Avances en tuberculosis en el 54° Congreso Chileno de enfermedades respiratorias. 3a parte: Prevención de la tuberculosis activa mediante el tratamiento de la tuberculosis latente / Advances in tuberculosis at the 54th Chilean Congress of Respiratory Diseases. Part 3: prevention of active tuberculosis by treating latent tuberculosis

La infección tuberculosa latente (ITL) es un estado asintomático de la infección por Mycobacterium tuberculosis incapaz de transmitir la infección a otros, pero con el potencial de originar una tuberculosis (TBC) activa en el infectado, especialmente ante la presencia de factores de riesgo inmunológico. Es importante en personas de riesgo de desarrollar TBC reconocer la ITL utilizando test como la reacción a la tuberculina (PPD o TST) y los ensayos de liberación de Interferón-γ (IGRAs). Sin embargo, estos tests tienen limitaciones en su capacidad de predicción de riesgo de evolución de infección a enfermedad lo que conlleva a tener que tratar muchas personas para evitar algún caso de enfermedad. Nuevos tests se encuentran en desarrollo para mejorar la sensibilidad de reconocimiento de la ITL, distinguir infecciones recientes (que tienen el mayor riesgo de progresión a enfermedad) e incluso con la capacidad de detectar enfermedad subclínica o inicial. Para reducir la probabilidad de enfermar por TBC se utilizan tratamientos preventivos con fármacos, pero la cobertura mundial de esta terapia es reducida y la adherencia a terapias auto-administradas, como en el caso del uso de isoniazida diaria oral, es también baja. Otro problema de esta terapia son los riesgos de reacciones adversas (hepatitis, erupciones cutáneas) aunque no frecuentes. La recomendación de terapia actual de la ITL incluye el uso de rifamicinas y sus derivados. La asociación de isoniazida con rifapentina en una dosis semanal durante tres meses, administrada bajo supervisión, es la terapia de primera línea para mayores de 2 años, mostrando menos riesgo de hepatotoxicidad y mayor adherencia.

Latent Tuberculosis infection (LTBI) is the asymptomatic state of infection caused by Mycobacterium tuberculosis. Although untransmissible, LTBI can progress to active tuberculosis (TB), especially in people with immune risk factors. It is important to recognize LTBI in people at risk of developing TB; tuberculin skin test (PPD or TST) or interferon-γ release assays (IGRAs) are current diagnostic tests. However, these tests have limitations in their ability to predict subjects who will evolve from infection to disease; consequently, a large number of people with LTBI need treatment to avoid a reduced number of future TB disease cases. Newer tests are under development to improve the sensitivity in recognizing LTBI, distinguish recent infections with highest risk of progression to disease, and even be able to detect initial subclinical disease. Antimicrobial preventive treatment effectively reduces the probability of getting sick with TB, but worldwide availability of TB preventive therapy is limited, and adherence to self-administered therapies, as in the case of the use of daily oral isoniazid, is low. Adverse reactions risk (hepatitis, skin rash) although infrequent, is another problem with these therapies. Currently, LTBI management guidelines include regimens with use of rifamycins and their derivatives. The combination of isoniazid and rifapentine in a weekly dose for three months administered under supervision is the first line choice for LTBI therapy in those over 2 years of age, showing less hepatoxicity risk and greater adherence.

The clinical utility of tuberculin skin tests: a single-center experience

Background: Tuberculin skin test (TST) has played an essential in the diagnosis of latent tuberculosis infection (LTBI) for nearly a century. Objective: This study aimed to investigate the general characteristics of patients tested with TST in a tertiary hospital within two years. Methods: All patients who were evaluated to screen for tuberculosis and received a TST were included. The Mantoux method was used for TST administration. Results: A total of 661 patients, 345 (52.2%) men and 316 (47.8%) women, with a mean age of 43.0 ±15.9 years, were included in the study. Accordingly, TST was performed prior to anti-TNF biological agent therapy for 50% (331) of the participants, for LTBI screening before solid organ and/or hematological stem cell transplantation for 20.4% (135), for screening following contact with tuberculosis for 25.1% (166), for screening of healthcare professionals for 1.1% (7), and medical report for 3.3% (22). 2.7% of the patients who took TST were diagnosed with active tuberculosis (14 with pulmonary tuberculosis and 4 with extrapulmonary tuberculosis). QuantiFERON-TB Gold (QFT) test was performed in 332 (50.2%) patients with anergic TST results. According to TST and QFT test results, 28.3% (187) of the patients were started on tuberculosis prophylaxis. Conclusion: While TST is most performed for LTBI screening prior to biological agent therapy, almost one-fourth of patients taking TST require tuberculosis prophylaxis. On the other hand, about half of the patients require an additional QFT test.

