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Halliday A, Whitworth H, Hermagild Kottoor S, et al., 2017, Stratification of latent tuberculosis infection by cellular immune profiling., Journal of Infectious Diseases, Vol: 215, Pages: 1480-1487, ISSN: 1537-6613
Background: Recently-acquired and remotely-acquired latent tuberculosis (TB) infection (LTBI) are clinically indistinguishable, yet recent acquisition of infection is the greatest risk factor for progression to active TB (ATB) in immunocompetent individuals. We aimed to evaluate the ability of cellular immune signatures which differ between ATB and LTBI, to distinguish recently from remotely acquired LTBI. Methods: Fifty-nine individuals were recruited: ATB (n=20); recent LTBI (n=19); remote LTBI (n=20). The proportion of mycobacteria-specific TNFα+IFNγ-IL-2-- secreting CD4+ T cells with a differentiated effector phenotype (TNFα-only TEFF), and the level of CD27 expression on IFNγ-producing CD4+ T cells, were detected by flow-cytometry. Results: The TNFα-only TEFF signature was significantly higher in recent compared to remote LTBI (p<0.0001), and discriminated between these groups with high sensitivity and specificity, with an area under the curve (AUC) = 0.87. Two signatures incorporating CD27 expression did not distinguish between recent and remote LTBI. Interestingly, the TNFα-only TEFF signature in recent LTBI was more similar to ATB than remote LTBI, suggesting that recent LTBI is immunologically more similar to ATB than remote LTBI. Conclusions: These findings reveal marked biological heterogeneity underlying the clinically homogeneous phenotype of LTBI, providing a rationale for immunological risk-stratification for improved targeting of LTBI treatment.
Eberhardt C, Thillai M, Parker R, et al., 2017, Proteomic analysis of Kveim reagent identifies targets of cellular immunity in sarcoidosis, PLOS ONE, Vol: 12, ISSN: 1932-6203
Background:Kveim-reagent (Kv) skin testing was a historical method of diagnosing sarcoidosis. Intradermal injection of treated sarcoidosis spleen tissue resulted in a granuloma response at injection site by 4–6 weeks. Previous work indicates proteins as the possible trigger of this reaction. We aimed to identify Kv-specific proteins and characterise the ex vivo response of Peripheral Blood Mononuclear Cells (PBMCs) from sarcoidosis, tuberculosis and healthy control patients when stimulated with both Kv and selected Kv-specific proteins.Methods:Kv extracts were separated by 1D-SDS-PAGE and 2D-DIGE and then underwent mass spectrometric analysis for protein identification. Sarcoidosis and control PBMCs were first stimulated with Kv and then with three selected recombinant protein candidates which were identified from the proteomic analysis. PBMC secreted cytokines were subsequently measured by Multiplex Cytokine Assay.Results:We observed significantly increased IFN-γ and TNF-α secretion from Kv-stimulated PBMCs of sarcoidosis patients vs. PBMCs from healthy volunteers (IFN-γ: 207.2 pg/mL vs. 3.86 pg/mL, p = 0.0018; TNF-α: 2375 pg/mL vs. 42.82 pg/mL, p = 0.0003). Through proteomic approaches we then identified 74 sarcoidosis tissue-specific proteins. Of these, 3 proteins (vimentin, tubulin and alpha-actinin-4) were identified using both 1D-SDS-PAGE and 2D-DIGE. Data are available via ProteomeXchange with identifier PXD005150. Increased cytokine secretion was subsequently observed with vimentin stimulation of sarcoidosis PBMCs vs. tuberculosis PBMCs (IFN-γ: 396.6 pg/mL vs 0.1 pg/mL, p = 0.0009; TNF-α: 1139 pg/mL vs 0.1 pg/mL, p<0.0001). This finding was also observed in vimentin stimulation of sarcoidosis PBMCs compared to PBMCs from healthy controls (IFN-γ: 396.6 pg/mL vs. 0.1 pg/mL, p = 0.014; TNF-α: 1139 pg/mL vs 42.29 pg/mL, p = 0.027). No difference was found in cytokine secretion between sarcoidosis and contr
Appleton SC, Connell DW, Singanayagam A, et al., 2017, Evaluation of prediagnosis emergency department presentations in patients with active tuberculosis: the role of chest radiography, risk factors and symptoms, BMJ Open Respiratory Research, Vol: 4, ISSN: 2052-4439
