Engaging with civil society to improve access to LTBI screening for new migrants in England: a qualitative study.

The latent tuberculous infection (LTBI) programme in England, UK, offers testing and treatment to new migrants from high tuberculosis incidence countries. However, the rates of LTBI testing, treatment acceptance and completion are suboptimal and appropriate access should be improved. To gain insight from the community, community-based organisations (CBOs) and public sector stakeholders on interventions that facilitate collaboration to improve health care outreach and delivery. Three stakeholder meetings and five focus group discussions were held using thematic analysis to identify themes arising from participants' perspectives. Four overarching themes emerged from the discussions. These were related to capacity of service providers, collaboration between stakeholders, migrant cultures and trust between migrants and service providers, and highlighted the complementary skill sets that different sectors bring to the collaboration, as well as the barriers that need to be surmounted. Stigma could be reduced by making LTBI testing routine. Community members could act as champions of health promotion to raise awareness on LTBI testing, and provide a bridge between communities and primary care services. Public service providers, community members and CBOs are willing to collaborate to support primary care delivery of testing for LTBI and other communicable and non-communicable diseases. Policy and commissioning support are needed to facilitate this collaboration. .

Mycobacterium chimaera infection following cardiac surgery in the United Kingdom: clinical features and outcome of the first 30 cases.

OBJECTIVES: Mycobacterium chimaera infection following cardiac surgery, due to contaminated cardiopulmonary bypass heater-cooler units, has been reported worldwide. However, the spectrum of clinical disease remains poorly understood. To address this, we report the clinical and laboratory features, treatment and outcome of the first 30 UK cases. METHODS: Case note review was performed for cases identified retrospectively through outbreak investigations and prospectively through ongoing surveillance. Case definition was Mycobacterium chimaera detected in any clinical specimen, history of cardiothoracic surgery with cardiopulmonary bypass, and compatible clinical presentation. RESULTS: Thirty patients were identified (28 with prosthetic material) exhibiting a spectrum of disease including prosthetic valve endocarditis (14/30), sternal wound infection (2/30), aortic graft infection (4/30) and disseminated (non-cardiac) disease (10/30). Patients presented a median of 14 months post surgery (maximum 5 years) most commonly complaining of fever and weight loss. Investigations frequently revealed lymphopenia, thrombocytopenia, liver cholestasis and non-necrotizing granulomatous inflammation. Diagnostic sensitivity for a single mycobacterial blood culture was 68% but increased if multiple samples were sent. In all, 27 patients started macrolide-based combination treatment and 14 had further surgery. To date, 18 patients have died (60%) a median of 30 months (interquartile range 20-39 months) after initial surgery. Survival analysis identified younger age, mitral valve surgery, mechanical valve replacement, higher serum sodium concentration and lower C-reactive protein as factors associated with better survival. CONCLUSIONS: Mycobacterium chimaera infection following cardiac surgery is associated with a wide spectrum of disease. The diagnosis should be considered in all patients who develop an unexplained illness following cardiac surgery.

Mycobacterium tuberculosis and whole-genome sequencing: how close are we to unleashing its full potential?

BACKGROUND: Nearly two decades after completion of the genome sequence of Mycobacterium tuberculosis (MTB), and with the advent of next generation sequencing technologies (NGS), whole-genome sequencing (WGS) has been applied to a wide range of clinical scenarios. Starting in 2017, England is the first country in the world to pioneer its use on a national scale for the diagnosis of tuberculosis, detection of drug resistance, and typing of MTB. AIMS: This narrative review critically analyses the current applications of WGS for MTB and explains how close we are to realizing its full potential as a diagnostic, epidemiologic, and research tool. SOURCES: We searched for reports (both original articles and reviews) published in English up to 31 May 2017, with combinations of the following keywords: whole-genome sequencing, Mycobacterium, and tuberculosis. MEDLINE, Embase, and Scopus were used as search engines. We included articles that covered different aspects of whole-genome sequencing in relation to MTB. CONTENT: This review focuses on three main themes: the role of WGS for the prediction of drug susceptibility, MTB outbreak investigation and genetic diversity, and research applications of NGS. IMPLICATIONS: Many of the original expectations have been accomplished, and we believe that with its unprecedented sensitivity and power, WGS has the potential to address many unanswered questions in the near future. However, caution is still needed when interpreting WGS data as there are some important limitations to be aware of, from correct interpretation of drug susceptibilities to the bioinformatic support needed.

Evaluation of prediagnosis emergency department presentations in patients with active tuberculosis: the role of chest radiography, risk factors and symptoms.

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.

Evaluation of serum inflammatory biomarkers as predictors of treatment outcome in pulmonary tuberculosis.

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 1.597.32, 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 2.2316.80, 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.