Antecedentes: La prueba de la tuberculina ha jugado un papel fundamental en el diagnóstico de la infección latente por tuberculosis durante casi un siglo. Objetivo: Investigar las características generales de los pacientes a los que se les realizó la prueba de tuberculina en un hospital de tercer nivel. Métodos: Se incluyeron todos los pacientes que fueron incluidos en un tamizaje de tuberculosis mediante la prueba de tuberculina. Se utilizó el método de Mantoux para la administración de esta prueba. Resultados: Se incluyeron en el estudio un total de 661 pacientes, 345 (52.2%) hombres y 316 (47.8%) mujeres, con una edad media de 43.0 ±15.9 años. La prueba de tuberculina se realizó en el 50% (331) de los participantes, antes de la terapia con agentes biológicos anti-TNF; En el 20.4% (135) se hizo la prueba antes del trasplante de órganos sólidos y/o células madre hematológicas; para el 25.1% (166) se realizó tras contacto con la tuberculosis, el 1.1% (7) para tamizaje de los profesionales sanitarios y con informe médico para el 3.3% (22). El 2.7% de los pacientes que se realizaron la prueba de tuberculina fueron diagnosticados con tuberculosis activa (14 pulmonar y 4 extrapulmonar). La prueba QuantiFERON-TB Gold (QFT) se realizó en 332 (50.2 %) pacientes con resultados anérgicos para tuberculina. Según los resultados de las pruebas de tuberculina y QFT, el 28.3% (187) de los pacientes iniciaron profilaxis antituberculosa. Conclusión: Si bien la prueba de tuberculina se realiza comúnmente para la detección de tuberculosis latente antes de la terapia con agentes biológicos, casi una cuarta parte de los pacientes que se les hizo la prueba de tuberculina requieren profilaxis para tuberculosis. Por otro lado, aproximadamente la mitad de los pacientes requieren una prueba QFT adicional.

A Systematic Review of Prevalence and Risk Factors of Latent Tuberculosis Infection Among Medical and Nursing Students

@#Introduction: Clinical training may expose medical and nursing students to workplace hazards comparable to those encountered by healthcare workers (HCWs). This study was designed to investigate the prevalence of latent tuberculosis infection (LTBI) and associated risk factors among medical and nursing students. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, a systematic review was conducted utilising four electronic databases to appraise and synthesise the literature on LTBI which used the tuberculin skin test (TST) and the blood interferon-gamma release assay (IGRA). Results: Original articles published in the English language between 2010 and 2020 were included, yielding 14 relevant articles. The average prevalence of LTBI in high-burden countries was 38.2% for TST and 20.6% for the IGRA test. According to TST and IGRA findings, the average prevalence of LTBI in nations with an intermediate burden was 16.7% and 4.7 %, respectively. The average prevalence was 2.8% and 1.1% from the TST and IGRA tests for low-burden countries, respectively. A greater risk of LTBI was shown to be related with an increase in age among postgraduate medical school students, a history of Bacillus Calmette-Guerin (BCG) vaccination, origin from high-risk tuberculosis (TB) countries, increased hours of hospital exposure, a history of contact with TB cases, a high body mass index, older age group students, and a lower TB knowledge score. Conclusion: The available evidence from this review emphasised the importance of developing and implementing efficient and cost-effective TB infection-control programmes, particularly in high-burden countries and amongst students at risk.

Application of enzyme-linked immunospot assay in the identification of culprit drugs in severe drug eruptions / 中华皮肤科杂志

Early identification of culprit drugs is crucial for the treatment and prevention of severe drug eruptions.At present,no accurate and effective methods are available for identifying the culprit drugs in severe drug eruptions.Commonly used tests include patch test,lymphocyte transformation test and so on.However,low sensitivity and specificity limit their clinical application.Enzyme-linked immunospot assay,an in vitro technique,can identify culprit drugs in cutaneous adverse drug reactions by detecting cytokines secreted by drug-specific T lymphocytes.It has high sensitivity and specificity in patients with severe drug eruptions,and can be carried out during the acute stage of disease or among immunocompromised patients.Therefore,enzyme-linked immunospot assay may be an effective method for identifying culprit drugs in severe drug eruptions.

Proposal to Revise the Screening Test for Latent Tuberculosis Infection in Close Contacts at Elementary Schools in Korea / 예방의학회지

The 2018 National Guideline for Tuberculosis Control, which was published by the Korea Centers for Diseases Prevention and Control (KCDC), mandates conducting an epidemiological survey among close contacts of active tuberculosis patients at public institutions such as schools. In the procedure for these surveys, the tuberculin skin test (TST) is mandated as the screening test for latent tuberculosis infection in elementary school students. However, several guidelines recommend using the interferon-gamma releasing assay (IGRA) for contacts aged over 5 years with a Bacillus Calmette–Guérin vaccination history. The main reason for this is that IGRA has a higher specificity and lower false positive rate than TST. In addition, IGRA requires only a single visit to draw blood and the results are available within 24 hours. These advantages could promote cooperation from both parents and students in conducting these surveys. Thus, these findings regarding the benefits of IGRA for surveys of close contacts at elementary schools should be incorporated into the KCDC guideline.

