Host transcriptional response to TB preventive therapy differentiates two sub-groups of IGRA-positive individuals.

We hypothesised that individuals with immunological sensitisation to Mycobacterium tuberculosis (Mtb), conventionally regarded as evidence of latent tuberculosis infection (LTBI), would demonstrate binary responses to preventive therapy (PT), reflecting the differential immunological consequences of the sterilisation of viable infection in those with active Mtb infection versus no Mtb killing in those who did not harbour viable bacilli. We investigated longitudinal whole blood transcriptional profile responses to PT of Interferon gamma release assay (IGRA)-positive tuberculosis contacts and IGRA-negative, tuberculosis-unexposed controls. Longitudinal unsupervised clustering analysis with a subset of 474 most variable genes in antigen-stimulated blood separated the IGRA-positive participants into two distinct subgroups, one of which clustered with the IGRA-negative controls. 117 probes were differentially expressed over time between the two cluster groups, many of them associated with immunological pathways important in mycobacterial control. We contend that the differential host RNA response reflects lack of Mtb viability in the group that clustered with the IGRA-negative unexposed controls, and Mtb viability in the group (1/3 of IGRA-positives) that clustered away. Gene expression patterns in the blood of IGRA-positive individuals emerging during the course of PT, which reflect Mtb viability, could have major implications in the identification of risk of progression, treatment stratification and biomarker development.

Chagas disease in the United Kingdom: A review of cases at the Hospital for Tropical Diseases London 1995-2018. The current state of detection of Chagas disease in the UK.

BACKGROUND: Chagas disease (CD), is a parasitic disease endemic in Latin America. Presentation in non-endemic areas is either in the asymptomatic indeterminate phase or the chronic phase with cardiac and/or gastrointestinal complications. METHODS: The Hospital for Tropical Diseases (HTD) based in central London, provides tertiary care for the management of CD. We reviewed all cases managed at this centre between 1995 and 2018. RESULTS: Sixty patients with serologically proven CD were identified. Most were female (70%), with a median age at diagnosis of 41 years. Three quarters of the patients were originally from Bolivia. 62% of all patients were referred to the HTD by their GP. Nearly half of the patients were asymptomatic (47%). Twelve patients had signs of cardiac involvement secondary to CD. Evidence of gastrointestinal damage was established in three patients. Treatment was provided at HTD for 31 patients (47%). Most patients (29) received benznidazole, five of them did not tolerate the course and were switched to nifurtimox. Of the seven patients receiving this second line drug, five completed treatment, whilst two interrupted it due to side effects. CONCLUSIONS: Despite the UK health system having all the resources required to diagnose, treat and follow up cases, there is lack of awareness of CD, such that the vast majority of cases remain undiagnosed and therefore do not receive treatment. We propose key interventions to improve the detection and management of this condition in the UK, especially in pregnant women and neonates.

Association between bacterial homoplastic variants and radiological pathology in tuberculosis.

BACKGROUND: Understanding how pathogen genetic factors contribute to pathology in TB could enable tailored treatments to the most pathogenic and infectious strains. New strategies are needed to control drug-resistant TB, which requires longer and costlier treatment. We hypothesised that the severity of radiological pathology on the chest radiograph in TB disease was associated with variants arising independently, multiple times (homoplasies) in the Mycobacterium tuberculosis genome. METHODS: We performed whole genome sequencing (Illumina HiSeq2000 platform) on M. tuberculosis isolates from 103 patients with drug-resistant TB in Lima between 2010 and 2013. Variables including age, sex, HIV status, previous TB disease and the percentage of lung involvement on the pretreatment chest radiograph were collected from health posts of the national TB programme. Genomic variants were identified using standard pipelines. RESULTS: Two mutations were significantly associated with more widespread radiological pathology in a multivariable regression model controlling for confounding variables (Rv2828c.141, RR 1.3, 95% CI 1.21 to 1.39, p<0.01; rpoC.1040 95% CI 1.77 to 2.16, RR 1.9, p<0.01). The rpoB.450 mutation was associated with less extensive radiological pathology (RR 0.81, 95% CI 0.69 to 0.94, p=0.03), suggestive of a bacterial fitness cost for this mutation in vivo. Patients with a previous episode of TB disease and those between 10 and 30 years of age also had significantly increased radiological pathology. CONCLUSIONS: This study is the first to compare the M. tuberculosis genome to radiological pathology on the chest radiograph. We identified two variants significantly positively associated with more widespread radiological pathology and one with reduced pathology. Prospective studies are warranted to determine whether mutations associated with increased pathology also predict the spread of drug-resistant TB.