Introduction London has a high rate of tuberculosis (TB) with 2572 cases reported in 2014. Cases are more common in non-UK born, alcohol-dependent or homeless patients. The emergency department (ED) presents an opportunity for the diagnosis of TB in these patient groups. This is the first study describing the clinico-radiological characteristics of such attendances in two urban UK hospitals for pulmonary TB (PTB) and extrapulmonary TB (EPTB).Methods We conducted a retrospective cohort study using the London TB Register (LTBR) and hospital records to identify patients who presented to two London ED's in the 6 months prior to their ultimate TB diagnosis 2011–2012.Results 397 TB cases were identified. 39% (154/397) had presented to the ED in the 6 months prior to diagnosis. In the study population, the presence of cough, weight loss, fever and night sweats only had prevalence rates of 40%, 34%, 34% and 21%, respectively. Chest radiography was performed in 76% (117/154) of patients. For cases where a new diagnosis of TB was suspected, 73% (41/56) had an abnormal radiograph, compared with 36% (35/98) of patients where it was not. There was an abnormality on a chest radiograph in 73% (55/75) of PTB cases and also in 40% (21/52) of EPTB cases where a film was requested.Conclusions A large proportion of patients with TB present to ED. A diagnosis was more likely in the presence of an abnormal radiograph, suggesting opportunities for earlier diagnosis if risk factors, symptoms and chest radiograph findings are combined.
Arnold A, Cooke GS, Kon OM, et al., 2016, Drug resistant TB: UK multicentre study (DRUMS): Treatment, management and outcomes in London and West Midlands 2008-2014, Journal of Infection, Vol: 74, Pages: 260-271, ISSN: 0163-4453
Objectives: Detailed information regarding treatment practices and outcomes ofMDR-TB treatment in the UK is required as a baseline for care improvements.Methods: 100 consecutive cases between 2008 and 2014 were reviewed retrospectively at 4MDR-TB treatment centres in England to obtain information on drug treatment choices, hospitaladmission duration and outcomes for MDR-TB.Results: Initial hospital admission was long, median 62.5 (IQR 20e106, n Z 92) days, and 13%(12/92) of patients lost their home during this period. Prolonged admission was associated withpulmonary cases, cavities on chest radiograph, a public health policy of waiting for sputum cultureconversion (CC) and loss of the patient’s home. Sputum CC occurred at a median of 33.5(IQR 16e55, n Z 46) days. Treatment success was high (74%, 74/100) and mortality low (1%, 1/100). A significant proportion of the cohort had “neutral” results due to deportation and transferoverseas (12%, (12/100)). 14% (14/100) had negative outcomes for which poor adherencewas the main reason (62%, 9/14).
Singanayagam A, Manalan K, Connell DW, et al., 2016, Evaluation of serum inflammatory biomarkers as predictors of treatment outcome in pulmonary tuberculosis, International Journal of Tuberculosis and Lung Disease, Vol: 20, Pages: 1653-1660, ISSN: 1815-7920
OBJECTIVE: To evaluate C-reactive protein (CRP), globulin and white blood cell (WBC) count as predictors of treatment outcome in pulmonary tuberculosis (PTB).METHODS: An observational study of patients with active PTB was conducted at a tertiary centre. All patients had serum CRP, globulin and WBC measured at baseline and at 2 months following commencement of treatment. The outcome of interest was requirement for extension of treatment beyond 6 months.RESULTS: There were 226 patients included in the study. Serum globulin >45 g/l was the only baseline biomarker evaluated that independently predicted requirement for treatment extension (OR 3.42, 95%CI 1.59–7.32, P < 0.001). An elevated globulin level that failed to normalise at 2 months was also associated with increased requirement for treatment extension (63.9% vs. 5.1%, P < 0.001), and had a low negative likelihood ratio (0.07) for exclusion of requirement for treatment extension. On multivariable analysis, an elevated globulin that failed to normalise at 2 months was independently associated with requirement for treatment extension (OR 6.13, 95%CI 2.23–16.80, P < 0.001).CONCLUSIONS: Serum globulin independently predicts requirement for treatment extension in PTB and outperforms CRP and WBC as a predictive biomarker. Normalisation of globulin at 2 months following treatment commencement is associated with low risk of requirement for treatment extension.
