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Introduction: NTM are increasingly isolated in respiratory samples. It is unclear how much this is true disease rather than colonisation or contamination. Development of endobronchial ultrasound (EBUS) allows mediastinal sampling. This may be considered a sterile site; though sampling is via large airways. Little data exists on the frequency of NTM isolation from EBUS; so we sought to investigate this question using our prospective dataset from the United Kingdom. Methods: EBUS-TBNA was performed with onsite cytology review. In suspected granulomatous disease needle washings were combined and submitted for mycobacterial culture. All EBUS performed between 01/2008 and 09/2013 were analysed. Results: 2539 EBUS cases were performed of which 42% were for staging/investigation of suspected lung cancer, 26% suspected TB or sarcoidosis and 32% other indications. In 845/2539(33%) samples were sent for mycobacterial culture. 176/845(21%) were positive for MTB while 14/845(2%) had positive cultures for NTM. M. avium-intracellulare (MAI) was isolated in 8/14 cases of which 5/8 were treated (all HIV-infected). M. kansasii in 2, both had FDG-avid nodes following bone marrow transplantation and were treated. M. malmoense was isolated in 1/14 and this was treated. M. chelonae, M. gordonae, and M. mucogenicum were cultured in 1 sample each but none were treated. 60% had positive MC&S cultures. Discussion: These data suggest that isolation of NTM from the mediastinum is rare. Clinically significant isolates were found mainly in patients with significant immune-suppression. Despite sampling via EBUS often not being sterile, these data suggest that NTM isolation due to either colonisation or contamination using this technique is not common.

OBJECTIVE To investigate whether HIV-infected individuals diagnosed with tuberculosis (HIV-TB) around the time of starting antiretroviral therapy (ART) have impaired CD4 cell responses to treatment. DESIGN Analysis of a national cohort of HIV-infected adults, linked to the national TB surveillance system for England, Wales and Northern Ireland, including individuals starting ART from 2005 to 2009. METHODS We compared CD4 cell responses in HIV-infected individuals starting ART with a TB diagnosis ('HIV-TB cohort') with those not known to have TB ('TB-free cohort'). The TB-free cohort was frequency-matched to the HIV-TB cases for sex, age strata, baseline CD4 strata and ethnicity. Median change in CD4 cell count from baseline (ΔCD4) was calculated at 6-monthly intervals until 36 months. RESULTS There were 593 and 1779 individuals in the HIV-TB and TB-free cohorts, respectively (median follow-up 3.8 years). In both cohorts, median age was 36 years, 49.2% were women and 74.9% were black-African. Median baseline CD4 at the start of treatment was similar in the HIV-TB and TB-free cohorts (74 vs. 80 cells/μl). Median ΔCD4 was similar in HIV-TB and TB-free cohorts at all time points [294 (inter-quartile range 198-424) cells/μl in HIV-TB cohort; 296 (inter-quartile range 196-431) cells/μl in TB-free cohort after 3 years of ART]. A higher proportion of the HIV-TB cohort than the TB-free cohort died during follow-up (4.2 vs. 2.2%; P = 0.01); 78.5% of all individuals who died had a baseline CD4 cell count below 100 cells/μl. CONCLUSIONS Long-term CD4 cell recovery during ART appears similar in HIV-TB and TB-free patients. Significant mortality in both cohorts highlights the need for earlier HIV diagnosis and ART initiation.

No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as ‘opportunistic infections’ (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as ‘indicator’ infections, defined as specific pathogens or presentations of pathogens that ‘indicate’ the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.

Unacceptable levels of Mycobacterium tuberculosis transmission are noted in high burden settings and a renewed focus on reducing person-to-person transmission in these communities is needed. We review recent developments in the understanding of airborne transmission. We outline approaches to measure transmission in populations and trials and describe the Wells-Riley equation, which is used to estimate transmission risk in indoor spaces. Present research priorities include the identification of effective strategies for tuberculosis infection control, improved understanding of where transmission occurs and the transmissibility of drug-resistant strains, and estimates of the effect of HIV and antiretroviral therapy on transmission dynamics. When research is planned and interventions are designed to interrupt transmission, resource constraints that are common in high burden settings-including shortages of health-care workers-must be considered.

Airway bacterial colonisation and respiratory symptoms are common in ambulatory HIV-positive UK adults http://ow.ly/Nug5A

The future of tuberculosis control need not be one of continuously failing to learn from the past

