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.

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.

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.

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.

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.

Tuberculosis preventive therapy: perspective from a multi-ethnic community.

This study explores the knowledge, attitudes and perception of tuberculosis (TB) and how they affect adherence to preventive treatment. A qualitative study of 24 subjects taking preventive therapy for TB was undertaken. Interviews were conducted in English using a structured questionnaire in a private room adjoining the outpatient clinic before the subject's appointment. The questionnaire included; (i) demographic details; (ii) background information on TB; (iii) knowledge and perception of TB and chemoprophylaxis. Data was analysed descriptively and thematically and subjected to statistical evaluation where appropriate. Outcome was assessed >6 months after the start of preventive treatment. The sample was representative of the ethnic mix of those attending the clinic. Knowledge of TB-was gained outside the family and covered transmission but few symptoms of active TB were recognized. The perceived threat from TB was high, although the estimated risk was low. Knowledge of preventive therapy exceeded the general knowledge of TB, although the latter was associated with better adherence. Most denied knowledge of the risk of hepatitis from isoniazid. Defaulters failed to attend their first appointment, attributed more side effects to isoniazid and perceived a longer waiting time in clinic. Adherence is better with a general knowledge of TB and attendance at the first appointment and could be improved by a single daily tablet, warnings about dizziness and discussion of the difficulties of taking a 6 month course of treatment.

Patient choice promotes adherence in preventive treatment for latent tuberculosis.

The aim of the present study was to compare the effect of patient choice on completion rates and adverse drug reactions for patients treated for latent tuberculosis infection (LTBI) using 3-month rifampicin and isoniazid treatment (3RH) or 6-month isoniazid treatment (6H). Data for all patients treated using 3RH or 6H for LTBI between 1998 and 2004 were analysed. In total, 675 patients attended for chemoprophylaxis. Of these, 314 received 3RH and 277 received 6H. From April 1, 2000, patients were offered a choice of regimen; 53.5% completed the regimen successfully, a further 10.3% potentially completed it successfully and 36.2% failed to complete treatment. Logistic regression analysis suggested that successful completion was more likely in patients who were younger (an association that was lost after removing all patients aged <16 yrs), were offered a choice of regimen and attended all clinic visits before commencing treatment. Treatment was discontinued due to adverse reactions in 16 (5.1%) patients who were prescribed 3RH and 16 (5.8%) who were prescribed 6H. Treatment failure was most likely during the first 4 weeks of treatment for both regimens. At 13 weeks of treatment, more patients taking 6H had stopped compared with those completing the 3RH regimen. Drug costs were greater using 6H compared with 3RH. In conclusion, offering a choice of regimen improves completion. Most patients chose the 3-month rifampicin and isoniazid treatment over the 6-month isoniazid treatment. Adverse drug reaction rates between the two regimens were similar.

Serological diagnosis of tuberculosis.

The past decade has seen dramatic developments in serological tests for tuberculosis. The long history of serological tests for tuberculosis is a testimony to the need for a sensitive diagnostic test, especially when the sputum smear is unhelpful. New reagents, both purified antigens and monoclonal antibodies, provide the means to obtain a sensitivity and specificity to rival the tuberculin skin test and equal other commonly used diagnostic blood tests. Evaluation with sera from patients with smear-positive pulmonary tuberculosis has identified one antigen (antigen 5, the 38 kDa antigen) as a potential screening reagent for infectious tuberculosis and another (16 kDa antigen) for monitoring compliance. A monoclonal antibody competition assay anti-38 kDa antibody is the most sensitive serological test for smear-negative tuberculosis so far. Tests for tuberculous meningitis need clinical evaluation. Serological tests for human immunodeficiency virus (HIV)-related tuberculosis are disappointing. In general, antibody levels in primary tuberculosis are low and appear directed towards cytoplasmic antigens, whilst in post-primary disease antibody levels are higher and appear to bind to secreted antigens. No single reagent gives a 100% sensitivity; future research should identify the best combination of antigens for the serodiagnosis of tuberculosis.

Clinical evaluation of a serological assay using a monoclonal antibody (TB72) to the 38 kDa antigen of Mycobacterium tuberculosis.

