Publications
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Hargreaves S, Lönnroth K, Nellums LB, et al., 2016, Multidrug-resistant tuberculosis and migration to Europe, Clinical Microbiology and Infection, Vol: 23, Pages: 141-146, ISSN: 1469-0691
Multidrug-resistant tuberculosis (MDR-TB) in low-incidence countries in Europe is more prevalent among migrants than the native population. The impact of the recent increase in migration to EU and EEA countries with a low incidence of TB (fewer than 20 cases per 100,000 [1]) on MDR-TB epidemiology is unclear. This narrative review synthesises evidence on MDR-TB and migration identified through an expert panel and database search. A significant proportion of MDR-TB cases in migrants result from reactivation of latent infection. Refugees and asylum seekers may have a heightened risk of MDR-TB infection and worse outcomes. Although concerns have been raised around ‘health tourists’ migrating for MDR-TB treatment, numbers are probably small and data are lacking. Migrants experience significant barriers to testing and treatment for MDR-TB, exacerbated by increasingly restrictive health systems. Screening for latent MDR-TB is highly problematic since current tests cannot distinguish drug-resistant latent infection, and evidence-based guidance for treatment of latent infection in contacts of MDR patients lacking. While there is evidence that transmission of TB from migrants to the general population is low – it predominantly occurs within migrant communities – there is a human rights obligation to improve the diagnosis, treatment, and prevention of MDR-TB in migrants. Further research is needed into MDR-TB and migration, the impact of screening on detection or prevention, and the potential consequences of failing to treat and prevent MDR-TB among migrants in Europe. An evidence-base is urgently needed to inform guidelines for effective approaches for MDR-TB management in migrant populations in Europe.
Brilha S, Sathyamoorthy T, Stuttaford LH, et al., 2016, ESAT-6 Drives MMP-10 Gene Expression and Secretion in Tuberculosis., American Journal of Respiratory Cell and Molecular Biology, Vol: 56, Pages: 223-232, ISSN: 1535-4989
Tuberculosis (TB) causes disease worldwide and multi-drug resistance is an increasing problem. Matrix metalloproteinases (MMPs), particularly the collagenase MMP-1, cause lung extracellular matrix destruction which drives disease transmission and morbidity. The role in such tissue damage of the stromelysin MMP-10, a key activator of the collagenase MMP-1, was investigated in direct Mycobacterium tuberculosis (Mtb) infected macrophages and in conditioned medium from Mtb infected monocytes (CoMtb)-stimulated cells. Mtb infection increased MMP-10 secretion from primary human macrophages 29-fold, while CoMtb increased secretion by 4.5-fold from pulmonary epithelial cells and 10.5-fold from fibroblasts. Inhibition of MMP-10 activity decreased collagen breakdown. In two independent cohorts of TB patients from different continents, MMP-10 was increased in both induced sputum and bronchoalveolar lavage fluid compared to controls and patients with other respiratory diseases (both p<0.05). Mtb drove 3.5-fold greater MMP-10 secretion from human macrophages than the vaccine strain BCG (p<0.001), whereas both mycobacteria upregulated TNFα secretion equally. Using overlapping short linear peptides covering the sequence of ESAT-6, a virulence factor secreted by Mtb but not BCG, we found that stimulation of human macrophages with a single specific 15 amino acid peptide sequence drove 3-fold greater MMP-10 secretion than any other peptide (p<0.001). Mtb-driven MMP-10 secretion was inhibited in a dose-dependent manner by p38 and ERK MAPK blockade (p<0.001 and p<0.01 respectively), but was not affected by inhibition of NF-ĸB. In summary, Mtb activates inflammatory and stromal cells to secrete MMP-10 and this is partly driven by the virulence factor ESAT-6, implicating it in TB-associated tissue destruction.
