Publications
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Ravensbergen SJ, Nellums LB, Hargreaves S, et al., 2018, National approaches to the vaccination of recently arrived migrants in Europe: A comparative policy analysis across 32 European countries, TRAVEL MEDICINE AND INFECTIOUS DISEASE, Vol: 27, Pages: 33-38, ISSN: 1477-8939
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- Citations: 15
Hargreaves S, Nellums L, Ravensbergen SJ, et al., 2018, Divergent approaches in the vaccination of recently arrived migrants to Europe: a survey of national experts from 32 countries, 2017, EUROSURVEILLANCE, Vol: 23, Pages: 21-29, ISSN: 1560-7917
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- Citations: 23
Nellums LB, Friedland JS, Hargreaves S, 2018, Antimicrobial resistance among migrants in Europe-Authors' reply (vol 18, pg 945, 2018), LANCET INFECTIOUS DISEASES, Vol: 18, Pages: 1063-1063, ISSN: 1473-3099
Brilha S, Ong CWM, Weksler B, et al., 2018, Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an <i>in vitro</i> model of CNS tuberculosis (vol 7, 16031, 2017), SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322
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- Citations: 1
Seedat F, Hargreaves S, Nellums LB, et al., 2018, How effective are approaches to migrant screening for infectious diseases in Europe? A systematic review, Lancet Infectious Diseases, Vol: 18, Pages: e259-e271, ISSN: 1473-3099
Rates of migration to Europe, and within Europe, have increased in recent years, with considerable implications for health systems. Migrants in Europe face a disproportionate burden of tuberculosis, HIV, and hepatitis B and C, yet experience a large number of barriers to accessing statutory health care on arrival. A better understanding of how to deliver effective and cost-effective screening, vaccination, and health services to this group is now crucial. We did a systematic review to document and assess the effectiveness and cost-effectiveness of approaches used for infectious diseases screening, and to explore facilitators and barriers experienced by migrants to accessing screening programmes. Following PRISMA guidelines, we searched Embase, PubMed, PsychINFO, the Cochrane Library, and Web of Science (1989 to July 1, 2015, updated on Jan 1, 2018), with no language restrictions, and systematically approached experts across the European Union (EU) for grey literature. Inclusion criteria were primary research studies assessing screening interventions for any infectious disease in the migrant (foreign-born) population residing in EU or European Economic Area (EEA) countries. Primary outcomes were the following effectiveness indicators: uptake of screening, coverage, infections detected, and treatment outcomes. Of 4112 unique records, 47 studies met our inclusion criteria, from ten European countries (Belgium, Denmark, France, Italy, the Netherlands, Norway, Spain, Sweden, Switzerland, and the UK) encompassing 248 402 migrants. We found that most European countries screening migrants focus on single diseases only-predominantly active or latent tuberculosis infection-and specifically target asylum seekers and refugees, with 22 studies reporting on other infections (including HIV and hepatitis B and C). An infection was detected in 3·74% (range 0·00-95·16) of migrants. Latent tuberculosis had the highest prevalence across all infections (median 15&mi
Friedland JS, Hargreaves S, 2018, Antimicrobial resistance among migrants in Europe reply, LANCET INFECTIOUS DISEASES, Vol: 18, Pages: 945-945, ISSN: 1473-3099
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- Citations: 2
Ong C, Fox K, Ettorre A, et al., 2018, Hypoxia increases neutrophil-driven matrix destruction after exposure to mycobacterium tuberculosis, Scientific Reports, Vol: 8, ISSN: 2045-2322
The importance of neutrophils in the pathology of tuberculosis (TB) has been recently established. We demonstrated that TB lesions in man are hypoxic, but how neutrophils in hypoxia influence lung tissue damage is unknown. We investigated the effect of hypoxia on neutrophil-derived enzymes and tissue destruction in TB. Human neutrophils were stimulated with M. tuberculosis (M.tb) or conditioned media from M.tb-infected monocytes (CoMTB). Neutrophil matrix metalloproteinase-8/-9 and elastase secretion were analysed by luminex array and gelatin zymography, gene expression by qPCR and cell viability by flow cytometry. Matrix destruction was investigated by confocal microscopy and functional assays and neutrophil extracellular traps (NETs) by fluorescence assay. In hypoxia, neutrophil MMP-8 secretion and gene expression were up-regulated by CoMTB. MMP-9 activity and neutrophil elastase (NE) secretion were also increased in hypoxia. Hypoxia inhibited NET formation and both neutrophil apoptosis and necrosis after direct stimulation by M.tb. Hypoxia increased TB-dependent neutrophil-mediated matrix destruction of Type I collagen, gelatin and elastin, the main structural proteins of the human lung. Dimethyloxalylglycin (DMOG), which stabilizes hypoxia-inducible factor-1α, increased neutrophil MMP-8 and -9 secretion. Hypoxia in our cellular model of TB up-regulated pathways that increase neutrophil secretion of MMPs that are implicated in matrix destruction.
