Measuring cough-related quality of life and cough frequency in pulmonary TB.

BACKGROUND: Cough is the key symptom of pulmonary TB (PTB) and is associated with transmission. No tool for measuring the subjective impact of cough in PTB has been previously validated. We sought to measure patientreported cough in PTB and investigate any relationship to objectively quantified daily cough frequency.METHODS: The validity of the Leicester Cough Questionnaire (LCQ) was assessed in sequential patients newly diagnosed with PTB at a UK hospital. Resulting LCQ scores were compared to non-cough clinical variables, and to 24-h, ambulatory, objective cough frequency measured using the Leicester Cough Monitor.RESULTS: The LCQ in 30 patients with PTB was acceptable to users and had high internal reliability (Cronbach's α = 0.93), concurrent validity (correlation with visual analogue scale for cough severity, Spearman's ρ = ???0.69) and responsiveness (substantial median increase score after 2 weeks of TB treatment: 5.1 points, IQR 1.8???9.7; P = 0.003). There was only moderate correlation between patient-reported cough and objectively-measured 24-h cough frequency in PTB (ρ = ???0.48, P = 0.008).CONCLUSION: The LCQ is valid for use in PTB, with applications that include monitoring treatment of the disease. However, there was a mismatch between objective and subjective assessment of cough, which has important implications for delayed diagnosis and transmissibility.

TB and MDR/XDR-TB in European Union and European Economic Area countries: managed or mismanaged?

In spite of the growing awareness of emerging drug-resistant Mycobacterium tuberculosis, the extent of inappropriate tuberculosis (TB) case management may be underestimated, even in Europe. We evaluated TB case management in the European Union/European Economic Area countries, with special focus on multidrug-resistant (MDR) and extensively drug-resistant (XDR)-TB, using a purposely developed, standardised survey tool. National reference centres in five countries representing different geographical, socioeconomic and epidemiological patterns of TB in Europe were surveyed. 40 consecutive, original clinical TB case records (30 MDR/XDR-TB cases) were reviewed in each of the five countries. The findings were recorded and, through the survey tool, compared with previously agreed and identified international standards. Deviations from international standards of TB care were observed in the following areas: surveillance (no information available on patient outcomes); infection control (lack of respiratory isolation rooms/procedures and negative-pressure ventilation rooms); clinical management of TB, MDR-TB and HIV co-infection (inadequate bacteriological diagnosis, regimen selection and treatment duration); laboratory support; and diagnostic/treatment algorithms. Gaps between present international standards of care and the management of MDR/XDR-TB patients were identified. Training, increased awareness, promotion of standards and allocation of appropriate resources are necessary to ensure appropriate care and management as well as to prevent further emergence of drug resistance.

Interferon-γ release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis.

We conducted a systematic review and meta-analysis to compare the accuracy of the QuantiFERON-TB® Gold In-Tube (QFT-G-IT) and the T-SPOT®.TB assays with the tuberculin skin test (TST) for the diagnosis of latent Mycobacterium tuberculosis infection (LTBI). The Medline, Embase and Cochrane databases were explored for relevant articles in November 2009. Specificities, and negative (NPV) and positive (PPV) predictive values of interferon-γ release assays (IGRAs) and the TST, and the exposure gradient influences on test results among bacille Calmette-Guérin (BCG) vaccinees were evaluated. Specificity of IGRAs varied 98-100%. In immunocompetent adults, NPV for progression to tuberculosis within 2 yrs were 97.8% for T-SPOT®.TB and 99.8% for QFT-G-IT. When test performance of an immunodiagnostic test was not restricted to prior positivity of another test, progression rates to tuberculosis among IGRA-positive individuals followed for 19-24 months varied 8-15%, exceeding those reported for the TST (2-3%). In multivariate analyses, the odd ratios for TST positivity following BCG vaccination varied 3-25, whereas IGRA results remained uninfluenced and IGRA positivity was clearly associated with exposure to contagious tuberculosis cases. IGRAs may have a relative advantage over the TST in detecting LTBI and allow the exclusion of M. tuberculosis infection with higher reliability.