A UK-based resource to support the monitoring and safe use of anti-TB drugs and second-line treatment of multidrug-resistant TB.

Using the best available evidence and expert consensus, this document provides guidance for adverse effect monitoring in multidrug-resistant TB (MDR-TB). It includes recommendations for baseline tests, routine drug and toxicity monitoring guides as well as individual drug monographs for all drugs currently available in the UK to treat TB. These recommendations provide a structure through which healthcare professionals can better manage the complex drug regimens required for the treatment of MDR-TB; minimising the risk of adverse incidents and helping to improve patients' tolerance, compliance and treatment completion.

CXC chemokines and antimicrobial peptides in rhinovirus-induced experimental asthma exacerbations.

RATIONALE: Rhinoviruses (RVs) are the major triggers of asthma exacerbations. We have shown previously that lower respiratory tract symptoms, airflow obstruction, and neutrophilic airway inflammation were increased in experimental RV-induced asthma exacerbations. OBJECTIVES: We hypothesized that neutrophil-related CXC chemokines and antimicrobial peptides are increased and related to clinical, virologic, and pathologic outcomes in RV-induced exacerbations of asthma. METHODS: Protein levels of antimicrobial peptides (SLPI, HNP 1-3, elafin, and LL-37) and neutrophil chemokines (CXCL1/GRO-α, CXCL2/GRO-ß, CXCL5/ENA-78, CXCL6/GCP-2, CXCL7/NAP-2, and CXCL8/IL-8) were determined in bronchoalveolar lavage (BAL) fluid of 10 asthmatics and 15 normal controls taken before, at day four during and 6 weeks post-experimental infection. RESULTS: BAL HNP 1-3 and Elafin were higher, CXCL7/NAP-2 was lower in asthmatics compared with controls at day 4 (P = 0.035, P = 0.048, and P = 0.025, respectively). BAL HNP 1-3 and CXCL8/IL-8 were increased during infection (P = 0.003 and P = 0.011, respectively). There was a trend to increased BAL neutrophils at day 4 compared with baseline (P = 0.076). BAL HNP 1-3 was positively correlated with BAL neutrophil numbers at day 4. There were no correlations between clinical parameters and HNP1-3 or IL-8 levels. CONCLUSIONS: We propose that RV infection in asthma leads to increased release of CXCL8/IL-8, attracting neutrophils into the airways where they release HNP 1-3, which further enhances airway neutrophilia. Strategies to inhibit CXCL8/IL-8 may be useful in treatment of virus-induced asthma exacerbations.

Two cases of culture proven Mycobacterium tuberculosis presenting with a broad-complex tachycardia and non-caseating granulomas.

Tuberculosis is a leading cause of death worldwide. It affects pulmonary and extra-pulmonary sites with a multitude of differing presentations. In this report, we describe two cases in which TB causes myopericarditis and presents with a broad-complex tachycardia that did not respond typically to standard anti-arrhythmic therapy; a very rare presentation with limited description in the literature. Both patients required extensive investigation culminating in identifying lymph nodes amenable to biopsy under endobronchial ultrasound guidance. It was not until both patients received anti-tuberculous chemotherapy alongside anti-arrhythmic management that any improvement to their condition was witnessed. Therefore, we recommend that the clinician should have a high index of suspicion for TB in any patient presenting with a broad-complex tachycardia that is not responding to standard first line management, especially if the patient is from a high risk background. We recommend an active diagnostic pursuit, and lymph node biopsy under endobronchial ultrasound guidance.

γδT cells suppress inflammation and disease during rhinovirus-induced asthma exacerbations.

Most asthma exacerbations are triggered by virus infections, the majority being caused by human rhinoviruses (RV). In mouse models, γδT cells have been previously demonstrated to influence allergen-driven airways hyper-reactivity (AHR) and can have antiviral activity, implicating them as prime candidates in the pathogenesis of asthma exacerbations. To explore this, we have used human and mouse models of experimental RV-induced asthma exacerbations to examine γδT-cell responses and determine their role in the immune response and associated airways disease. In humans, airway γδT-cell numbers were increased in asthmatic vs. healthy control subjects during experimental infection. Airway and blood γδT-cell numbers were associated with increased airways obstruction and AHR. Airway γδT-cell number was also positively correlated with bronchoalveolar lavage (BAL) virus load and BAL eosinophils and lymphocytes during RV infection. Consistent with our observations of RV-induced asthma exacerbations in humans, infection of mice with allergic airways inflammation increased lung γδT-cell number and activation. Inhibiting γδT-cell responses using anti-γδTCR (anti-γδT-cell receptor) antibody treatment in the mouse asthma exacerbation model increased AHR and airway T helper type 2 cell recruitment and eosinophilia, providing evidence that γδT cells are negative regulators of airways inflammation and disease in RV-induced asthma exacerbations.