Fox KA, Kirwan DE, Whittington AM, et al., 2018, Platelets regulate pulmonary inflammation and tissue destruction in tuberculosis, American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 245-255, ISSN: 1073-449X
RATIONALE: Platelets may interact with the immune system in tuberculosis (TB) to regulate human inflammatory responses that lead to morbidity and spread of infection. OBJECTIVES: To identify a functional role of platelets in the innate inflammatory and matrix degrading response in TB. METHODS: Markers of platelet activation were examined in plasma from 50 TB patients pre-treatment, and 50 controls. 25 patients were followed longitudinally. Platelet-monocyte interactions were studied in a co-culture model infected with live, virulent Mycobacterium tuberculosis (M.tb) and dissected using qPCR, Luminex multiplex arrays, matrix degradation assays and colony counts. Immunohistochemistry detected CD41 expression in a pulmonary TB murine model and secreted platelet factors were measured in bronchoalveolar lavage fluid (BALF) from 15 TB patients and matched controls. MEASUREMENTS AND MAIN RESULTS: Five of six platelet-associated mediators were upregulated in plasma of TB patients compared to controls, with concentrations returning to baseline by day 60 of treatment. Gene expression of the monocyte collagenase MMP-1 was upregulated by platelets in M.tb infection. Platelets also enhanced M.tb-induced MMP-1 and -10 secretion which drove Type I collagen degradation. Platelets increased monocyte IL-1 and IL-10 and decreased IL-12 and monocyte-derived chemokine (MDC, also known as CCL-22) secretion, as consistent with an M2 monocyte phenotype. Monocyte killing of intracellular M.tb was decreased. In the lung, platelets were detected in a TB mouse model and secreted platelet mediators were upregulated in human BALF, and correlated with MMP and IL-1β concentrations. CONCLUSIONS: Platelets drive a pro-inflammatory, tissue-degrading phenotype in TB.
Knight G, Zimic M, Funk S, et al., 2018, The relative fitness of drug-resistant Mycobacterium tuberculosis: a modelling study of household transmission in Peru, Journal of the Royal Society Interface, Vol: 15, ISSN: 1742-5662
The relative fitness of drug-resistant versus susceptible bacteria in an environment dictates resistance prevalence. Estimates for the relative fitness of resistant Mycobacterium tuberculosis (Mtb) strains are highly heterogeneous and mostly derived from in vitro experiments. Measuring fitness in the field allows us to determine how the environment influences the spread of resistance. We designed a household structured, stochastic mathematical model to estimate the fitness costs associated with multidrug resistance (MDR) carriage in Mtb in Lima, Peru during 2010–2013. By fitting the model to data from a large prospective cohort study of TB disease in household contacts, we estimated the fitness, relative to susceptible strains with a fitness of 1, of MDR-Mtb to be 0.32 (95% credible interval: 0.15–0.62) or 0.38 (0.24–0.61), if only transmission or progression to disease, respectively, was affected. The relative fitness of MDR-Mtb increased to 0.56 (0.42–0.72) when the fitness cost influenced both transmission and progression to disease equally. We found the average relative fitness of MDR-Mtb circulating within households in Lima, Peru during 2010–2013 to be significantly lower than concurrent susceptible Mtb. If these fitness levels do not change, then existing TB control programmes are likely to keep MDR-TB prevalence at current levels in Lima, Peru.
Dos Santos Brilha S, Chong D, Khawaja A, et al., 2018, Integrin α2β1 expression regulates matrix metalloproteinase-1-dependent bronchial epithelial repair in pulmonary tuberculosis, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224
Pulmonary tuberculosis (TB) is caused by inhalation of Mycobacterium tuberculosis, which damages the bronchial epithelial barrier to establish local infection. Matrix metalloproteinase-1 plays a crucial role in the immunopathology of TB, causing breakdown of type I collagen and cavitation, but this collagenase is also potentially involved in bronchial epithelial repair. We hypothesized that the extracellular matrix (ECM) modulates M. tuberculosis-driven matrix metalloproteinase-1 expression by human bronchial epithelial cells (HBECs), regulating respiratory epithelial cell migration and repair. Medium from monocytes stimulated with M. tuberculosis induced collagenase activity in bronchial epithelial cells, which was reduced by ~87% when cells were cultured on a type I collagen matrix. Matrix metalloproteinase-1 had a focal localization, which is consistent with cell migration, and overall secretion decreased by 32% on type I collagen. There were no associated changes in the specific tissue inhibitors of metalloproteinases. Decreased matrix metalloproteinase-1 secretion was due to ligand-binding to the α2β1 integrin and was dependent on the actin cytoskeleton. In lung biopsies, samples from patients with pulmonary TB, integrin α2β1 is highly expressed on the bronchial epithelium. Areas of lung with disrupted collagen matrix showed an increase in matrix metalloproteinases-1 expression compared with areas where collagen was comparable to control lung. Type I collagen matrix increased respiratory epithelial cell migration in a wound-healing assay, and this too was matrix metalloproteinase-dependent, since it was blocked by the matrix metalloproteinase inhibitor GM6001. In summary, we report a novel mechanism by which α2β1-mediated signals from the ECM modulate matrix metalloproteinase-1 secretion by HBECs, regulating their migration and epithelial repair in TB.