Large outbreak of isoniazid-monoresistant tuberculosis in London, 1995 to 2006: case-control study and recommendations.

We conducted a case­control study to examine risk factors for isoniazid-monoresistant Mycobacterium tuberculosis in an ongoing outbreak in London. Cases were defined as individuals with an isoniazid-monoresistant strain diagnosed from 1995 to the third quarter of 2006 with an indistinguishable restriction fragment length polymorphism (RFLP) or mycobacterial interspersed repetitive unit (MIRU)-variable number tandem repeats (VNTR) pattern who were resident in or had epidemiological links with London. Controls were all other individuals reported with tuberculosis to the Health Protection Agency London regional epidemiology unit or the HPA London TB Register during 2000 to 2005. Of 293 cases, 153 (52%) were sputum smear-positive compared with 3,266 (18%) of controls. Cases were more likely to be young adults (aged between 15 and 34 years), born in the United Kingdom (OR: 2.4; 95% CI: 1.7­3.4) and of white (OR: 2.9; 95% CI: 1.8­4.8) or black Caribbean (OR: 12.5; 95% CI: 7.7­20.4) ethnicity, a prisoner at the time of diagnosis (OR: 20.2; 95% CI: 6.7­60.6), unemployed (OR: 4.1; 95% CI: 3.0­5.6), or a drug dealer or sex worker (OR: 187.1; 95% CI: 28.4­1,232.3). A total of 113 (39%) of cases used drugs and 54 (18%) were homeless. Completion of treatment gradually improved in cases from 55% among those diagnosed up to the end of 2002 compared with 65% by the end of 2006. Treatment completion increased from 79% to 83% in controls from 2000 to 2005. There are complex social challenges facing many cases in this outbreak that need to be addressed if medical interventions are to be successful.

Tuberculosis contact investigation in low prevalence countries: a European consensus.

Contact investigation to identify individuals with tuberculosis and latent infection with Mycobacterium tuberculosis is an important component of tuberculosis control in low tuberculosis incidence countries. This document provides evidence-based and best-practice policy recommendations for contact tracing among high- and medium-priority contacts in a variety of settings. It provides a basis for national guidelines on contact investigation and tuberculosis outbreak management, and should support countries and tuberculosis control managers in evaluating and revising national policies. A review of existing guidelines, a literature search, several meetings and consultation with experts were used to formulate and grade recommendations for action during contact investigation. Available tests to identify individuals with latent infection with M. tuberculosis are designed to identify immune response against mycobacterial antigens and have variable predictive value for the likelihood to develop active tuberculosis in different populations. Contact investigation should therefore be limited to situations with a clear likelihood of transmission or to those with a higher probability of developing active tuberculosis, for instance, young children and immunocompromised persons. A risk assessment-based approach is recommended, where the need to screen contacts is prioritised on the basis of the infectiousness of the index case, intensity of exposure and susceptibility of contacts.

LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement.

Tuberculosis control relies on the identification and preventive treatment of individuals who are latently infected with Mycobacterium tuberculosis. However, direct identification of latent tuberculosis infection is not possible. The diagnostic tests used to identify individuals latently infected with M. tuberculosis, the in vivo tuberculin skin test and the ex vivo interferon-gamma release assays (IGRAs), are designed to identify an adaptive immune response against, but not necessarily a latent infection with, M. tuberculosis. The proportion of individuals who truly remain infected with M. tuberculosis after tuberculin skin test or IGRA conversion is unknown. It is also uncertain how long adaptive immune responses towards mycobacterial antigens persist in the absence of live mycobacteria. Clinical management and public healthcare policies for preventive chemotherapy against tuberculosis could be improved, if we were to gain a better understanding on M. tuberculosis latency and reactivation. This statement by the TBNET summarises knowledge and limitations of the currently available tests used in adults and children for the diagnosis of latent tuberculosis infection. In summary, the main issue regarding testing is to restrict it to those who are known to be at higher risk of developing tuberculosis and who are willing to accept preventive chemotherapy.

Management of patients with multidrug-resistant tuberculosis.