Belton M, dos santos Brilha S, Manavaki R, et al., 2016, Hypoxia and tissue destruction in pulmonary tuberculosis, Thorax, Vol: 71, Pages: 1145-1153, ISSN: 1468-3296
Background: It is unknown whether lesions in human tuberculosis (TB) are hypoxic or whether this influences disease pathology. Human TB is characterized by extensive lung destruction driven by host MMPs, particularly collagenases such as MMP-1. Methods: We investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by siRNA inhibition.Results: [18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine, a small molecule inhibitor which stabilises the transcription factor Hypoxia Inducible Factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multi-nucleate giant cells express HIF-1α. HIF-1α blockade including by targeted siRNA inhibited TB-driven MMP-1 gene expression and secretion. Conclusions: Human TB lesions are severely hypoxic and M.tb drives HIF- 1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation
Saunders MS, Tovar MA, Zevallos KZ, et al., 2016, Can micronutrient supplementation prevent TB in vulnerable household contacts? A randomised controlled trial, 47th Union World Conference on Lung Health
Proaño A, Bravard MA, Tracey BH, et al., 2016, Protocol for studying cough frequency in people with pulmonary tuberculosis, BMJ open, Vol: 6, Pages: e010365-e010365, ISSN: 2044-6055
INTRODUCTION: Cough is a key symptom of tuberculosis (TB) as well as the main cause of transmission. However, a recent literature review found that cough frequency (number of coughs per hour) in patients with TB has only been studied once, in 1969. The main aim of this study is to describe cough frequency patterns before and after the start of TB treatment and to determine baseline factors that affect cough frequency in these patients. Secondarily, we will evaluate the correlation between cough frequency and TB microbiological resolution. METHODS: This study will select participants with culture confirmed TB from 2 tertiary hospitals in Lima, Peru. We estimated that a sample size of 107 patients was sufficient to detect clinically significant changes in cough frequency. Participants will initially be evaluated through questionnaires, radiology, microscopic observation drug susceptibility broth TB-culture, auramine smear microscopy and cough recordings. This cohort will be followed for the initial 60 days of anti-TB treatment, and throughout the study several microbiological samples as well as 24 h recordings will be collected. We will describe the variability of cough episodes and determine its association with baseline laboratory parameters of pulmonary TB. In addition, we will analyse the reduction of cough frequency in predicting TB cure, adjusted for potential confounders. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the ethics committees at each participating hospital in Lima, Peru, Asociación Benéfica PRISMA in Lima, Peru, the Universidad Peruana Cayetano Heredia in Lima, Peru and Johns Hopkins University in Baltimore, USA. We aim to publish and disseminate our findings in peer-reviewed journals. We also expect to create and maintain an online repository for TB cough sounds as well as the statistical analysis employed.
Martin LJ, Roper MH, Grandjean L, et al., 2016, Rationing tests for drug-resistant tuberculosis - who are we prepared to miss?, BMC Medicine, Vol: 14, ISSN: 1741-7015
Kubler A, Larsson C, Luna B, et al., 2016, Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis, JOURNAL OF INFECTIOUS DISEASES, Vol: 213, Pages: 618-627, ISSN: 0022-1899
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- Citations: 23
Hargreaves S, Nellums L, Friedland JS, et al., 2016, Extending migrant charging into emergency services, BMJ-BRITISH MEDICAL JOURNAL, Vol: 352, ISSN: 0959-535X
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- Citations: 12
Noori M, Nellums L, Hargreaves S, et al., 2016, Pregnancy outcomes in non-UK born women in a tertiary level maternity unit: a pilot study, British Maternal and Fetal Medicine Society, Publisher: Wiley: 12 months, ISSN: 1471-0528
Nellums LB, Goldberg J, Hargreaves S, et al., 2016, Patterns of emergency department use among migrants in Europe and implications for infectious disease screening: a systematic review and meta-analysis, 26th European Congress of Clinical Microbiology and Infectious Diseases
Kirwan D, Ugarte-Gil C, Gilman RH, et al., 2015, Microscopic Observation Drug Susceptibility Assay for Rapid Diagnosis of Lymph Node Tuberculosis and Detection of Drug Resistance, Journal of Clinical Microbiology, Vol: 54, Pages: 185-189, ISSN: 1098-660X
In the study, 132 patients with lymphadenopathy were investigated. 52 (39.4%) were diagnosed with TB. MODS provided rapid (13 days), accurate diagnosis (sensitivity 65.4%), and reliable DST. Despite lower sensitivity than other methods, faster results and simultaneous DST are advantageous in resource-poor settings, supporting incorporation of MODS into diagnostic algorithms for extrapulmonary TB.