Ahern N, Jarvis H, Charif R, et al., 2016, THE USE OF TUBERCULOSIS CHEMOPROPHYLAXIS IN PATIENTS OF RENAL REPLACEMENT THERAPY, THORAX, Vol: 71, Pages: A51-A51, ISSN: 0040-6376
Ritchie A, Singanayagam A, Manalan K, et al., 2016, SERUM INFLAMMATORY BIOMARKERS AS PREDICTORS OF TREATMENT OUTCOME IN PULMONARY TUBERCULOSIS, THORAX, Vol: 71, Pages: A143-A144, ISSN: 0040-6376
O'Donoghue M, Jarvis H, Drey N, et al., 2016, THE IMPACT OF TB NICE GUIDANCE ON RESOURCE CAPACITY AND CONTACT SCREENING OUTCOMES: A RETROSPECTIVE, OBSERVATIONAL STUDY WITHIN A CENTRAL LONDON TB CENTRE, THORAX, Vol: 71, Pages: A142-A142, ISSN: 0040-6376
Abbara A, Mahomed Z, Collin SM, et al., 2016, OLDER PATIENTS WITH TUBERCULOSIS HAVE LESS TYPICAL CHANGES ON CHEST RADIOGRAPHS, THORAX, Vol: 71, Pages: A143-A143, ISSN: 0040-6376
Abbara A, Hardman E, Collin SM, et al., 2016, THE NATURE AND DURATION OF SYMPTOMS AND TIME TO STARTING TREATMENT COMPARING OLDER WITH YOUNGER PULMONARY TUBERCULOSIS PATIENTS, THORAX, Vol: 71, Pages: A51-A52, ISSN: 0040-6376
Rawson T, Abbara A, Kranzer K, et al., 2016, Factors which influence treatment initiation for pulmonary non-tuberculous mycobacterium infection in HIV negative patients; a multicentre observational study, Respiratory Medicine, Vol: 120, Pages: 101-108, ISSN: 1532-3064
BackgroundClinical, radiological and microbiological criteria inform diagnosis of pulmonary Non-Tuberculous Mycobacteria (NTM) disease and treatment decisions. This multicentre, review aims to characterise NTM disease meeting ATS/IDSA criteria and define factors associated with initiation of treatment.MethodsSputum samples growing NTM from 5 London hospitals between 2010 and 2014 were identified. Data for HIV-negative individuals meeting ATS/IDSA guidelines for pulmonary NTM disease were extracted. Associations between clinical variables and treatment decision were investigated using Chi-squared, Fishers-exact or Mann Whitney tests. Factors associated with treatment in univariate analysis (p < 0.150) were included in a multivariate logistic regression model.ResultsNTM were identified from 817 individuals' sputum samples. 108 met ATS/IDSA criteria. 42/108 (39%) were initiated on treatment. Median age was 68 (56–78) in the cohort.On multivariate analysis, factors significantly associated with treatment of pulmonary NTM infection were: Cavitation on HRCT (OR: 6.49; 95% CI: 2.36–17.81), presenting with night sweats (OR 4.18; 95% CI: 1.08–16.13), and presenting with weight loss (OR 3.02; 95% CI: 1.15–7.93).Of those treated, 18(43%) have completed treatment, 9(21%) remain on treatment, 10(24%) stopped due to side effects, 5(12%) died during treatment. Mortality was 31% (n = 13) in treated versus 21% (n = 14) in the non-treated cohort. Subgroup analysis of individual NTM species did not observe any differences in treatment initiation or outcomes between groups.DiscussionDecision to treat pulmonary NTM infection requires clinical judgement when interpreting clinical guidelines. Factors independently associated with decision to treat in this HIV-negative cohort include cavitation on HRCT and presenting with night sweats or weight loss.
Ritchie A, Singanayagam A, Manalan K, et al., 2016, Evaluation of serum inflammatory biomarkers as predictors of treatment outcome in pulmonary tuberculosis, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Kee AR, Gonzalez-Lopez JJ, Al-Hity A, et al., 2016, Anti-tubercular therapy for intraocular tuberculosis: A systematic review and meta-analysis, Survey of Ophthalmology, Vol: 61, Pages: 628-653, ISSN: 0039-6257
Intraocular tuberculosis remains a diagnostic and management conundrum for both ophthalmologists and pulmonologists. We analyze the efficacy and safety of anti-tubercular therapy (ATT) in patients with intraocular tuberculosis and factors associated with favorable outcome. Twenty-eight studies are included in this review, with a total of 1,917 patients. Nonrecurrence of inflammation was observed in pooled estimate of 84% of ATT-treated patients (95% CI 79-89). There was minimal difference in the outcome between patients treated with ATT alone (85% successful outcome; 95% CI 25-100) and those with concomitant systemic corticosteroid (82%; 95% CI 73-90). The use of ATT may be of benefit to patients with suspected intraocular tuberculosis; however, this conclusion is limited by the lack of control group analysis and standardized recruitment and treatment protocols. We propose further prospective studies to better establish the efficacy of ATT and ascertain the factors associated with favorable treatment outcomes.