Experiences of Latent Tuberculosis Infection Treatment for the North Korean Refugees / 결핵

BACKGROUND: Tuberculosis (TB) is increasing in immigrants. We aimed to investigate the current status of latent tuberculosis infection (LTBI) treatment for North Korean Refugees (NKR) compared to South Koreans Contacts (SKC). METHODS: TB close contacts in a closed facility of SKC and NKR who underwent LTBI screening in a settlement support center for NKR were analyzed retrospectively. RESULTS: Among tuberculin skin test (TST) ≥10 mm (n=298) reactors, the males accounted for 72.2% in SKC (n=126) and 19.5% in NKR (n=172) (p<0.01). The mean age was higher in South Korea (42.8±9.9 years vs. 35.4±10.0 years, p<0.01). Additionally, the mean TST size was significantly bigger in NKR (17.39±3.9 mm vs. 16.57±4.2 mm, p=0.03). The LTBI treatments were initiated for all screened NKR, and LTBI completion rate was only 68.0%. However, in NKR, LTBI treatment completion rate was significantly increased by shorter 4R regimen (odds ratio [OR], 9.296; 95% confidence interval [CI], 4.159–20.774; p<0.01) and male (OR, 3.447; 95% CI, 1.191–9.974; p=0.02). CONCLUSION: LTBI treatment compliance must be improved in NKR with a shorter regimen. In addition, a larger study regarding a focus on LTBI with easy access to related data for NKR should be conducted.

Treatment of Latent Tuberculosis Infection and Its Clinical Efficacy / 결핵

The role of the treatment for latent tuberculosis infection (LTBI) has been underscored in the intermediate tuberculosis (TB) burden countries like South Korea. LTBI treatment is recommended only for patients at risk for progression to active TB―those with frequent exposure to active TB cases, and those with clinical risk factors (e.g., immunocompromised patients). Recently revised National Institute for Health and Care Excellence (NICE) guideline recommended that close contacts of individuals with active pulmonary or laryngeal TB, aged between 18 and 65 years, should undergo LTBI treatment. Various regimens for LTBI treatment were recommended in NICE, World Health Organization (WHO), and Centers for Disease Control and Prevention guidelines, and superiority of one recommended regimen over another was not yet established. Traditional 6 to 9 months of isoniazid (6H or 9H) regimen has an advantage of the most abundant evidence for clinical efficacy―60%–90% of estimated protective effect. However, 6H or 9H regimen is related with hepatotoxicity and low compliance. Four months of rifampin regimen is characterized by less hepatotoxicity and better compliance than 9H, but has few evidence of clinical efficacy. Three months of isoniazid plus rifampin was proved equivalence with 6H or 9H regimen in terms of efficacy and safety, which was recommended in NICE and WHO guidelines. The clinical efficacy of isoniazid plus rifapentine once-weekly regimen for 3 months was demonstrated recently, which is not yet introduced into South Korea.

Systemic review: agreement between the latent tuberculosis screening tests among patients with rheumatic diseases

BACKGROUND/AIMS: To estimate the level of agreement and positivity rates of latent tuberculosis infection (LTBI) tests prior to the use of tumor necrosis factor (TNF) inhibitors in relation to underlying rheumatic diseases and endemic tuberculosis levels. METHODS: The Ovid-Medline, Embase, and Cochrane Libraries were searched for articles before October 2013 involving LTBI screening in rheumatic patients, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), juvenile idiopathic arthritis (JIA), and psoriatic arthritis. RESULTS: In pooled analyses, 5,224 rheumatic patients had undergone both a tuberculin skin test (TST) and an interferon-gamma release assay (IGRA) before TNF inhibitors use. The positivity of TST, QuantiFERON-TB Gold In Tube (QFT-GIT), and T-SPOT.TB (T-SPOT) tests were estimated to be 29%, 17%, and 18%, respectively. The agreement percentage between the TST and QFT-GIT, and between the TST and T-SPOT were 73% and 75%. Populations from low-to-moderate endemic TB presented with slightly less agreement (71% between TST and QFT-GIT, and 74% between TST and T-SPOT) than patients from high endemic countries (73% between TST and QFT-GIT, and 81% between TST and T-SPOT). By underlying disease stratification, a lower level of agreement between TST and QFT-GIT was found among AS (64%) than among JIA (77%) and RA patients (73%). CONCLUSIONS: We reaffirm the current evidence for accuracy of LTBI test done by TST and IGRA among rheumatic patients is inconsistent. Our stratified analysis suggests different screening strategies might be needed in clinical settings considering the endemic status in the patient’s country of origin and the precise nature of underlying diseases.

