[Disseminated tuberculosis in a patient with overlap syndrome, challenges in preventing]. / Tuberculosis diseminada en una paciente con síndrome de sobreposición, retos en la prevención.

Patients with autoimmune rheumatic diseases are at increased risk for developing infections and these are associated with increased morbidity and mortality from these diseases, especially in patients with systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and autoimmune inflammatory myopathies. The objective of this paper is to address the challenges in detecting latent tuberculosis in immunosuppressed patients and the initiation of prophylactic treatment because currently there are no well-defined guidelines indicating what action to take for detection and treatment; so far the available scientific evidence is scarce and some methodological shortcomings.

Los pacientes con enfermedades reumáticas autoinmunes tienen un elevado riesgo para el desarrollo de infecciones, y estas se asocian al incremento de la morbimortalidad de estas enfermedades, principalmente en pacientes con lupus eritematoso sistémico, artritis reumatoide, esclerosis sistémica y con miopatías inflamatorias autoinmunes. El objetivo de este trabajo es abordar los retos en la detección de tuberculosis latente en pacientes inmunosuprimidos y el inicio del tratamiento profiláctico ya que en la actualidad no existen lineamientos bien definidos que indiquen la conducta a seguir para su detección y tratamiento; por el momento la evidencia científica disponible es escasa y con algunas deficiencias metodológicas.

Pulmonary tuberculosis in a Pediatric Reference Hospital in Bogotá, Colombia.

BACKGROUND: In Colombia, epidemiological and clinical information related to pediatric tuberculosis (TB) is scarce. Data are needed to define the impact of the disease and to strengthen measures for detection and treatment. It is proposed to analyze the pediatric population diagnosed with pulmonary TB in a national reference institution. METHODS: Retrospective observational study including pediatric patients with pulmonary and miliary TB, and pulmonary and extrapulmonary involvement, treated between January 1, 2008 and December 31, 2016. A descriptive analysis of the selected variables was done. RESULTS: A total of 93 cases of diagnosed TB were identified, of which 61 cases were classified as pulmonary (65.6%). The location of TB occurred only in lungs in 51 patients (83.6%), was miliar in 3 (4.9%), pulmonary and extrapulmonary involvement in 7 patients (11.5%). The mean age was 7.5 years (0.5-18 years). Clinical criteria used for diagnosis was related to 98.3% of the cases, whereas radiological criteria in 90.2%. Bacteriological criterion was met in 42.6% of the cases. The most frequent symptoms were coughing (83.6%), fever (63.9%), and weight loss (26.2%); human immunodeficiency virus co-infection occurred in 3 cases (4.9%). During treatment, 5 mortality cases were recorded, although they were not attributable to TB. CONCLUSIONS: The epidemiological characterization of pediatric patients with pulmonary TB helps to achieve a better diagnostic approach in this population. Improving monitoring and follow-up activities in children with pulmonary TB, as well as promoting actions for adequate prevention and treatment is highly necessary.

Disseminated Mycobacterium tuberculosis following renal transplant with alemtuzumab induction.

Mycobacterium tuberculosis presents unique challenges in the peritransplant period. Here, we describe a case of disseminated tuberculosis following renal transplantation with alemtuzumab induction immunosuppression in a patient with remotely treated pulmonary tuberculosis and ongoing risk factors for re-infection. We also review the available literature regarding the prevalence of tuberculosis infection following solid organ transplant and management of high-risk patients, including the role for isoniazid preventative therapy.

Tuberculosis extrapulmonar, una revisión / Extrapulmonary tuberculosis

Hasta en un 25% de los casos de tuberculosis existe afectación extrapulmonar. Esta afectación es producida por la diseminación hematógena y linfática del bacilo de M. tuberculosis hacia otros órganos. Las localizaciones más frecuentes son la ganglionar, pleural y osteo-articular. El problema de estas formas de tuberculosis radica en la dificultad para llegar a su diagnóstico definitivo, ya que tanto los síntomas clínicos, como las pruebas de imagen pueden ser inespecíficos. La mayoría de las veces es necesario recurrir a pruebas diagnósticas invasivas como PAAF guiada con ecografía o TAC, para la recolección de muestras biológicas para su diagnóstico. A pesar del auge y el avance, en los últimos años, de los métodos moleculares para la detección precoz de ADN de la micobacteria, el cultivo sigue siendo el gold estándar que permite el diagnóstico microbiológico definitivo. El tratamiento de estas formas de tuberculosis, no va diferir de las pautas de tratamiento de las formas pulmonares. Se recomienda utilizar los mismos regímenes de antibióticos con una duración de 6 meses y únicamente prolongar la duración en las tuberculosis con afectación del sistema nervioso y en la espondilitis tuberculosa con afectación neurológica (AU)