Kirresh A, Everitt A, Kon OM, et al., 2016, Trapped without a diagnosis: Tumour necrosis factor receptor-associated periodic syndrome (TRAPS)., Practical Neurology, Vol: 16, Pages: 304-307, ISSN: 1474-7766
Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant condition caused by mutations in the TNFRSF1A gene. It is characterised by recurrent episodes of myalgia, followed by prolonged fever, migratory rashes, headache, serositis, arthralgia, abdominal pain and periorbital oedema. We describe a 49-year-old man with a self-limiting episode of paraparesis who reported recurrent bouts of abdominal symptoms and headaches since childhood. He had a persistent inflammatory response with night sweats and weight loss. We diagnosed TRAPS 2 years after having identified a TNFRSF1A gene mutation. His symptoms and inflammatory response resolved dramatically with the interleukin-1 receptor antagonist anakinra.
Jozwik A, Habibi MS, Paras A, et al., 2016, Erratum: RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection, Nature Communications, Vol: 7, ISSN: 2041-1723
Kon OM, Oldfield WG, 2016, Why should we continue to do acute general takes?, Future Hosp J, Vol: 3, Pages: 68-69, ISSN: 2055-3323
Specialist Physicians currently provide a substantive contribution towards acute medical takes in hospitals but there is debate as to the role of acute physicians in removing the need for this role. We discuss the benefits and advantages in continuing to provide this general internal medicine component to our patients and propose that it is an important part of most medical specialities. We argue that removing our participation will potentially diminish our overall skills as specialist physicians and advocate that we continue to provide this key component of medical care.
Agrawal R, Kee AR, Ang L, et al., 2016, Tuberculosis or sarcoidosis: Opposite ends of the same disease spectrum?, Tuberculosis, Vol: 98, Pages: 21-26, ISSN: 1873-281X
Tuberculosis and sarcoidosis are chronic systemic diseases that have similar pulmonary and extra-pulmonary manifestations. Multiple studies have found an epidemiological, molecular, and immunological link between the two. It has been suggested that mycobacterium tuberculosis could be a common pathophysiologic mechanism for tuberculosis and sarcoidosis, and that both clinical entities can trigger similar immunological response in patients. Due to this close association, together with possible coexistence in the same patient, the diagnosis of one disease from another may be difficult. In our paper, we suggest that tuberculosis and sarcoidosis are two ends of the same spectrum. Given the pathophysiological and clinical link between the two, we also propose a classification system for tuberculosis and sarcoidosis: Sarcoidosis (S); Sarcoid-Tuberculous (ST); Tuberculous Sarcoid (TS) and Tuberculosis (TB). More research and clinical trials should first be done to affirm the link between the two disease entities.
Pollock KM, Montamat-Sicotte D, Grass L, et al., 2016, PD-1 expression and cytokine secretion profiles of Mycobacterium tuberculosis-specific CD4+ T-cell subsets; potential correlates of containment in HIV-TB co-infection, PLOS One, Vol: 11, ISSN: 1932-6203
HIV co-infection is an important risk factor for tuberculosis (TB) providing a powerful model in which to dissect out defective, protective and dysfunctional Mycobacterium tuberculosis (MTB)-specific immune responses. To identify the changes induced by HIV co-infection we compared MTB-specific CD4+ responses in subjects with active TB and latent TB infection (LTBI), with and without HIV co-infection. CD4+ T-cell subsets producing interferon-gamma (IFN-γ), interleukin-2 (IL-2) and tumour necrosis factor-alpha (TNF-α) and expressing CD279 (PD-1) were measured using polychromatic flow-cytometry. HIV-TB co-infection was consistently and independently associated with a reduced frequency of CD4+ IFN-γ and IL-2-dual secreting T-cells and the proportion correlated inversely with HIV viral load (VL). The impact of HIV co-infection on this key MTB-specific T-cell subset identifies them as a potential correlate of mycobacterial immune containment. The percentage of MTB-specific IFN-γ-secreting T-cell subsets that expressed PD-1 was increased in active TB with HIV co-infection and correlated with VL. This identifies a novel correlate of dysregulated immunity to MTB, which may in part explain the paucity of inflammatory response in the face of mycobacterial dissemination that characterizes active TB with HIV co-infection.