High risk of tuberculosis during infliximab therapy despite tuberculosis screening in inflammatory bowel disease patients in India

BACKGROUND/AIMS: The data on the risk of tuberculosis (TB) reactivation with infliximab (IFX) in patients with inflammatory bowel disease (IBD) from TB endemic countries, like India, is limited. The risk of TB reactivation on IFX and its predictors in patients with IBD was assessed. METHODS: This retrospective review included consecutive patients with IBD who received IFX, and were on follow-up from January 2005 to November 2017. The data was recorded on age/disease duration, indications for IFX, screening for latent tuberculosis (LTB) before IFX, response to IFX, incidence and duration when TB developed after IFX, and type of TB (pulmonary [PTB]/extra-pulmonary [EPTB]/disseminated). RESULTS: Of 69 patients (22 ulcerative colitis/47 Crohn’s disease; mean age, 35.6±14.5 years; 50.7% males; median follow-up duration after IFX, 19 months [interquartile range, 5.5–48.7 months]), primary non-response at 8 weeks and secondary loss of response at 26 and 52 weeks were seen in 14.5%, 6% and 15% patients respectively. Prior to IFX, all patients were screened for LTB, 8 (11.6%) developed active TB (disseminated, 62.5%; EPTB, 25%; PTB, 12.5%) after a median of 19 weeks (interquartile range, 14.0–84.5 weeks) of IFX. Of these 8 patients’ none had LTB, even when 7 of 8 were additionally screened with contrast-enhanced chest tomography. Though not statistically significant, more patients with Crohn’s disease than ulcerative colitis (14.9% vs. 4.5%, P=0.21), and those with past history of TB (25% vs. 9.8%, P=0.21), developed TB. Age, gender, disease duration, or extraintestinal manifestations could not predict TB reactivation. CONCLUSIONS: There is an extremely high rate of TB with IFX in Indian patients with IBD. Current screening techniques are ineffective and it is difficult to predict TB after IFX.

Frequency of indeterminate results from an interferon-gamma release assay among HIV-infected individuals / Taxa de resultados indeterminados de ensaio de liberação de interferon-gama entre pessoas infectadas pelo HIV

ABSTRACT Objective: To evaluate the frequency of and factors associated with indeterminate interferon-gamma release assay (IGRA) results in people living with HIV/AIDS (PLWHA). Methods: We tested 81 PLWHA in the central-west region of Brazil, using the tuberculin skin test and an IGRA. Information on sociodemographic and clinical variables was gathered through the use of questionnaires and from medical records. The association of those variables with indeterminate results was analyzed by calculating the adjusted ORs in a multivariate logistic regression model. Concordance was evaluated by determining the kappa statistic. Results: Among the 81 patients evaluated, the tuberculin skin test results were positive in 18 (22.2%) of the patients, and the IGRA results were positive in 10 (12.3%), with a kappa of 0.62. The IGRA results were indeterminate in 22 (27.1%) of the patients (95% CI: 17.8-38.1%). The odds of obtaining indeterminate results were significantly higher in smokers (adjusted OR = 6.0; 95% CI: 1.4-26.7) and in samples stored for less than 35 days (adjusted OR = 14.0; 95% CI: 3.1-64.2). Patients with advanced immunosuppression (CD4+ T-cell count < 200 cells/mm3) were at a higher risk for indeterminate results (OR adjusted for smoking and inadequate duration of sample storage = 4.7; 95% CI: 0.91-24.0), although the difference was not significant. Conclusions: The high prevalence of indeterminate results can be a major limitation for the routine use of IGRAs in PLWHA. The need to repeat the test increases its costs and should be taken into account in cost-effectiveness studies. The processing of samples can significantly alter the results.

RESUMO Objetivo: Avaliar a frequência de resultados indeterminados de um interferon-gamma release assay (IGRA, ensaio de liberação de interferon-gama) e os fatores relacionados com esses resultados em pessoas vivendo com HIV/AIDS (PVHA). Métodos: Foram avaliadas 81 PVHA na região Centro-Oeste do Brasil, por meio do teste tuberculínico e de um IGRA. Informações a respeito de variáveis sociodemográficas e clínicas foram obtidas por meio de questionários e prontuários médicos. A relação entre essas variáveis e os resultados indeterminados foi avaliada por meio do cálculo da OR ajustada em um modelo de regressão logística multivariada. A concordância foi avaliada por meio do coeficiente kappa. Resultados: Os resultados do teste tuberculínico e do IGRA foram positivos em 18 (22,2%) e 10 (12,3%), respectivamente, dos 81 pacientes avaliados (κ = 0,62). O resultado do IGRA foi indeterminado em 22 (27,1%) dos pacientes (IC95%: 17,8-38,1%). A chance de resultados indeterminados foi significativamente maior em fumantes (OR ajustada = 6,0; IC95%: 1,4-26,7) e em amostras armazenadas durante menos de 35 dias (OR ajustada = 14,0; IC95%: 3,1-64,2). Pacientes com imunossupressão avançada (contagem de células T CD4+ < 200 células/mm3) apresentaram maior risco de resultados indeterminados (OR ajustada para tabagismo e tempo inadequado de armazenamento das amostras = 4,7; IC95%: 0,91-24,0), embora a diferença não tenha sido significativa. Conclusões: A alta prevalência de resultados indeterminados pode ser um grande obstáculo ao uso rotineiro de IGRAs em PVHA. A necessidade de repetir o teste aumenta seu custo e deve ser levada em conta em estudos da relação entre custo e eficácia. O processamento das amostras pode alterar significativamente os resultados.

