Luis Anibarro

Documento de consenso sobre diagnóstico, tratamiento y prevención de la tuberculosis

Pulmonary TB should be suspected in patients with respiratory symptoms longer than 2-3 weeks. Immunosuppression may modify clinical and radiological presentation. Chest X-ray shows very suggestive, albeit sometimes atypical, signs of TB. Complex radiological tests (CT scan, MR) are more useful in extrapulmonary TB. At least 3 serial representative samples of the clinical location are used for diagnosis whenever possible. Bacilloscopy and liquid medium cultures are indicated in all cases. Genetic amplification techniques are coadjuvant in moderate or high TB suspicion. Administration of isoniazid, rifampicin, ethambutol and pyrazinamide (HREZ) for 2 months and HR for 4 additional months is recommended in new cases of TB, except in cases of meningitis in which treatment should continue for up to 12 months and up to 9 months in spinal TB with neurological involvement, and in silicosis. Appropriate adjustments with antiretroviral treatment should be made in HIV patients. Combined therapy is recommended to avoid development of resistance. An antibiogram to first line drugs should be performed in all the initial isolations of new patients. Treatment control is one of the most important activities in TB management. The Tuberculin Skin Test (TST) is positive in TB infection when >or=5mm, and Interferon-Gamma Release Assays (IGRA) are recommended in combination with TT. The standard treatment schedule for infection is 6 months with isoniazid. In pulmonary TB, respiratory isolation is applied for 3 weeks or until 3 negative bacilloscopy samples are obtained.

[Consensus document on the diagnosis, treatment and prevention of tuberculosis].

Abstract Pulmonary tuberculosis must be suspected in patients with respiratory symptoms longer than 2–3 weeks. Immunosuppression may modify the clinical and radiological presentation. The chest X-ray is highly suggestive of tuberculosis (TB), but is occasionally atypical. The complex radiological tests (CT scan, MRI) are more useful in extrapulmonary TB. At least 3 consecutive representative samples from the clinical location are used for diagnosis, whenever possible. Bacilloscopy and liquid medium cultures are indicated in all cases. Genetic amplification techniques are coadjuvant in moderate or high suspicion of TB. In new cases of TB, administration of isoniazid, rifampin, ethambutol, and pyrazinamide (HREZ) for 2 months and isoniazid plus rifampin for 4 months is recommended. For meningitis cases, treatment should continue for up to 12 months, and up to 9 months in spinal TB with neurological affectation and silicosis. Appropriate adjustments with antiretroviral treatment must be made in HIV patients. Combined therapy is recommended to prevent development of resistance. An antibiogram for first line drugs should be performed in all initial extractions from new patients. Treatment control is one of the most important activities in TB management. The Tuberculin Skin Test (TST) is positive in TB infection when ≥ 5mm, and Interferon-Gamma Release Assays (IGRA) are recommended in combination with TST. The standard treatment schedule for infection is 6 months with isoniazid. In pulmonary TB, respiratory isolation is applied for 3 weeks or until 3 negative bacilloscopy samples are obtained.

Factores sociales de riesgo para la falta de cumplimiento terapéutico en pacientes con tuberculosis en Pontevedra

Objetivo: Conocer la prevalencia y caracteristicas de los factores sociales de riesgo (FSR) para la falta de cumplimiento terapeutico entre los enfermos de tuberculosis de Pontevedra. Metodos: Analisis descriptivo de los enfermos de tuberculosis con FSR diagnosticados entre 1996 y 2002. Se considero FSR la presencia de aislamiento social (alcoholismo, uso de drogas por via parenteral, presidiario, sin domicilio fijo-sin techo, inadaptacion social) o la inmigracion. Se calculo la prevalencia y la tendencia anual de los FSR, la situacion final de los pacientes y la influencia de la administracion directamente observada del tratamiento en la situacion final. Resultados: De los 775 casos de TB, 156 pacientes (20,1%) tenian algun FSR, 86 pacientes presentaban alcoholismo, 41 eran usuarios de drogas por via parenteral, 24 eran inmigrantes, 14 no tenian domicilio fijo, 11 se consideraron con inadaptacion social y 10 eran presidiarios. La presencia de FSR entre los enfermos de tuberculosis no mostro una tendencia a aumentar o disminuir durante el periodo de estudio, excepto por el incremento de inmigrantes (χ2 para la tendencia lineal = 12,24; p = 0,005). La proporciσn de pacientes con situaciσn final satisfactoria (curaciσn bacteriolσgica o tratamiento finalizado) fue significativamente mayor en el grupo de pacientes sin FSR (el 90,4 frente al 70,8%; p < 0,001). La administraciσn directamente observada del tratamiento a los pacientes con FSR no mejorσ de manera significativa el porcentaje de enfermos con situaciσn final satisfactoria. Conclusiones: Los pacientes con FSR tienen una mayor probabilidad de presentar una situacion final no satisfactoria. La presencia de FSR entre los enfermos con tuberculosis es baja en nuestro medio. Existe una incipiente tendencia al aumento de enfermos inmigrantes procedentes de paises con mayor prevalencia de tuberculosis, hecho que debe considerarse de cara a un mejor control de la enfermedad.

