Abstract INTRODUCTION: Biomarkers are critical tools for finding new approaches for controlling the spread of tuberculosis (TB), including for predicting the development of TB therapeutics, vaccines, and diagnostic tools. METHODS: Expression of immune biomarkers was analyzed in peripheral blood cells stimulated and non-stimulated with M. tuberculosis antigens ESAT-6, CFP10 and TB7.7. in Warao indigenous individuals. These biomarkers may be able to differentiate TB states, such as active tuberculosis (ATB) cases and latent tuberculosis infection (LTBI) from non-infected controls (NIC). A real-time reverse transcription polymerase chain reaction (RT-qPCR) assay was performed on 100 blood samples under non-stimulation or direct ex vivo conditions (NS=50) and stimulation conditions (S=50). RESULTS: The findings are shown as the median and interquartile range (IQR) of relative gene expression levels of IFN-γ, CD14, MMP9, CCR5, CCL11, CXCL9/MIG, and uPAR/PLAUR immune biomarkers. MMP9 levels were significantly higher in the LTBI-NS and LTBI-S groups compared with the NIC-NS and NIC-S groups. However, CCR5 levels were significantly lower in the LTBI-S group compared with both NIC-NS and NIC-S groups. CCL11 levels were significantly lower in the LTBI-S group compared with the NIC-NS group. CONCLUSIONS: Preliminary findings showed that MMP9 immune biomarkers separated LTBI indigenous individuals from NIC indigenous individuals, while CCR5, CCL11, CD14, and IFN-γ did not differentiate TB states from NIC. MMP9 may be useful as a potential biomarker for LTBI and new infected case detection among Warao indigenous individuals at high risk of developing the disease. It may also be used to halt the epidemic, which will require further validation in larger studies.

ABSTRACT Objectives. To determine the rate of optimal cytoreduction in patients with advanced ovarian cancer who received neoadjuvant chemotherapy with dose-dense carboplatin and paclitaxel followed by interval debulking surgery (IDS). Materials and Methods. A retrospective study of a series of cases of Peruvian women treated with neoadjuvant chemotherapy with carboplatin (6 AUC mg/mL/min) and paclitaxel (80 mg/m2 weekly) followed by IDS, at the National Institute of Neoplastic Diseases during the 2010-2014 period. Results. The 41 patients who made it to the interval surgery had a median age of 59 years (range: 47-73 years). In 37 (90.2%) patients, high-grade serous adenocarcinoma histology was reported. Thirty-four (82.9%) achieved optimal cytoreduction and five (14.7%), a complete pathological response. Progression-free survival at one year and two years was 74.7% and 51.8%, respectively. Overall survival at one year and two years was 85.2% and 71.4%, respectively. The risk of progression and death was greater in patients without optimal cytoreduction and in patients with postsurgery levels of carcinoembryonic antigen 125 > 30 U/mL. Conclusions. Neoadjuvant therapy with dose-dense carboplatin and paclitaxel achieved an elevated frequency of optimal cytoreduction. The post-surgery levels of carcinoembryonic antigen 125 and optimal cytoreduction were independent factors of progression-free survival and overall survival.

RESUMEN Objetivos. Determinar la tasa de citorreducción óptima en pacientes con cáncer de ovario avanzado que recibieron quimioterapia neoadyuvante con carboplatino y paclitaxel dosis densa seguido de cirugía de citorreducción de intervalo (CCI). Materiales y métodos. Estudio de una serie de casos retrospectiva de mujeres peruanas tratadas con quimioterapia neoadyuvante con carboplatino (AUC 6 mg/ml/min) y paclitaxel (80 mg/m2 semanal) seguido de CCI, en el Instituto Nacional de Enfermedades Neoplásicas durante el período 2010-2014. Resultados . Los 41 pacientes que alcanzaron cirugía de intervalo, tuvieron una mediana de edad de 59 años (rango: 47-73 años). En 37 (90,2%) pacientes se reportó histología de adenocarcinoma seroso de alto grado. Treinta y cuatro (82,9%) lograron citorreducción óptima y cinco (14,7%) respuesta patológica completa. La sobrevida libre de progresión al año y 2 años fueron 74,7% y 51,8%, respectivamente. La sobrevida global al año y 2 años fue 85,2% y 71,4%, respectivamente. El riesgo de progresión y muerte fue mayor en pacientes sin citorreducción óptima y pacientes con niveles de dosaje del antígeno carcinoembrionario 125 postoperatorio > 30 U/ml. Conclusiones . La neoadyuvancia con carboplatino y paclitaxel dosis densa logró una frecuencia elevada de citorreducción óptima. Los niveles de antígeno carcinoembrionario 125 postoperatorios y citorreducción óptima resultaron factores independientes de sobrevida libre de progresión y sobrevida global.