Whether the incidence of tuberculosis in HIV-positive people receiving long-term antiretroviral therapy (ART) remains above background population rates is unclear. We compared tuberculosis incidence in people receiving ART with background rates in England, Wales, and Northern Ireland.We analysed a national cohort of HIV-positive individuals linked to the national tuberculosis register. Tuberculosis incidence in the HIV-positive cohort (2007-11) was stratified by ethnic origin and time on ART and compared with background rates (2009). Ethnic groups were defined as follows: the black African group included all individuals of black African origin, including those born in the UK and overseas; the white ethnic group included all white individuals born in the UK and overseas; the south Asian group included those of Indian, Pakistani, and Bangladeshi origin, born in the UK and overseas; and the other ethnic group included all other ethnic origins, including black Afro-Caribbeans.The HIV-positive cohort comprised 79 919 individuals, in whom there were 1550 incident cases in 231 664 person-years of observation (incidence 6·7 cases per 1000 person-years). Incidence of tuberculosis in the HIV-positive cohort was 13·6 per 1000 person-years in black Africans and 1·7 per 1000 person-years in white individuals. Incidence of tuberculosis during long-term ART (≥5 years) in black Africans with HIV was 2·4 per 1000 person-years, similar to background rates of 1·9 per 1000 person-years in this group (rate ratio 1·2, 95% CI 0·96-1·6; p=0·083); but in white individuals with HIV on long-term ART the incidence of 0·5 per 1000 person-years was higher than the background rate of 0·04 per 1000 person-years (rate ratio 14·5, 9·4-21·3; p0·0001). The increased incidence relative to background in white HIV-positive individuals persisted when analysis was restricted to person-time accrued on ART with CD4 counts of at least 500 cells per μL and when white HIV-positive individuals born abroad were excluded.Tuberculosis incidence is unacceptably high irrespective of HIV status in black Africans. In white individuals with HIV, tuberculosis incidence is significantly higher than background rates in white people despite long-term ART. Expanded testing and treatment for latent tuberculosis infection to all HIV-infected adults, irrespective of ART status and CD4 cell count, might be warranted.Public Health England.

Advanced human immunodeficiency virus (HIV) disease can be defined as a cluster of differentiation 4 (CD4) count

We compared 156 human immunodeficiency virus (HIV)-infected patients who had tuberculosis with control populations of similar size. Of 111 patients with HIV infection and tuberculosis who received highly active antiretroviral therapy (HAART) and therapy for tuberculosis concurrently, 92 (83%) achieved or maintained virus loads of50 copies/mL, and 99 (89%) achieved or maintained aor=2 log10 reduction in virus load after 6 months. Virological response and changes in CD4 cell count were equivalent to those in 111 matched HIV-infected subjects without tuberculosis starting HAART. Tuberculosis recurrence rates were similar to those found in an HIV-uninfected population of 156 subjects (3% and 1%, respectively). Treatment for HIV and tuberculosis does not compromise outcomes for either disease.

Objectives: To describe the characteristics of deaths that occur among HIV-positive individuals in the HAART era.Design: Observational database.Methods: Deaths were reviewed that occurred among HIV-positive individuals seen at the Royal Free Hospital, London between January 1998 and December 2003.Results: Over the study period, there were 121 deaths; death rates declined from approximately 2.0/100 person-years of follow-up in 1998-2000 to approximately 1.0/ 100 person-years of follow-up in 2001-2003. Approximately one half of deaths (45.5%) were from AIDS-related causes and 74 deaths (61.2%) occurred in individuals who had received HAART: patients had been exposed to a median of seven (range 214) antiretroviral drugs and two-fifths had started treatment in the pre-HAART era. Another 15 patients had received only non-HAART treatment regimens prior to death. The median pre-death CD4 cell counts were 68 and 167 cells/mu l among those who had and had not received HAART; 23 (31.1 %) and 4 (8.5%) had HIV RNA < 400 copies/ml, respectively. Of the patients exposed to HAART for at least 6 months and who experienced viral rebound, information was available on resistance for 26 (21.5% of the total deaths) and 19 of those tested had at least one resistance mutation (median 5, range, 1-16).Conclusions: While mortality rates among HIV-infected individuals at our centre have fallen since 1988, the deaths that do now occur are more diverse and are the result of a number of factors, including late presentation, delayed uptake of HAART and the previous use of treatment combinations that are now viewed as suboptimal. (C) 2006 Lippincott Williams & Wilkins.

Background: Correcting the Th2 shift in HIV/AIDS represents a potential intervention strategy. However data on interleukin (IL)-4 expression in HIV or AIDS are uninterpretable because of failure to distinguish between IL-4 and its splice variant and natural antagonist, IL-4d2. Objective: To determine Th1 [interferon (IFN)-g], IL-4d2 and Th2 (IL-4) expression in whole blood and lung lavage from healthy volunteers and in HIV or HIV–tuberculosis (TB) co-infection. Design: Cross-sectional with prospective cohort. Methods: Expression of IL-4d2, IL-4 and IFN-g were determined by quantitative realtime PCR, using unstimulated cells from whole blood and lung lavage, in 20 HIV–TB (pulmonary) co-infected patients, 20 matched HIV-positive controls and 20 HIVnegative healthy volunteers. Results were correlated with plasma viral load, CD4 cell counts, radiological scores and response to anti-TB treatment. Results: Compared to HIV negative donors, stable HIV-positive donors did not have increased levels of mRNA encoding IL-4, IL-4d2 or IFN-g in blood or lavage. By contrast, the HIV–TB co-infected donors had increased IL-4 and IFN-g in both compartments. However the antagonist, IL-4d2 was increased only in lavage. Consequently the dominant form was IL-4d2 in lavage, but IL-4 itself in blood. The lung IL-4/IFN-g ratio correlated with radiological disease extent. With anti-TB treatment, IL-4 levels did not change whilst IL-4d2 levels increased significantly. Conclusions: IL-4 and its natural antagonist, IL-4d2 and are not upregulated in the absence of opportunistic infection. However in HIV-TB co-infection both cytokines increase in lung, but only IL-4 in the periphery. Further studies are required to determine if IL-4 facilitates systemic HIV progression.

