01. Tuberculosis

Ong, CW., Elkington, PT., Brilha, S., Ugarte,-Gil C., Tome-Esteban, MT., Tezera, LB., Pabisiak, PJ., Moores, RC., Sathyamoorthy, T., Patel, V., Gilman, RH., Porter, JC., Friedland, JS..

PLoS Pathog. 2015 May 21;11(5)

Abstract

Pulmonary cavities, the hallmark of tuberculosis (TB), are characterized by high mycobacterial load and perpetuate the spread of M. tuberculosis. The mechanism of matrix destruction resulting in cavitation is not well defined. Neutrophils are emerging as key mediators of TB immunopathology and their influx are associated with poor outcomes. We investigated neutrophil-dependent mechanisms involved in TB-associated matrix destruction using a cellular model, a cohort of 108 patients, and in separate patient lung biopsies. Neutrophil-derived NF-kB-dependent matrix metalloproteinase-8 (MMP-8) secretion was up-regulated in TB and caused matrix destruction both in vitro and in respiratory samples of TB patients. Collagen destruction induced by TB infection was abolished by doxycycline, a licensed MMP inhibitor. Neutrophil extracellular traps (NETs) contain MMP-8 and are increased in samples from TB patients. Neutrophils lined the circumference of human pulmonary TB cavities and sputum MMP-8 concentrations reflected TB radiological and clinical disease severity. AMPK, a central regulator of catabolism, drove neutrophil MMP-8 secretion and neutrophils from AMPK-deficient patients secrete lower MMP-8 concentrations. AMPK-expressing neutrophils are present in human TB lung biopsies with phospho-AMPK detected in nuclei. These data demonstrate that neutrophil-derived MMP-8 has a key role in the immunopathology of TB and is a potential target for host-directed therapy in this infectious disease.

Quispe, R., Bazo-Alvarez, J., Burroughs, M., Poterico, J., Gilman, R, Checkley, W., Bernabé-Ortiz, A., Huffman, M., Miranda, J.

J Am Heart Assoc. 2015 Aug; 4(8)

Background

Short-term risk assessment tools for prediction of cardiovascular disease events are widely recommended in clinical practice and are used largely for single time-point estimations; however, persons with low predicted short-term risk may have higher risks across longer time horizons.

Methods and Results

We estimated short-term and lifetime cardiovascular disease risk in a pooled population from 2 studies of Peruvian populations. Short-term risk was estimated using the atherosclerotic cardiovascular disease Pooled Cohort Risk Equations. Lifetime risk was evaluated using the algorithm derived from the Framingham Heart Study cohort. Using previously published thresholds, participants were classified into 3 categories: low short-term and low lifetime risk, low short-term and high lifetime risk, and high short-term predicted risk. We also compared the distribution of these risk profiles across educational level, wealth index, and place of residence. We included 2844 participants (50% men, mean age 55.9 years [SD 10.2 years]) in the analysis. Approximately 1 of every 3 participants (34% [95% CI 33 to 36]) had a high short-term estimated cardiovascular disease risk. Among those with a low short-term predicted risk, more than half (54% [95% CI 52 to 56]) had a high lifetime predicted risk. Short-term and lifetime predicted risks were higher for participants with lower versus higher wealth indexes and educational levels and for those living in urban versus rural areas (P<0.01). These results were consistent by sex.

Conclusions

These findings highlight potential shortcomings of using short-term risk tools for primary prevention strategies because a substantial proportion of Peruvian adults were classified as low short-term risk but high lifetime risk. Vulnerable adults, such as those from low socioeconomic status and those living in urban areas, may need greater attention regarding cardiovascular preventive strategies.

Keywords: cardiovascular risk, lifetime cardiovascular risk, Pooled Cohort Risk Equations, risk estimation tools, short-term cardiovascular risk

Background

Short-term risk assessment tools for prediction of cardiovascular disease events are widely recommended in clinical practice and are used largely for single time-point estimations; however, persons with low predicted short-term risk may have higher risks across longer time horizons.

Methods and Results

We estimated short-term and lifetime cardiovascular disease risk in a pooled population from 2 studies of Peruvian populations. Short-term risk was estimated using the atherosclerotic cardiovascular disease Pooled Cohort Risk Equations. Lifetime risk was evaluated using the algorithm derived from the Framingham Heart Study cohort. Using previously published thresholds, participants were classified into 3 categories: low short-term and low lifetime risk, low short-term and high lifetime risk, and high short-term predicted risk. We also compared the distribution of these risk profiles across educational level, wealth index, and place of residence. We included 2844 participants (50% men, mean age 55.9 years [SD 10.2 years]) in the analysis. Approximately 1 of every 3 participants (34% [95% CI 33 to 36]) had a high short-term estimated cardiovascular disease risk. Among those with a low short-term predicted risk, more than half (54% [95% CI 52 to 56]) had a high lifetime predicted risk. Short-term and lifetime predicted risks were higher for participants with lower versus higher wealth indexes and educational levels and for those living in urban versus rural areas (P<0.01). These results were consistent by sex.

Conclusions

These findings highlight potential shortcomings of using short-term risk tools for primary prevention strategies because a substantial proportion of Peruvian adults were classified as low short-term risk but high lifetime risk. Vulnerable adults, such as those from low socioeconomic status and those living in urban areas, may need greater attention regarding cardiovascular preventive strategies.