Granulomatous mediastinal adenopathy: can endoscopic ultrasound-guided fine-needle aspiration differentiate between tuberculosis and sarcoidosis?

BACKGROUND AND STUDY AIMS: Mediastinal lymphadenopathy may indicate diseases such as tuberculosis or sarcoidosis, and it is often difficult to establish a diagnosis when standard medical work-up is inconclusive. In this study we investigated the diagnostic yield of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in the differentiation between tuberculosis and sarcoidosis. PATIENTS AND METHODS: In this prospective study, 72 consecutive patients with mediastinal lymphadenopathy, negative endoscopic investigations including bronchoscopic procedures, and no radiological evidence of lung cancer or other malignancies on computed tomography were enrolled. EUS-FNA and subsequent cytology, microscopy for acid-fast bacilli, and culture were performed. At least 12 months' follow-up including further investigations was included to exclude tuberculosis. RESULTS: Adequate samples were obtained from 71/72 patients (36 male; mean age 50.2 years). No complications occurred. The final diagnosis included 30 cases of sarcoidosis, 28 of tuberculosis, four malignancies, one abscess, and nine benign lymphadenopathies. The size of lymph nodes on EUS varied from 0.5 cm to 4.2 cm. Tuberculosis nodes were significantly smaller than those in sarcoidosis. Unrelated nodes were significantly smaller than in either tuberculosis or sarcoidosis. The sensitivity, specificity, and positive and negative predictive values of EUS - FNA for tuberculosis were 86 %, 100 %, 100 %, and 91 %, respectively; those for sarcoidosis were 100 %, 93 %, 91 %, and 100 %, respectively. For culture of tuberculosis, they were 71 %, 100 %, 100 %, and 84 %, respectively. EUS - FNA led to a definite diagnosis in 64/72 cases (89 %) that had not been previously diagnosed by routine methods. CONCLUSION: EUS - FNA offers a high diagnostic yield for the differential diagnosis of tuberculosis and sarcoidosis that have not been diagnosed by conventional methods.

Parasitic infections of the lung: a guide for the respiratory physician.

Parasitic infections of the lung occur worldwide among both immunocompetent and immunocompromised patients and may affect the respiratory system in a variety of ways. This review provides an update on the presenting symptoms, signs, investigation and management of diseases affecting the lung caused by protozoa, nematodes and trematodes. The clinical presentations and radiographic findings of several of these diseases may mimic tuberculosis and malignancy. It is important to consider parasitic infections in the differential diagnosis of such lung diseases. If identified early, most parasitic diseases that affect the lung are curable with medical or surgical treatments.

The use of thoracic computed tomography scanning and EBUS-TBNA to diagnose tuberculosis of the central nervous system: two case reports.

Herein, we report two cases of tuberculosis (TB) of the central nervous system where accessing the cerebrospinal fluid for diagnostic purposes was relatively or absolutely contraindicated at presentation. The finding of mediastinal lymphadenopathy on thoracic computed tomography scans, which was not visible on plain chest radiography, allowed endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of these lymph nodes to support the diagnosis of TB in each patient and rule out other disease processes. EBUS-TBNA is a new bronchoscopic technique and in this case report appears to be a safe and useful option in the diagnosis of TB. Moreover, it proved to be so in cases where the main focus of disease was outside the thorax.

Rhinovirus induces MUC5AC in a human infection model and in vitro via NF-κB and EGFR pathways.

Rhinovirus (RV) infections are the major cause of asthma exacerbations, the major cause of morbidity and mortality in asthma. MUC5AC is the major mucin produced by bronchial epithelial cells. Whether RV infection upregulates MUC5AC in vivo is unknown and the molecular mechanisms involved are incompletely understood. We investigated RV induction of MUC5AC in vivo and in vitro to identify targets for development of new therapies for asthma exacerbations. RV infection increased MUC5AC release in normal and asthmatic volunteers experimentally infected with RV-16, and in asthmatic, but not normal, subjects, this was related to virus load. Bronchial epithelial cells were confirmed a source of MUC5AC in vivo. RV induction of MUC5AC in bronchial epithelial cells in vitro occurred via nuclear factor-κB-dependent induction of matrix metalloproteinase-mediated transforming growth factor-α release, thereby activating an epidermal growth factor receptor-dependent cascade culminating, via mitogen-activated protein kinase activation, in specificity protein-1 transactivation of the MUC5AC promoter. RV induction of MUC5AC may be an important mechanism in RV-induced asthma exacerbations in vivo. Revealing the complex serial signalling cascade involved identifies targets for development of pharmacologic intervention to treat mucus hypersecretion in RV-induced illness.