Up to 25% of tuberculosis cases present extrapulmonary involvement. This is produced by haematogenous and lymphatic spread of the M. tuberculosis bacillus to other organs. The most common locations are the lymph nodes, pleura and the osteoarticular system. The problem with these types of tuberculosis is the difficulty in establishing a definitive diagnosis, since the clinical symptoms and results of imaging tests may be vague. It is often necessary to resort to invasive diagnostic testing such as ultrasound or CAT-guided FNAB, used to collect biological samples for diagnosis. Despite the growing use of and advances in recent years of molecular methods for early detection of mycobacteria DNA, cultures continue to be the gold standard that enable a firm microbiological diagnosis to be made. Treatment for these types of tuberculosis do not differ from treatment regimens for pulmonary forms of the same disease. The same antibiotic regimens for 6 months are recommended, and any extension of this period is advisable solely in tuberculosis affecting the central nervous system and in Pott’s disease (AU)

Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials.

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

Development of miliary tuberculosis under infliximab in a patient with spondyloarthritis and suspected Crohn's disease.

Tuberculosis (TB) infection is a major concern in patients with chronic autoimmune conditions under immunosuppressive therapy. Gastrointestinal tuberculosis can be misdiagnosed as Crohn's disease with detrimental consequences for the patient. We report on a 40-year old ethnic Turkish patient with HLA-B27 positive spondyloarthritis who developed gastrointestinal symptoms under immunosuppressive treatment with infliximab. Crohn's disease was diagnosed at a primary care hospital and immunosuppressive treatment was escalated. Initial diagnostic tests for tuberculosis were negative. When the clinical condition deteriorated, the patient was transferred to our intensive care unit for further diagnosis and treatment. Tuberculosis was suspected due to clinical presentation and radiological signs and anti-tuberculous treatment was initiated. After the onset of treatment, first microbiological results confirmed the diagnosis of miliary TB with Mycobacterium bovis. As an infection route we assume primary gastrointestinal infection with M. bovis during the patient's annual holidays in Turkey with a rapid development of miliary TB under infliximab and escalated immunosuppressive therapy. This case report demonstrates the difficulties in differentiating intestinal TB from other granulomatous conditions such as Crohn's disease. The diagnostic tools for gastrointestinal tuberculosis are discussed in detail regarding their sensitivity, specificity as well as positive and negative predictive values.

Miliary tuberculosis occurred after immunosuppressive drug in PNH patient with completely cured tuberculosis; a case report.

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disorder that presents with hemolytic anemia, marrow failure and thrombophilia. During acute attacks, corticosteroid can alleviate the hemolytic paroxysm, but the prolonged administration induces serious toxicity including immunosuppression. So American thoracic society (ATS) for tuberculosis (TB) recommends prophylactic anti-TB medication in patients with a long-term steroid therapy. However, in the patient who was treated for active TB in the past, there are no guidelines of the test for determining patients who have latent TB infection (LTBI) and no recommendations of TB prophylaxis if there is no evidence of reactivation at present. A 40-year-old male patient presented with fever and aggravated weakness for a week. He was diagnosed with PNH a month ago and took corticosteroid for 3 weeks. In the past, he was diagnosed with pulmonary TB and completely cured after treatment. According to guideline, he was not indicated with TB prophylaxis. However, he caught miliary TB, progressed to acute respiratory distress syndrome. We experience this embarrassing case, and emphasize the need to investigate multicentral TB prevalence and to make the guidelines of anti-TB medication in subgroups of hematologic diseases including PNH.

A multi-valent vaccinia virus-based tuberculosis vaccine molecularly adjuvanted with interleukin-15 induces robust immune responses in mice.

Tuberculosis caused by Mycobacterium tuberculosis is responsible for nearly two million deaths every year globally. A single licensed vaccine derived from Mycobacterium bovis, bacille Calmette-Guerin (BCG) administered perinatally as a prophylactic vaccine has been in use for over 80 years and confers substantial protection against childhood tuberculous meningitis and miliary tuberculosis. However, the BCG vaccine is virtually ineffective against the adult pulmonary form of tuberculosis that is pivotal in the transmission of tuberculosis that has infected almost 33% of the global population. Thus, an effective vaccine to both prevent tuberculosis and reduce its transmission is urgently needed. We have generated a multi-valent, vectored vaccine candidate utilizing the modified virus Ankara (MVA) strain of vaccinia virus to tandemly express five antigens, ESAT6, Ag85A, Ag85B, HSP65 and Mtb39A of M. tuberculosis that have been reported to be protective individually in certain animal models together with an immunostimulatory cytokine interleukin-15 (MVA/IL-15/5Mtb). Although, immunological correlates of protection against tuberculosis in humans remain to be established, we demonstrate that our vaccine induced comparable CD4(+) T cell and greater CD8(+) T cell and antibody responses against M. tuberculosis in vaccinated mice in a direct comparison with the BCG vaccine and conferred protection against an aerogenic challenge of M. tuberculosis, thus warranting its further preclinical development.