Elkington PT, Friedland JS, 2015, Permutations of time and place in tuberculosis, Lancet Infectious Diseases, Vol: 15, Pages: 1357-1360, ISSN: 1473-3099
Tuberculosis remains a global health pandemic. The current depiction of the Mycobacterium tuberculosis life cycle proposes that airborne bacilli are inhaled and phagocytosed by alveolar macrophages, resulting in the formation of a granuloma that ruptures into the airways to reinitiate the infectious cycle. However, this widely proposed model overlooks the fact, established 100 years ago, that the initial site of M tuberculosis implantation is in the lower zones of the lungs, whereas infectious cavitary pulmonary disease develops at the lung apices. The immunological events at these two pulmonary locations are different—cavitation only occurs in the apices and not in the bases. Yet the current conceptual model of tuberculosis renders the immunology of these two temporally and spatially separated events identical. One key consequence is that prevention of primary childhood tuberculosis at the lung bases is regarded as adequate immunological protection, but extensive evidence shows that greater immunity could predispose to immunopathology and transmission at the lung apex. A much greater understanding of time and place in the immunopathological mechanisms underlying human tuberculosis is needed before further pre-exposure vaccination trials can be done.
Al Shammari B, Shiomi T, Tezera L, et al., 2015, The extracellular matrix regulates granuloma necrosis in tuberculosis, Journal of Infectious Diseases, Vol: 212, Pages: 463-473, ISSN: 1537-6613
A central tenet of tuberculosis pathogenesis is that caseous necrosis leads to extracellular matrix destruction and bacterial transmission. We reconsider the underlying mechanism of tuberculosis pathology and demonstrate that collagen destruction may be a critical initial event, causing caseous necrosis as opposed to resulting from it. In human tuberculosis granulomas, regions of extracellular matrix destruction map to areas of caseous necrosis. In mice, transgenic expression of human matrix metalloproteinase 1 causes caseous necrosis, the pathological hallmark of human tuberculosis. Collagen destruction is the principal pathological difference between humanised mice and wild-type mice with tuberculosis, whereas the release of proinflammatory cytokines does not differ, demonstrating that collagen breakdown may lead to cell death and caseation. To investigate this hypothesis, we developed a 3-dimensional cell culture model of tuberculosis granuloma formation, using bioelectrospray technology. Collagen improved survival of Mycobacterium tuberculosis–infected cells analyzed on the basis of a lactate dehydrogenase release assay, propidium iodide staining, and measurement of the total number of viable cells. Taken together, these findings suggest that collagen destruction is an initial event in tuberculosis immunopathology, leading to caseous necrosis and compromising the immune response, revealing a previously unappreciated role for the extracellular matrix in regulating the host-pathogen interaction.
Nathavitharana RR, Friedland JS, 2015, A tale of two global emergencies: tuberculosis control efforts can learn from the Ebola outbreak, EUROPEAN RESPIRATORY JOURNAL, Vol: 46, Pages: 293-296, ISSN: 0903-1936
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- Citations: 29
Friedland JS, Sathyamoorthy T, Tezera L, et al., 2015, Membrane Type 1 Matrix Metalloproteinase Regulates Monocyte Migration and Collagen Destruction in Tuberculosis, Journal of Immunology, Vol: 195, Pages: 822-891, ISSN: 0022-1767
Tuberculosis (TB) remains a global pandemic and drug resistance is rising. Multicellular granulomaformation is the pathological hallmark of Mycobacterium tuberculosis (Mtb) infection. The membranetype1 MMP (MT1-MMP or MMP-14) is a collagenase that is key in leukocyte migration and collagendestruction. In patients with TB, induced sputum MT1-MMP mRNA levels were increased 5.1-foldcompared to matched controls and correlated positively with extent of lung infiltration on chestradiographs (r=0.483; p<0.05). Mtb infection of primary human monocytes increased MT1-MMPsurface expression 31.7-fold and gene expression 24.5-fold. Mtb-infected monocytes degradedcollagen matrix in an MT1-MMP-dependent manner, and MT1-MMP neutralisation decreased collagendegradation by 73%. In human TB granulomas, MT1-MMP immunoreactivity was observed inmacrophages throughout the granuloma. Monocyte-monocyte networks caused a 17.5-fold increase inMT1-MMP surface expression dependent on p38 MAP kinase and GPCR-dependent signalling.Monocytes migrating towards agarose beads impregnated with conditioned media from Mtb-infectedmonocytes expressed MT1-MMP. Neutralization of MT1-MMP activity decreased this Mtb networkdependentmonocyte migration by 44%. Taken together, we demonstrate that MT1-MMP is central totwo key elements of TB pathogenesis, causing collagen degradation and regulating monocyte migration.