Friedland JS, Proano A, Bui D, et al., 2018, Cough frequency during treatment associated with baseline cavitary volume and proximity to the airway in pulmonary tuberculosis, Chest, Vol: 153, Pages: 1358-1367, ISSN: 0012-3692
Background: Cough frequency, and its duration, is a lab-free biomarker that can be used in low-resource settings and has been associated with transmission and treatment response.Radiological characteristics associated with increased cough frequency may be important in understanding transmission. The relationship between cough frequency and cavitary lung disease has never been studied. Methods: We analyzed 41 human immunodeficiency virus-negative adults with culture- confirmed, drug-susceptible pulmonary tuberculosis throughout treatment. Cough recordings were based on the Cayetano Cough Monitor and sputum samples were evaluated using microscopic-observation drug susceptibility broth culture, among culture-positive samples bacillary burden was assessed by time to positivity. Computerized tomography scans were analyzed by a U.S. board-certified radiologist and an automated-computer algorithm. The algorithm evaluates cavity volume and cavitary proximity to the airway. Computerized tomography scans were taken within one month of treatment initiation. We compared small cavities (≤7-mL) versus large cavities (>7-mL) and cavities located closer to (≤10-mm) and farther (>10-mm) from the airway to cough frequency and cough cessation until treatment day 62.Results: Cough frequency during treatment was two-fold higher in participants with large cavity volumes (Rate Ratio [RR]=1.98, p=0.01) and cavities located closer to the airway (RR=2.44, p=0.001). Comparably, cough ceased three times faster in smaller cavities (adjusted hazard ratio [HR]=2.89, p=0.06) and those farther from the airway (adjusted HR=3.61, p=0.02). Similar results are found for bacillary burden and culture conversion during treatment. Conclusions: Cough frequency during treatment is greater and lasts for longer in patients with larger cavities, especially those closer to the airway
Lopez J, Loader M, Smith D, et al., 2018, Exhaled nitric oxide is not a biomarker for pulmonary tuberculosis, American Journal of Tropical Medicine and Hygiene, Vol: 98, Pages: 1637-1639, ISSN: 0002-9637
To reduce transmission of tuberculosis (TB) in resource-limited countries where TB remains a major cause of mortality, novel diagnostic tools are urgently needed. We evaluated the fractional concentration of exhaled nitric oxide (FeNO) as an easily measured, non-invasive potential biomarker for diagnosis and monitoring of treatment response in participants with pulmonary TB including multi-drug resistant (MDR)-TB in Lima, Peru. In a longitudinal study however, we found no differences in baseline median FeNO levels between 38 TB participants and 93 age-matched controls (13 parts per billion (ppb) (IQR 8-26), vs. 15 ppb (IQR 12-24)), and there was no change over 60 days of treatment (15 ppb (IQR 10-19) at day 60). Taking this and previous evidence together we conclude FeNO is not of value in either the diagnosis of pulmonary TB nor as a marker of treatment response.
Nellums LB, Thompson H, Holmes A, et al., 2018, Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis, Lancet Infectious Diseases, Vol: 18, Pages: 796-811, ISSN: 1473-3099
BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus
Hargreaves S, Nellums LB, Ramsay M, et al., 2018, Who is responsible for the vaccination of migrants in Europe?, Lancet, Vol: 391, Pages: 1752-1754, ISSN: 0140-6736
Nakken C, Skovdal M, Nellums LB, et al., 2018, Vaccination status and needs of asylum-seeking children in Denmark: a retrospective data analysis, Public Health, Vol: 158, Pages: 110-116, ISSN: 0033-3506
ObjectivesAsylum-seekers to Europe may come from war-torn countries where health systems have broken down, and there is evidence that asylum-seeking children have low coverage of childhood vaccinations, as well as uptake of immunisations in host countries. Such gaps in immunisation have important implications for effective national vaccination programmes. How we approach vaccination in children and adults entering Western Europe, where as a group they face barriers to health services and screening, is a growing debate, however there is limited data on the vaccination status of these hard to reach communities and robust evidence is needed to inform immunisation strategies. The aim of this study was to explore the vaccination status and needs of asylum-seeking children and adolescents in Denmark.Study designWe conducted a retrospective data analysis of anonymised patient records for asylum-seeking children and adolescents extracted from the Danish Red Cross database.MethodsWe retrospectively searched the Danish Red Cross database for children and adolescents (age 3 months to 18 years) with active asylum applications in Denmark as of October 28th, 2015. Data were extracted for demographic characteristics, vaccination status, and vaccinations needed by asylum-seeking children presenting to Red Cross asylum centres for routine statutory health screening. ResultsWe explored the vaccination status and needs of 2,126 asylum-seeking children and adolescents. 