Compression and paralysis of the left recurrent laryngeal nerve by a dilated pulmonary artery is a rare complication of pulmonary hypertension. We here report the case of a patient with severe haemophilia A and HIV infection who presented with a persistent hoarseness of voice and a left vocal cord palsy caused by HIV-associated pulmonary hypertension. This case suggests that HIV-associated pulmonary hypertension should be suspected in any HIV patient presenting with unexplained left vocal cord palsy.

AL Pozniak, RF Miller, MCI Lipman, AR Freedman, LP Ormerod, MA Johnson, S Collins and SB Lucas, on behalf of the BHIVA Guidelines Writing Committee Chelsea and Westminster NHS Healthcare Trust, London, UK, Centre for Sexual Health and HIV Research, Department of Primary Care and Population Sciences, Royal Free and University College Medical School, University College London, London, UK, Royal Free Hospital, London, UK, Cardiff University School of Medicine, Cardiff, UK, Blackburn Royal Infirmary, Blackburn, Lancashire, UK, HIV i-Base, London, UK, Department of Histopathology, GKT School of Medicine, St Thomas’ Hospital, London, UK

Objectives. To describe changes in treatment decisions after receipt of nucleic acid amplification (NAA) test for the diagnosis of A tuberculosis.Methods. Retrospective notes review of treatment decisions in patients receiving a NAA test for suspected pulmonary or non-pulmonary tuberculosis at the Royal Free Hospital in London between March 2001 and February 2002. Notes were sought on a 50% random sample of patients with both smear and NAA negative specimens and at patients with other specimen results.Results. Two hundred and fifty patients were tested with NAA; clinical details were obtained on 138; 61 were ever treated. Seventeen (17/18) smear-negative patients were started on treatment after a positive NAA; none of six smear-negative patients treated prior to a negative NAA result had treatment stopped. Seventeen (17/21) smear-positive patients were treated prior to NAA result and all were NAA positive; treatment was delayed in four smear-positive patients until receipt of an NAA and one NAA-negative patient was not treated.Conclusions. In routine practice a positive test in an untreated smear-negative patient leads to decision to treat in almost all, but the proportion testing positive is low (8% or 17/219). In patients already on treatment negative tests did not lead to decisions to stop. (c) 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved.

Anti-tuberculosis drug regimens are efficacious, but drug intolerance can be severe and may impact on treatment completion rates. The Enhanced Tuberculosis Surveillance (ETS) system is a case register of all new notifications of tuberculosis in England, Wales and Northern Ireland. We conducted a cohort study to estimate the incidence of, and risk factors for, drug intolerance reported through ETS between 2001 and 2010 and to assess its relationship with treatment non-completion. Reports of drug intolerance were found for 868/67 547 (1.28%) patients in the cohort, and important risk factors were female sex, older age, later case report year and white ethnicity. Drug intolerance was associated with an approximate fivefold increased odds of treatment non-completion (p

To the Editor: Multidrug-resistant tuberculosis (MDR-TB) is an increasing global problem. The World Health Organization (WHO) guidelines state that all patients suspected of MDR-TB should be given a group 2 injectable agent, usually an aminoglycoside. However, when taken for extended periods, these can cause nephrotoxicity, neurotoxicity and irreversible ototoxicity [1, 2]. Aminoglycoside-associated progressive hearing loss, from high to low conversational frequency sounds (0.5–2 KHz), affects at least 19% of MDR-TB patients [3, 4]. Most assessments are based on self-reported hearing loss, which is likely to significantly under-estimate the true proportion affected. Although both cochlear and vestibular functions can be impaired, the cochlea is predominantly damaged. This makes audiology testing, in particular serial audiograms that detect tone threshold changes, a useful way to assess ototoxicity, especially for non-conversational ultra-high frequency losses [3–5]. Despite this, there is no widely accepted protocol to monitor for ototoxicity in aminoglycoside-treated MDR-TB patients. Weekly to fortnightly audiograms are recommended after baseline evaluation, though financial and logistical barriers can limit this to monthly assessment [4]. We sought to determine the practicality of intensive assessments in subjects using long-term amikacin, and whether we detected early changes in high frequency hearing loss that could assist in clinical management and so avoid subjective ototoxicity. A retrospective data review of all MDR-TB patients treated with amikacin at a single site London MDR-TB service between 2009 and 2011 was performed. This included information on audiology testing, renal assessments and serum trough level drug concentration. Amikacin was administered intravenously at 15 mg·kg−1 …

Cohort review has been used internationally to support tuberculosis (TB) control. We describe its first use in the UK by a London TB service. Improvements were noted in case management and contact tracing, weaknesses identified and important service changes put in place. Key areas of impact were directly observed therapy (DOT) provision (a greater proportion of cases offered DOT, and in response to low uptake resources diverted to create posts responsible for patient-centred DOT delivery), and contact tracing (more contacts per case screened and assessed). Cohort review enables whole system review and improvement. It has subsequently been adopted across the UK.

Active tuberculosis (TB) in the UK predominantly affects the non-UK born, but is generally not manifest at the time of UK entry. Strategies to detect latent TB infection (LTBI) in this population are, therefore, important. To date, targeted screening has focused on TB risk estimates based on the incidence in the country of origin. Using TB incidence in the UK and migration data, we estimated the numbers needed to be tested and treated for LTBI to prevent one case of TB disease. Numbers were the lowest in Somalian and the highest in South African and Filipino migrants, which contrasts with TB rates in these countries. Targeting screening on the basis of incidence in the UK may thus improve effectiveness.