Objectives. To determine the rate of optimal cytoreduction in patients with advanced ovarian cancer who received neoadjuvant chemotherapy with dose-dense carboplatin and paclitaxel followed by interval debulking surgery (IDS). Materials and Methods. A retrospective study of a series of cases of Peruvian women treated with neoadjuvant chemotherapy with carboplatin (6 AUC mg/mL/min) and paclitaxel (80 mg/m² weekly) followed by IDS, at the National Institute of Neoplastic Diseases during the 2010-2014 period. Results. The 41 patients who made it to the interval surgery had a median age of 59 years (range: 47-73 years). In 37 (90.2%) patients, high-grade serous adenocarcinoma histology was reported. Thirty-four (82.9%) achieved optimal cytoreduction and five (14.7%), a complete pathological response. Progression-free survival at one year and two years was 74.7% and 51.8%, respectively. Overall survival at one year and two years was 85.2% and 71.4%, respectively. The risk of progression and death was greater in patients without optimal cytoreduction and in patients with postsurgery levels of carcinoembryonic antigen 125 > 30 U/mL. Conclusions. Neoadjuvant therapy with dose-dense carboplatin and paclitaxel achieved an elevated frequency of optimal cytoreduction. The post-surgery levels of carcinoembryonic antigen 125 and optimal cytoreduction were independent factors of progression-free survival and overall survival.

Objetivos. Determinar la tasa de citorreducción óptima en pacientes con cáncer de ovario avanzado que recibieron quimioterapia neoadyuvante con carboplatino y paclitaxel dosis densa seguido de cirugía de citorreducción de intervalo (CCI). Materiales y métodos. Estudio de una serie de casos retrospectiva de mujeres peruanas tratadas con quimioterapia neoadyuvante con carboplatino (AUC 6 mg/ml/min) y paclitaxel (80 mg/m² semanal) seguido de CCI, en el Instituto Nacional de Enfermedades Neoplásicas durante el período 2010-2014. Resultados. Los 41 pacientes que alcanzaron cirugía de intervalo, tuvieron una mediana de edad de 59 años (rango: 47-73 años). En 37 (90,2%) pacientes se reportó histología de adenocarcinoma seroso de alto grado. Treinta y cuatro (82,9%) lograron citorreducción óptima y cinco (14,7%) respuesta patológica completa. La sobrevida libre de progresión al año y 2 años fueron 74,7% y 51,8%, respectivamente. La sobrevida global al año y 2 años fue 85,2% y 71,4%, respectivamente. El riesgo de progresión y muerte fue mayor en pacientes sin citorreducción óptima y pacientes con niveles de dosaje del antígeno carcinoembrionario 125 postoperatorio > 30 U/ml. Conclusiones. La neoadyuvancia con carboplatino y paclitaxel dosis densa logró una frecuencia elevada de citorreducción óptima. Los niveles de antígeno carcinoembrionario 125 postoperatorios y citorreducción óptima resultaron factores independientes de sobrevida libre de progresión y sobrevida global.