64% of the study population was male and 36% was female. Eight nationalities were represented, where 33% of the total of children and adolescents were not immunised in accordance with Danish national guidelines, while 7% were considered partly vaccinated, and 60% were considered adequately vaccinated. Afghan (57% not vaccinated/unknown) and Eritrean (54% not vaccinated/unknown) children were the least likely to be vaccinated of all nationalities represented, as were boys (37% not vaccinated/unknown) compared with girls
Nellums LB, Rustage K, Hargreaves S, et al., 2018, Multidrug-resistant tuberculosis treatment adherence in migrants: a systematic review and meta-analysis, BMC Medicine, Vol: 16, ISSN: 1741-7015
BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is a growing concern in meeting global targets for TB control. In high-income low-TB-incidence countries, a disproportionate number of MDR-TB cases occur in migrant (foreign-born) populations, with concerns about low adherence rates in these patients compared to the host non-migrant population. Tackling MDR-TB in this context may, therefore, require unique approaches. We conducted a systematic review and meta-analysis to identify and synthesise data on MDR-TB treatment adherence in migrant patients to inform evidence-based strategies to improve care pathways and health outcomes in this group. METHODS: This systematic review and meta-analysis was conducted in line with PRISMA guidelines (PROSPERO 42017070756). The databases Embase, MEDLINE, Global Health and PubMed were searched to 24 May 2017 for primary research reporting MDR-TB treatment adherence and outcomes in migrant populations, with no restrictions on dates or language. A meta-analysis was conducted using random-effects models. RESULTS: From 413 papers identified in the database search, 15 studies reporting on MDR-TB treatment outcomes for 258 migrants and 174 non-migrants were included in the systematic review and meta-analysis. The estimated rate of adherence to MDR-TB treatment across migrant patients was 71% [95% confidence interval (CI) = 58-84%], with non-adherence reported among 20% (95% CI = 4-37%) of migrant patients. A key finding was that there were no differences in estimated rates of adherence [risk ratio (RR) = 1.05; 95% CI = 0.82-1.34] or non-adherence (RR = 0.97; 95% CI = 0.79-1.36) between migrants and non-migrants. CONCLUSIONS: MDR-TB treatment adherence rates among migrants in high-income low-TB-incidence countries are approaching global targets for treatment success (75%), and are comparable to rates in non-migrants. The findings highlight that only jus
Singh S, Maniakis-Grivas G, Singh U, et al., 2018, Interleukin-17 regulates matrix metalloproteinase activity in human pulmonary tuberculosis, Journal of Pathology, Vol: 244, Pages: 311-322, ISSN: 0022-3417
Tuberculosis (TB) is characterised by extensive pulmonary matrix breakdown. Interleukin-17 (IL-17) is key in host defence in TB but its role in TB-driven tissue damage is unknown. We investigated the hypothesis that respiratory stromal cell matrix metalloproteinase (MMP) production in TB is regulated by T helper-17 (TH-17) cytokines. Biopsies of patients with pulmonary TB were analysed by immunohistochemistry (IHC) and patient bronchoalveolar lavage fluid (BALF) MMP and cytokine concentrations measured by Luminex assays. Primary human airway epithelial cells were stimulated with conditioned medium from human monocytes infected with Mycobacterium tuberculosis (Mtb) and TH-17 cytokines. MMP secretion, activity and gene expression were determined by ELISA, Luminex assay, zymography, RT-qPCR and dual luciferase reporter assays. Signalling pathways were examined using phospho-western analysis and siRNA. IL-17 is expressed in TB patient granulomas and MMP-3 is expressed in adjacent pulmonary epithelial cells. IL-17 had a divergent, concentration-dependent effect on MMP secretion, increasing epithelial secretion of MMP-3 (p<0.001) over 72 h whilst decreasing that of MMP-9 (p<0.0001); mRNA levels were similarly affected. Both IL-17 and Interleukin-22 (IL-22) increased fibroblast Mtb-dependent MMP-3 secretion but IL-22 did not modulate epithelial MMP-3 expression. Both IL-17 and IL-22, but not Interleukin-23 (IL-23), were significantly upregulated in BALF from TB patients. IL-17-driven MMP-3 was dependent on p38 MAP kinase and the PI 3-K p110α subunit. In summary, IL-17 drives airway stromal cell-derived MMP-3, a mediator of tissue destruction in TB, alone and with monocyte-dependent networks in TB. This is regulated by p38 MAP kinase and PI3-K pathways.