Friedland JS, Ong CWN, Elkington PT, et al., 2015, Neutrophil-derived MMP-8 drives AMPK- dependant matrix destruction in human pulmonary tuberculosis, PLOS Pathogens, Vol: 11, ISSN: 1553-7366
Ugarte-Gil C, Elkington PT, Gotuzzo E, et al., 2015, Induced Sputum Is Safe and Well-Tolerated for TB Diagnosis in a Resource-Poor Primary Healthcare Setting, AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, Vol: 92, Pages: 633-635, ISSN: 0002-9637
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- Citations: 3
Kuebler A, Luna B, Larsson C, et al., 2015, <i>Mycobacterium tuberculosis</i> dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation, JOURNAL OF PATHOLOGY, Vol: 235, Pages: 431-444, ISSN: 0022-3417
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- Citations: 70
Sathyamoorthy T, Sandhu G, Tezera LB, et al., 2015, Gender-Dependent Differences in Plasma Matrix Metalloproteinase-8 Elevated in Pulmonary Tuberculosis, PLOS One, Vol: 10, ISSN: 1932-6203
Tuberculosis (TB) remains a global health pandemic and greater understanding of underlyingpathogenesis is required to develop novel therapeutic and diagnostic approaches. Matrixmetalloproteinases (MMPs) are emerging as key effectors of tissue destruction in TBbut have not been comprehensively studied in plasma, nor have gender differences beeninvestigated. We measured the plasma concentrations of MMPs in a carefully characterised,prospectively recruited clinical cohort of 380 individuals. The collagenases, MMP-1and MMP-8, were elevated in plasma of patients with pulmonary TB relative to healthy controls,and MMP-7 (matrilysin) and MMP-9 (gelatinase B) were also increased. MMP-8 wasTB-specific (p<0.001), not being elevated in symptomatic controls (symptoms suspicious ofTB but active disease excluded). Plasma MMP-8 concentrations inversely correlated withbody mass index. Plasma MMP-8 concentration was 1.51-fold higher in males than femaleswith TB (p<0.05) and this difference was not due to greater disease severity in men. Gender-specificanalysis of MMPs demonstrated consistent increase in MMP-1 and -8 in TB,but MMP-8 was a better discriminator for TB in men. Plasma collagenases are elevated inpulmonary TB and differ between men and women. Gender must be considered in investigationof TB immunopathology and development of novel diagnostic markers.
Watts NS, Pajuelo M, Clark T, et al., 2014, Taenia solium infection in Peru: a collaboration between peace corps volunteers and researchers in a community based study, PLOS One, Vol: 9, ISSN: 1932-6203
BackgroundNeurocysticercosis is a leading cause of seizures and epilepsy in most of the world, and it occurs when Taenia solium larval cysts infect the central nervous system. T. solium tapeworm infection is endemic in much of Peru, but there are scarce data on the prevalence in many rural highland communities where it is likely to be hyper-endemic. Peace Corps Volunteers live and work in these communities; however, to our knowledge, they have not been used to facilitate public health research.Materials and MethodsWe utilized Peace Corps Volunteers to estimate the prevalence of T. solium tapeworm infection in seven rural communities in northern Peru. A convenience non-random sampling frame was used. Peace Corps Volunteers facilitated the collection of stool samples (N = 2,328), which were analyzed by sedimentation and microscopy. Niclosamide treatment and purgation preceded species identification, which was done by PCR-REA.ResultsTaenia sp. egg-positive stool samples were found in three of the seven communities we surveyed. The overall prevalence of Taenia sp. egg positivity was 2.1% (49/2,328) (95% CI = 1.6–2.8%) with prevalence up to 4.3% (42/977) (95% CI = 3.1–5.8%) by community. All 34 of the specimens tested by PCR-REA were T. solium. The overall prevalence of T. solium tapeworm infection was 1.5% (34/2,328) (95% CI = 1.0–2.0%). Prevalence up to 2.9% (28/977) (95% CI = 1.9–4.1%) by community was observed.Conclusion/SignificanceThis study recorded high T. solium tapeworm prevalence, and identified hyper-endemic rural communities. It demonstrates that synergy between researchers and Peace Corps Volunteers can be an effective means to conducting large-scale, community-based studies in remote areas of Peru.