Footitt J, Mallia P, Durham AL, et al., 2016, Oxidative and Nitrosative Stress and Histone Deacetylase-2 Activity in Exacerbations of COPD., Chest, Vol: 149, Pages: 62-73, ISSN: 1931-3543
BACKGROUND: Respiratory virus infections are commonly associated with COPD exacerbations, but little is known about the mechanisms linking virus infection to exacerbations. Pathogenic mechanisms in stable COPD include oxidative and nitrosative stress and reduced activity of histone deacetylase-2 (HDAC2), but their roles in COPD exacerbations is unknown. We investigated oxidative and nitrosative stress (O&NS) and HDAC2 in COPD exacerbations using experimental rhinovirus infection. METHODS: Nine subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II), 10 smokers, and 11 nonsmokers were successfully infected with rhinovirus. Markers of O&NS-associated cellular damage, and inflammatory mediators and proteases were measured in sputum, and HDAC2 activity was measured in sputum and bronchoalveolar macrophages. In an in vitro model, monocyte-derived THP-1 cells were infected with rhinovirus and nitrosylation and activity of HDAC2 was measured. RESULTS: Rhinovirus infection induced significant increases in airways inflammation and markers of O&NS in subjects with COPD. O&NS markers correlated with virus load and inflammatory markers. Macrophage HDAC2 activity was reduced during exacerbation and correlated inversely with virus load, inflammatory markers, and nitrosative stress. Sputum macrophage HDAC2 activity pre-infection was inversely associated with sputum virus load and inflammatory markers during exacerbation. Rhinovirus infection of monocytes induced nitrosylation of HDAC2 and reduced HDAC2 activity; inhibition of O&NS inhibited rhinovirus-induced inflammatory cytokines. CONCLUSIONS: O&NS, airways inflammation, and impaired HDAC2 may be important mechanisms of virus-induced COPD exacerbations. Therapies targeting these mechanisms offer potential new treatments for COPD exacerbations.
Telcian AG, Zdrenghea MT, Caramori G, et al., 2015, Soluble major histocompatibility complex class I-related chain B molecules are increased and correlate with clinical outcomes during rhinovirus infection in healthy subjects, Chest, Vol: 146, Pages: 32-40, ISSN: 1931-3543
BACKGROUND:Surface major histocompatibility complex class I-related chain (MIC) A and B molecules are increased by IL-15 and have a role in the activation of natural killer group 2 member D-positive natural killer and CD8 T cells. MICA and MICB also exist in soluble forms (sMICA and sMICB). Rhinoviruses (RVs) are the major cause of asthma exacerbations, and IL-15 levels are decreased in the airways of subjects with asthma. The role of MIC molecules in immune responses in the lung has not been studied. Here, we determine the relationship between MICA and MICB and RV infection in vitro in respiratory epithelial cells and in vivo in healthy subjects and subjects with asthma.METHODS:Surface MICA and MICB, as well as sMICA and sMICB, in respiratory epithelial cells were measured in vitro in response to RV infection and exposure to IL-15. Levels of sMICA and sMICB in serum, sputum, and BAL were measured and correlated with blood and bronchoalveolar immune cells in healthy subjects and subjects with asthma before and during RV infection.RESULTS:RV increased MICA and MICB in vitro in epithelial cells. Exogenous IL-15 upregulated sMICB levels in RV-infected epithelial cells. Levels of sMICB molecules in serum were increased in healthy subjects compared with subjects with stable asthma. Following RV infection, airway levels of sMIC are upregulated, and there are positive correlations between sputum MICB levels and the percentage of bronchoalveolar natural killer cells in healthy subjects but not subjects with asthma.CONCLUSIONS:RV infection induces MIC molecules in respiratory epithelial cells in vitro and in vivo. Induction of MICB molecules is impaired in subjects with asthma, suggesting these molecules may have a role in the antiviral immune response to RV infections.