Abstract INTRODUCTION: Interferon-γ (IFN-γ) plays a crucial role in resistance to mycobacterial diseases; accordingly, variants of the gene encoding this cytokine may be associated with elevated risk of contracting pulmonary tuberculosis (TB). METHODS: Blood samples were collected from 135 Warao indigenous individuals with newly diagnosed sputum culture-positive TB. Of these, 24 were diagnosed with active tuberculosis (ATB). The study comprised 111 participants, who were grouped as follows: 1) 14 tuberculin skin test (TST)-positive Warao indigenous individuals and 4 that were QuantiFERON-TB?Gold In-Tube (QFT-IT) test-positive, collectively comprising the latent TB infection group (LTBI), n = 18), and 2) healthy controls who were QFT-IT- and TST-negative, comprising the control group (CTRL, n = 93). Detection of the IFN γ gene (IFNG) +874A/T polymorphism was performed via PCR and quantification of IFNG expression via qPCR. RESULTS: Relative to indigenous and white Americans, ATB and CTRL groups had a higher frequency of the IFNG SNP (+874A): 23 (95.8%) and 108 (97.3%), respectively. Indigenous Warao individuals homozygous for the IFNG (+874) A allele exhibited 3.59-fold increased risk of developing TB (95% confidence interval, 2.60-4.96, p =0.0001). A decreased frequency of the AT genotype was observed in individuals with pulmonary TB (4.16%) and controls (0.90%). The frequency of the TT genotype was decreased among controls (1.80%); none of the patients with TB were found to have this genotype. The differences in IFNG expression between the groups, under unstimulated and stimulated conditions, were not statistically significant. CONCLUSIONS: Preliminary results demonstrate concordance between IFNG +874 A/A genotype and low expression of IFNG.

ABSTRACT Objective To assess 1) the burden and socio-demographic and clinical characteristics of tuberculosis (TB) cases, and 2) the quality of TB care provided to patients who entered and remained within each health care service level (primary, secondary, or tertiary) and those who moved from one level to another, using process and results indicators. Methods This cross-sectional operational research study assessed new smear-positive pulmonary TB cases diagnosed in Brazilian state capitals in 2013 using TB program records and the TB surveillance system. Quality of care was assessed based on process and results indicators including HIV screening, TB contact screening, Directly Observed Treatment (DOT), sputum smear microscopy monitoring, and treatment outcomes. Results There were 12 977 new smear-positive TB cases reported. Of these, 7 964 (61.4%) cases were diagnosed and treated at the primary care level, 1 195 (9.2%) at the secondary level, 1 521 (11.7%) at the tertiary level, and 2 296 (17.7%) at more than one level, with 65% of the latter group moved from the tertiary level to the primary level. The proportion of cases tested for HIV was significantly higher in patients receiving care at the primary level compared to those receiving care at the secondary level (prevalence ratio (PR): 1.17; 95% confidence interval (CI): 1.07–1.28) and those attending more than one service level. Patients attending the tertiary health care level had a 122% higher PR for not doing DOT (“DOT not done”) compared to patients at the primary level (PR: 2.22; CI: 2.12–2.32). When the two levels were compared, the prevalence for an unfavorable outcome (lost to follow-up, death from TB, death with TB, transferred out, or not evaluated) was higher at the tertiary health care level. Conclusions Primary health services are successfully incorporating the management of new smear-positive TB cases. Primary health care obtained better operational indicators than secondary or tertiary levels.

RESUMEN Objetivo Evaluar 1) la carga de morbilidad por tuberculosis y las características sociodemográficas y clínicas de los pacientes y 2) la calidad de la atención de la tuberculosis que se presta a los pacientes que acuden y permanecen en cada nivel de los servicios de salud (primario, secundario o terciario) y a los pacientes que se transfirieron a otro nivel, mediante el análisis de los indicadores de funcionamiento de los procesos y los indicadores de resultados. Métodos En el presente estudio transversal de investigación operativa se analizaron los casos nuevos de tuberculosis pulmonar con baciloscopia positiva que se diagnosticaron en las capitales estatales del Brasil en el 2013, a partir de los registros del programa contra la tuberculosis y los datos del sistema de vigilancia de la enfermedad. Se evaluó la calidad de la atención en función de los indicadores de funcionamiento y los indicadores de resultados como la detección sistemática de la infección por el virus de la inmunodeficiencia humana (VIH), el tamizaje de los contactos de casos de tuberculosis, el tratamiento estrictamente supervisado (conocido como DOT, por su sigla en inglés), la supervisión de la baciloscopia del esputo y los desenlaces terapéuticos. Resultados Se notificaron 12 977 casos nuevos de tuberculosis con baciloscopia positiva. De los casos notificados, 7 964 (61,4%) se diagnosticaron y recibieron tratamiento en el nivel de atención primaria, 1 195 (9,2%) en el nivel secundario, 1 521 (11,7%) en el nivel terciario y 2 296 pacientes (17,7%) recibieron asistencia en servicios de varios niveles de atención; de este último grupo, el 65% pasó del nivel terciario al nivel primario de atención. La proporción de casos en los cuales se practicó la detección de la infección por el VIH fue significativamente mayor en los pacientes que acudieron al nivel primario de atención, al compararlos con los que recibieron atención en el nivel secundario (razón de prevalencia, [RP]: 1,17; intervalo de confianza [IC] de 95%: de 1,07 a 1,28) y los pacientes tratados en servicios de varios niveles de atención. En los pacientes que acudieron al nivel terciario de atención de salud, la razón de prevalencia de no seguir el DOT fue 122% más alta que en los pacientes atendidos en el nivel primario (RP: 2,22; IC de 95%: de 2,12 a 2,32). Cuando se compararon ambos niveles, la prevalencia de un resultado desfavorable (pérdida durante el seguimiento, defunción por tuberculosis, defunción con tuberculosis, transferido a otro centro o no evaluado) fue más alta en el nivel terciario de atención sanitaria. Conclusiones Los servicios de atención primaria de salud han incorporado de manera eficaz el tratamiento de los casos nuevos de tuberculosis con baciloscopia positiva. Los indicadores operativos de la atención primaria de salud fueron mejores que los indicadores de la atención de nivel secundario o terciario.