The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before in the history of mankind have more patients been affected by MDR-TB than is the case today. The World Health Organization reports that MDR-TB outcomes are poor despite staggeringly high management costs. Moreover, treatment is prolonged, adverse events are common, and the majority of affected patients do not receive adequate treatment. As MDR-TB strains are often resistant to one or more second-line anti-TB drugs, in-depth genotypic and phenotypic drug susceptibility testing is needed to construct personalised treatment regimens to improve treatment outcomes. For the first time in decades, the availability of novel drugs such as bedaquiline allow us to design potent and well-tolerated personalised MDR-TB treatment regimens based solely on oral drugs. In this article, we present management guidance to optimise the diagnosis, algorithm-based treatment, drug dosing and therapeutic drug monitoring, and the management of adverse events and comorbidities, associated with MDR-TB. We also discuss the role of surgery, physiotherapy, rehabilitation, palliative care and smoking cessation in patients with MDR-TB. We hope that incorporating these recommendations into patient care will be helpful in optimising treatment outcomes, and lead to more MDR-TB patients achieving a relapse-free cure.

Active case finding of tuberculosis in Europe: a Tuberculosis Network European Trials Group (TBNET) survey.

Tuberculosis control depends on successful case finding and treatment of individuals infected with Mycobacterium tuberculosis. Passive case finding is widely practised: the present study aims to ascertain the consensus and possible improvements in active case finding across Europe. Recommendations from national guidelines were collected from 50 countries of the World Health Organization European region using a standard questionnaire. Contacts are universally screened for active tuberculosis and latent tuberculosis infection (LTBI). Most countries (>70%) screen those with HIV infection, prisoners and in-patient contacts. Screening of immigrants is related to their contribution to national rates of tuberculosis. Only 25 (50%) out of 50 advise a request for symptoms in their guidelines. A total of 36 (72%) out of 50 countries recommend sputum examination for those with a persistent cough; 13 countries do not, even if the chest radiograph suggests tuberculosis. Nearly all countries (49 out of 50) use tuberculin skin testing (TST); 27 (54%) out of 50 countries also perform chest radiography irrespective of the TST result. Interpretation of the TST varies widely. All countries use 6-9 months of isoniazid for treatment of LTBI, with an estimated median (range) uptake of 55% (5-92.5%). Symptoms and sputum examination could be used more widely when screening for active tuberculosis. Treatment of latent tuberculosis infection might be better focused by targeted use of interferon-gamma release assays.

Agreement between expert thoracic radiologists and the chest radiograph reports provided by consultant radiologists and reporting radiographers in clinical practice: Review of a single clinical site.

INTRODUCTION: To compare the clinical chest radiograph (CXR) reports provided by consultant radiologists and reporting radiographers with expert thoracic radiologists. METHODS: Adult CXRs (n = 193) from a single site were included; 83% randomly selected from CXRs performed over one year, and 17% selected from the discrepancy meeting. Chest radiographs were independently interpreted by two expert thoracic radiologists (CTR1/2).Clinical history, previous and follow-up imaging was available, but not the original clinical report. Two arbiters compared expert and clinical reports independently. Kappa (Ƙ), Chi Square (χ2) and McNemar tests were performed to determine inter-observer agreement. RESULTS: CTR1 interpreted 187 (97%) and CTR2 186 (96%) CXRs, with 180 CXRs interpreted by both experts. Radiologists and radiographers provided 93 and 87 of the original clinical reports respectively. Consensus between both expert thoracic radiologists and the radiographer clinical report was 70 (CTR1; Ƙ = 0.59) and 70 (CTR2; Ƙ = 0.62), and comparable to agreement between expert thoracic radiologists and the radiologist clinical report (CTR1 = 76, Ƙ = 0.60; CTR2 = 75, Ƙ = 0.62). Expert thoracic radiologists agreed in 131 cases (Ƙ = 0.48). There was no difference in agreement between either expert thoracic radiologist, when the clinical report was provided by radiographers or radiologists (CTR1 χ = 0.056, p = 0.813; CTR2 χ = 0.014, p = 0.906), or when stratified by inter-expert agreement; radiographer McNemar p = 0.629 and radiologist p = 0.701. CONCLUSION: Even when weighted with chest radiographs reviewed at discrepancy meetings, content of CXR reports from trained radiographers were indistinguishable from content of reports issued by radiologists and expert thoracic radiologists.