Jozwik A, Habibi MS, Paras A, et al., 2015, RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection, Nature Communications, Vol: 6, Pages: 1-17, ISSN: 2041-1723
In animal models, resident memory CD8+ T (Trm) cells assist in respiratory virus elimination but their importance in man has not been determined. Here, using experimental human respiratory syncytial virus (RSV) infection, we investigate systemic and local virus-specific CD8+ T cell responses in adult volunteers. Having defined the immunodominance hierarchy, we analyze phenotype and function longitudinally in blood and by serial bronchoscopy. Despite rapid clinical recovery, we note surprisingly extensive lower airway inflammation with persistent viral antigen and cellular infiltrates. Pulmonary virus-specific CD8+ T cells display a CD69+CD103+ Trm phenotype and accumulate to strikingly high frequencies into convalescence without continued proliferation. These are more highly differentiated but express fewer cytotoxicity markers than in blood, but their abundance prior to infection correlates with protection from more severe disease.
Rawson TM, Abbara A, Kranzer K, et al., 2015, A MULTI-CENTRE REVIEW OF THE MANAGEMENT OF PULMONARY NON-TUBERCULOUS MYCOBACTERIAL (NTM) INFECTION IN HIV-NEGATIVE SUBJECTS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A210-A211, ISSN: 0040-6376
Abbara A, Lang S, Kon OM, et al., 2015, WEEKLY AUDIOGRAMS PRE-EMPTIVELY IDENTIFY AMIKACIN RELATED OTOTOXICITY IN MDR-TB, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A25-A25, ISSN: 0040-6376
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Abbara A, Buell KG, Sullivan JAL, et al., 2015, TUBERCULOSIS IN OLDER VERSUS YOUNGER ADULT PATIENTS: A RETROSPECTIVE COMPARISON OF PATIENT CHARACTERISTICS AND TREATMENT OUTCOMES AT A MAJOR UK REFERRAL CENTRE, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A203-A203, ISSN: 0040-6376
Ho W, Connell DW, Singanayagam A, et al., 2015, PREDICTIVE ACCURACY AND CLINICAL IMPACT OF XPERT MTB/RIF FOR THE DIAGNOSIS OF SPUTUM SMEAR-NEGATIVE PULMONARY TUBERCULOSIS USING BRONCHOALVEOLAR LAVAGE FLUID, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A26-A26, ISSN: 0040-6376
Lalvani A, Pareek M, Sridhar S, et al., 2015, Vitamin d deficiency and tuberculosis disease phenotype, Thorax, Vol: 70, Pages: 1171-1180, ISSN: 1468-3296
Background Extrapulmonary TB is increasinglycommon, yet the determinants of the wide clinicalspectrum of TB are poorly understood.Methods We examined surveillance data (Birmingham,UK: 1980–2009 and USA Centers for Disease Control:1993–2008) to identify demographic factorsassociated with extrapulmonary TB. We then directlytested association of these factors and serum 25-hydroxycholecalciferol (25(OH)D) concentration withextrapulmonary TB by multivariable analysis in aseparate UK cohort.Results Data were available for 10 152 and 277 013TB cases for Birmingham and US, respectively.Local-born individuals of white ethnicity had a lowerproportion of extrapulmonary disease when comparedwith local-born non-whites (p<0.0001); both groupshad a lower proportion of extrapulmonary disease whencompared with foreign-born non-whites (p<0.0001). Ina separate UK cohort (n=462), individuals withextrapulmonary TB had lower mean serum 25(OH)Dconcentration than those with pulmonary TB (11.4 vs15.2 nmol/L, respectively, p=0.0001). On multivariableanalysis, vitamin D deficiency was strongly associated withextrapulmonary TB independently of ethnicity, gender andother factors. Doubling in serum 25(OH)D concentrationconferred substantially reduced risk of extrapulmonarydisease (OR 0.55, 95% CI 0.41 to 0.73).Conclusions We identify vitamin D deficiency as aprobable risk factor for extrapulmonary dissemination inTB, which may account for the associations of darkskinnedethnicity and female gender with extrapulmonarydisease. Our findings implicate vitamin D status inMycobacterium tuberculosis containment in vivo and, given the high prevalence of deficiency, may informdevelopment of novel TB prevention strategies.