Nucleic acid amplification techniques (NAATs) have been demonstrated to make significant improvements in the diagnosis of tuberculosis (TB), particularly in the time to diagnosis and the diagnosis of smear-negative TB. The BD ProbeTec strand displacement amplification (SDA) system for the diagnosis of pulmonary and non-pulmonary tuberculosis was evaluated. A total of 689 samples were analysed from patients with clinically suspected TB. Compared with culture, the sensitivity and specificity for pulmonary samples were 98 and 89 %, and against final clinical diagnosis 93 and 92 %, respectively. This assay has undergone limited evaluation for non-respiratory samples and so 331 non-respiratory samples were tested, identifying those specimens that were likely to yield a useful result. These were CSF (n = 104), fine needle aspirates (n = 64) and pus (n = 41). Pleural fluid (n = 47) was identified as a poor specimen. A concern in using the SDA assay was that low-positive samples were difficult to interpret; 7.8 % of specimens fell into this category. Indeed, 64 % of the discrepant results, when compared to final clinical diagnosis, could be assigned as low-positive samples. Specimen type did not predict likelihood of a sample being in the low-positive zone. Although the manufacturers do not describe the concept of a low-positive zone, we have found that it aids clinical diagnosis.

Background: It has been suggested that deterioration of tuberculosis (TB) during appropriate treatment, termed a paradoxical reaction (PR), is more common and severe in HIV positive individuals on highly active antiretroviral therapy (HAART). Method: A study was undertaken to determine the frequency of PR and its associated features in a population of HIV+TB+ patients and a similar sized group of HIV−TB+ individuals. Results: PR occurred in 28% of 50 HIV+TB+ patients and 10% of 50 HIV−TB+ patients. Disseminated TB was present in eight of 13 HIV+TB+ patients and four of five HIV−TB+ patients with PR. In 28 HIV+TB+ patients starting HAART, PR was significantly associated with commencing HAART within 6 weeks of starting antituberculosis treatment (p = 0.03) and was more common in those with disseminated TB (p = 0.09). No association was found between development of PR and baseline CD4 count or CD4 response to HAART. Conclusions: PR is common in HIV infected and uninfected individuals with TB. Early introduction of HAART and the presence of disseminated TB appear to be important in co-infected patients.

We report treatment decisions and outcomes for 20 patients who were infected with human immunodeficiency virus type 1 (HIV-1) and were receiving highly active antiretroviral therapy (HAART) who had respiratory symptoms and from whom Mycobacterium xenopi was isolated. All patients also had coexisting pulmonary pathologic conditions. The median blood T cell CD4 count was 37 cells/microL (range, 2-480 cells/microL). Fifteen of 20 patients received no antimycobacterial therapy and remain healthy after a median of approximately 4 years of follow-up, and 2 patients required treatment specifically for M. xenopi infection, both showing clinical improvement. We conclude that pulmonary M. xenopi isolation in HIV-1 patients receiving HAART does not usually require specific treatment.

OBJECTIVE: To audit the use of antiretroviral (ARV) treatment in a large treatment clinic in the UK against the British HIV Association (BHIVA) ARV treatment guidelines. METHODS: All patients under follow-up between 1st January 2000 and 1st January 2001 were included. The most recent CD4 count and HIV RNA level prior to 1st January 2001, and the nadir CD4 count and peak HIV RNA level over follow-up, were used to identify which patients should be receiving HAART according to the guidelines. RESULTS: One thousand two hundred and sixty-four patients were included in the analysis (63.8% homosexual, 29.0% heterosexual risk; 72.9% white; 79.2% male). Almost half of patients had ever had a CD4 count below 200 cells/ micro L and over 80% had previously had a viral load above 4 log10 HIV-1 RNA copies/mL. Under 2000 BHIVA guidelines, treatment would be recommended in 77.4% patients. Overall, 819 patients were receiving ARV therapy. Two hundred and eighty-five patients were not receiving treatment when guidelines suggest they should (including 33 patients who were receiving regimens not recommended in the guidelines). These patients were younger, less likely to be homosexual and had higher CD4 nadirs than those who were receiving ARV treatment. Almost half of these patients had previously received ARV therapy but were not currently receiving it. CONCLUSION: Only a small proportion of patients at our centre were not receiving ARV treatment in line with national guidelines. While genuine reasons may exist for these departures from optimal care, this may simply reflect the limitations of using observational databases when auditing treatment use in a clinic setting.