Comparing tuberculin skin test and interferon γ release assay (T-SPOT.TB) to diagnose latent tuberculosis infection in household contacts

BACKGROUND/AIMS: The tuberculin skin test (TST) and interferon γ release assay are currently used as diagnostic tools to detect latent tuberculosis (TB) infection; however, there are inconsistencies about the degree of agreement between the tests. We aimed to evaluate the concordance rate between the two tests in household contacts of a country with intermediate TB burden, where most people were vaccinated. METHODS: We recruited household contacts who spent > 8 hours daily with patients with microbiologically confirmed active pulmonary TB, and received both TST and T-SPOT.TB (Oxford Immunotec) simultaneously. The degree of agreement was analysed according to TST cutoff and Bacille Calmette-Guerin (BCG) vaccination status. Relevant factors were analysed to establish the association with TST or T-SPOT.TB. RESULTS: Among 298 household contacts, 122 (40.9%) were spouses, and 250 (83.9%) had received BCG vaccination. In the contact sources, 117 (39.3%) showed a positive result for acid-fast bacillus (AFB) sputum smear and 109 (36.6%) had cavities. The highest agreement rate of 69.5% and κ value of 0.378 were found with a 10 mm cutoff. Spouse, time interval from TB diagnosis to test, and AFB sputum smear positivity were significantly associated with a positive result for T-SPOT.TB. Sex, BCG vaccination, and cavity on chest computed tomography were related to TST positivity. CONCLUSIONS: The present study suggested it was not possible for TST and T-SPOT.TB to replace each other because of considerable discrepancy between the two tests in household contacts in a country with intermediate TB prevalence.

Comparing tuberculin skin test and interferon γ release assay (T-SPOT.TB) to diagnose latent tuberculosis infection in household contacts

BACKGROUND/AIMS: The tuberculin skin test (TST) and interferon γ release assay are currently used as diagnostic tools to detect latent tuberculosis (TB) infection; however, there are inconsistencies about the degree of agreement between the tests. We aimed to evaluate the concordance rate between the two tests in household contacts of a country with intermediate TB burden, where most people were vaccinated. METHODS: We recruited household contacts who spent > 8 hours daily with patients with microbiologically confirmed active pulmonary TB, and received both TST and T-SPOT.TB (Oxford Immunotec) simultaneously. The degree of agreement was analysed according to TST cutoff and Bacille Calmette-Guerin (BCG) vaccination status. Relevant factors were analysed to establish the association with TST or T-SPOT.TB. RESULTS: Among 298 household contacts, 122 (40.9%) were spouses, and 250 (83.9%) had received BCG vaccination. In the contact sources, 117 (39.3%) showed a positive result for acid-fast bacillus (AFB) sputum smear and 109 (36.6%) had cavities. The highest agreement rate of 69.5% and κ value of 0.378 were found with a 10 mm cutoff. Spouse, time interval from TB diagnosis to test, and AFB sputum smear positivity were significantly associated with a positive result for T-SPOT.TB. Sex, BCG vaccination, and cavity on chest computed tomography were related to TST positivity. CONCLUSIONS: The present study suggested it was not possible for TST and T-SPOT.TB to replace each other because of considerable discrepancy between the two tests in household contacts in a country with intermediate TB prevalence.

Qualitative and quantitative results of interferon-γ release assays for monitoring the response to anti-tuberculosis treatment

BACKGROUND/AIMS: The usefulness of interferon-γ release assays (IGRAs) in monitoring to responses to anti-tuberculosis (TB) treatment is controversial. We compared the results of two IGRAs before and after anti-TB treatment in same patients with active TB. METHODS: From a retrospective review, we selected patients with active TB who underwent repeated QuantiFERON-TB Gold (QFN-Gold, Cellestis Limited) and T-SPOT.TB (Oxford Immunotec) assays before and after anti-TB treatment with first-line drugs. Both tests were performed prior to the start of anti-TB treatment or within 1 week after the start of anti-TB treatment and after completion of treatment. RESULTS: A total of 33 active TB patients were included in the study. On the QFN-Gold test, at baseline, 23 cases (70%) were early secreted antigenic target 6-kDa protein 6 (ESAT-6) or culture filtrate protein 10 (CFP-10) positive. On the T-SPOT. TB test, at baseline, 31 cases (94%) were ESAT-6 or CFP-10 positive. Most of patients remained both test-positive after anti-TB treatment. Although changes in interferon-γ release responses over time were highly variable in both tests, there was a mean decline of 27 and 24 spot-forming counts for ESAT-6 and CFP-10, respectively on the T-SPOT.TB test (p < 0.05 for all). CONCLUSIONS: Although limited by the small number of patients and a short-term follow-up, there was significant decline in the quantitative result of the T-SPOT. TB test with treatment. However, both commercial IGRAs may not provide evidence regarding the cure of disease in Korea, a country where the prevalence of TB is within the intermediate range.