Nellums LB, Rustage K, Hargreaves S, et al., 2017, MDR-TB treatment adherence in migrants: a systematic review and meta-analysis, BMC Medicine, ISSN: 1741-7015
Background: MDR-TB is a growing concern in meeting globaltargets for TB control. In high-income low TB-incidence countries,a disproportionate number of MDR-TB cases occur in migrant(“foreign born”) populations, with concerns about low adherence rates in these patients compared to the host non-migrant population. Tackling MDR-TB in this context may therefore require unique approaches. We conducted a systematic review and meta-analysis to identify and synthesise data on MDR-TB treatment adherence in migrant patients to inform evidence-based strategies to improve care pathways and health outcomes in this group.Methods: This systematic review and meta-analysis was conducted in line with PRISMA guidelines (PROSPERO 42017070756). The databases Embase, Medline, Global Health and PubMed were searched to 24 May 2017 for primary research reporting MDR-TB treatment adherence and outcomes in migrant populations, with no restrictions on dates or language. Meta-analysis was conducted using random-effects models. Results: From 413 papers identified in the database search, 15 studies reporting on MDR-TB treatment outcomes for 258 migrants and 174 non-migrants, were included in the systematic review and meta-analysis. The estimated rate of adherence to MDR-TB treatment across migrant patients was 71% (95% CI:58-84%), with non-adherence reported among 20% (95% CI:4-37%) of migrant patients. A key finding was there were no Differences in estimated rates of adherence (RR = 1.05; 95% CI:0.82-1.34) or non-adherence (RR = 0.97; 95% CI:0.79-1.36) between migrants and non-migrants.Conclusions: MDR-TB treatment adherence rates among migrants in high-income low TB-incidence countries are approachingglobal targets for treatment success (75%), and are comparable to rates in non-migrants. The findings highlight that only just over 70% of migrant and non-migrant patients adhere to MDR-TB treatment. The results point to the importance of increasing adherence in all patient groups, incl
Friedland JS, dos santos brilha S, ong C, et al., 2017, Matrix metalloproteinase-9 activity and a downregulated hedgehog pathway impair blood-brain barrier function in an in vitro model of CNS tuberculosis, Scientific Reports, Vol: 7, ISSN: 2045-2322
Central nervous system tuberculosis (CNS TB) has a high mortality and morbidity associated with severe inflammation. The blood-brain barrier (BBB) protects the brain from inflammation but the mechanisms causing BBB damage in CNS TB are uncharacterized. We demonstrate that Mycobacterium tuberculosis (Mtb) causes breakdown of type IV collagen and decreases tight junction protein (TJP) expression in a co-culture model of the BBB. This increases permeability, surface expression of endothelial adhesion molecules and leukocyte transmigration. TJP breakdown was driven by Mtb-dependent secretion of matrix metalloproteinase (MMP)-9. TJP expression is regulated by Sonic hedgehog (Shh) through transcription factor Gli-1. In our model, the hedgehog pathway was downregulated by Mtb-stimulation, but Shh levels in astrocytes were unchanged. However, Scube2, a glycoprotein regulating astrocyte Shh release was decreased, inhibiting Shh delivery to brain endothelial cells. Activation of the hedgehog pathway by addition of a Smoothened agonist or by addition of exogenous Shh, or neutralizing MMP-9 activity, decreased permeability and increased TJP expression in the Mtb-stimulated BBB co-cultures. In summary, the BBB is disrupted by downregulation of the Shh pathway and breakdown of TJPs, secondary to increased MMP-9 activity which suggests that these pathways are potential novel targets for host directed therapy in CNS TB.
Saunders MJ, Wingfield T, Tovar MA, et al., 2017, A score to predict and stratify risk of tuberculosis in adult contacts of tuberculosis index cases: a prospective derivation and external validation cohort study, Lancet Infectious Diseases, Vol: 17, Pages: 1190-1199, ISSN: 1473-3099
BACKGROUND: Contacts of tuberculosis index cases are at increased risk of developing tuberculosis. Screening, preventive therapy, and surveillance for tuberculosis are underused interventions in contacts, particularly adults. We developed a score to predict risk of tuberculosis in adult contacts of tuberculosis index cases. METHODS: In 2002-06, we recruited contacts aged 15 years or older of index cases with pulmonary tuberculosis who lived in desert shanty towns in Ventanilla, Peru. We followed up contacts for tuberculosis until February, 2016. We used a Cox proportional hazards model to identify index case, contact, and household risk factors for tuberculosis from which to derive a score and classify contacts as low, medium, or high risk. We validated the score in an urban community recruited in Callao, Peru, in 2014-15. FINDINGS: In the derivation cohort, we identified 2017 contacts of 715 index cases, and median follow-up was 10·7 years (IQR 9·5-11·8). 178 (9%) of 2017 contacts developed tuberculosis during 19 147 person-years of follow-up (incidence 0·93 per 100 person-years, 95% CI 0·80-1·08). Risk factors for tuberculosis were body-mass index, previous tuberculosis, age, sustained exposure to the index case, the index case being in a male patient, lower community household socioeconomic position, indoor air pollution, previous tuberculosis among household members, and living in a household with a low number of windows per room. The 10-year risks of tuberculosis in the low-risk, medium-risk, and high-risk groups were, respectively, 2·8% (95% CI 1·7-4·4), 6·2% (4·8-8·1), and 20·6% (17·3-24·4). The 535 (27%) contacts classified as high risk accounted for 60% of the tuberculosis identified during follow-up. The score predicted tuberculosis independently of tuberculin skin test and index-case drug sensitivity results. In the external validation cohort, 65 (3%)