Dhariwal J, Kitson J, Jones RE, et al., 2015, Nasal Lipopolysaccharide Challenge and Cytokine Measurement Reflects Innate Mucosal Immune Responsiveness, PLOS One, Vol: 10, ISSN: 1932-6203
BackgroundPractical methods of monitoring innate immune mucosal responsiveness are lacking. Lipopolysaccharide(LPS) is a component of the cell wall of Gram negative bacteria and a potentactivator of Toll-like receptor (TLR)-4. To measure LPS responsiveness of the nasalmucosa, we administered LPS as a nasal spray and quantified chemokine and cytokine levelsin mucosal lining fluid (MLF).MethodsWe performed a 5-way cross-over, single blind, placebo-controlled study in 15 healthy nonatopicsubjects (n = 14 per protocol). Doses of ultrapure LPS (1, 10, 30 or 100μg/100μl) orplacebo were administered by a single nasal spray to each nostril. Using the recently developedmethod of nasosorption with synthetic adsorptive matrices (SAM), a series of sampleswere taken. A panel of seven cytokines/chemokines were measured by multiplex immunoassayin MLF. mRNA for intercellular cell adhesion molecule-1 (ICAM-1) was quantifiedfrom nasal epithelial curettage samples taken before and after challenge.ResultsTopical nasal LPS was well tolerated, causing no symptoms and no visible changes to thenasal mucosa. LPS induced dose-related increases in MLF levels of IL-1β, IL-6, CXCL8 (IL-8) and CCL3 (MIP-1α) (AUC at 0.5 to 10h, compared to placebo, p<0.05 at 30 and 100μgLPS). At 100μg LPS, IL-10, IFN-α and TNF-α were also increased (p<0.05). Dose-relatedchanges in mucosal ICAM-1 mRNA were also seen after challenge, and neutrophilsappeared to peak in MLF at 8h. However, 2 subjects with high baseline cytokine levelsshowed prominent cytokine and chemokine responses to relatively low LPS doses (10μgand 30μg LPS).
Nooredinvand HA, Connell DW, Asgheddi M, et al., 2015, Viral hepatitis prevalence in patients with active and latent tuberculosis, World Journal of Gastroenterology, Vol: 21, Pages: 8920-8926, ISSN: 1007-9327
AIM: To assess the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and association with drug induced liver injury (DILI) in patients undergoing anti-tuberculosis (TB) therapy.METHODS: Four hundred and twenty nine patients with newly diagnosed TB - either active disease or latent infection - who were due to commence anti-TB therapy between September 2008 and May 2011 were included. These patients were prospectively tested for serological markers of HBV, HCV and human immunodeficiency virus (HIV) infections - hepatitis B core antigen (HBcAg), hepatitis B surface antigen (HBsAg), hepatitis B e antigen, IgG and IgM antibody to HBcAg (anti-HBc), HCV IgG antibody and HIV antibody using a combination of enzyme-linked immunosorbent assay, Western blot assay and polymerase chain reaction techniques. Patients were reviewed at least monthly during the TB treatment initiation phase. Liver function tests were measured prior to commencement of anti-TB therapy and 2-4 wk later. Liver function tests were also performed at any time the patient had significant nausea, vomiting, rash, or felt non-specifically unwell. Fisher’s exact test was used to measure significance in comparisons of proportions between groups. A P value of less than 0.05 was considered statistically significant.RESULTS: Of the 429 patients, 270 (62.9%) had active TB disease and 159 (37.1%) had latent TB infection. 61 (14.2%) patients had isolated anti-HBc positivity, 11 (2.6%) were also HBsAg positive and 7 (1.6%) were HCV-antibody positive. 16/270 patients with active TB disease compared to 2/159 patients with latent TB infection had markers of chronic viral hepatitis (HBsAg or HCV antibody positive; P = 0.023). Similarly the proportion of HBsAg positive patients were significantly greater in the active vs latent TB infection group (10/43 vs 1/29, P = 0.04). The prevalence of chronic HBV or HCV was significantly higher than the estimated United Kingdom prevalence of 0.3% for each
Pedrazzoli D, Abubakar I, Potts H, et al., 2015, Risk factors for the misdiagnosis of tuberculosis in the UK, 2001-2011, EUROPEAN RESPIRATORY JOURNAL, Vol: 46, Pages: 564-567, ISSN: 0903-1936
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Gielen V, Sykes A, Zhu J, et al., 2015, Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons, Journal of Allergy and Clinical Immunology, Vol: 136, Pages: 177-188e.11, ISSN: 1097-6825
BackgroundRhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/β/λ in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown.ObjectiveWe sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients.MethodsWe assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes.ResultsWe report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation–related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients.ConclusionWe describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations.
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