We examined an enzyme-linked immunosorbent assay (ELISA) modification of a radioimmunoassay, using the TB72 monoclonal antibody, as a serological test for tuberculosis in a clinical setting. Sera were obtained from 238 patients with suspected pulmonary tuberculosis, 30 patients treated for tuberculosis, 28 contacts, and 480 random samples from inpatients. Antibody levels were measured as the dilution of serum causing 50% inhibition of binding of the TB72 monoclonal antibody, which binds to an epitope of the 38 kDa antigen specific to the Mycobacterium tuberculosis complex, a positive titre being > 3. Positive antibody titres were present in 21 out of 25 (84%) patients with smear-positive and 22 out of 27 (82%) patients with smear-negative, culture-positive tuberculosis, and 37 out of 41 (90%) patients successfully treated for tuberculosis but without bacteriological confirmation of disease. Three out of 82 (4%) patients with a firm alternative diagnosis to tuberculosis gave a positive result. Serological tests were negative within 2.5 yrs of successful treatment. Patients without a definite diagnosis one year after tuberculosis had been suspected, and those who had received inadequate treatment for tuberculosis, were frequently positive (21 out of 31 and 21 out of 32, respectively). Positive tests concurred with tuberculin reactivity in 8 out of 11 contacts given chemoprophylaxis. Screening of 480 random serum samples gave 22 positive titres, 16 of which were not associated with tuberculosis; none of these 16 had an antibody titre > 10. We conclude that the TB72 test provides additional information in the diagnosis and treatment of tuberculosis. Antibody titres > 10 suggests active tuberculosis; titres of 3-10 merit observation.

Clinical value of the measurement of Mycobacterium tuberculosis specific antibody in pulmonary tuberculosis.

BACKGROUND: A serological test that could help to diagnose tuberculosis, especially smear negative disease, would contribute to patient management. METHODS: Levels of antibody to distinct antigens of Mycobacterium tuberculosis were assessed for their value in the diagnosis and management of pulmonary tuberculosis. Serum was taken from 52 patients who were smear positive, from 27 patients who were smear negative but with evidence of active tuberculosis (sputum culture positive in 16, response to antituberculosis chemotherapy in 11), from 11 patients with old healed tuberculosis (pre-antibiotic era), and from 39 healthy subjects vaccinated with BCG. RESULTS: In smear positive tuberculosis an enzyme linked immunosorbent assay using a single 38 kDa antigen gave a diagnostic sensitivity of 80% with a 100% specificity. In smear negative pulmonary tuberculosis, however, combination of the 19 kDa antigen, lipoarabinomannan (ML 34 epitope), and hsp 65 (TB 78 epitope) was needed to achieve a sensitivity of 64% with a specificity of 95%. Recurrent and extensive radiographic disease with a poor prognosis was associated with high anti-38 kDa and low anti-14 kDa antibody levels in patients with active disease. Patients with less pulmonary cavitation had high anti-19 kDa titres. Bacteriological relapse during treatment was indicated by a rise in anti-14 kDa (TB68 epitope) antibodies. Four patients with non-tuberculous mycobacterial infection showed no anti-38 kDa antibody. CONCLUSION: Antigen or epitope specific serology may help in the diagnosis, assessment of prognosis, and monitoring of chemotherapy in patients with pulmonary tuberculosis.

Levels of antibody to defined antigens of Mycobacterium tuberculosis in tuberculous meningitis.

The aim of the study was to develop an antibody immunoassay for tuberculous meningitis with a sensitivity greater than that of the initial bacterial smear while maintaining a 100% specificity. Antibody titers to five purified antigens of Mycobacterium tuberculosis were measured in cerebrospinal fluid by using an enzyme-linked immunosorbent assay technique. Seventy-four patients with tuberculous meningitis (26 culture positive) were compared with 26 patients with purulent meningitis, 69 patients with suspected but excluded tuberculous meningitis, and 29 patients with other neurological diseases. Antibody responses to both the 14-kilodalton (kDa) antigen and lipoarabinomannan were immunodominant, accounting for 74% of those with any antibody titer to a soluble extract of M. tuberculosis. A sensitivity of 61% was achieved (77% for the culture-positive samples) by using immunoglobulin G titers to lipoarabinomannan and the 14-, 19-, and 38-kDa antigens. Thus, estimation of levels of antibody in cerebrospinal fluid to selected mycobacterial antigens would be valuable in the diagnosis of tuberculous meningitis. The possible reasons for the immunodominance of the 14-kDa antigen and lipoarabinomannan in the pathogenesis of tuberculous meningitis are discussed.

Specificity of antibodies and tuberculin response after occupational exposure to tuberculosis.

Specific antibody levels and delayed-type hypersensitivity skin responses to antigens of Mycobacterium tuberculosis in 39 hospital staff who were heavily exposed to tuberculosis (TB) were compared with those in 36 factory employees from Indonesia. Antibody levels to the TB68 epitope of the 14-kDa antigen were significantly greater, while titers to the TB23 (19-kDa) and TB72 (38-kDa) epitopes and lipoarabinomannan (LAM) were lower in exposed than in nonexposed subjects (all P less than .02). The intensity of tuberculin responses correlated positively with anti-LAM and negatively with anti-19-kDa antibody levels. Possible reasons for the selective humoral response of chronically exposed healthy subjects to the 14-kDa antigen, but not to other antigens immunogenic in patients with tuberculosis, are discussed.

