Use of Interferon-Gamma Release Assays in Children <2 Years Old.

While interferon-gamma release assays (IGRAs) are widely used for detecting tuberculosis (TB) infection, tuberculin skin tests (TSTs) remain preferred for children under the age of 2 years. The preference for TST stems from concern over IGRA sensitivity in young children. However, TSTs are susceptible to false-positive results following Bacille Calmette-Guérin (BCG) vaccination, which is common in infancy, and exposure to nontuberculous mycobacteria. We reviewed available data for IGRA performance in children under age 2 years. Across four cohorts of high-risk children under age 2 (mostly case contacts or those born in tuberculosis endemic regions), 0 of 575 untreated children with negative IGRA test results progressed to tuberculosis disease-including 0 of 70 who were TST positive but IGRA negative. While neither TSTs nor IGRAs are perfectly sensitive for the diagnosis of tuberculosis infection, IGRAs are an acceptable alternative to TST in children <2 years of age.

Implementation of Bedaquiline, Pretomanid, and Linezolid in the United States: Experience Using a Novel All-Oral Treatment Regimen for Treatment of Rifampin-Resistant or Rifampin-Intolerant Tuberculosis Disease.

BACKGROUND: Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring. METHODS: Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring. RESULTS: Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months. CONCLUSIONS: BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.

Novel 6-Month Treatment for Drug-Resistant Tuberculosis, United States.

The US Food and Drug Administration approved a 6-month regimen of pretomanid, bedaquiline, and linezolid for extensively drug-resistant or multidrug-intolerant tuberculosis after a trial in South Africa demonstrated 90% effectiveness 6 months posttreatment. We report on a patient who completed the regimen using a lower linezolid dose.

Measuring child survival for the Millennium Development Goals in Africa: what have we learned and what more is needed to evaluate the Sustainable Development Goals?

Reducing child mortality is a key global health challenge. We examined reasons for greater or lesser success in meeting under-five mortality rate reductions, i.e. Millennium Development Goal #4, between 1990 and 2015 in Sub-Saharan Africa where child mortality remains high. We first examined factors associated with child mortality from all World Health Organization African Region nations during the Millennium Development Goal period. This analysis was followed by case studies of the facilitators and barriers to Millennium Development Goal #4 in four countries - Kenya, Liberia, Zambia, and Zimbabwe. Quantitative indicators, policy documents, and qualitative interviews and focus groups were collected from each country to examine factors within and across countries related to child mortality. We found familiar themes that highlighted the need for both specific services (e.g. primary care access, emergency obstetric and neonatal care) and general management (e.g. strong health governance and leadership, increasing community health workers, quality of care). We also identified methodological opportunities and challenges to assessing progress in child health, which can provide insights to similar efforts during the Sustainable Development Goal period. Specifically, it is important for countries to adapt general international goals and measurements to their national context, considering baseline mortality rates and health information systems, to develop country-specific goals. It will also be critical to develop more rigorous measurement tools and indicators to accurately characterize maternal, neonatal, and child health systems, particularly in the area of governance and leadership. Valuable lessons can be learned from Millennium Development Goal successes and failures, as well as how they are evaluated. As countries seek to lower child mortality further during the Sustainable Development Goal period, it will be necessary to prioritize and support countries in quantitative and qualitative data collection to assess and contextualize progress, identifying areas needing improvement.

Tuberculosis in the United States: Medical Consultation Services Provided by 5 Tuberculosis Regional Training and Medical Consultation Centers, 2013-2017.

With only 9105 new US tuberculosis (TB) cases reported in 2017, expert consultation is essential for TB care. Data were captured 2013-2017 from consultations by 5 CDC-funded centers, now the TB Centers of Excellence (COEs). 14 586 consultations were provided to TB providers, most related to TB disease and treatment regimens.

Promoting progress in child survival across four African countries: the role of strong health governance and leadership in maternal, neonatal and child health.