Preventing the Transmission of Tuberculosis in Health Care Settings: Administrative Control / 결핵및호흡기질환

It is well established that health care workers (HCWs) have a considerably higher risk of occupationally acquired tuberculosis (TB). To reduce the transmission of TB to HCWs and patients, TB infection control programs should be implemented in health care settings. The first and most important level of all protection and control programs is administrative control. Its goals are to prevent HCWs, other staff, and patients from being exposed to TB, and to reduce the transmission of infection by ensuring rapid diagnosis and treatment of affected individuals. Administrative control measures recommended by the United States Centers for Disease Control and Prevention and the World Health Organization include prompt identification of people with TB symptoms, isolation of infectious patients, control of the spread of the pathogen, and minimization of time spent in health care facilities. Another key component of measures undertaken is the baseline and serial screening for latent TB infection in HCWs who are at risk of exposure to TB. Although the interferon-gamma release assay has some advantages over the tuberculin skin test, the former has serious limitations, mostly due to its high conversion rate.

Infecciones en pacientes reumatológicos asociadas a corticosteroides y antagonistas del factor de necrosis tumoral α / Infections in patients affected by rheumatologic diseases associated to glucocorticoid use or tumor necrosis factor-alpha inhibitors

A great diversity of infectious agents can affect patients that use steroids at immunosuppressive doses or tumor necrosis factor α (TNF-α) antagonists. The list of participating microorganisms is more restricted in the case of anti TNF-α blockers. Overlapping agents include intracellular bacteria, Mycobacterium tuberculosis, geographic fungal agents that have the ability to establish granulamotous infections, herpes zoster, and reactivation of chronic hepatitis B virus infection. An important conceptual issue for these infections is the existence of a threshold prednisone daily dose for the emergence of opportunistic infections but higher levels of immunosuppression and cofactors are required in the case of Pneumocystis jiroveci and cytomegalovirus infections. In order to prevent these threats, a detailed medical evaluation is needed before prescription to detect potential risks and manage them properly. Prevention rules must be prescribed in every case, that include common sense behaviors, vaccines, and in selected cases, chemoprophylaxis for latent tuberculosis (TB) infection, P. jiroveci pneumonia (PCP) or other specific requirements. Latent TB infection is probable and requires chemoprophylaxis in the case of remote or recent exposure to a patient with lung TB, a positive tuberculin or interferon-gamma release assay result or residual lung scars in a chest x-ray exam. PCP prevention is suggested when the patient reaches a daily dose of prednisone of 30 mg but might be needed at lower doses in case of other concomitant immunosuppressive drugs or when lymphopenia arises shortly after prednisone initiation.

Una gran diversidad de agentes infecciosos puede afectar a los pacientes que usan corticosteroides en dosis inmunosupresoras o antagonistas del factor de necrosis tumoral o (FNTα). La lista de microorganismos participantes es más restringida en el caso de los bloqueadores del FNTα. Los agentes que se sobreponen incluyen bacterias intracelulares, Mycobacterium tuberculosis, hongos geográficos que son capaces de establecer infecciones granulomatosas, herpes zoster y reactivación de hepatitis crónica por virus de hepatitis B. Existe una dosis umbral diaria de prednisona (o equivalente), sobre la cual emergen estas infecciones oportunistas, pero el nivel de inmunosupresión parece ser más alto en el caso de Pneumocystis jiroveci o citomegalovirus. Para prevenir estas amenazas, se requiere una evaluación médica detallada antes de su prescripción para detectar riesgos potenciales y manejarlos apropiadamente. Se deben indicar medidas de prevención en cada caso, las que incluyen conductas de sentido común y en casos seleccionados, quimioprofilaxis para infección latente por tuberculosis (TBC), neumonía por P. jiroveci u otros requerimientos específicos. La existencia de TBC latente es probable en el caso de exposición reciente o remota a un bacilífero pulmonar, prueba de tuberculina o de liberación de interferón γ positiva, o lesiones residuales en la radiografía de tórax. La prevención de neumonía por P. jiroveci se recomienda cuando se usan al menos 30 mg de prednisona al día pero puede ser necesario a dosis menores si se aplican otros fármacos inmunosupresores concomitantes o si aparece linfopenia poco después del inicio de los corticosteroides.