Keywords: cardiovascular risk, lifetime cardiovascular risk, Pooled Cohort Risk Equations, risk estimation tools, short-term cardiovascular risk

Wingfield, T., Boccia, D., Tovar, MA., Huff, D., Montoya, R., Lewis, JJ., Gilman, RH., Evans, CA..

BMC Public Health. 2015 Aug 21;15

Abstract

BACKGROUND:

Cash transfers are key interventions in the World Health Organisation’s post-2015 global TB policy. However, evidence guiding TB-specific cash transfer implementation is limited. We designed, implemented and refined a novel TB-specific socioeconomic intervention that included cash transfers, which aimed to support TB prevention and cure in resource-constrained shantytowns in Lima, Peru for: the Community Randomized Evaluation of a Socioeconomic Intervention to Prevent TB (CRESIPT) project.

METHODS:

Newly-diagnosed TB patients from study-site healthposts were eligible to receive the intervention consisting of economic and social support. Economic support was provided to patient households through cash transfers on meeting the following conditions: screening for TB in household contacts and MDR TB in patients; adhering to TB treatment and chemoprophylaxis; and engaging with CRESIPT social support (household visits and community meetings). To evaluate project acceptability, quantitative and qualitative feedback was collected using a mixed-methods approach during formative activities. Formative activities included consultations, focus group discussions and questionnaires conducted with the project team, project participants, civil society and stakeholders.

RESULTS:

Over 7 months, 135 randomly-selected patients and their 647 household contacts were recruited from 32 impoverished shantytown communities. Of 1299 potential cash transfers, 964 (74 %) were achieved, 259 (19 %) were not achieved, and 76 (7 %) were yet to be achieved. Of those achieved, 885/964 (92 %) were achieved optimally and 79/964 (8 %) sub-optimally. Key project successes were identified during 135 formative activities and included: strong multi-sectorial collaboration; generation of new evidence for TB-specific cash transfer; and the project being perceived as patient-centred and empowering. Challenges included: participant confidence being eroded through cash transfer delays, hidden account-charges and stigma; access to the initial bank-provider being limited; and conditions requiring participation of all TB-affected household members (e.g. community meetings) being hard to achieve. Refinements were made to improve project acceptability and future impact: the initial bank-provider was changed; conditional and unconditional cash transfers were combined; cash transfer sums were increased to a locally-appropriate, evidence-based amount; and cash transfer size varied according to patient household size to maximally reduce mitigation of TB-related costs and be more responsive to household needs.

CONCLUSIONS:

A novel TB-specific socioeconomic intervention including conditional cash transfers has been designed, implemented, refined and is ready for impact assessment, including by the CRESIPT project. The lessons learnt during this research will inform policy-makers and decision-makers for future implementation of related interventions.

Oberhelman, RA., Soto-Castellares, G., Gilman, RH., Castillo, ME., Kolevic, L., Delpino, T., Saito, M., Salazar-Lindo, E., Negron, E., Montenegro, S., Laguna-Torres, VA., Maurtua-Neumann, P., Datta, S., Evans, CA.

PLoS One. 2015 Apr 30;10(4)

Diagnosing tuberculosis in children is challenging because specimens are difficult to obtain and contain low tuberculosis concentrations, especially with HIV-coinfection. Few studies included well-controls so test specificities are poorly defined. We studied tuberculosis diagnosis in 525 children with and without HIV-infection.

Escombe AR, Moore DA, Gilman RH, Navincopa M, Ticona E, Mitchell B, Noakes C, Martínez C, Sheen P, Ramirez R, Quino W, Gonzalez A, Friedland JS, Evans CA.

PLoS Med. 2009 Mar 17;6(3):e43.

Institutional tuberculosis (TB) transmission is an important public health problem highlighted by the HIV/AIDS pandemic and the emergence of multidrug- and extensively drug-resistant TB. Effective TB infection control measures are urgently needed. We evaluated the efficacy of upper-room ultraviolet (UV) lights and negative air ionization for preventing airborne TB transmission using a guinea pig air-sampling model to measure the TB infectiousness of ward air. Upper-room UV lights and negative air ionization each prevented most airborne TB transmission detectable by guinea pig air sampling. Provided there is adequate mixing of room air, upper-room UV light is an effective, low-cost intervention for use in TB infection control in high-risk clinical settings.

Ford C, Bayer A, Gilman RH, Onifade D, Acosta C, Cabrera L, Vidal C, Evans CA

Am J Trop Med Hyg. 2009 Dec; 81(6): 1097–1102.

This study aimed to determine the psychosocial factors associated with delayed test-seeking among tuberculosis patients. The duration of symptoms before seeking medical care was assessed by interview for 108 newly diagnosed pulmonary tuberculosis patients in the city of Iquitos in the Peruvian Amazon, which has high tuberculosis incidence. Beliefs associated with test-seeking behavior and delay was assessed in these patients. The median delay from symptom onset to seeking diagnostic testing was 61 days (inter-quartile range 30–91 days). The belief that tuberculosis is curable was associated with a 100% longer test-seeking delay; the perception that tuberculosis was common was associated with a 57% longer delay; male gender was associated with a 48% longer delay; and education less than complete secondary schooling was associated with a 44% longer delay. In conclusion, current health promotion activities that emphasize tuberculosis curability and high prevalence may paradoxically increase test-seeking delay and therefore require prospective evaluation.