The present study aimed at measuring seropositivities for infection by Ascaris suum and Toxocara canis using the excretory/secretory (E/S) antigens from Ascaris suum (AES) and Toxocara canis (TES) within an indigenous population. In addition, quantification of cytokine expressions in peripheral blood cells was determined. A total of 50 Warao indigenous were included; of which 43 were adults and seven children. In adults, 44.1% were seropositive for both parasites; whereas children had only seropositivity to one or the other helminth. For ascariosis, the percentage of AES seropositivity in adults and children was high; 23.3% and 57.1%, respectively. While that for toxocariosis, the percentage of TES seropositivity in adults and children was low; 9.3% and 14.3%, respectively. The percentage of seronegativity was comparable for AES and TES antigens in adults (27.9%) and children (28.6%). When positive sera were analyzed by Western blotting technique using AES antigens; three bands of 97.2, 193.6 and 200.2 kDas were mostly recognized. When the TES antigens were used, nine major bands were mostly identified; 47.4, 52.2, 84.9, 98.2, 119.1, 131.3, 175.6, 184.4 and 193.6 kDas. Stool examinations showed that Blastocystis hominis, Hymenolepis nana and Entamoeba coli were the most commonly observed intestinal parasites. Quantification of cytokines IFN-γ, IL-2, IL-6, TGF-β, TNF-α, IL-10 and IL-4 expressions showed that there was only a significant increased expression of IL-4 in indigenous with TES seropositivity (p < 0.002). Ascaris and Toxocara seropositivity was prevalent among Warao indigenous.

El objetivo del presente estudio fue determinar la seropositividad de infección por Ascaris suum y Toxocara canis, utilizando antígenos de excreción/secreción (E/S) de Ascaris suum (AES) y Toxocara canis (TES) en una población indígena. Adicionalmente, se cuantificó la expresión de citocinas a partir de células de sangre periférica. Un total de 50 indígenas Warao se incluyeron en el estudio; 43 fueron adultos y 7 niños. Entre los adultos, 44,1% fueron seropositivos para ambos parásitos; mientras que los niños sólo mostraron seropositividad a uno u otro de los helmintos. Para ascariosis, el porcentaje de seropositividad para los antígenos AES fue alto tanto en adultos como en niños; 23,3% y 57,1%, respectivamente. Para toxocariosis, el porcentaje de seropositividad para los antígenos TES fue bajo en adultos así como en niños; 9,3% y 14,3%, respectivamente. El porcentaje de seronegatividad fue similar tanto para los antígenos AES como para TES en adultos (27,9%) y niños (28,6%). Cuando la seropositividad fue analizada a través de la técnica de Western blotting utilizando los antígenos AES; 3 bandas de 97,2, 193,6 y 200,2 kDas fueron principalmente reconocidas. Para los antígenos TES, 9 bandas fueron mayormente identificadas; 47,4, 52,2, 84,9, 98,2, 119,1, 131,3, 175,6, 184,4 y 193,6 kDas. Los análisis coproparasitológicos mostraron que los parásitos Blastocystis hominis, Hymenolepis nana y Entamoeba coli fueron los parásitos intestinales más comúnmente observados. La cuantificación de la expresión de las citocinas IFN-γ, IL-2, IL-6, TGF-β, TNF-α, IL-10 e IL-4 mostró que hubo un significante incremento de la expresión de IL-4 entre los indígenas con seropositividad para los antígenos TES (p < 0.002). La seropositividad para Ascaris y Toxocara fue prevalente entre los indígenas Warao.