Tuberculin skin test and interferon-γ release assay show better correlation after the tuberculin ‘window period’ in tuberculosis contacts

Abstract Background: T-cell interferon-gamma release assays (IGRAs) have been shown to be effective tools for the detection of Mycobacterium tuberculosis infection, offering an enhanced specificity compared to the tuberculin skin test (TST). Most tuberculosis (TB) contact studies have shown a better correlation of IGRA with the intensity of M. tuberculosis exposure than that obtained using the TST. However, the correlation between tests performed before and after the tuberculin ‘window period’ (time between infection and when the immunological response becomes measurable) remains to be studied. Methods: A longitudinal prospective analysis was performed in TB contacts. We analyzed the correlation between a commercially available IGRA (QuantiFERON®-TB Gold in-Tube, QFT) and the TST before and after the tuberculin window period (2 months). Concordance between both tests was assessed using the Kappa coefficient (κ). Correlation of both tests with the degree of TB exposure was also analyzed. Results: One hundred and fifty-two TB contacts were included in the study. Agreement between the TST and IGRA was better after the window period (κ = 0.60 at the first visit and κ = 0.73 after 2 months), especially for non-BCG vaccinated subjects (κ = 0.81). Both a positive TST and QFT were correlated, after the window period, with the size of place of contact (the smaller the place of contact, the higher the probability of having a positive test) (p = 0.022 and p = 0.02, respectively) and with the total numbers of hours spent with the index case (p = 0.006 for TST and p = 0.007 for QFT). Conclusions: IGRAs are a good alternative to the TST in contact tracing studies, especially after the tuberculin window period.

Safety and efficacy of the C-Tb skin test to diagnose Mycobacterium tuberculosis infection, compared with an interferon γ release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial

BACKGROUND Targeted screening and treatment of Mycobacterium tuberculosis infection substantially reduces the risk of developing active tuberculosis. C-Tb (Statens Serum Institute, Copenhagen, Denmark) is a novel specific skin test based on ESAT-6 and CFP10 antigens. We investigated the safety and diagnostic potential of C-Tb compared with established tests in the contact-tracing setting. METHODS Negative controls, close contacts, occasional contacts, and patients with active pulmonary tuberculosis were enrolled at 13 centres in Spain. We compared C-Tb with the QuantiFERON-TB Gold In-Tube ([QFT] Qiagen, Hilden, Germany) interferon γ release assay (IGRA) and the purified protein derivative (PPD) RT 23 tuberculin skin test ([TST] Statens Serum Institute). All participants older than 5 years were tested with QFT. Some participants in the negative control group received C-Tb without the TST to test for potential interactions between C-Tb and PPD RT 23. The rest were randomly assigned in blocks of ten and tested with both C-Tb and TST, with five in each block receiving injection of C-Tb in the right arm and the TST in the left arm and five vice versa. The primary and safety analyses were done in all participants randomly assigned to a group who received any test. This trial is registered with ClinicalTrials.gov, number NCT01631266, and with EudraCT, number 2011-005617-36. FINDINGS From July 24, 2012, to Oct 2, 2014, 979 participants were enrolled, of whom 263 were negative controls, 299 were occasional contacts, 316 were close contacts, and 101 were patients with tuberculosis. 970 (99%) participants completed the trial. Induration sizes were similar for C-Tb and TST, but TST positivity was affected by BCG vaccination status. We found a strong positive trend towards C-Tb test positivity with increasing risk of infection, from 3% in negative controls to 16% in occasional contacts, to 43% in close contacts. C-Tb and QFT results were concordant in 785 (94%) of 834 participants aged 5 years and older, and results did not differ significantly between exposure groups. The safety profile of C-Tb was similar to that for the TST. INTERPRETATION C-Tb delivered IGRA-like results in a field-friendly format. Being unaffected by BCG vaccination status, the C-Tb skin test might provide more accurate treatment guidance in settings where the TST is commonly used. FUNDING Statens Serum Institut.