Kirwan D, Ugarte-Gil C, Gilman RH, et al., 2017, Histological examination in obtaining a diagnosis in patients with lymphadenopathy in Lima, Peru, American Journal of Tropical Medicine and Hygiene, Vol: 97, Pages: 1271-1276, ISSN: 1476-1645
The differential diagnosis for lymphadenopathy is wide and clinical presentations overlap, making obtaining an accurate diagnosis challenging. We sought to characterize the clinical and radiological characteristics, histological findings, and diagnoses for a cohort of patients with lymphadenopathy of unknown etiology. 121 Peruvian adults with lymphadenopathy underwent lymph node biopsy for microbiological and histopathological evaluation. Mean patient age was 41 years (Interquartile Range 26–52), 56% were males, and 39% were HIV positive. Patients reported fever (31%), weight loss (23%), and headache (22%); HIV infection was associated with fever (P < 0.05) and gastrointestinal symptoms (P < 0.05). Abnormalities were reported in 40% of chest X-rays (N = 101). Physicians suspected TB in 92 patients (76%), lymphoma in 19 patients (16%), and other malignancy in seven patients (5.8%). Histological diagnoses (N = 117) included tuberculosis (34%), hyperplasia (27%), lymphoma (13%), and nonlymphoma malignancy (14%). Hyperplasia was more common (P < 0.001) and lymphoma less common (P = 0.005) among HIV-positive than HIV-negative patients. There was a trend toward reduced frequency of caseous necrosis in samples from HIV-positive than HIV-negative TB patients (67 versus 93%, P = 0.055). The spectrum of diagnoses was broad, and clinical and radiological features correlated poorly with diagnosis. On the basis of clinical features, physicians over-diagnosed TB, and under-diagnosed malignancy. Although this may not be inappropriate in resource-limited settings where TB is the most frequent easily treatable cause of lymphadenopathy, diagnostic delays can be detrimental to patients with malignancy. It is important that patients with lymphadenopathy undergo a full diagnostic work-up including sampling for histological evaluation to obtain an accurate diagnosis.
Dos Santos Brilha S, Wysoczanski R, Whittington A, et al., 2017, Monocyte adhesion, migration and extracellular matrix breakdown is regulated by integrin αVβ3 in Mycobacterium tuberculosis infection, Journal of Immunology, Vol: 199, Pages: 982-991, ISSN: 1550-6606
In tuberculosis (TB), the innate inflammatory immune response drives tissue destruction, morbidity, and mortality. Monocytes secrete matrix metalloproteinases (MMPs), which have key roles in local tissue destruction and cavitation. We hypothesized that integrin signaling might regulate monocyte MMP secretion in pulmonary TB during cell adhesion to the extracellular matrix (ECM). Adhesion to type I collagen and fibronectin by Mycobacterium tuberculosis–stimulated monocytes increased MMP-1 gene expression by 2.6-fold and 4.3-fold respectively, and secretion by 60% (from 1208.1 ± 186 to 1934.4 ± 135 pg/ml; p < 0.0001) and 63% (1970.3 ± 95 pg/ml; p < 0.001). MMP-10 secretion increased by 90% with binding to type I collagen and 55% with fibronectin, whereas MMP-7 increased 57% with collagen. The ECM did not affect the secretion of tissue inhibitors of metalloproteinases-1 or -2. Integrin αVβ3 surface expression was specifically upregulated in stimulated monocytes and was further increased after adhesion to type I collagen. Binding of either β3 or αV integrin subunits increased MMP-1/10 secretion in M. tuberculosis–stimulated monocytes. In a cohort of TB patients, significantly increased integrin β3 mRNA accumulation in induced sputum was detected, to our knowledge, for the first time, compared with control subjects (p < 0.05). Integrin αVβ3 colocalized with areas of increased and functionally active MMP-1 on infected monocytes, and αVβ3 blockade markedly decreased type I collagen breakdown, and impaired both monocyte adhesion and leukocyte migration in a transwell system (p < 0.0001). In summary, our data demonstrate that M. tuberculosis stimulation upregulates integrin αVβ3 expression on monocytes, which upregulates secretion of MMP-1 and -10 on adhesion to the ECM. This leads to increased monocyte recruitment and collagenase activity, which will drive inflammatory t
Hargreaves S, Duarte R, Friedland JS, 2017, The role of pre-migration medical screening in high TB burden countries, INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE, Vol: 21, Pages: 718-719, ISSN: 1027-3719
Brace P, Tezera L, Bielecka M, et al., 2017, Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology, PLOS Pathogens, Vol: 13, ISSN: 1553-7366
Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negative regulatory pathways to augment immunopathology. Inhibition of signalling through the PI3K/AKT/mTORC1 pathway increased matrix metalloproteinase-1 (MMP-1) gene expression and secretion, a collagenase central to TB pathogenesis, and multiple pro-inflammatory cytokines. In patients with confirmed pulmonary TB, PI3Kδ expression was absent within granulomas. Furthermore, Mtb infection suppressed PI3Kδ gene expression in macrophages. Interestingly, inhibition of the MNK pathway, downstream of pro-inflammatory p38 and ERK MAPKs, also increased MMP-1 secretion, whilst suppressing secretion of TH1 cytokines. Cross-talk between the PI3K and MNK pathways was demonstrated at the level of eIF4E phosphorylation. Mtb globally suppressed the MMP-inhibitory pathways in macrophages, reducing levels of mRNAs encoding PI3Kδ, mTORC-1 and MNK-1 via upregulation of miRNAs. Therefore, Mtb disrupts negative regulatory pathways at multiple levels in macrophages to drive a tissue-destructive phenotype that facilitates transmission.