The goal of this study was to demonstrate the usefulness of an enzyme-linked immunosorbent assay (ELISA) for the serodiagnosis of pulmonary tuberculosis (PTB) and extrapulmonary TB (EPTB). This assay used 20 amino acid-long, non-overlapped synthetic peptides that spanned the complete Mycobacterium tuberculosis ESAT-6 and Ag85A sequences. The validation cohort consisted of 1,102 individuals who were grouped into the following five diagnostic groups: 455 patients with PTB, 60 patients with EPTB, 40 individuals with non-EPTB, 33 individuals with leprosy and 514 healthy controls. For the PTB group, two ESAT-6 peptides (12033 and 12034) had the highest sensitivity levels of 96.9% and 96.2%, respectively, and an Ag85A-peptide (29878) was the most specific (97.4%) in the PTB groups. For the EPTB group, two Ag85A peptides (11005 and 11006) were observed to have a sensitivity of 98.3% and an Ag85A-peptide (29878) was also the most specific (96.4%). When combinations of peptides were used, such as 12033 and 12034 or 11005 and 11006, 99.5% and 100% sensitivities in the PTB and EPTB groups were observed, respectively. In conclusion, for a cohort that consists entirely of individuals from Venezuela, a multi-antigen immunoassay using highly sensitive ESAT-6 and Ag85A peptides alone and in combination could be used to more rapidly diagnose PTB and EPTB infection.

Recientemente existe un gran interés hacia un mejor y más rápido diagnóstico de tuberculosis (TB), especialmente de tuberculosis pleural, el cual es difícil. Al presente las principales herramientas diagnósticas son la baciloscopia y el cultivo de líquido pleural; desafortunadamente, las sensibilidades de estos métodos son bajas, por lo que el desarrollo de nuevas herramientas diagnósticas es necesario. El objetivo del presente estudio consistió en encontrar un algoritmo que permita la rápida identificación de la mayoría de los pacientes con TB pleural que ingresan en el Hospital Vargas de Caracas a un buen costo-beneficio. Para esto se evaluaron los niveles de las citocinas Interferón-gamma (IFN-g) y la Interleucina 12p40 (IL-12p40) en líquido pleural y suero, así como la reactividad de anticuerpos contra antígenos de Mycobacterium tuberculosis. Se estudiaron 60 individuos con derrame pleural; 20 individuos con líquido pleural tuberculoso (LPT) conformaron el grupo de pacientes y 40 individuos con líquido pleural no tuberculoso (LPNT) el grupo de controles. La técnica de inmunoensayo de ELISA fue utilizada para medir los niveles de IFN-g y IL-12p40; así como las reactividades de los diversos isotipos y subclases de inmunoglobulina G (IgG) frente a antígenos del bacilo. La utilidad de los métodos fue evaluada utilizando el análisis de las curvas ROC (receiver operating characteristic). Los resultados de los 11 métodos inmunológicos evaluados mostraron que el método IgG2 anti-PPD alcanzó la mayor especificidad de 95%, (CI: 88,3-101,8) con un valor predictivo positivo (VPP) de 75. La sensibilidad de los métodos estuvo entre 30% y 95%; dos métodos alcanzaron altas sensibilidades: los altos niveles de IFN-g en líquido pleural, con sensibilidad de 95% (CI: 85,5-104,5), con un valor predictivo negativo (VPN) de 97, seguido de los bajos niveles de IL-12p40 en suero, con una sensibilidad de 95% (CI: 85,5-104,5) con un VPN de 95,2. En contraste, los métodos microbiológicos mostraron una baja sensibilidad, en el caso de la baciloscopia sólo del 20%; mientras que la combinación baciloscopia más el cultivo alcanzó 70%. Considerando que las LPT representan el 15% de todos los casos de TB diagnosticados en el Hospital Vargas de Caracas; aquellos pacientes con una microbiología preliminar negativa en líquido pleural, la realización del análisis de IFN-g en líquido y el método serológico IgG2 anti-PPD podrían constituir un algoritmo diagnóstico rápido y efectivo, previo al resultado del cultivo para micobacteria, lo cual permitiría iniciar el tratamiento antituberculoso de forma más precoz o considerar la realización de la biopsia