Daily cough frequency in tuberculosis and association with household infection.

SETTING: Although cough in tuberculosis (TB) is presumed to be important for transmission, there is little objective supporting evidence. OBJECTIVE: To describe 24-h cough frequency in a group with TB, and investigate associations with household rates of infection. DESIGN: Patients with a new diagnosis of pulmonary TB underwent 24-h cough frequency measurement at or just before initiation of anti-tuberculosis treatment. A group with latent Mycobacterium tuberculosis infection (LTBI) acted as controls. Rates of infection among household contacts of sputum smear-positive TB were measured using the interferon-gamma release assay and the tuberculin skin test, and compared with variables relating to the contacts themselves, and to the index case, including cough frequency. RESULTS: Daily cough frequency in TB patients (n = 44) was variable (geometric mean [GM] 174, interquartile range [IQR] 68-475 coughs/24 h), higher than in LTBI (n = 17; GM 19 coughs/24 h, IQR 8-53; P < 0.001), and higher during the day than overnight (GM 8.9 coughs/h, IQR 4.1-19.0 vs. GM 2.9 coughs/h, IQR 0.7-13.4; P < 0.0001). Also, 24-h cough frequency in TB was associated with sputum smear status (P = 0.040), but not smoking (P = 0.475). Multivariable logistic regression confirmed that infection in contacts was independently associated with index case sputum smear grade (P = 0.014) and cough frequency (P = 0.022). CONCLUSION: Measurement of 24-h cough frequency in pulmonary TB helps predict infectiousness and transmission patterns.

Team approach to manage difficult-to-treat TB cases: Experiences in Europe and beyond.

As recommended by the World Health Organization (WHO), optimal management of MDR-TB cases can be ensured by a multi-speciality consultation body known as 'TB Consilium'. This body usually includes different medical specialities, competences and perspectives (e.g., clinical expertise both for adults and children; surgical, radiological and public health expertise; psychological background and nursing experience, among others), thus lowering the risk of making mistakes - or managing the patients inappropriately, in order to improve their clinical outcomes. At present, several high MDR-TB burden countries in the different WHO regions (and beyond) have introduced TB Consilium-like bodies at the national or subnational level to reach consensus on the best treatment approach for their patients affected by TB. In addition, in countries/settings where a formal system of consultation does not exist, specialized staff from MDR-TB reference centres or international organizations usually spend a considerable amount of their working time responding to phone or e-mail clinical queries on how to manage M/XDR-TB cases. The aim of this manuscript is to describe the different experiences with the TB Consilia both at the international level (European Respiratory Society - ERS/WHO TB Consilium) and in some of the countries where this experience operates successfully in Europe and beyond. The Consilium experiences are described around the following topics: (1) history, aims and focus; (2) management and funding; (3) technical functioning and structure; (4) results achieved. In addition a comparative analysis of the TB Consilia in the different countries has been performed.

Perceptions and experiences of tuberculosis among African patients attending a tuberculosis clinic in London.

SETTING: Little is known of the social and cultural issues influencing the uptake of and attitudes to tuberculosis (TB) care by people of African extraction living in the UK. OBJECTIVE: To describe the perceptions and experiences of African patients with TB in London, focusing on issues relating to diagnosis, treatment adherence and stigma. DESIGN: Qualitative study using in-depth interviews. RESULTS: Misinterpretation of early symptoms led to delays in seeking health care. Although half of the respondents reported denial of the diagnosis, they reported good treatment adherence, noting the role of TB specialist nurses in promoting adherence. Respondents felt stigmatised by the diagnosis, although actual experiences of stigma were rare. Experience of TB in a known person mitigated stigma. Human immunodeficiency virus (HIV) disease was perceived to have worsened TB stigma, and most patients offered HIV testing initially declined, fearing stigmatisation and poor illness outcomes if positive. CONCLUSIONS: Awareness of TB can be improved among migrants at high risk of developing the disease and among health professionals. Counselling around HIV testing for TB patients must take their beliefs into account if a high uptake of testing is to be achieved.