Implementation science to improve the quality of tuberculosis diagnostic services in Uganda.

Nucleic acid amplification tests such as Xpert MTB/RIF (Xpert) have the potential to revolutionize tuberculosis (TB) diagnostics and improve case finding in resource-poor settings. However, since its introduction over a decade ago in Uganda, there remain significant gaps along the cascade of care for patients undergoing TB diagnostic evaluation at peripheral health centers. We utilized a systematic, implementation science-based approach to identify key reasons at multiple levels for attrition along the TB diagnostic evaluation cascade of care. Provider- and health system-level barriers fit into four key thematic areas: human resources, material resources, service implementation, and service coordination. Patient-level barriers included the considerable costs and time required to complete health center visits. We developed a theory-informed strategy using the PRECEDE framework to target key barriers by streamlining TB diagnostic evaluation and facilitating continuous quality improvement. The resulting SIMPLE TB strategy involve four key components: 1) Single-sample LED fluorescence microscopy; 2) Daily sputum transport to Xpert testing sites; 3) Text message communication of Xpert results to health centers and patients; and 4) Performance feedback to health centers using a quality improvement framework. This combination of interventions was feasible to implement and significantly improved the provision of high-quality care for patients undergoing TB diagnostic evaluation. We conclude that achieving high coverage of Xpert testing services is not enough. Xpert scale-up should be accompanied by health system co-interventions to facilitate effective implementation and ensure that high quality care is delivered to patients.

Systematic analysis of funding awarded to institutions in the United Kingdom for infectious disease research, 1997-2010.

OBJECTIVES: This study aimed to assess the research investments made to UK institutions for all infectious disease research and identify the direction of spend by institution. DESIGN: Systematic analysis. Databases and websites were systematically searched for information on relevant studies funded for the period 1997-2010. SETTING: UK institutions carrying out infectious disease research. PARTICIPANTS: None. MAIN OUTCOME MEASURES: Twenty academic institutions receiving greatest sum investments across infection are included here, also NHS sites, Sanger Institute, Health Protection Agency and the Medical Research Council. We measured total funding, median award size, disease areas and position of research along the R&D value chain. RESULTS: Included institutions accounted for £2.1 billion across 5003 studies. Imperial College and University of Oxford received the most investment. Imperial College led the most studies. The Liverpool and London Schools of Tropical Medicine had highest median award size, whereas the NHS sites combined had many smaller studies. Sum NHS funding appears to be declining over time, whilst university income is relatively stable. Several institutions concentrate almost exclusively on pre-clinical research. In some areas, there is clearly a leading institution, e.g. Aberdeen and mycology research or UCL and antimicrobial resistance. CONCLUSION: UK institutions carry out research across a wide range of infectious disease areas. This analysis can identify centres of excellence and help inform future resource allocation for research priorities. Institutions can use this analysis for establishing expertise within their groups, identifying external collaborators and informing local research strategy.

Comorbilidad de tuberculosis y diabetes: Problema aún sin resolver / Tuberculosis and diabetes co-morbidity: An unresolved problem

La comorbilidad entre tuberculosis y diabetes ha sido descrita desde principios del siglo XX. En países desarrollados donde se ha pasado de la disminución de la enfermedades infecciosas a un incremento de enfermedades no transmisibles, así como en aquellos países que aún tienen alta prevalencia de enfermedades infecciosas pero con incremento de las no transmisibles, se observa que la prevalencia de la comorbilidad entre tuberculosis y diabetes se está incrementando, volviendo el manejo clínico y el control a nivel de salud pública un nuevo reto para cualquier sistema de salud. Esta revisión intenta mostrar las evidencias disponibles hasta la actualidad y poner en conocimiento algunas líneas de investigación que se están comenzando a desarrollar para entender dicho problema. En países como el Perú donde hay una transición epidemiológica, mayor investigación permitiría conocer y describir mejor las características y el impacto de esta comorbilidad.

Co-morbidity between tuberculosis and diabetes has been described since the early 20th century. In developed countries, where there has been a decrease of infectious diseases with an increase of non-communicable diseases, as well as those countries who still have a high prevalence of infectious diseases but an increase of non-communicable diseases, it is observed that the prevalence of co-morbidity between tuberculosis and diabetes is increasing, making clinical management and control at the public health level a new challenge for health systems. This review aims to show the current available evidence that can inform research lines being developed to understand the problem. In countries like Peru, where there is an epidemiological transition, further research could allow us to understand and describe in a better way the characteristics and impact of this co-morbidity.