In recent years, better diagnostics for tuberculosis (TB) has received increasing attention, especially the diagnosis of tuberculous pleural effusion, which is difficult and at present the main tool in TPE diagnostic is pleural effusion smear and culture, but unfortunately, sensitivities are low, therefore better TPE diagnostic tools are needed. The aim of this study was to find a diagnostic algorithm to assess the progress in TPE diagnostic at the Hospital Vargas de Caracas, that permits identification of the majority of patients, at a satisfactory cost-benefit ratio, evaluating the levels of IFN-g and IL-12p40 in pleural effusion and serum, as well as the antibody reactivity in order to compare it with microbiological tests. A total of 60 individuals with pleural effusion were studied; 20 patients with tuberculous pleural effusion (TPE) formed the patient group and 40 patients with non-tuberculous pleural effusion (NTPE) formed the control group. The levels of IFN-g and IL-12p40 in effusion and serum and class and subclasses of IgG reactivity to Mycobacterium tuberculosis antigens were measured by ELISA. The utility of these methods for diagnosis of TPE was evaluated using receiver operating characteristic (ROC) curve analysis. The results of the 11 immunological methods evaluated showed that the anti-PPD IgG2 method was able to reach the highest specificity of 95% (CI: 88.3-101.8), positive predictive value (PPV)=75 (at 30% sensitivity); while that the overall sensitivity of methods was between 95% and 30%, of these, two methods reached higher sensitivities; increased levels of pleural IFN-g, with a sensitivity of 95% (CI: 85.5-104.5) with the highest negative predictive value (NPV)=97, (at 82.5% specificity), followed by decreased levels of serum IL-12p40 with a sensitivity of 95% (CI: 85.5-104.5), NPV=95.2 (at 50% specificity). In contrast, microbiological methods showed that smear had a sensitivity of only 20%, while smear plus culture had, a sensitivity of 70%. Considering that TPE represents approximately 15 percent of all the TB clinically diagnosed at the Hospital Vargas de Caracas, in those patients with preliminary microbiology negativity in the effusion, the combined analysis of pleural IFN-g and anti-PPD IgG2 could represent a fast and effective diagnostic algorithm for improving the diagnosis previous to obtain culture results. In this way treatment against TB could be initiated or the need to cytological and pleural biopsy could be considered

Observational studies on the humoural immune responses of the Warao indigenous people from Delta Amacuro, an isolated area, were compared with urban residents of the Venezuelan capital. Mycobacterium tuberculosis-specific reactivities (IgM, IgE, sIgA, IgG and IgG subclasses) were measured by ELISA using PPD and 38-kDa M. tuberculosis antigens. A total of 294 individuals were studied, 162 Warao (indigenous people) and 132 Creole (non-indigenous people). The patient group consisted of 87 Warao patients and 58 Creole patients, while the control group consisted of 75 Warao controls and 74 Creole controls. Combinations among the isotypes studied were performed. The findings showed that for the Warao people, sensitivity to the combination including anti-PPD IgG and IgE was 92.0%, while for the Creole people, sensitivity to the combination including anti-PPD IgG but more so anti-PPD IgG1 and IgG2 was 90.0%. Simple tests were able to show higher specificities, which were population-specific; specificities were anti-PPD IgG3, 100.0% and anti-PPD IgM, 97.4% for the Warao and Creole peoples, respectively. In conclusion, while simple tests reached high specificity, the multi-isotype tests improved sensitivity; the latter shows this approach may be useful in diagnostic testing.