Moores R, Dos Santos Brilha S, Schutgens F, et al., 2017, Epigenetic regulation of Matrix metalloproteinase-1 and -3 expression in mycobacterium tuberculosis infection, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
In pulmonary tuberculosis (TB), the inflammatory immune response against Mycobacterium tuberculosis (Mtb) is associated with tissue destruction and cavitation, which drives disease transmission, chronic lung disease, and mortality. Matrix metalloproteinase (MMP)-1 is a host enzyme critical for the development of cavitation. MMP expression has been shown to be epigenetically regulated in other inflammatory diseases, but the importance of such mechanisms in Mtb-associated induction of MMP-1 is unknown. We investigated the role of changes in histone acetylation in Mtb-induced MMP expression using inhibitors of histone deacetylases (HDACs) and histone acetyltransferases (HAT), HDAC siRNA, promoter-reporter constructs, and chromatin immunoprecipitation assays. Mtb infection decreased Class I HDAC gene expression by over 50% in primary human monocyte-derived macrophages but not in normal human bronchial epithelial cells (NHBEs). Non-selective inhibition of HDAC activity decreased MMP-1/-3 expression by Mtb-stimulated macrophages and NHBEs, while class I HDAC inhibition increased MMP-1 secretion by Mtb-stimulated NHBEs. MMP-3 expression, but not MMP-1, was downregulated by siRNA silencing of HDAC1. Inhibition of HAT activity also significantly decreased MMP-1/-3 secretion by Mtb-infected macrophages. The MMP-1 promoter region between −2,001 and −2,942 base pairs from the transcriptional start site was key in control of Mtb-driven MMP-1 gene expression. Histone H3 and H4 acetylation and RNA Pol II binding in the MMP-1 promoter region were increased in stimulated NHBEs. In summary, epigenetic modification of histone acetylation via HDAC and HAT activity has a key regulatory role in Mtb-dependent gene expression and secretion of MMP-1 and -3, enzymes which drive human immunopathology. Manipulation of epigenetic regulatory mechanisms may have potential as a host-directed therapy to improve outcomes in the era of rising TB drug resistance.
Walker NF, Wilkinson KA, Meintjes G, et al., 2017, Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study, Clinical Infectious Diseases, Vol: 65, Pages: 121-132, ISSN: 1058-4838
Background. Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, butthe underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a keyprocess but has not been systematically studied in HIV-associated TB.Methods. We performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)–infected and –uninfected TB patientsand controls, and a prospective cohort study of HIV-1–infected TB patients at risk of TB immune reconstitution inflammatorysyndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasmaprocollagen III N-terminal propeptide (PIIINP) by enzyme-linked immunosorbent assay, and urinary lipoarabinomannan (LAM)by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacteriumtuberculosis and extracellular matrix in a 3D model of TB granuloma formation.Results. MMP activity differed between HIV-1–infected and –uninfected TB patients and corresponded with specific TB clinicalphenotypes. HIV-1–infected TB patients had reduced pulmonary MMP concentrations, associated with reduced cavitation,but increased plasma PIIINP, compared to HIV-1–uninfected TB patients. Elevated extrapulmonary extracellular matrix turnoverwas associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likelyneutrophil derived and M. tuberculosis–antigen driven. Mycobacterium tuberculosis–induced matrix degradation was suppressed bythe MMP inhibitor doxycycline in vitro.Conclusions. MMP activity in TB differs by HIV-1 status and compartment, and releases matrix degradation products. Matrixturnover in HIV-1–infected patients is increased before and during TB-IRIS, informing novel diagnostic strategies. MMP inhibitionis a potential host-directed therapy
Ong C, Pabisiak P, Dos Santos Brilha S, et al., 2017, Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis, Journal of Neuroinflammation, Vol: 14, ISSN: 1742-2094
BackgroundCentral nervous system tuberculosis (CNS-TB) may be fatal even with treatment. Neutrophils are the key mediators of TB immunopathology, and raised CSF matrix metalloproteinase-9 (MMP-9) which correlates to neutrophil count in CNS-TB is associated with neurological deficit and death. The mechanisms by which neutrophils drive TB-associated CNS matrix destruction are not clearly defined.MethodsHuman brain biopsies with histologically proven CNS-TB were stained for neutrophils, neutrophil elastase, and MMP-9. Neutrophil MMP-9 secretion and gene expression were analyzed using Luminex and real-time PCR. Type IV collagen degradation was evaluated using confocal microscopy and quantitative fluorescent assays. Intracellular signaling pathways were investigated by immunoblotting and chemical inhibitors.ResultsMMP-9-expressing neutrophils were present in tuberculous granulomas in CNS-TB and neutrophil-derived MMP-9 secretion was upregulated by Mycobacterium tuberculosis (M.tb). Concurrent direct stimulation by M.tb and activation via monocyte-dependent networks had an additive effect on neutrophil MMP-9 secretion. Destruction of type IV collagen, a key component of the blood-brain barrier, was inhibited by neutralizing neutrophil MMP-9. Monocyte-neutrophil networks driving MMP-9 secretion in TB were regulated by MAP-kinase and Akt-PI3 kinase pathways and the transcription factor NF-kB. TNFα neutralization suppressed MMP-9 secretion to baseline while dexamethasone did not.ConclusionsMultiple signaling paths regulate neutrophil-derived MMP-9 secretion, which is increased in CNS-TB. These paths may be better targets for host-directed therapies than steroids currently used in CNS-TB.