Despite numerous international and national efforts, only 12 countries in the World Health Organization's African Region met the Millennium Development Goal #4 (MDG#4) to reduce under-five mortality by two-thirds by 2015. Given the variability across sub-Saharan Africa, a four-country study was undertaken to examine barriers and facilitators of child survival prior to 2015. Liberia and Zambia were chosen to represent countries making substantial progress towards MDG#4, while Kenya and Zimbabwe represented countries making less progress. Our individual case studies suggested that strong health governance and leadership (HGL) was a significant driver of the greater success in Liberia and Zambia compared with Kenya and Zimbabwe. To elucidate specific components of national HGL that may have substantially influenced the pace of reductions in child mortality, we conducted a cross-country analysis of national policies and strategies pertaining to maternal, neonatal and child health (MNCH) and qualitative interviews with individuals working in MNCH in each of the four study countries. The three aspects of HGL identified in this study which most consistently contributed to the different progress towards MDG#4 among the four study countries were (1) establishing child survival as a top national priority backed by a comprehensive policy and strategy framework and sufficient human, financial and material resources; (2) bringing together donors, strategic partners, health and non-health stakeholders and beneficiaries to collaborate in strategic planning, decision-making, resource-allocation and coordination of services; and (3) maintaining accountability through a 'monitor-review-act' approach to improve MNCH. Although child mortality in sub-Saharan Africa remains high, this comparative study suggests key health leadership and governance factors that can facilitate reduction of child mortality and may prove useful in tackling current Sustainable Development Goals.

Factors influencing rapid progress in child health in post-conflict Liberia: a mixed methods country case study on progress in child survival, 2000-2013.

OBJECTIVES: Only 12 countries in the WHO's African region met Millennium Development Goal 4 (MDG 4) to reduce under-five mortality by two-thirds by 2015. Given the variability across the African region, a four-country mixed methods study was undertaken to examine barriers and facilitators of child survival prior to 2015. Liberia was selected for an in-depth case study due to its success in reducing under-five mortality by 73% and thus successfully meeting MDG 4. Liberia's success was particularly notable given the civil war that ended in 2003. We examined some factors contributing to their reductions in under-five mortality. DESIGN: A case study mixed methods approach drawing on data from quantitative indicators, national documents and qualitative interviews was used to describe factors that enabled Liberia to rebuild their maternal, neonatal and child health (MNCH) programmes and reduce under-five mortality following the country's civil war. SETTING: The interviews were conducted in Monrovia (Montserrado County) and the areas in and around Gbarnga, Liberia (Bong County, North Central region). PARTICIPANTS: Key informant interviews were conducted with Ministry of Health officials, donor organisations, community-based organisations involved in MNCH and healthcare workers. Focus group discussions were conducted with women who have experience accessing MNCH services. RESULTS: Three prominent factors contributed to the reduction in under-five mortality: national prioritisation of MNCH after the civil war; implementation of integrated packages of services that expanded access to key interventions and promoted intersectoral collaborations; and use of outreach campaigns, community health workers and trained traditional midwives to expand access to care and improve referrals. CONCLUSIONS: Although Liberia experiences continued challenges related to limited resources, Liberia's effective strategies and rapid progress may provide insights for reducing under-five mortality in other post-conflict settings.

The introduction of new policies and strategies to reduce inequities and improve child health in Kenya: A country case study on progress in child survival, 2000-2013.

As of 2015, only 12 countries in the World Health Organization's AFRO region had met Millennium Development Goal #4 (MDG#4) to reduce under-five mortality by two-thirds by 2015. Given the variability across the African region, a four-country study was undertaken to examine barriers and facilitators of child survival prior to 2015. Kenya was one of the countries selected for an in-depth case study due to its insufficient progress in reducing under-five mortality, with only a 28% reduction between 1990 and 2013. This paper presents indicators, national documents, and qualitative data describing the factors that have both facilitated and hindered Kenya's efforts in reducing child mortality. Key barriers identified in the data were widespread socioeconomic and geographic inequities in access and utilization of maternal, neonatal, and child health (MNCH) care. To reduce these inequities, Kenya implemented three major policies/strategies during the study period: removal of user fees, the Kenya Essential Package for Health, and the Community Health Strategy. This paper uses qualitative data and a policy review to explore the early impacts of these efforts. The removal of user fees has been unevenly implemented as patients still face hidden expenses. The Kenya Essential Package for Health has enabled construction and/or expansion of healthcare facilities in many areas, but facilities struggle to provide Emergency Obstetric and Neonatal Care (EmONC), neonatal care, and many essential medicines and commodities. The Community Health Strategy appears to have had the most impact, improving referrals from the community and provision of immunizations, malaria prevention, and Prevention of Mother-to-Child Transmission of HIV. However, the Community Health Strategy is limited by resources and thus also unevenly implemented in many areas. Although insufficient progress was made pre-2015, with additional resources and further scale-up of new policies and strategies Kenya can make further progress in child survival.

Improving access to child health services at the community level in Zambia: a country case study on progress in child survival, 2000-2013.