Specificity of antibodies to immunodominant mycobacterial antigens in pulmonary tuberculosis.

A serological survey was performed in groups of patients with active sputum smear-positive or smear-negative pulmonary tuberculosis, healthy household contacts, and controls. Sera were tested for titers of antibodies which bound to each of five purified mycobacterial antigens by enzyme immunoassay and for competition of binding to single epitopes, using six radiolabeled monoclonal antibodies directed toward corresponding molecules. The evaluation of diagnostic specificity was based on a positive score represented by titers above the cutoff point of 2 standard deviations above the mean titer of a control group. For smear-positive samples, the best sensitivity (83%) was achieved by exclusive use of the 38-kilodalton (kDa) antigen or its corresponding monoclonal antibodies. For smear-negative samples, levels of antibodies binding to the 19-kDa antigen showed a lower sensitivity of 62% compared with the control group or 38% compared with the contact group. Titers of antibody binding to the 14-kDa antigen were raised in Mycobacterium bovis BCG-vaccinated contacts, indicating that the greatest potential of this antigen may be in the detection of infection in a population for which tuberculin testing is unreliable. The results demonstrated the differing antibody responses to each of the tested antigens and distinct associations with the stage of infection or disease.

Delayed hypersensitivity and HLA in smear-positive pulmonary tuberculosis.

Tuberculin responses were quantified by induration of the skin, velocity of blood flow in dermal microcirculation and composition of the cellular infiltrate in 125 patients with tuberculosis and 39 healty controls. The diameters of the tuberculin responses were greater in HLA-DR15-positive patients than in DR15-negative patients. The density of infiltrating CD(4+)-positive cells showed a positive correlation with induration in DR15-negative subjects (r = 0.54). A fraction of DR15-positive patients gave large tuberculin responses (> or = 15 mm) but with few CD4+ cells in the test site (< 500/mm2); these patients had a greater percentage of cells in the diffuse dermal infiltrate than in the perivascular region, greater blood flow velocities in the tuberculin response but more frequently with central relative slowing of blood flow and had higher total IgG and specific antimycobacterial antibody levels compared to other DR15-positive patients. If the inflammatory infiltrate in the lungs parallels that in the tuberculin skin test, the lack of immunocompetent cells and tissue hypoxia could permit pulmonary cavitation and explain the association of HLA-DR15 with smear-positive pulmonary tuberculosis.

Total and anti-mycobacterial IgE levels in serum from patients with tuberculosis and leprosy.

A radioallergosorbent assay (RAST) was developed and used to determine the levels of IgE antibodies to soluble antigens of Mycobacterium tuberculosis (BCG vaccine strain) in sera from patients with tuberculosis and leprosy and in healthy control subjects. Total IgE levels in the same sera were quantitated with a commercial radioimmunoassay kit. Patients with tuberculosis and leprosy had higher total and specific IgE levels than the control groups but the overlap of levels in patients and controls was too great to render the difference diagnostically useful. Specific IgE levels were elevated in both tuberculosis and leprosy patients, suggesting that this antibody response is towards the shared mycobacterial antigens. No differences in total or specific IgE levels were found between healthy hospital workers occupationally exposed to patients with tuberculosis and factory workers who are not exposed.

Association of tuberculosis and M. tuberculosis-specific antibody levels with HLA.

In the search for HLA-linked immune response genes that control susceptibility to tuberculosis, we performed HLA typing and measured antibody titers to well-defined Mycobacterium tuberculosis antigenic determinants in 101 patients with sputum smear-positive pulmonary tuberculosis and 64 healthy controls from Surabaya, Indonesia. HLA-DR2 and DQw1 were associated with sputum smear-positive pulmonary tuberculosis (attributable risk = 36% and 39%, respectively), while DQw3 was associated even more strongly with the control group (preventive fraction = 57%). Antibody titers to the TB71 and TB72 epitopes of the 38-kDa protein, present only on tubercle bacilli, were strongly associated with DR2 (Pcorr = .001 and .024, respectively). The association of both the disease and the antibody response to the 38-kDa antigen of M. tuberculosis with Class II HLA genes HLA-DR2 indicates that Ir-gene-mediated regulation of the immune response to this antigen may be of pathogenic significance for the development of sputum smear-positive tuberculosis.