Proano A, Bravard M, Lopez JW, et al., 2017, Dynamics of cough frequency in adults undergoing treatment for pulmonary tuberculosis, Clinical Infectious Diseases, Vol: 64, Pages: 1174-1181, ISSN: 1537-6591
Background.Cough is the major determinant of tuberculosis transmission. Despite this, there is a paucity of information regarding characteristics of cough frequency throughout the day and in response to tuberculosis therapy. Here we evaluate the circadian cycle of cough, cough frequency risk factors, and the impact of appropriate treatment on cough and bacillary load.Methods.We prospectively evaluated human immunodeficiency virus–negative adults (n = 64) with a new diagnosis of culture-proven, drug-susceptible pulmonary tuberculosis immediately prior to treatment and repeatedly until treatment day 62. At each time point, participant cough was recorded (n = 670) and analyzed using the Cayetano Cough Monitor. Consecutive coughs at least 2 seconds apart were counted as separate cough episodes. Sputum samples (n = 426) were tested with microscopic-observation drug susceptibility broth culture, and in culture-positive samples (n = 252), the time to culture positivity was used to estimate bacillary load.Results.The highest cough frequency occurred from 1 pm to 2 pm, and the lowest from 1 am to 2 am (2.4 vs 1.1 cough episodes/hour, respectively). Cough frequency was higher among participants who had higher sputum bacillary load (P < .01). Pretreatment median cough episodes/hour was 2.3 (interquartile range [IQR], 1.2–4.1), which at 14 treatment days decreased to 0.48 (IQR, 0.0–1.4) and at the end of the study decreased to 0.18 (IQR, 0.0–0.59) (both reductions P < .001). By 14 treatment days, the probability of culture conversion was 29% (95% confidence interval, 19%–41%).Conclusions.Coughs were most frequent during daytime. Two weeks of appropriate treatment significantly reduced cough frequency and resulted in one-third of participants achieving culture conversion. Thus, treatment by 2 weeks considerably diminishes, but does not eliminate, the potential for airborne tuberculosis transmission.
Dudley MZ, Sheen P, Gilman RH, et al., 2016, Detecting mutations in the Mycobacterium tuberculosis pyrazinamidase gene pncA to improve infection control and decrease drug resistance rates in human immunodeficiency virus coinfection, American Journal of Tropical Medicine and Hygiene, Vol: 95, Pages: 1239-1246, ISSN: 1476-1645
Hospital infection control measures are crucial to tuberculosis (TB) control strategies within settings caring for human immunodeficiency virus (HIV)-positive patients, as these patients are at heightened risk of developing TB. Pyrazinamide (PZA) is a potent drug that effectively sterilizes persistent Mycobacterium tuberculosis bacilli. However, PZA resistance associated with mutations in the nicotinamidase/pyrazinamidase coding gene, pncA, is increasing. A total of 794 patient isolates obtained from four sites in Lima, Peru, underwent spoligotyping and drug resistance testing. In one of these sites, the HIV unit of Hospital Dos de Mayo (HDM), an isolation ward for HIV/TB coinfected patients opened during the study as an infection control intervention: circulating genotypes and drug resistance pre- and postintervention were compared. All other sites cared for HIV-negative outpatients: genotypes and drug resistance rates from these sites were compared with those from HDM. HDM patients showed high concordance between multidrug resistance, PZA resistance according to the Wayne method, the two most common genotypes (spoligotype international type [SIT] 42 of the Latino American-Mediterranean (LAM)-9 clade and SIT 53 of the T1 clade), and the two most common pncA mutations (G145A and A403C). These associations were absent among community isolates. The infection control intervention was associated with 58-92% reductions in TB caused by SIT 42 or SIT 53 genotypes (odds ratio [OR] = 0.420, P = 0.003); multidrug-resistant TB (OR = 0.349, P < 0.001); and PZA-resistant TB (OR = 0.076, P < 0.001). In conclusion, pncA mutation typing, with resistance testing and spoligotyping, was useful in identifying a nosocomial TB outbreak and demonstrating its resolution after implementation of infection control measures.
Hargreaves S, Nellums L, Friedland JS, 2016, Time to rethink approaches to migrant health screening, Lancet, Vol: 388, Pages: 2456-2457, ISSN: 1474-547X
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