Diagnosis and Treatment of Latent Tuberculosis Infection due to Initiation of Anti-TNF Therapy / 결핵및호흡기질환

Patients with immune-mediated inflammatory diseases (IMIDs) are increasingly being treated with anti-tumor necrosis factor (TNF) agents and are at increased risk of developing tuberculosis (TB). Therefore, diagnosis and treatment of latent TB infection (LTBI) is recommended in these patients due to the initiation of anti-TNF therapy. Traditionally, LTBI has been diagnosed on the basis of clinical factors and a tuberculin skin test. Recently, interferon-gamma releasing assays (IGRAs) that can detect TB infection have become available. Considering the high-risk of developing TB in patients on anti-TNF therapy, the use of both a tuberculin skin test and an IGRA should be considered to detect and treat LTBI in patients with IMIDs. The traditional LTBI treatment regimen consisted of isoniazid monotherapy for 9 months. However, shorter regimens such as 4 months of rifampicin or 3 months of isoniazid/rifampicin are increasingly being used to improve treatment completion rates. In this review, the screening methods for diagnosing latent and active TB before anti-TNF therapy in patients with IMIDs will be briefly described, as well as the current LTBI treatment regimens, the recommendations for managing TB that develops during anti-TNF therapy, the necessity of regular monitoring to detect new TB infection, and the re-initiation of anti-TNF therapy in patients who develop TB.

The Usefulness of Interferon-gamma Release Assay for Diagnosis of Tuberculosis-related Uveitis in Korea

PURPOSE: To evaluate the usefulness of the interferon-gamma release assay (IGRA) for diagnosing tuberculosis (TB)-related uveitis (TRU). METHODS: Records from 181 patients with ocular signs and symptoms suggestive of TRU and intraocular inflammation of unknown etiology were reviewed. All subjects underwent clinical and laboratory testing, including IGRA, to rule out presence of underlying disease. A diagnosis of presumed TRU was made based on an internist's TB diagnosis and a patient's response to anti-TB therapy. Sensitivity, specificity, and positive predictive values of IGRA for TRU diagnosis were calculated. Clinical characteristics were compared between patients with positive and negative IGRA results. RESULTS: The sensitivity and specificity of IGRA for TRU were 100% and 72.0%, respectively. Mean age, percentage of patients with retinal vasculitis, and the anatomic type of uveitis were significantly different between patients with positive and negative IGRA results (all p < or = 0.001). Positive IGRA rates and false-positive rates were significantly different between age and anatomic type groups (both p = 0.001). The positive predictive value of the IGRA among patients with intraocular inflammation was high (70%) when all of younger age (< or =40 years), posterior uveitis, and retinal vasculitis were present. CONCLUSIONS: The IGRA is useful for diagnosing TRU in the Korean population, especially when it is used as a screening test. Clinical characteristics, including younger age (< or =40 years), posterior uveitis, and retinal vasculitis in IGRA-positive patients, increase the likelihood of the patient having TRU.

18F-FDG Positron-Emission Tomography/Computed Tomography Findings of Radiographic Lesions Suggesting Old Healed Tuberculosis

The presence of radiographic lesions suggesting old healed tuberculosis (TB) is one of the strongest risk factors for the subsequent development of active TB. We elucidated the metabolic activity of radiographic lesions suggesting old healed TB using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). This cross-sectional study included 63 participants with radiographic lesions suggesting old healed TB and with available 18F-FDG PET/CT scans. The maximum standardized uptake value (SUVmax) measured in the lesions, the clinical characteristics, results of the tuberculin skin test (TST) and interferon-gamma release assay (IGRA) were analyzed. The SUVmax in old healed TB was 1.5 or higher among nine (14.3%) participants. Age (adjusted odds ratio [aOR], 1.23; 95% CI, 1.03-1.46), history of previous TB (aOR, 60.43; 95% CI, 1.71-2131.65), and extent of the lesions (aOR, 1.34; 95% CI, 1.02-1.75) were associated with higher SUVmax. The positive rates for the TST and IGRA were not different between groups with and without increased FDG uptake. Increased FDG uptake on 18F-FDG PET/CT was observed in a subset of patients with radiographic lesions suggesting old healed TB. Given that the factors associated with increased FDG uptake are known risk factors for TB development, the possibility exists that participants with old healed TB lesions with higher SUV on 18F-FDG PET/CT scans might be at higher risk for active TB.