Interferon-gamma responses to ESAT-6 in tuberculosis patients early into and after anti-tuberculosis treatment.

OBJECTIVE: To investigate T-cell responses to ESAT-6 by an interferon-gamma (IFN-gamma) ex vivo enzyme-linked immunospot (ELISpot) assay in tuberculosis (TB) patients early during treatment and in patients who have completed a course of anti-tuberculosis chemotherapy. DESIGN: T-cell responses following overnight stimulation with 6-kD early secretory antigenic target (ESAT-6) antigen were compared to responses obtained using cells cultured with ESAT-6 for 6 days, using an ELISpot assay. RESULTS: In the ex vivo ELISpot assay, the median IFN-gamma responses in TB patients, irrespective of treatment status, were significantly higher than in healthy BCG-vaccinated controls. In the 6-day ELISpot assay, median IFN-gamma responses were significantly higher in TB patients who had completed treatment than in patients early during therapy. There was considerable individual variability in the degree of expansion of ESAT-6 specific T-cells from day 1 to day 6 in both treatment groups. CONCLUSION: Further studies are required to assess which type of assay provides the best indicator of a memory T-cell response and how ESAT-6 specific T-cells relate to protective immunity in TB infection.

Early delayed hypersensitivity responses in tuberculin skin tests after heavy occupational exposure to tuberculosis.

The early (six hours) reaction to tuberculin skin testing was studied in 33 Indonesian hospital workers with frequent occupational exposure to M tuberculosis and compared with responses maximal at the usual time (48 hours) in factory workers, from the same locality but with only occasional occupational exposure, to determine the nature of the early reaction. The early reaction had the same general histopathological appearance as that seen in the conventional (48 hour) reaction, and both had an infiltrate consisting largely of T lymphocytes and macrophages. The cell densities were lower in the six hour reactions, but the relative concentration of macrophages was greater in the earlier response. These histometric measurements suggested that the six hour reaction was an accelerated delayed hypersensitivity reaction. Moreover, the absence of a specific IgE response or of particulate masses of Ig or complement, made it unlikely an anaphylactoid or Arthus-type reaction could have been responsible. It is concluded that those with frequent occupational exposure to M tuberculosis have larger numbers of circulating T cells reactive with mycobacterial antigens, so that the development of the skin test response to tuberculin is less dependent on "by-stander" cell infiltration to mediate the delayed hypersensitivity reaction than the reactions in those with less intense and less frequent natural exposure. The skin test response maximal at six hours is probably a hyperimmune reaction to an antigen recognised by T cells.

Drug treatment for tuberculosis during pregnancy: safety considerations.

Untreated tuberculosis in pregnancy poses a significant threat to the mother, fetus and family. Adherence to treatment is especially difficult in pregnancy because of the general fear of any medication and pregnancy-related nausea. Supervised treatment is especially helpful in encouraging adherence. All 4 first line drugs [isoniazid, rifampicin (rifampin), ethambutol and pyrazinamide] have an excellent safety record in pregnancy and are not associated with human fetal malformations. Drug-induced hepatitis, especially with isoniazid, is a significant problem in treating tuberculosis, not peculiar to pregnancy; close monitoring of liver function is recommended. Liver enzyme induction by rifampicin alters the metabolism of other drugs, e.g. methadone doses will need to be increased. Streptomycin should not be used in pregnancy, as perhaps 1 in 6 babies will have problems with hearing and/or balance. Ciprofloxacin has the best safety profile of second line drugs in the treatment of drug-resistant tuberculosis. Preventive treatment with isoniazid can be undertaken safely during pregnancy. Pyridoxine (vitamin B6) should be added to the drug treatment of tuberculosis in all pregnant women taking isoniazid. Neither tuberculin nor the bacille Calmette Guérin (BCG) vaccine are treatments for tuberculosis, but they play an important role in the management of the disease. Tuberculin testing is safe, but BCG vaccination should be avoided in pregnancy and instead given earlier in life.