Interferon-γ release assays in tuberculosis contacts: is there a window period?

The tuberculin skin test (TST) is the established procedure for diagnosis of latent tuberculosis infection (LTBI) among the contacts of an infectious tuberculosis (TB) case. TST may convert to positive ≤8 weeks after Mycobacterium tuberculosis infection, an interval that is usually referred to as the “window period”. A negative TST obtained <8 weeks before does not exclude infection, and a second test is recommended 1, 2. However, TST has some limitations, such as cross-reactivity with Bacille Calmette–Guerin (BCG) and with nontubercular mycobacterial infections. T-cell interferon-γ release assays (IGRA) are emerging as new screening tools for LTBI diagnosis. IGRAs incorporate specific antigens of M. tuberculosis that are absent in BCG strains and in the majority of nontubercular mycobacteria, offering enhanced specificity for detecting M. tuberculosis infection 3. In addition, their use has been approved for screening of infection in contacts 1, 4. Most TB contact studies have shown a better correlation of IGRA with the intensity of M. tuberculosis exposure than that obtained using TST, particularly in patients previously vaccinated with BCG 5. Yet, to our knowledge, no study has considered carefully the window period after M. tuberculosis exposure while simultaneously evaluating responses for TST and IGRA. The aim of this study was to find out which of the two tests converts earlier to positive in persons with recent infection after contact with an infectious TB case. We used a longitudinal prospective analysis to study 184 healthy adults, all having had recent contact with a microbiologically confirmed pulmonary TB index patient. The setting was a specialized TB clinic in Pontevedra, Spain, where the incidence of TB has historically been among the highest in Western …

Value of the tuberculin skin testing and of an interferon-gamma release assay in haemodialysis patients after exposure to M. tuberculosis

BackgroundPatients with end-stage renal disease (ESRD) and Mycobacterium tuberculosis infection pose a high risk of developing active TB disease. It is therefore important to detect latent TB infection (LTBI) to be able to offer treatment and prevent progression to TB disease. We assessed the value of the tuberculin skin test (TST) and of an interferon-gamma release assay (Quantiferon®-TB Gold in-Tube, QFT) for diagnosing LTBI in ESRD patients, after prolonged exposure to a highly contagious TB case in a haemodialysis unit. As a high number of patients presented erythema without induration in the TST response, this type of reaction was also analysed.MethodThe TST and QFT were simultaneously performed twelve weeks after the last possible exposure to a bacilliferous TB patient. If the first TST (TST-1) was negative, a second TST (TST-2) was performed 15 days later to detect a booster response. A comparison was made between the TST responses (including those cases with erythema without induration) and those for the QFT. The correlation with risk of infection and the concordance between tests were both analysed.ResultsA total of 52 patients fulfilled the inclusion criteria. Overall, 11 patients (21.2%) had a positive TST response: 3 for TST-1 and 8 for TST-2, and 18 patients (34.6%) showed a positive QFT response (p = 0.065). Erythema without induration was found in 3 patients at TST-1 and in a further 9 patients at TST-2. The three patients with erythema without induration in TST-1 had a positive TST-2 response. Concordance between TST and QFT was weak for TST-1 (κ = 0.21); it was moderate for overall TST (κ = 0.49); and it was strong if both induration and erythema (κ = 0.67) were considered.ConclusionsIn patients with ESRD, erythema without induration in the TST response could potentially be an indicator of M. tuberculosis infection. The QFT shows better accuracy for LTBI diagnosis than the TST.