Reductions in under-five mortality in Africa have not been sufficient to meet the Millennium Development Goal #4 (MDG#4) of reducing under-five mortality by two-thirds by 2015. Nevertheless, 12 African countries have met MDG#4. We undertook a four country study to examine barriers and facilitators of child survival prior to 2015, seeking to better understand variability in success across countries. The current analysis presents indicator, national document, and qualitative data from key informants and community women describing the factors that have enabled Zambia to successfully reduce under-five mortality over the last 15 years and achieve MDG#4. Results identified a Zambian national commitment to ongoing reform of national health strategic plans and efforts to ensure universal access to effective maternal, neonatal and child health (MNCH) interventions, creating an environment that has promoted child health. Zambia has also focused on bringing health services as close to the family as possible through specific community health strategies. This includes actively involving community health workers to provide health education, basic MNCH services, and linking women to health facilities, while supplementing community and health facility work with twice-yearly Child Health Weeks. External partners have contributed greatly to Zambia's MNCH services, and their relationships with the government are generally positive. As government funding increases to sustain MNCH services, national health strategies/plans are being used to specify how partners can fill gaps in resources. Zambia's continuing MNCH challenges include basic transportation, access-to-care, workforce shortages, and financing limitations. We highlight policies, programs, and implementation that facilitated reductions in under-five mortality in Zambia. These findings may inform how other countries in the African Region can increase progress in child survival in the post-MDG period.

Treatment of Latent Tuberculosis Infection.

There are approximately 56 million people who harbor Mycobacterium tuberculosis that may progress to active tuberculosis (TB) at some point in their lives. Modeling studies suggest that if only 8% of these individuals with latent TB infection (LTBI) were treated annually, overall global incidence would be 14-fold lower by 2050 compared to incidence in 2013, even in the absence of additional TB control measures. This highlights the importance of identifying and treating latently infected individuals, and that this intervention must be scaled up to achieve the goals of the Global End TB Strategy. The efficacy of LTBI treatment is well established, and the most commonly used regimen is 9 months of daily self-administered isoniazid. However, its use has been hindered by limited provider awareness of the benefits, concern about potential side effects such as hepatotoxicity, and low rates of treatment completion. There is increasing evidence that shorter rifamycin-based regimens are as effective, better tolerated, and more likely to be completed compared to isoniazid. Such regimens include four months of daily self-administered rifampin monotherapy, three months of once weekly directly observed isoniazid-rifapentine, and three months of daily self-administered isoniazid-rifampin. The success of LTBI treatment to prevent additional TB disease relies upon choosing an appropriate regimen individualized to the patient, monitoring for potential adverse clinical events, and utilizing strategies to promote adherence. Safer, more cost-effective, and more easily completed regimens are needed and should be combined with interventions to better identify, engage, and retain high-risk individuals across the cascade from diagnosis through treatment completion of LTBI.

Impact of a critical health workforce shortage on child health in Zimbabwe: a country case study on progress in child survival, 2000-2013.

Despite notable progress reducing global under-five mortality rates, insufficient progress in most sub-Saharan African nations has prevented the achievement of Millennium Development Goal four (MDG#4) to reduce under-five mortality by two-thirds between 1990 and 2015. Country-level assessments of factors underlying why some African countries have not been able to achieve MDG#4 have not been published. Zimbabwe was included in a four-country study examining barriers and facilitators of under-five survival between 2000 and 2013 due to its comparatively slow progress towards MDG#4. A review of national health policy and strategy documents and analysis of qualitative data identified Zimbabwe's critical shortage of health workers and diminished opportunities for professional training and education as an overarching challenge. Moreover, this insufficient health workforce severely limited the availability, quality, and utilization of life-saving health services for pregnant women and children during the study period. The impact of these challenges was most evident in Zimbabwe's persistently high neonatal mortality rate, and was likely compounded by policy gaps failing to authorize midwives to deliver life-saving interventions and to ensure health staff make home post-natal care visits soon after birth. Similarly, the lack of a national policy authorizing lower-level cadres of health workers to provide community-based treatment of pneumonia contributed to low coverage of this effective intervention and high child mortality. Zimbabwe has recently begun to address these challenges through comprehensive policies and strategies targeting improved recruitment and retention of experienced senior providers and by shifting responsibility of basic maternal, neonatal and child health services to lower-level cadres and community health workers that require less training, are geographically broadly distributed, and are more cost-effective, however the impact of these interventions could not be assessed within the scope and timeframe of the current study.

High HIV prevalence and the internet as a source of HIV-related service information at a community-based organization in Peru: a cross-sectional study of men who have sex with men.