Propuesta de esquemas de tratamiento antituberculosis basados en la susceptibilidad a isoniacida y rifampicina / Proposal of anti-tuberculosis regimens based on susceptibility to isoniazid and rifampicin

Objetivo. Elaborar esquemas de tratamiento para tuberculosis de acuerdo con sus perfiles de susceptibilidad a isoniacida (H) y rifampicina (R). Materiales y métodos. Un total de 12 311 aislamientos de M. tuberculosis (Instituto Nacional de Salud, 2007-2009) se clasificaron en cuatro grupos de acuerdo con su susceptibilidad a H y R. En cada grupo se analizó la sensibilidad a etambutol (E), pirazinamida (Z), estreptomicina (S), kanamicina (Km), capreomicina (Cm), ciprofloxacina (Cfx), etionamida (Eto), cicloserina (Cs) y ácido p-amino salicílico (PAS). En base a los perfiles de resistencia, principios de terapéutica de la Organización Mundial de la Salud y costos en el país, se elaboraron los esquemas más adecuados para cada grupo. Se definió la eficacia potencial (EP) como la proporción de cepas sensibles a tres o cuatro drogas del esquema evaluado. Resultados. Los esquemas con el menor costo y la mayor EP a tres y cuatro drogas para tuberculosis sensible a H y R fueron: HRZ (EP=99,5%), HREZ (EP=99,1%); REZCfx (EP=98,9%) y para tuberculosis resistente a H: REZCfxKm (EP=97,7%). Para tuberculosis resistente a R: HEZCfx (EP=96,8%) y HEZCfxKm (EP=95,4%); el esquema con mejor eficacia potencial para tuberculosis multidrogorresistente fue EZCfxKmEtoCs (EP=82,9%). Conclusión. Basados en la resistencia a H y R se han elaborado y seleccionado esquemas de tratamiento con la más alta probabilidad de eficacia. Esta propuesta es una alternativa viable para hacer frente a la tuberculosis en Perú donde el acceso a pruebas de sensibilidad rápida a H y R se viene expandiendo. (AU)

Objective: To elaborate optimal anti-tuberculosis regimens following drug susceptibility testing (DST) to isoniazid (H) and rifampicin (R). Design: 12 311 M. tuberculosis strains (National Health Institute of Peru 2007-2009) were classified in four groups according H and R resistance. In each group the sensitivity to ethambutol (E), pirazinamide (Z), streptomycin (S), kanamycin (Km), capreomycin (Cm), ciprofloxacin (Cfx), ethionamide (Eto), cicloserine (Cs) and p-amino salicilic acid (PAS) was determined. Based on resistance profiles, domestic costs, and following WHO guidelines, we elaborated and selected optimal putative regimens for each group. The potential efficacy (PE) variable was defined as the proportion of strains sensitive to at least three or four drugs for each regimen evaluated. Results: Selected regimes with the lowest cost, and highest PE of containing 3 and 4 effective drugs for TB sensitive to H and R were: HRZ (99,5%) and HREZ (99,1%), respectively; RZECfx (PE=98,9%) and RZECfxKm (PE=97,7%) for TB resistant to H; HZECfx (96,8%) and HZECfxKm (95,4%) for TB resistant to R; and EZCfxKmEtoCs (82.9%) for MDR-TB. Conclusion: Based on resistance to H and R it was possible to select anti-tuberculosis regimens with high probability of success. This proposal is a feasible alternative to tackle tuberculosis in Peru where the access to rapid DST to H and R is improving progressively. (AU)

Propuesta de esquemas de tratamiento antituberculosis basados en la susceptibilidad A isoniacida y rifampicina / Proposal of anti-tuberculosis regimens based on susceptibility to isoniazid and rifampicin