Hargreaves S, Seedat F, Car J, et al., 2014, Screening for latent TB, HIV, and hepatitis B/C in new migrants in a high prevalence area of London, UK: a cross-sectional study, BMC INFECTIOUS DISEASES, Vol: 14, ISSN: 1471-2334
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- Citations: 32
Brilha S, Wysoczanski R, Porter JC, et al., 2014, The extracellular environment regulates matrix metalloproteinase secretion in pulmonary tuberculosis, IMMUNOLOGY, Vol: 143, Pages: 94-94, ISSN: 0019-2805
Brilha S, Ong CWM, Friedland JS, 2014, Matrix metalloproteinases cause blood-brain barrier disruption in central nervous system tuberculosis, 12th International Congress of Neuroimmunology (ISNI), Publisher: ELSEVIER SCIENCE BV, Pages: 27-27, ISSN: 0165-5728
Friedland JS, Seedat F, Hargreaves S, 2014, Engaging New Migrants in Infectious Disease Screening: A Qualitative Semi-Structured Interview Study of UK Migrant Community Health-Care Leads, PLOS One, Vol: 9, ISSN: 1932-6203
Migration to Europe - and in particular the UK - has risen dramatically in the past decades, with implications for public health services. Migrants have increased vulnerability to infectious diseases (70% of TB cases and 60% HIV cases are in migrants) and face multiple barriers to healthcare. There is currently considerable debate as to the optimum approach to infectious disease screening in this often hard-to-reach group, and an urgent need for innovative approaches. Little research has focused on the specific experience of new migrants, nor sought their views on ways forward. We undertook a qualitative semi-structured interview study of migrant community health-care leads representing dominant new migrant groups in London, UK, to explore their views around barriers to screening, acceptability of screening, and innovative approaches to screening for four key diseases (HIV, TB, hepatitis B, and hepatitis C). Participants unanimously agreed that current screening models are not perceived to be widely accessible to new migrant communities. Dominant barriers that discourage uptake of screening include disease-related stigma present in their own communities and services being perceived as non-migrant friendly. New migrants are likely to be disproportionately affected by these barriers, with implications for health status. Screening is certainly acceptable to new migrants, however, services need to be developed to become more community-based, proactive, and to work more closely with community organisations; findings that mirror the views of migrants and health-care providers in Europe and internationally. Awareness raising about the benefits of screening within new migrant communities is critical. One innovative approach proposed by participants is a communitybased package of health screening combining all key diseases into one general health check-up, to lessen the associated stigma. Further research is needed to develop evidence-based community-focused screening models
Friedland JS, 2014, Targeting the Inflammatory Response in Tuberculosis, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 371, Pages: 1354-1356, ISSN: 0028-4793
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- Citations: 13
Martin L, Coronel J, Faulx D, et al., 2014, A Field Evaluation of the Hardy TB MODS Kit™ for the Rapid Phenotypic Diagnosis of Tuberculosis and Multi-Drug Resistant Tuberculosis, PLOS ONE, Vol: 9, ISSN: 1932-6203
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- Citations: 10
Wingfield T, Schumacher SG, Sandhu G, et al., 2014, The Seasonality of Tuberculosis, Sunlight, Vitamin D, and Household Crowding, JOURNAL OF INFECTIOUS DISEASES, Vol: 210, Pages: 774-783, ISSN: 0022-1899
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- Citations: 63
Singh S, Kubler A, Singh UK, et al., 2014, Antimycobacterial Drugs Modulate Immunopathogenic Matrix Metalloproteinases in a Cellular Model of Pulmonary Tuberculosis, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 58, Pages: 4657-4665, ISSN: 0066-4804
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- Citations: 26
Garcia HH, Rodriguez S, Friedland JS, 2014, Immunology of <i>Taenia solium</i> taeniasis and human cysticercosis, PARASITE IMMUNOLOGY, Vol: 36, Pages: 388-396, ISSN: 0141-9838
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- Citations: 38
Ong CWM, Elkington PT, Friedland JS, 2014, Tuberculosis, Pulmonary Cavitation, and Matrix Metalloproteinases, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 190, Pages: 9-18, ISSN: 1073-449X
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- Citations: 139
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