Application of T-SPOT.TB in connective tissue disease combined with tuberculosis / 中华检验医学杂志

Objective To investigate the diagnostic value of the T-SPOT.TB in connective tissue disease(CTD) combined with tuberculosis.Methods This is a case-control study.Forty-four patients with CTD combined with tuberculosis were enrolled from Xiangya Hospital of Central South University from September 2011 to July 2012.Another forty-four CTD patients without tuberculosis were evaluated as a control group.The diagnostic value of T-SPOT.TB and risk factors of the false negative results by T-SPOT.TB were analyzed.Results The sensitivity of T-SPOT.TB (70.5％,31/44) was significantly higher than that of TST(27.3％,12/44) for CTD combined with tuberculosis patients (x2 =16.42,P ＜ 0.001).The specificity of T-SPOT.TB and TST were 93.2％ (41/44) and 88.6％ (39/44),respectively.There was no significant difference between the specificity (x2 =0.14,P =0.711).The positive predictive value of T-SPOT.TB was 91.2％ (31/34).The negative predictive value was 75.9％ (41/54).Youden's index was 0.64,and the positive likelihood ratio was 10.3.All the index were higher than that of TST (0.16 and 2.4).While the negative likelihood ratio which was 0.32 was lower than that of TST (0.82).When spot forming cell frequencies of T-SPOT.TB of PBMC was set to 38SFCs/106 PBMC,it had the best cut-off value.Age,use of glucocorticoids or immunosuppressant therapy,lymphocytopenia and hypoalbuminemia were not associated with false negative T-SPOT.TB assay.Conclusion The T-SPOT.TB assay is much more useful than TST for diagnosing CTD combined with tuberculosis.

Perfil de células natural killer e dendríticas em casos de soroconversão espontânea e infecção crônica pelo vírus da Hepatite C / Profile of natural killer and dendritic cells in cases of spontaneous clearance and chronic infection with Hepatitis C virus

INTRODUÇÃO: O fato do vírus da Hepatite C (HCV) estabelecer uma infecção crônica persistente, na maioria dos casos, mesmo sendo reconhecido e alvejado pelos sistemas imune inato e adaptativo sugere que o mesmo tenha desenvolvido estratégias eficazes para driblar a ação desses sistemas. O HCV interfere na fase inicial de ativação da resposta imune adaptativa alterando a função das células dendríticas (DCs), o que provavelmente leva a uma ativação deficiente das células natural killer (NKs) e de linfócitos T. Portanto, a realização de estudos sobre DCs e NKs na infecção pelo HCV se torna de fundamental importância para a compreensão da patogênese e persistência desta infecção. MÉTODOS: Foram selecionados indivíduos com resolução espontânea da infecção pelo HCV, indivíduos com infecção crônica e indivíduos saudáveis. A técnica de citometria de fluxo foi utilizada para a determinação da frequência e do fenótipo de células dendríticas e NKs nesses indivíduos. Além disso, foi avaliada a atividade citotóxica das células NKs sob estímulo de IL-12 e IL-18, e também da linhagem K-562. RESULTADOS: A frequência de DC mielóides (mDC) expressando CD86, nos indivíduos crônicos, foi elevada e uma correlação positiva com a carga viral foi observada. Na análise do ensaio funcional foi observado que as populações de células NKs CD7+ CD57+ apresentaram maior expressão da molécula CD107a e baixa produção de IFNy nos indivíduos com infecção crônica. A constante exposição das células imunes ao IFN-alfa, induzido durante a infecção pelo HCV, resulta na polarização do fenótipo citotóxico, caracterizado por células NK ativadas com elevado poder de degranulação, mas com deficiente produção de IFN-y. CONCLUSÕES: As frequências das células DCs e NKs eram semelhantes em todos os indivíduos. A expressão da molécula CD86 na superfície das mDCs pode ter sido induzida pela presença do HCV, uma vez que foi observada correlação positiva com a carga viral...

INTRODUCTION: Hepatitis C virus (HCV) develops a chronic persistent infection in most of the cases, even being recognized and targeted by the innate and adaptive immune systems, suggests that the virus have developed effective strategies to circumvent the action of these systems. HCV interferes in the initial activation of the adaptive immune response by altering the function of dendritic cells (DCs), which probably leads to a deficient activation of natural killer cells (NK) and T lymphocytes. Therefore, studies of DCs and NK in HCV infection are very important for understanding the pathogenesis and the persistence of this infection. METHODS: We selected subjects with spontaneous resolution of HCV infection, with chronic infection and healthy subjects. Flow Cytometry was used to determine the frequency and phenotype of dendritic cells and NK cells of these individuals. In addition, we evaluated the NK cell cytotoxic activity in response to stimulation of IL-12 and IL-18 and in co-cultivation with the cell line K-562. RESULTS: In individuals with chronic infection, the frequency of myeloid (m) DC cells expressing CD86 was elevated and a positive correlation between these cells and viral load was observed. It was observed in chronic infected individuals that NK cells co-expressing CD7 and CD57 showed higher expression of CD107a and low production of IFN gamma. The constant exposure of immune cells to IFN-alfa induced during HCV infection results in the polarization of cytotoxic phenotype characterized by activated NK cells with high power degranulation, but with impaired production of IFN-y. CONCLUSIONS: The frequency of DCs and NK cells were similar in all individuals. The expression of CD86 molecule on the surface of mDCs may have been induced by the presence of HCV, since a positive correlation was observed with viral load. Cytotoxic NK cells, highly differentiated and unable to produce IFN-y, were the most frequent in chronic HCV infection...