Objetivo. Elaborar esquemas de tratamiento para tuberculosis de acuerdo con sus perfiles de susceptibilidad a isoniacida (H) y rifampicina (R). Materiales y métodos. Un total de 12 311 aislamientos de M. tuberculosis (Instituto Nacional de Salud, 2007-2009) se clasificaron en cuatro grupos de acuerdo con su susceptibilidad a H y R. En cada grupo se analizó la sensibilidad a etambutol (E), pirazinamida (Z), estreptomicina (S), kanamicina (Km), capreomicina (Cm), ciprofloxacina (Cfx), etionamida (Eto), cicloserina (Cs) y ácido p-amino salicílico (PAS). En base a los perfiles de resistencia, principios de terapéutica de la Organización Mundial de la Salud y costos en el país, se elaboraron los esquemas más adecuados para cada grupo. Se definió la eficacia potencial (EP) como la proporción de cepas sensibles a tres o cuatro drogas del esquema evaluado. Resultados. Los esquemas con el menor costo y la mayor EP a tres y cuatro drogas para tuberculosis sensible a H y R fueron: HRZ (EP=99,5%), HREZ (EP=99,1%); REZCfx (EP=98,9%) y para tuberculosis resistente a H: REZCfxKm (EP=97,7%). Para tuberculosis resistente a R: HEZCfx (EP=96,8%) y HEZCfxKm (EP=95,4%); el esquema con mejor eficacia potencial para tuberculosis multidrogorresistente fue EZCfxKmEtoCs (EP=82,9%). Conclusión. Basados en la resistencia a H y R se han elaborado y seleccionado esquemas de tratamiento con la más alta probabilidad de eficacia. Esta propuesta es una alternativa viable para hacer frente a la tuberculosis en Perú donde el acceso a pruebas de sensibilidad rápida a H y R se viene expandiendo.

Objective: To elaborate optimal anti-tuberculosis regimens following drug susceptibility testing (DST) to isoniazid (H) and rifampicin (R). Design: 12 311 M. tuberculosis strains (National Health Institute of Peru 2007-2009) were classified in four groups according H and R resistance. In each group the sensitivity to ethambutol (E), pirazinamide (Z), streptomycin (S), kanamycin (Km), capreomycin (Cm), ciprofloxacin (Cfx), ethionamide (Eto), cicloserine (Cs) and p-amino salicilic acid (PAS) was determined. Based on resistance profiles, domestic costs, and following WHO guidelines, we elaborated and selected optimal putative regimens for each group. The potential efficacy (PE) variable was defined as the proportion of strains sensitive to at least three or four drugs for each regimen evaluated. Results: Selected regimes with the lowest cost, and highest PE of containing 3 and 4 effective drugs for TB sensitive to H and R were: HRZ (99,5%) and HREZ (99,1%), respectively; RZECfx (PE=98,9%) and RZECfxKm (PE=97,7%) for TB resistant to H; HZECfx (96,8%) and HZECfxKm (95,4%) for TB resistant to R; and EZCfxKmEtoCs (82.9%) for MDR-TB. Conclusion: Based on resistance to H and R it was possible to select anti-tuberculosis regimens with high probability of success. This proposal is a feasible alternative to tackle tuberculosis in Peru where the access to rapid DST to H and R is improving progressively.

The MODS method for diagnosis of tuberculosis and multidrug resistant tuberculosis.

Patients with active pulmonary tuberculosis (TB) infect 10-15 other persons per year, making diagnosing active TB essential to both curing the patient and preventing new infections. Furthermore, the emergence of multidrug resistant tuberculosis (MDRTB) means that detection of drug resistance is necessary for stopping the spread of drug-resistant strains. The microscopic-observation drug-susceptibility (MODS) assay is a low-cost, low-tech tool for high-performance detection of TB and MDRTB. The MODS assay is based on three principles: 1) mycobacterium tuberculosis (MTB) grows faster in liquid media than on solid media 2) microscopic MTB growth can be detected earlier in liquid media than waiting for the macroscopic appearance of colonies on solid media, and that growth is characteristic of MTB, allowing it to be distinguished from atypical mycobacteria or fungal or bacterial contamination 3) the drugs isoniazid and rifampicin can be incorporated into the MODS assay to allow for simultaneous direct detection of MDRTB, obviating the need for subculture to perform an indirect drug susceptibility test. Competing current diagnostics are hampered by low sensitivity with sputum smear, long delays until diagnosis with solid media culture, prohibitively high cost with existing liquid media culture methods, and the need to do subculture for indirect drug susceptibility testing to detect MDRTB. In contrast, the non-proprietary MODS method has a high sensitivity for TB and MDRTB, is a relatively rapid culture method, provides simultaneous drug susceptibility testing for MDRTB, and is accessible to resource-limited settings at just under $3 for testing for TB and MDRTB.