La vacuna BCG administrada al nacimiento o en los primeros días de vida es coste-efectiva y eficaz para la prevención de casos de meningitis tuberculosa y tuberculosis miliar en países de baja renta / BCG vaccination administred to newborns is cost-effective and clinically effective in the prevention of tuberculous meningitis and miliary tuberculosis in low-income countries

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BCG vaccine: efficacy and indications for vaccination and revaccination.

OBJECTIVES: To review the protective efficacy of the first and second doses of BCG vaccine and to assess its major indications and contraindications. SOURCES OF DATA: A systematic review of the literature was made by searching PubMed and selecting studies carried out in the last 50 years. The studies were grouped according to their design (clinical trials, case-control studies, and meta-analyses) and the results were presented separately for each type of study. Other relevant topics such as BCG and HIV/AIDS, use of tuberculin skin test, issues related to vaccine scars and to the development of new vaccines were also reviewed. SUMMARY OF THE FINDINGS: BCG vaccine has been used since 1921. However, the data concerning its use are variable and inconsistent. The protective efficacy of the first dose of BCG vaccine against miliary tuberculosis or tuberculous meningitis is remarkably important. Nevertheless, results regarding pulmonary tuberculosis have been inconsistent, either showing no efficacy or a protective efficacy rate around 80%. There is some evidence that a second dose of BCG vaccine does not increase its protective efficacy. Studies have shown that BCG vaccine protects against leprosy. The development of new vaccines to replace BCG in the future has been investigated. CONCLUSIONS: Despite the hope that a new vaccine against tuberculosis will be available in the future, BCG vaccine, in spite of its deficiencies, is today and will be for many years to come an important tool in controlling the harmful effects of tuberculosis, especially in countries where this disease has moderate to high levels of incidence.

Vacina BCG: eficácia e indicações da vacinação e da revacinação / BCG vaccine: efficacy and indications for vaccination and revaccination

OBJETIVOS: Revisar aspectos relacionados ao efeito protetor da primeira e segunda doses da vacina BCG e discutir as suas principais indicações e contra-indicações. FONTES DOS DADOS: Utilizando o PubMed, foi realizada uma revisão sistemática da literatura abrangendo um período de, aproximadamente, 50 anos. Os estudos foram agrupados por tipo de desenho, apresentando-se separadamente os principais resultados de ensaios clínicos, estudos de caso-controle e meta-análises. Outros tópicos relevantes, como a BCG e HIV/AIDS, o uso do teste tuberculínico, aspectos relacionados à cicatriz vacinal e ao desenvolvimento de novas vacinas, dentre outros, foram também revistos. SíNTESE DOS DADOS: A vacina BCG é utilizada desde 1921. Apesar disso, ainda apresenta controvérsias e aspectos não esclarecidos. O efeito protetor da primeira dose da vacina BCG contra a tuberculose na forma miliar ou na meningite é bastante significativa. No entanto, em relação à forma pulmonar, os resultados são discordantes, variando de ausência de efeito a níveis próximos a 80 por cento. Há evidências de que uma segunda dose da BCG não aumenta o seu efeito protetor. Estudos demonstram proteção da vacina contra a hanseníase. Pesquisas sobre novas vacinas que, no futuro, poderão vir a substituir a BCG estão sendo realizadas. CONCLUSÕES:Apesar da expectativa de que, no futuro, venhamos a ter uma nova vacina para a tuberculose, no presente e ainda por muitos anos, a vacina BCG, apesar de suas deficiências, mantém-se como um importante instrumento nos esforços para controle dos efeitos danosos da tuberculose, sobretudo em países em que essa doença ocorre em médias e elevadas taxas de incidência.

Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness.

BACKGROUND: BCG vaccine has shown consistently high efficacy against childhood tuberculous meningitis and miliary tuberculosis, but variable efficacy against adult pulmonary tuberculosis and other mycobacterial diseases. We assess and compare the costs and effects of BCG as an intervention against severe childhood tuberculosis in different regions of the world. METHODS: We calculated the number of tuberculous meningitis and miliary tuberculosis cases that have been and will be prevented in all children born in 2002, by combining estimates of the annual risk of tuberculosis infection, the proportion of infections that lead to either of these diseases in unvaccinated children, the number of children vaccinated, and BCG efficacy. FINDINGS: We estimated that the 100.5 million BCG vaccinations given to infants in 2002 will have prevented 29,729 cases of tuberculous meningitis (5th-95th centiles, 24,063-36,192) in children during their first 5 years of life, or one case for every 3435 vaccinations (2771-4177), and 11,486 cases of miliary tuberculosis (7304-16,280), or one case for every 9314 vaccinations (6172-13,729). The numbers of cases prevented would be highest in South East Asia (46%), sub-Saharan Africa (27%), the western Pacific region (15%), and where the risk of tuberculosis infection and vaccine coverage are also highest. At US2-3 dollars per dose, BCG vaccination costs US206 dollars (150-272) per year of healthy life gained. INTERPRETATION: BCG vaccination is a highly cost-effective intervention against severe childhood tuberculosis; it should be retained in high-incidence countries as a strategy to supplement the chemotherapy of active tuberculosis.