Background Injecting drugs substantially increases the risk of hepatitis C virus (HCV) infection and is common in homeless people and prisoners. Capturing accurate data on disease prevalence within these groups is challenging, and this problem hinders efforts to develop targeted strategies to reduce HCV transmission. The aim of this study was to estimate the prevalence of HCV in these vulnerable populations. Methods We conducted a cross-sectional study between May 1, 2011, and June 30, 2013, in London, UK. Using the National Health Service Find and Treat service, we recruited participants from 39 hostels for the homeless, 20 drug treatment services, and a prison. Inclusion criteria were age over 18 years, capacity to consent, and being identified as homeless (living in a homeless hotel), having a history of drug use (using services at drug treatment centres), or being a prisoner at the time of the study. A questionnaire was administered and blood samples were collected to be tested for HCV. Findings We recruited 1207 individuals, of whom 491 were homeless (40·7%), 205 were drug users (17·0%), and 511 were prisoners (42·3%). 98 (8·1%) of the 1207 participants had active HCV infection and 38 (3·1%) had a previous HCV infection. Among HCV-positive individuals, 77 (56·6%) had a history all three risk factors (homelessness, imprisonment, and drug use), 37 (27·3%) had two risk factors, and 22 (15·4%) had one risk factor. Multivariate logistic regression identified three factors associated with increased risk of HCV infection: duration of injecting (odds ratio for Interpretation Homeless services, drug treatment services, and prisons provide good opportunities for identifying HCV-positive individuals. More than half of HCV-infected individuals had the three intersecting risk factors, highlighting the vulnerability of these patients. Reducing the burden of HCV among these vulnerable groups is fundamental to lessen HCV transmission. Funding National Institute for Health Research (NIHR) under the Programme Grants for Applied Research programme (reference number RP-PG-0407-10340). RWA is funded by a Wellcome Trust research training fellowship (097980/Z/11/Z). DNA is funded by an Indonesia Presidential Scholarship.

No evidence that drug-resistant TB results in fewer infections or cases in contacts than drug-susceptible TB http://ow.ly/dgez30f87dr

Headaches are a common complaint in HIV positive patients attending emergency services. A thorough understanding of the differential diagnoses, initial investigations and empirical management of this presentation is essential for the assessing physician. We discuss a case of a patient with known advanced HIV infection presenting with headache to the emergency department. Given the range of possible diagnoses, broad-spectrum antimicrobial therapy was initially commenced. This was stopped when magnetic resonance imaging confirmed a diagnosis of venous sinus thrombosis. Anticoagulation therapy was started in accordance with current clinical guidelines after discussing the rationale and options for treatment with the patient. Here, we review the guidelines and supporting evidence for management of venous sinus thrombosis, and consider the challenges and strategies for engaging a patient with previous poor attendance in their ongoing care.

Background (UK) National Institute for Health and Clinical Excellence tuberculosis (TB) guidance (2006) recommends that occupational health services send annual TB symptom reminders to staff at increased risk of occupational TB exposure. Aims To evaluate the effectiveness of annual TB symptom reminders. Methods Retrospective analysis of returns from 4 years' annual TB symptom reminders compared with numbers of hospital staff diagnosed with active TB in the same time period. Results There were 405 responses to symptom reminders received during the period studied that represented a response rate of 16%. None of the respondents declared TB symptoms. Twelve staff were diagnosed with active TB over the same period. From their work location, only two of these would have received TB symptom reminders according to local TB policy. Conclusions Annual TB symptom reminders as currently used result in little direct benefit.

Rationale: As overall survival improves, individuals with HIV infection become susceptible to other chronic diseases, including accelerated chronic obstructive pulmonary disease (COPD).

Small RNA (smRNA) is a diverse family of translation regulation molecules, which includes microRNA (miRNA). Changes in miRNA have been reported in association with respiratory disease [1] and in mycobacterial infection [2]. Studies have measured concentrations of miRNA pooled from multiple subjects with active tuberculosis (TB) disease compared with latently infected individuals and healthy controls [3]. However, this approach cannot assess variation between individuals, nor does it describe changes that might occur with treatment, both of which may be helpful in characterising and predicting patient outcome. Plasma small RNA concentration declines in response to anti-tuberculosis therapy and is independent of HIV-status We would like to thank S. Bokhari and S. Christou (Centre for Clinical Microbiology, Dept of Infection, University College London, London, UK) for assistance with sample processing and C. Smith (Research Dept of Infection and Population Health, University College London, London, UK) for statistical support.

Summary Objectives Testing for HIV is a standard of care for people with active tuberculosis (TB). People investigated for TB in the UK often originate from areas with a high prevalence of HIV and other blood borne viruses (BBV). However, assessment for these infections is patchy. We determined the yield and costs of different testing strategies for BBV in a UK TB clinic. Methods Since 2009, it has been routine to test all TB clinic attendees. Demographic, clinical and virological data were retrospectively extracted from patient notes and hospital databases. Results Over 3 years, 1036 people were assessed in the TB service. 410 had a final diagnosis of active TB. HIV testing of the latter population diagnosed 27 new HIV cases at a cost of £3017. When BBV testing was offered to all clinic attendees, a further 6 (total 33) new HIV, 5 Hepatitis B (HBV) and 2 Hepatitis C (HCV) diagnoses were made at a total cost of £22,170. Conclusions We have identified previously undiagnosed HIV, HBV and HCV in a TB clinic population. Our data suggest that despite increasing upfront expense, the associated yield argues strongly for BBV testing to be offered to all patients being investigated for possible TB, irrespective of their final diagnosis.

Community-acquired pneumonia continues to be an important complication of HIV infection. Rates of pneumonia decrease with the use of antiretroviral therapy but continue to be higher than in HIV uninfected individuals. Risk factors for pneumonia include low blood CD4+ count, unsuppressed plasma HIV load, smoking, injection drug use and renal impairment. Immunization against Streptococcus pneumoniae and smoking cessation can reduce this risk. It is unclear whether newly reported viral respiratory pathogens (such as the Middle East respiratory syndrome coronavirus, will be more of a problem in HIV-infected individuals than the general population.