La tuberculosis (TB) es una de las principales causas de muerte por infección con Mycobacterium tuberculosis en seres humanos en el ámbito mundial, y es preocupante que su incidencia esté aumentado en los últimos años, debido principalmente a la infección por el virus de inmunodeficiencia humano (VIH). Considerando que los métodos diagnósticos utilizados actualmente para detectar la enfermedad no son totalmente efectivos y rápidos, debido a que el cultivo no es útil como primera opción diagnóstica porque ya que requiere más de 4 semanas y el examen microscópico tiene una sensibilidad de 50 a 60% y es aún más baja en pacientes pediátricos, múltiples esfuerzos se realizan con el objetivo de caracterizar cada vez más los antígenos de M. tuberculosis asociados con protección y para desarrollar rápidos y mejores métodos de diagnóstico. Entre los antígenos secretados de M. tuberculosis y que han sido descritos como inductores de la secreción de mediadores asociados a protección contra la infección por M. tuberculosis están CPF-10, ESAT-6, 27 kDa y 38 kDa, por inducir la producción de IFN-γ, TNF-α y óxido nítrico, todos estos relacionados con una respuesta inmunitaria protectora. A través del estudio de las funciones y composición de estos antígenos, se hacen esfuerzos por encontrar métodos más efectivos en el diagnóstico de la enfermedad, en sus diversas etapas de evolución. La presente revisión tiene como finalidad describir los antígenos que han sido reportados como antígenos relevantes de M. tuberculosis por participar en la respuesta inmunitaria protectora frente a la infección y su posible utilidad en el diagnóstico.

Tuberculosis (TB) is one of the main causes of death by M. tuberculosis infection in humans worldwide and, it is worrying that the number of cases have been increasing in recent years, largely due to HIV infection. Since the diagnostic methods for detecting the disease are not totally effective because of their lack of specificity and sensitivity, efforts are being made to characterize the M. tuberculosis antigens associated with protection and, thereby develop better diagnostic methods. Among the antigens which are secreted by M. tuberculosis -and which have been described as inducers of the secretion of mediators associated with protection- are CPF-10, ESAT-6, 27 kDa and 38 kDa, which induce the production of IFN-γ; TNF-α and nitric oxide. By means of the study of the functions and composition of these antigens, which are mainly secreted by the bacteria, efforts are being made to find more effective methods of diagnosing the disease in its different stages of evolution. The present review aims to describe the antigens which have been reported as being relevant in the case of M. tuberculosis, since they participate in the immune response to infection and therefore, may be important in terms of diagnosis.

Foram dosados anticorpos sIgA anti-Purified Protein Derivative e 38kDa da saliva de 127 crianças, das quais 31 eram de pacientes altamente suspeitos de tuberculose e 96 eram provenientes de crianças saudáveis, que tiveram contato com pacientes. Os resultados referentes à porcentagem de crianças, reativas ao PPD e ao antígeno 38kDa, mostraram que destes dois antígenos, o 38kDa induziu maior reatividade em pacientes positivos e negativos ao Tuberculin Skin Test (28% e 16,6%, respectivamente), em comparação aos controles positivos e negativos ao TST (11,7% e 7,1%, respectivamente). Houve diferença estatisticamente significativa entre pacientes positivos e controles negativos ao Tuberculin Skin Test. Em relação ao antígeno PPD, enquanto 14,2% de pacientes positivos ao TST mostraram anticorpos reativos ao antígeno Purified Protein Derivative, nenhum paciente negativo ao TST foi reativo ao antígeno. Os achados sugerem que, aparentemente, estes dois antígenos estão associados a desenvolvimento distinto dos mecanismos de defesa da mucosa mediados por sIgA contra Mycobacterium tuberculosis.

We report on the measurement of saliva anti-Purified Protein Derivative sIgA and 38kDa antibodies from 127 children, of whom 31 were strong tuberculosis suspects and 96 were healthy contact children. The results concerning the percentage of children with antibody reactivity to PPD and 38kDa antigens showed that, of these 2 antigens, 38kDa induced higher reactivity in patients positive and negative for the Tuberculin Skin Test (28% and 16.6%, respectively) in comparison to controls positive and negative for the TST (11.7% and 7.1%, respectively). There was a statistically significant difference between patients positive and controls negative for the TST. In relation to the Purified Protein Derivative antigen, while 14.2% of patients positive for the TST showed antibody reactivity to the PPD antigen, no patients negative for the TST had reactivity to this antigen. The findings suggest that these two antigens seem be associated with a different development of the mucosal defence mechanisms mediated by sIgA against Mycobacterium tuberculosis.