BACKGROUND: The HIV prevalence among men who have sex with men (MSM) in Peru (12.4 %) is 30 times higher than in the general adult population (0.4 %). It is critical for community-based organizations to understand how to provide HIV services to MSM while maximizing limited resources. This study describes the HIV prevalence and risk profiles of MSM seeking HIV services at a community-based organization in Lima, Peru. It then compares HIV prevalence between those who found out about the HIV services through different sources. METHODS: A cross-sectional study of MSM seeking HIV services at Epicentro Salud in Lima, Peru for the first time between April 2012 and October 2013. We compared HIV prevalence among MSM who found out about Epicentro via online sources of information (N = 419), those using in-person sources (friends, partners) (N = 907), and sex workers (N = 140) using multivariable logistic regression models. RESULTS: HIV prevalence was 18.3 % overall: 23.2 % among MSM using online sources, 19.3 % among sex workers, and 15.9 % among MSM using in-person sources. However, when compared to the in-person group, sexual risk behaviors were not statistically higher among MSM using online sources. For the sex worker group, some behaviors were more common, while others were less. After adjusting for confounders, the odds of having HIV was higher for the online group (Odds Ratio = 1.61; 95 % Confidence Interval: 1.19-2.18), but not for the sex worker group (OR = 1.12; 95 % CI: 0.68-1.86), compared to the in-person group. CONCLUSION: Internet-based promotion appears to successfully reach MSM at high risk of HIV in Peru. Outreach via this medium can facilitate HIV diagnosis, which is the critical first step in getting infected individuals into HIV care. For community-based organizations working in resource-limited settings, this may be an effective strategy for engaging a subset of high-risk persons in HIV care.

Factors associated with declining under-five mortality rates from 2000 to 2013: an ecological analysis of 46 African countries.

OBJECTIVE: Inadequate overall progress has been made towards the 4th Millennium Development Goal of reducing under-five mortality rates by two-thirds between 1990 and 2015. Progress has been variable across African countries. We examined health, economic and social factors potentially associated with reductions in under-five mortality (U5M) from 2000 to 2013. SETTING: Ecological analysis using publicly available data from the 46 nations within the WHO African Region. OUTCOME MEASURES: We assessed the annual rate of change (ARC) of 70 different factors and their association with the annual rate of reduction (ARR) of U5M rates using robust linear regression models. RESULTS: Most factors improved over the study period for most countries, with the largest increases seen for economic or technological development and external financing factors. The median (IQR) U5M ARR was 3.6% (2.8 to 5.1%). Only 4 of 70 factors demonstrated a strong and significant association with U5M ARRs, adjusting for potential confounders. Higher ARRs were associated with more rapidly increasing coverage of seeking treatment for acute respiratory infection (ß=0.22 (ie, a 1% increase in the ARC was associated with a 0.22% increase in ARR); 90% CI 0.09 to 0.35; p=0.01), increasing health expenditure relative to gross domestic product (ß=0.26; 95% CI 0.11 to 0.41; p=0.02), increasing fertility rate (ß=0.54; 95% CI 0.07 to 1.02; p=0.07) and decreasing maternal mortality ratio (ß=-0.47; 95% CI -0.69 to -0.24; p<0.01). The majority of factors showed no association or raised validity concerns due to missing data from a large number of countries. CONCLUSIONS: Improvements in sociodemographic, maternal health and governance and financing factors were more likely associated with U5M ARR. These underscore the essential role of contextual factors facilitating child health interventions and services. Surveillance of these factors could help monitor which countries need additional support in reducing U5M.

Moving toward tuberculosis elimination: implementation of statewide targeted tuberculin testing in Tennessee.

RATIONALE: From 1993 to 2010, annual U.S. tuberculosis (TB) rates declined by 58%. However, this decline has slowed and disproportionately occurred among U.S.-born (78%) versus foreign-born persons (47%). Addressing the high burden of latent TB infection (LTBI) must be prioritized. OBJECTIVES: Only Tennessee has implemented a statewide program for finding and treating people with LTBI. The program was designed to address high statewide TB rates and growing burden among the foreign-born. We sought to assess the feasibility and yield of Tennessee's program. METHODS: Analyzing data from the 4.8-year period from program inception in March 2002 through December 2006, we quantified patients screened using a TB risk assessment tool, tuberculin skin tests (TST) placed and read, TST results, and patients initiating and completing LTBI treatment. We then estimated the number needed to screen to find and treat one person with LTBI and to prevent one case of TB. MEASUREMENTS AND MAIN RESULTS: Of 168,517 persons screened, 102,709 had a TST placed and read. Among 9,090 (9%) with a positive TST result, 53% initiated treatment, 54% of whom completed treatment. An estimated 195 TB cases were prevented over the 4.8 years analyzed, and program performance measures improved annually. The number of TSTs placed to prevent one TB case ranged from 150 for foreign-born persons to 9,834 for persons without TB risk. CONCLUSIONS: Targeted tuberculin testing and LTBI treatment is feasible and likely to reduce TB rates over time. Yield and cost-effectiveness are maximized by prioritizing foreign-born persons, a large population with high TB risk.