[A preventable case who died of miliary tuberculosis after receiving contact examination].

A 30-year-old-man was admitted to our hospital because of headache and fever. His consciousness on admission was clouding. Sputum examination was positive for acid fast bacilli which later identified as Mycobacterium tuberculosis. Chest-X-ray and computed tomogram on admission showed multiple cavitary lesions on bilateral upper lung fields and bilateral diffuse nodular shadow. He was diagnosed as miliary tuberculosis with tuberculous meningitis. His mother admitted because of pulmonary tuberculosis four months ago, and her sputum examination was smear positive for acid fast bacilli, Gaffky 4, and she complained of cough for 6 months before admission. Because of this situation, he rapidly underwent the contact examination with chest X-ray, but not examined by tuberculin skin test because he was 30-year-old. As then chest X-ray was normal, he was not indicated of chemoprophylaxis, and he died of miliary tuberculosis and tuberculous meningitis 4 months after the contact examination.

Short-course therapy for tuberculosis in infants and children. Infectious Diseases and Immunization Committee, Canadian Paediatric Society.

OBJECTIVE: To improve efficacy of and compliance with therapy for tuberculosis in children. OPTIONS: Short-course (6-month) multi-drug therapy, either non-supervised or directly supervised, versus long-course (more than 6-month) multi-drug therapy. OUTCOMES: Success (more than 90% of cases cured without relapse or serious side effects), development of drug resistance and compliance with treatment. EVIDENCE: Review of published reports of efficacy trials of tuberculosis therapy in children, side effects and compliance studies; consensus of expert opinion. VALUES: Values were assigned to the evidence by the Infectious Disease and Immunization Committee of the Canadian Paediatric Society through review of the data and consensus. BENEFITS, HARMS AND COSTS: Improved efficacy and compliance with short-course protocols should lower the rate of treatment failure among children in Canada and the cost of tuberculosis care. RECOMMENDATIONS: A short-course (6-month) protocol of four drugs for the first 2 months and two drugs for the subsequent 4 months is recommended to treat pulmonary tuberculosis or extrapulmonary disease causing lymphadenopathy. Tuberculous meningitis, disease involving bones and joints and tuberculosis with HIV infection require longer courses of treatment. Asymptomatic tuberculosis should be treated with daily doses of isoniazid for 9 months. Intermittent directly observed therapy is recommended if compliance cannot be ensured. Routine liver function testing is not recommended for prepubescent children taking isoniazid, but monthly assessment for clinical symptoms and periodic liver function evaluation is advised in adolescent women, especially post partum. VALIDATION: This report was reviewed by the directors of the Canadian Paediatric Society, the Hepatitis and Special Pathogens Division of the Laboratory Centre for Disease Control and the Canadian Thoracic Society. The recommendations are similar to those of the American Academy of Pediatrics. SPONSOR: The recommendations were developed and endorsed by the Infectious Disease and Immunization Committee of the Canadian Paediatric Society.

Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis.

The protective effect of BCG against tuberculosis (TB) estimated in randomized controlled trials and observational studies ranges from negative to close to a 100%. One of the many explanations offered for this is that different immunological mechanisms may be associated with protective effect against different forms and sites of disease. In this investigation, we recalculated vaccine protective effect separately for pulmonary disease and for meningeal/miliary disease in randomized controlled trials and case-control studies, tested for heterogeneity in site-specific estimates of protective effect and calculated a summary measure when appropriate. We found protective effect against pulmonary disease to be heterogeneous to a statistically significant degree, and thus we did not calculate a summary measure of protection. Protective effect against meningeal and miliary TB was higher than against pulmonary disease and, except for a single study with two cases only, appeared to be homogenous. Summary BCG protective effect against miliary or meningeal TB in randomized controlled trials was 86% (95% confidence interval [CI] 65, 95) and in case-control studies 75% (95% CI: 61, 84). The fact that protective effect appeared to be homogeneous against meningitis and miliary TB but not against pulmonary disease may result from the fact that patients with meningitis are on average younger and thus less likely to have been exposed to atypical bacteria; to a waning of the protective effect of BCG; or from the diversity of mechanisms of pathogenesis of pulmonary disease, which can originate from reinfection, reactivation or primary progression.