key cytokines such as interferon-gamma is discussed, as is the role of CD4+ and CD8+ T cells in immune regulation in tuberculosis, particularly with regard to implications for vaccine development and evaluation.

What is the role of nitric oxide in murine and human host defense against tuberculosis?Current knowledge.

The production of reactive oxygen intermediates and reactive nitrogen intermediates by innate immune cells is considered to be an effective host-defense mechanism against microbial pathogens. In the murine model of tuberculosis (TB), nitric oxide (NO) plays an essential role in the killing of Mycobacterium tuberculosis by mononuclear phagocytes. For example, in the mouse strain with a genetic disruption for inducible NO synthase (iNOS-/-), infection with M. tuberculosis is associated with a significantly higher risk of dissemination and mortality. Although more controversial in humans, there is a growing body of evidence that NO produced by TB-infected macrophages and by epithelial cells also has antimycobacterial effects against M. tuberculosis. The precise mechanism(s) by which NO and other reactive nitrogen species antagonize M. tuberculosis is not known, but may involve disruption of bacterial DNA, proteins, signaling, and/or induction of apoptosis of macrophages that harbor mycobacteria. In addition to cytokines such as tumor necrosis factor-alpha and interleukin 1-beta, mycobacterial cell wall components such as lipoarabinomannan and 19 kD lipoprotein, along with the T-cell-derived interferon-gamma, may also induce NO expression. In a Darwinian fashion, it also appears that certain strains of M. tuberculosis have evolved strategies to combat the toxic effects of NO.

Tuberculosis and HIV infection: epidemiology, immunology, and treatment.

Tuberculosis and HIV have combined to present a major threat to global public health. Each disease has a negative effect on the other, and mortality in patients with both tuberculosis and HIV is higher than that caused by either condition alone. In regions such as sub-Saharan Africa, as many as a third or more of all patients with tuberculosis have concomitant HIV infection. In urban centers in developed nations, HIV co-infection may also be quite common. Treatment of latent tuberculosis infection in persons with HIV is successful in preventing many cases of active disease, and newer ultra-short course regimens, such as those consisting of 2 months of rifampin and pyrazinamide, should aid in this effort. Diagnosis and treatment of active tuberculosis in HIV-infected patients may be difficult. Although treatment of active tuberculosis is generally successful in patients with HIV, drug interactions between anti-tuberculosis medications and antiretrovirals often complicate the matter, and expert guidance should be sought for proper management.

Characterization of the secreted MPT53 antigen of Mycobacterium tuberculosis.

MPT53 is a secreted protein of Mycobacterium tuberculosis. Southern transfer and hybridization showed mpt53 to be conserved in the M. tuberculosis complex and to have homology with DNA from Mycobacterium avium and other nontuberculous mycobacteria. However, anti-MPT53 polyclonal antibodies detected no antigen in the culture filtrates of M. avium and other nontuberculous mycobacteria. MPT53 of M. tuberculosis induced strong, tuberculosis-specific antibody responses in guinea pigs but induced no delayed-type hypersensitivity. Involvement in immune responses during human tuberculosis was very modest.

The effects of increasing incentives on adherence to tuberculosis directly observed therapy.

SETTING: Six New York State Department of Health tuberculosis (TB) directly observed therapy (DOT) programs in public, private and community facilities in New York City. OBJECTIVE: A key feature of the TB DOT program was provision of incentives to motivate patients and increase adherence to therapy. The study hypothesis was that adherence will improve as the value of incentives increases and bonuses are added in a schedule of increasing rewards. DESIGN: The study population consisted of 365 patients in six inner city TB DOT programs. Interviews, clinical data and attendance records for 3+ years were analyzed. RESULTS: Patients who adhered (attending 80% of prescribed DOT visits each month of treatment) and those who did not were similar on seven demographic factors (e.g., age and sex), but were significantly different on clinical and social variables. Previous TB, resistance to rifampin, human immunodeficiency virus infection, psychiatric illness, homelessness, smoking and drug use were related to non-adherence. High adherence was significantly associated with fewer months in treatment (P < 0.016). Logistic regression showed that the odds that a patient would adhere to therapy were greater with increased incentives. Odds of adherence were significantly lower with rifampin resistance and psychiatric illness. CONCLUSION: Increasing incentives is associated with improved adherence to therapy in inner city TB populations.