S. Bertel Squire

Vulnerability to malaria, tuberculosis, and HIV/AIDS infection and disease. Part 1: determinants operating at individual and household level

A high burden of malaria, tuberculosis, and HIV infection contributes to national and individual poverty. We have reviewed a broad range of evidence detailing factors at individual, household, and community levels that influence vulnerability to malaria, tuberculosis, and HIV infection and used this evidence to identify strategies that could improve resilience to these diseases. This first part of the review explores the concept of vulnerability to infectious diseases and examines how age, sex, and genetics can influence the biological response to malaria, tuberculosis, and HIV infection. We highlight factors that influence processes such as poverty, livelihoods, gender discrepancies, and knowledge acquisition and provide examples of how approaches to altering these processes may have a simultaneous effect on all three diseases.

The Uptake and Accuracy of Oral Kits for HIV Self-Testing in High HIV Prevalence Setting: A Cross-Sectional Feasibility Study in Blantyre, Malawi

Augustine Choko and colleagues assess the uptake and acceptability of home-based supervised oral HIV self-testing in Malawi, demonstrating the feasibility of this approach in a high-prevalence, low-income environment.

Risk for tuberculosis among children

Risk among children is underestimated in countries with a high incidence of this disease.

Tuberculosis Diagnostics and Biomarkers: Needs, Challenges, Recent Advances, and Opportunities

Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostics.

Rural poverty and delayed presentation to tuberculosis services in Ethiopia

To measure time to initial presentation and assess factors influencing the decision to seek medical attention, we interviewed 243 patients undergoing sputum examination for the diagnosis of tuberculosis (TB) at a rural health centre near Awassa, Ethiopia. A structured questionnaire was used. Median (mean + SD) patient delay was 4.3 (9.8 + 12.4) weeks. Delays over 4 weeks were significantly associated with rural residence, transport time over 2 h, overnight travel, transport cost exceeding US

Vulnerability to malaria, tuberculosis, and HIV/AIDS infection and disease. Part II: determinants operating at environmental and institutional level

1.40, having sold personal assets prior to the visit, and use of traditional medicine. The majority of patients cited economic or logistical barriers to health care when asked directly about causes of delay. Case‐finding strategies for TB must be sensitive to patient delay and health systems must become more accessible in rural areas.

Mycobacterium tuberculosis Resides in Nonacidified Vacuoles in Endocytically Competent Alveolar Macrophages from Patients with Tuberculosis and HIV Infection

This review summarises a wide range of evidence about environmental and institutional factors that influence vulnerability to malaria, tuberculosis, and HIV infection. By combining this information with that obtained on factors operating at individual, household, and community level, we have identified potential common strategies for improving resilience to all three diseases simultaneously. These strategies depend on collaborations with non-health sectors and include progress in rapid access to funds, provision of education about disease transmission and management, reduction of the burden on carers (predominantly women), and improvement in the quality of health services.

Do high rates of empirical treatment undermine the potential effect of new diagnostic tests for tuberculosis in high-burden settings?

Alveolar macrophages (AM) are the first professional phagocytes encountered by aerosols containing infections in the lungs, and their phagocytic capacity may be affected by these infections or environmental particles. The aim of this study was to evaluate the innate endocytic and phagocytic properties of human AM obtained from patients with pulmonary tuberculosis and to characterize the vacuoles in which Mycobacterium tuberculosis bacilli reside in vivo. AM were obtained by bronchoalveolar lavage from patients with suspected tuberculosis and from asymptomatic volunteers (controls). Clinical case definitions were based on mycobacterial culture of respiratory specimens and HIV serology. To assess phagocytosis, endocytosis, and acidification of the endosomal system, AM were cultured with IgG-coated polystyrene beads, dextran, and a pH-sensitive reporter (3-(2,4-dinitroanilino)-3-amino-N-methyldipropylamine) and were evaluated by light and immunoelectron microscopy. Cells from 89 patients and 10 controls were studied. We found no significant difference between the two groups in the ability of AM either to ingest beads and dextran or to deliver them to acidified lysosomes. In AM from patients with tuberculosis, the bacilli were located in vacuoles that failed to accumulate endocytosed material and were not acidified. We concluded that AM from patients with tuberculosis and HIV infections were competent to endocytose and phagocytose material and to deliver the material to functional, acidified lysosomes. M. tuberculosis residing in these AM arrests the progression of their phagosomes, which fail to fuse with acidified lysosomes. This confirms, for the first time in humans with tuberculosis and HIV, the conclusions from previous animal and in vitro studies.

Which New Diagnostics for Tuberculosis, and When?

In tuberculosis-endemic settings, patients are often treated empirically, meaning that they are placed on treatment based on clinical symptoms or tests that do not provide a microbiological diagnosis (eg, chest radiography). New tests for tuberculosis, such as the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA), are being implemented at substantial cost. To inform policy and rationally drive implementation, data are needed for how these tests affect morbidity, mortality, transmission, and population-level tuberculosis burden. If people diagnosed by use of new diagnostics would have received empirical treatment a few days later anyway, then the incremental benefit might be small. Will new diagnostics substantially improve outcomes and disease burden, or simply displace empirical treatment? Will the extent and accuracy of empirical treatment change with the introduction of a new test? In this Personal View, we review emerging data for how empirical treatment is frequently same-day, and might still be the predominant form of treatment in high-burden settings, even after Xpert implementation; and how Xpert might displace so-called true-positive, rather than false-positive, empirical treatment. We suggest types of studies needed to accurately assess the effect of new tuberculosis tests and the role of empirical treatment in real-world settings. Until such questions can be addressed, and empirical treatment is appropriately characterised, we postulate that the estimated population-level effect of new tests such as Xpert might be substantially overestimated.

How affordable are tuberculosis diagnosis and treatment in rural China? An analysis from community and tuberculosis patient perspectives

Recently, new diagnostic tools for tuberculosis detection and resistance testing have become available. The World Health Organization endorses new tuberculosis diagnostics by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process. This endorsement process takes place when limited evidence beyond test accuracy is available. There is a need to provide guidance to tuberculosis programs about which new diagnostics to scale up and how best to position them in diagnostic algorithms. To speed adoption of new diagnostics for tuberculosis, the policy recommendation process should be revised to consist of 2 steps: technical recommendation and programmatic recommendation. Technical recommendation would follow the GRADE process and be based on accuracy with limited cost and feasibility data, while programmatic recommendation would include patient-important outcomes, cost-effectiveness when implemented under routine conditions, and factors critical to successful scale-up. The evidence for both steps should be systematically collected, but each requires different study designs.