Renal transplantation significantly increases the risk of active tuberculosis (TB) in individuals with latent TB infection (LTBI). UK transplant recipients are often born in TB endemic areas. Using a self-completed questionnaire, we evaluated how the 23 UK renal transplant units' LTBI management compared with recently published national guidance. Three-quarters had a management protocol, but only one-third of these were in line with the guidance. Interferon-gamma release assays were rarely used to confirm LTBI. Almost half of the units prescribed LTBI treatment at the wrong dose or duration. We conclude that units should develop local protocols in line with evidence-based guidance. This must be in a format that enables national audit programmes and quality improvement to be routinely performed.

The incidence of nontuberculous mycobacteria is increasing worldwide. However, the evidence base for clinical management comprises mostly expert opinion, case series, and few randomized clinical trials. Most currently recommended treatment regimens entail prolonged use of multiple antimicrobial agents associated with multiple self-limited and persistent potential adverse effects, including irreversible impairments of hearing, vision, and kidney function. Yet, little is known about how treatment impacts an individual patient's overall health status. Current treatment guidelines, although of undoubted value, are constrained by these limitations. Here we call for new studies that reassess recommendations for medical management of pulmonary nontuberculous mycobacteria infections, in particular Mycobacterium avium-intracellulare complex and Mycobacterium abscessus complex. We propose pragmatic, person-centered outcome measures that might be used in clinical assessments and new research studies, including patient-reported experience measures and patient-reported outcome measures. This will enable patients and their health-care providers to make clinical management decisions that derive from a realistic view of what they can hope to achieve from treatment.

The use of human whole blood for transcriptomic analysis has potential advantages over the use of isolated immune cells for studying the transcriptional response to pathogens and their products. Whole blood stimulation can be carried out in a laboratory without the expertise or equipment to isolate immune cells from blood, with the added advantage of being able to undertake experiments using very small volumes of blood. Toll like receptors (TLRs) are a family of pattern recognition receptors which recognise highly conserved microbial products. Using the TLR2 ligand (Pam3CSK4) and the TLR4 ligand (LPS), human whole blood was stimulated for 0, 1, 3, 6, 12 or 24 hours at which times mRNA was isolated and a comparative microarray was undertaken. A common NFκB transcriptional programme was identified following both TLR2 and TLR4 ligation which peaked at between 3 to 6 hours including upregulation of many of the NFκB family members. In contrast an interferon transcriptional response was observed following TLR4 but not TLR2 ligation as early as 1 hour post stimulation and peaking at 6 hours. These results recapitulate the findings observed in previously published studies using isolated murine and human myeloid cells indicating that in vitro stimulated human whole blood can be used to interrogate the early transcriptional kinetic response of innate cells to TLR ligands. Our study demonstrates that a transcriptomic analysis of mRNA isolated from human whole blood can delineate both the temporal response and the key transcriptional differences following TLR2 and TLR4 ligation.

We describe the case of a 65-year-old woman with multiple pulmonary nodules on a chest radiograph where subsequent investigations led to diagnostic difficulties.

To determine whether organisms are present in the HIV-infected lung prior to clinical respiratory disease, a cross-sectional bronchoscopic comparative analysis of 39 asymptomatic HIV-positive subjects and 31 healthy controls with 2-year prospective bronchoscopic monitoring of the HIV study group was performed. Pathological examination of bronchoalveolar lavage (BAL) fluid using standard microbiological techniques was undertaken. Organisms were recovered from similar numbers of HIV-positive and control subjects (7 of 39 and 3 of 31) and comprised predominantly scanty growths of bacteria. Five subjects developed respiratory disease during follow-up. Repeat BAL was performed in 11 asymptomatic HIV-positive patients; no relationship was found between the organisms isolated at the two procedures. The findings suggest that the asymptomatic HIV-positive lung is not a frequent site of either microbial colonisation or subclinical infection. This has implications for the understanding of the pathogenesis of HIV-related pulmonary disease.

OBJECTIVE To describe the changes over time in incidence of hospital admissions among patients with HIV, reasons for hospital admission, duration of stay, relationship with CD4 T-cell count and with antiretroviral treatment. METHODS The incidence of hospital admissions during each calendar year from 1988 to 1997 inclusive was calculated using a person-years analysis. In addition the proportion of patient follow-up spent in hospital and the impact of changing treatment regimens among all patients with HIV aged > or = 14 years and with at least one CD4 T-cell count seen at the Royal Free Hospital, London was also described. RESULTS A total of 1806 patients were investigated with median follow-up of 21.1 months. Among all patients, the proportion of follow-up time spent as an in-patient decreased from 3.9% in 1988 to 1.3% in 1997 (P = 0.0015; test for trend). Hospital admissions for any cause peaked during 1989 at 72.0 per 100 patient years of follow-up (PYFU) and was 28.5 per 100 PYFU during 1997 (P 30% before 1990 to < 5% during 1997 (P = 0.026; test for trend). Hospital admissions varied greatly according to treatment regimen; in 1996 and 1997 just 0.1% of follow-up time of patients on triple antiretroviral treatment regimens was spent as a hospital admission. CONCLUSIONS Admissions to hospital began falling before the introduction of combination therapy and declined strikingly during 1996 and 1997 following the introduction of highly active antiretroviral therapy. These results have important implications for future allocation of resources and for patient management.