Risk-based screening for latent tuberculosis infection.

BACKGROUND: National guidelines recommend targeted tuberculin testing and treatment of latent tuberculosis infection (LTBI) among high-risk groups but discourage testing low-risk persons. METHODS: We determined the LTBI prevalence (tuberculin skin test [TST] reaction > or = 10 mm) among adults with and without TB exposure risk factors screened in Tennessee from 1/2/2002 to 4/19/2005. We then quantified LTBI risk among groups at high-risk for TB using multivariate analysis. RESULTS: Of 53,061 adults tested, the LTBI prevalence was 34% among foreign-born persons, compared with 3.2% among nonforeign-born persons (prevalence odds ratio [POR] 15.7, 95% confidence interval [CI] 14.5-16.8). Among nonforeign-born adults, Asian race (POR 11.7, 95% CI 5.9-23.4), and Hispanic ethnicity (POR 11.7, 95% CI 9.0-15.2) were most strongly associated with LTBI. Only 2.4% of low-risk persons had LTBI. CONCLUSIONS: Risk-based screening can effectively distinguish persons who will benefit from LTBI testing and treatment. Targeted testing programs should prioritize foreign-born persons. Testing of low-risk persons is unnecessary.

Tuberculosis among foreign-born persons in the United States: achieving tuberculosis elimination.

RATIONALE: In the United States, the number of annual reported cases of tuberculosis (TB) among U.S.-born persons declined by 62% from 1993 to 2004, but increased by 5% among foreign-born persons. Over half of all reported cases of TB in the United States occur among foreign-born persons, most of these due to activation of latent TB infection (LTBI). Current guidelines recommend targeting only foreign-born persons who entered the United States within the previous 5 yr for LTBI testing. OBJECTIVE: We sought to assess the epidemiologic basis for this guideline. METHODS: We calculated TB case rates among foreign-born persons, stratified by duration of United States residence and world region of origin. We determined the number of cases using 2004 U.S. TB surveillance data, and calculated case rates using population data from the 2004 American Community Survey. MEASUREMENTS AND MAIN RESULTS: In 2004, a total of 14,517 cases of TB were reported; 3,444 (24%) of these were among foreign-born persons who had entered the United States more than 5 yr previously. The rate of TB disease among foreign-born persons was 21.5/100,000, compared with 2.7/100,000 for U.S.-born persons, and varied by duration of residence and world region of origin. CONCLUSIONS: Almost one-quarter of all TB cases in the United States occur among foreign-born persons who have resided in the United States for longer than 5 yr; case rates for such persons from selected regions of origin remain substantially elevated. To eliminate TB, we must address the burden of LTBI in this high-risk group.

Use of intermittent rifampin and pyrazinamide therapy for latent tuberculosis infection in a targeted tuberculin testing program.

BACKGROUND: To determine the rates of hepatotoxicity and treatment completion associated with intermittent rifampin and pyrazinamide (RZ) therapy for latent tuberculosis infection, we evaluated a cohort of patients from a targeted tuberculin testing site in Tennessee. METHODS: From 4 February 2000 through 9 November 2001, a total of 423 patients with latent tuberculosis infection received directly observed preventive therapy (DOPT) with RZ given twice weekly for 2 months. Most of the patients were young, Hispanic males who had recently immigrated to the United States. RESULTS: During treatment, hepatotoxicity developed in 29 patients (6.9%; hereafter referred to as "case patients"), and peak alanine aminotransferase (ALT) levels that were >10 times the upper limit of normal were noted in 18 case patients. Of the case patients, 14 had asymptomatic hepatotoxicity, and 2 required hospitalization; none of the case patients died. Hepatotoxicity developed after the receipt of 12 doses in more than half of the case patients, and 4 case patients received all 16 doses. The risk of RZ-associated hepatotoxicity was independently associated with older age (odds ratio [OR], 1.07 per year; P=.01). In total, 352 patients (83.2%) completed RZ therapy. The strongest predictors for noncompletion of RZ treatment were the development of a clinical symptom (OR, 9.73; P<.001) and older age (OR, 1.08 per year; P=.001). CONCLUSIONS: Despite the use of DOPT, intermittent dosing, and vigilant monitoring throughout therapy, RZ was associated with an unacceptable risk of hepatotoxicity.