Social risk factors for noncompliance with tuberculosis treatment in Pontevedra [Spain]

OBJECTIVE To determine the prevalence and characteristics of social risk factors (SRF) for noncompliance with treatment in patients with tuberculosis (TB) in Pontevedra. METHODS We performed a descriptive analysis of patients with TB and SRF diagnosed between 1996 and 2002. A patient was considered as having SRF if he or she was socially isolated (alcoholism, intravenous drug use, prison inmate, homelessness or social maladjustment) or was an immigrant. The prevalence, annual trend of SRF and patient outcomes were calculated. The influence of direct observation of treatment administration on the outcome of patients with SRF was also analyzed. RESULTS Of 775 patients with TB, 156 (20.1%) had at least one SRF. Eighty-six patients were alcoholic, 41 were intravenous drug users, 24 were immigrants, 11 were homeless, 11 showed social maladjustment and 10 were prison inmates. The presence of SRF among TB patients showed no tendency to increase or decrease during the study period, except for the increasing number of immigrants (chi 2 for lineal tendency = 12.24; p = 0.005). Final outcomes were significantly better in patients without SRF (90.4 vs 70.8% of satisfactory final outcomes; p < 0.001). Direct observation of treatment did not increase satisfactory outcomes in patients with SRF. CONCLUSIONS Patients with TB and SRF have a significantly higher proportion of unsatisfactory final outcomes. The presence of SRF is relatively low in our environment. The number of immigrants from countries with a high prevalence of TB shows an incipient tendency to increase. This finding should be taken into account to achieve better control of the disease.

Epidemiology of tuberculosis in Galicia, Spain, 16 years after the launch of the Galician tuberculosis programme.

SETTING Galicia, Spain. OBJECTIVE To describe changes in tuberculosis (TB) epidemiology and characteristics in Galicia, Spain, during the period 1996-2011. DESIGN Retrospective observational descriptive study of data obtained from the Tuberculosis Information System. The Galician Tuberculosis Prevention and Control Programme, created in 1994, is based in seven tuberculosis units that actively collect data on case finding and follow-up of all cases of TB in the region. RESULTS TB incidence fell from 72.9 cases per 100,000 population in 1996 to 24.6 in 2011 (respectively 40.5 and 14.2 in patients aged <15 years). In 2011, 49.8% (n = 343) of patients were aged between 25-54 years; 62.3% (n = 429) were male; 52.1% (n = 359) had pulmonary TB (PTB) alone, of whom 33.5% (n = 144) had cavitary lesions; 50.7% (n = 218 PTB cases) were sputum smear-positive and 80.5% (346 PTB cases) were culture-positive. The median diagnostic delay was 56 days; 4.6% (n = 32) were human immunodeficiency virus positive and 5.2% (n = 36) were immigrants. The treatment success rate was close to 90%. Contacts of 86.7% of the smear-positive index cases were evaluated. CONCLUSION TB incidence in Galicia is progressively decreasing; however, it is still higher than that of neighbouring regions. A long diagnostic delay was observed, which may have contributed to the high incidence rate in children.

QuantiFERON-TB Gold In-Tube as a Confirmatory Test for Tuberculin Skin Test in Tuberculosis Contact Tracing: A Noninferiority Clinical Trial

Background Screening strategies based on interferon-γ release assays in tuberculosis contact tracing may reduce the need for preventive therapy without increasing subsequent active disease. Methods We conducted an open-label, randomized trial to test the noninferiority of a 2-step strategy with the tuberculin skin test (TST) followed by QuantiFERON-TB Gold In-Tube (QFT-GIT) as a confirmatory test (the TST/QFT arm) to the standard TST-alone strategy (TST arm) for targeting preventive therapy in household contacts of patients with tuberculosis. Participants were followed for 24 months after randomization. The primary endpoint was the development of tuberculosis, with a noninferiority margin of 1.5 percentage points. Results A total of 871 contacts were randomized. Four contacts in the TST arm and 2 in the TST/QFT arm developed tuberculosis. In the modified intention-to-treat analysis, this accounted for 0.99% in the TST arm and 0.51% in the TST/QFT arm (-0.48% difference; 97.5% confidence interval [CI], -1.86% to 0.90%); in the per-protocol analysis, the corresponding rates were 1.67% and 0.82% in the TST and TST/QFT arms, respectively (-0.85% difference; 97.5% CI, -3.14% to 1.43%). Of the 792 contacts analyzed, 65.3% in the TST arm and 42.2% in the TST/QFT arm were diagnosed with tuberculosis infection (23.1% difference; 95% CI, 16.4% to 30.0%). Conclusions In low-incidence settings, screening household contacts with the TST and using QFT-GIT as a confirmatory test is not inferior to TST-alone for preventing active tuberculosis, allowing a safe reduction of preventive treatments. Clinical Trials Registration NCT01223534.