A 46-yr-old injecting drug user was admitted with a history of repeated haemoptysis, pleuritic chest pain and fevers. He had a neutrophilia and elevated C-reactive protein. A pulmonary embolus was diagnosed by computed tomography (CT) pulmonary angiography and he was treated with low molecular weight heparin. He received i.v. antibiotics (flucloxacillin, amoxicillin, gentamicin and metronidazole) for polymicrobial bacteraemia (methicillin-sensitive S taphylococcus aureus , Enterococcus , viridans type Streptococcus) caused by a right groin abscess, which was subsequently incised and drained, and was associated with iliofemoral thrombosis. No valvular vegetation was seen on transthoracic or subsequent transoesophageal echocardiogram. The patient had a fluctuating clinical course, requiring respiratory support with supplemental oxygen and noninvasive ventilation. He had a persistent neutrophil leukocytosis and greatly elevated C-reactive protein at >100 mg·L−1. Clinically, there was evidence of bilateral pleural effusions, which cultured Enterococcus on aspiration. Attempted thoracocentesis was unsuccessful with minimal fluid drained. An ultrasound scan of the chest revealed loculated pleural effusions. He continued to cough blood and 17 days after admission had an episode of massive haemoptysis requiring a blood transfusion. At this point the anticoagulation was discontinued given the risk of further massive haemoptysis. A repeat CT of the chest was performed to clarify the cause of the continuing haemoptysis (fig. 1⇓). Despite halting the anticoagulation, further fresh haemoptysis occurred a few days later and he was referred to a cardiothoracic surgeon with a view to surgical intervention. Due to …

Forty-seven HIV-infected adults had broncho-alveolar lavage stimulated with purified protein derivate of Mycobacterium tuberculosis. Eighteen of 19 (95%) with tuberculosis co-infection had interferon-gamma synthetic CD4 lymphocyte responses > 1% versus three of 28 (11%) without (P < 0.0001). Lung response was unrelated to blood CD4 cell count. BAL HIV tuberculosis responses were similar in 25 HIV-uninfected tuberculosis patients. Responses in matched blood samples were often undetectable. Therefore, immunological tuberculosis assays seem less affected by HIV co-infection when lung-based.

Objective: We have compared the phenotypic and functional changes found in alveolar macrophages recovered from the lungs of 39 HIV-positive individuals with no respiratory disease with those from 33 HIV-positive individuals with pneumonitis and 31 healthy controls.Method: Bronchoalveolar lavage (BAL) cell cytospin preparations were stained using monoclonal antibody immunoperoxidase and double immunofluorescence techniques. Cytokine levels within supernatant BAL were determined using enzyme immunoassay.Results: There were marked differences in alveolar macrophage phenotype between the three groups. In particular, the relative proportion of cells staining RFD1+RFD7-(inducer cells) was reduced in the HIV-positive individuals without respiratory disease. This was correlated with measures of declining systemic immunity. Patients with pneumonitis had the highest levels of measured cytokines [interleukin-1 beta, tumour necrosis factor-alpha and transforming growth factor (TGF)-beta 2], followed by the HIV-positive individuals without respiratory disease. In this latter population a negative correlation was found between active (non-acid dissociated) TGF-beta 2 and blood CD4 cell count.Conclusions: The differences between the three groups suggest that alterations of potential relevance to the pulmonary immune response are occurring in alveolar macrophages prior to the onset of respiratory disease. This study confirms the importance of investigating asymptomatic HIV-positive individuals.

BACKGROUND: Randomized trials assessing BCG vaccine protection against tuberculosis have widely varying results, for reasons that are not well understood. METHODS: We examined associations of trial setting and design with BCG efficacy against pulmonary and miliary or meningeal tuberculosis by conducting a systematic review, meta-analyses, and meta-regression. RESULTS: We identified 18 trials reporting pulmonary tuberculosis and 6 reporting miliary or meningeal tuberculosis. Univariable meta-regression indicated efficacy against pulmonary tuberculosis varied according to 3 characteristics. Protection appeared greatest in children stringently tuberculin tested, to try to exclude prior infection with Mycobacterium tuberculosis or sensitization to environmental mycobacteria (rate ratio [RR], 0.26; 95% confidence interval [CI], .18-.37), or infants (RR, 0.41; 95% CI, .29-.58). Protection was weaker in children not stringently tested (RR, 0.59; 95% CI, .35-1.01) and older individuals stringently or not stringently tested (RR, 0.88; 95% CI, .59-1.31 and RR, 0.81; 95% CI, .55-1.22, respectively). Protection was higher in trials further from the equator where environmental mycobacteria are less and with lower risk of diagnostic detection bias. These associations were attenuated in a multivariable model, but each had an independent effect. There was no evidence that efficacy was associated with BCG strain. Protection against meningeal and miliary tuberculosis was also high in infants (RR, 0.1; 95% CI, .01-.77) and children stringently tuberculin tested (RR, 0.08; 95% CI, .03-.25). CONCLUSIONS: Absence of prior M. tuberculosis infection or sensitization with environmental mycobacteria is associated with higher efficacy of BCG against pulmonary tuberculosis and possibly against miliary and meningeal tuberculosis. Evaluations of new tuberculosis vaccines should account for the possibility that prior infection may mask or block their effects.

Human immunodeficiency virus (HIV)-1 and Mycobacterium tuberculosis (M. tuberculosis) both target macrophages, which are key cells in inflammatory responses and their resolution. Therefore, we tested the hypothesis that HIV-1 may modulate macrophage responses to coinfection with M. tuberculosis. HIV-1 caused exaggerated proinflammatory responses to M. tuberculosis that supported enhanced virus replication, and were associated with deficient stimulus-specific induction of anti-inflammatory interleukin (IL)-10 and attenuation of mitogen-activated kinase signaling downstream of Toll-like receptor 2 and dectin-1 stimulation. Our in vitro data were mirrored by lower IL-10 and higher proinflammatory IL-1β in airway samples from HIV-1-infected patients with pulmonary tuberculosis compared with those with non-tuberculous respiratory tract infections. Single-round infection of macrophages with HIV-1 was sufficient to attenuate IL-10 responses, and antiretroviral treatment of replicative virus did not affect this phenotype. We propose that deficient homeostatic IL-10 responses may contribute to the immunopathogenesis of active tuberculosis and propagation of virus infection in HIV-1/M. tuberculosis coinfection.

BACKGROUND: Recent evidence suggests that the duration of protection by bacillus Calmette-Guerin (BCG) may exceed previous estimates with potential implications for estimating clinical and cost-efficacy. OBJECTIVES: To estimate the protection and duration of protection provided by BCG vaccination against tuberculosis, explore how this protection changes with time since vaccination, and examine the reasons behind the variation in protection and the rate of waning of protection. DATA SOURCES: Electronic databases including MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Databases, NHS Economic Evaluation Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE), Web of Knowledge, Biosciences Information Service (BIOSIS), Latin American and Caribbean Health Sciences Literature (LILACs), MEDCARIB Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from inception to May 2009. Index to Theses, System for Information on Grey Literature in Europe (SIGLE), Centre for Agricultural Bioscience International (CABI) Abstracts, Scopus, Article First, Academic Complete, Africa-Wide Information, Google Scholar, Global Health, British National Bibliography for Report Literature, and clinical trial registration websites were searched from inception to October 2009. REVIEW METHODS: Electronic databases searches, screening of identified studies, data extraction and analysis were undertaken. Meta-analysis was used to present numerical and graphical summaries of clinical efficacy and efficacy by time since vaccination. Evidence of heterogeneity was assessed using the tau-squared statistic. Meta-regression allowed the investigation of observed heterogeneity. Factors investigated included BCG strain, latitude, stringency of pre-BCG vaccination tuberculin testing, age at vaccination, site of disease, study design and vulnerability to biases. Rate of waning of protection was estimated using the ratio of the measure of efficacy after 10 years compared with the efficacy in the first 10 years of a study. RESULTS: Study selection. A total of 21,030 references were identified, providing data on 132 studies after abstract and full-text review. Efficacy. Protection against pulmonary tuberculosis in adults is variable, ranging from substantial protection in the UK MRC trial {rate ratio 0.22 [95% confidence interval (CI) 0.16 to 0.31]}, to absence of clinically important benefit, as in the large Chingleput trial [rate ratio 1.05 (95% CI 0.88 to 1.25)] and greater in latitudes further away from the equator. BCG vaccination efficacy was usually high, and varied little by form of disease (with higher protection against meningeal and miliary tuberculosis) or study design when BCG vaccination was given only to infants or to children after strict screening for tuberculin sensitivity. High levels of protection against death were observed from both trials and observational studies. The observed protective effect of BCG vaccination did not differ by the strain of BCG vaccine used in trials. DURATION: Reviewed studies showed that BCG vaccination protects against pulmonary and extrapulmonary tuberculosis for up to 10 years. Most studies either did not follow up participants for long enough or had very few cases after 15 years. This should not be taken to indicate an absence of effect: five studies (one trial and four observational studies) provided evidence of measurable protection at least 15 years after vaccination. Efficacy declined with time. The rate of decline was variable, with faster decline in latitudes further from the equator and in situations where BCG vaccination was given to tuberculin-sensitive participants after stringent tuberculin testing. LIMITATIONS: The main limitation of this review relates to quality of included trials, most of which were conducted before current standards for reporting were formulated. In addition, data were lacking in some areas and the review had to rely on evidence from observational studies. CONCLUSIONS: BCG vaccination protection against tuberculosis varies between populations, to an extent that cannot be attributed to chance alone. Failure to exclude those already sensitised to mycobacteria and study latitude closer to the equator were associated with lower efficacy. These factors explained most of the observed variation. There is good evidence that BCG vaccination protection declines with time and that protection can last for up to 10 years. Data on protection beyond 15 years are limited; however, a small number of trials and observational studies suggest that BCG vaccination may protect for longer. Further studies are required to investigate the duration of protection by BCG vaccination. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Cohort review has been used internationally to support tuberculosis (TB) control. We describe its first use in the UK by a London TB service. Improvements were noted in case management and contact tracing, weaknesses identified and important service changes put in place. Key areas of impact were directly observed therapy (DOT) provision (a greater proportion of cases offered DOT, and in response to low uptake resources diverted to create posts responsible for patient-centred DOT delivery), and contact tracing (more contacts per case screened and assessed). Cohort review enables whole system review and improvement. It has subsequently been adopted across the UK.