The levels of complement C3 and C4 components were determined in non-indigenous (creoles) and indigenous (Warao) populations, the latter with an extremely high tuberculosis (TB) rate. Serum samples from 209 adults were studied and classified in 4 groups taking into account tuberculin skin tests (TST): (1) the group of Warao patients (58 positive for the TST, WP TST+ and 9 negative for the TST, WP TST-), (2) the group of creole patients (34 positive for the TST, CP TST+ and 9 negative for the TST, CP TST-), (3) the group of healthy Warao controls (38 positive and 14 negative for TST, WC TST+ and WC TST-, respectively), (4) the creole controls (26 positive and 21 negative for the TST, CC TST+ and CC TST-, respectively). With respect to the results concerning the measurement of both complement C3 and C4 components with the exception of the WC TST and the CC groups, the WP TST+ and WP TST- as well as WC TST+ groups showed a significant frequency of individuals with decreased levels of complement C3 component (20.6, 33.3, and 26.3%, respectively) and also C4 component (12.0, 11.1, and 13.3%, respectively) in comparison to both creole patients (CP TST+, 8.82% and CP TST-, 0% and CP TST+, 5.88% and CP TST-, 0%) for C3 and C4, respectively. The study of these parameters carried out in 15 Warao subjects with active infection, before and after anti-TB chemotherapy,statisticallyconfirmedthat the effective chemotherapy did not restore normal levels of the complement C3 and C4 components among Warao patients. Aditional tests for hepatitis B or hepatitis C infection, and the profile of the hepatic proteins were not associated to the deficiency in production of the complement components.In conclusion, the results show that within the Warao population, a high percentage of subjects exhibit decreased levels of both complement C3 and C4 components independent of latent or active infection and the status of TST.

El sistema respiratorio se encuentra en contacto con patógenos, sin embargo, gracias a la respuesta inmune innata de este, solo en raras ocasiones se establece la enfermedad. Las células epiteliales del tracto respiratorio juegan un papel importante para evitar la colonización del pulmón por agentes infecciosos, identificando a los microorganismos a través de receptores especializados, como los Toll-like,. Las células epiteliales son capaces de secretar citocinas, péptidos antimicrobianos y otras moléculas proinflamatorias las cuales evitan el establecimiento de patógenos.

La tuberculosis (TBC) pulmonar humana, un problema de salud pública en el mundo, es una enfermedad infecciosa causada por Mycobacterium tuberculosis. Se conoce que una minoría de las personas que son infectadas por M. tuberculosis son capaces de progresar a enfermedad clínica. Se puede decir, en términos generales, que el 90% de las personas tendrán controlados los bacilos en estado latente para toda la vida, por medio de su sistema inmunológico. Un 5% presentará TBC primaria progresiva y el otro 5% presentará la enfermedad en estados tardíos de la vida, lo que se denomina TBC de reactivación o post-primaria. En los individuos resistentes, el control de la infección o de los bacilos tuberculosos que se encuentran en la región alveolar requiere principalmente del desarrollo de una respuesta de inmunidad celular (RIC) del tipo Th1. Este tipo de respuesta incluye la participación de los macrófagos alveolares, los linfocitos T CD4+ y CD8+, principalmente los linfocitos T <FONT FACE=Symbol>gd</FONT> y la producción de citocinas como: IL-2, IFN-gamma, IL-12, IL-18 y TNF-alfa. Aunado están las quimiocinas como RANTES, MCP-1, MIP-1alfae IL-8 que juegan un papel muy importante en la migración de las diferentes subpoblaciones celulares al sitio de infección para la formación del granuloma. Además, es primordial el papel de las células "natural killer" (NK), y de las células epiteliales como parte de la respuesta de inmunidad innata

Human pulmonary tuberculosis (TB) is a worldwide public health problem, which is caused by Mycobacterium tuberculosis. It is a fact that one third of the world´s population is infected with this mycobacteria, however, only a minority of people infected by M. tuberculosis may develop a clinical disease. In general, about 90% have their bacilli under control in a latent state throughout their lives by means of their immune responses. About 5% will develop primary progressive TB and the remaining 5% will develop the disease in the later stages of their lives, which is known as reactivation or post-primary TB. In resistant individuals, control of the infection mainly requires development of a Th1 cell immunity response. This type of response involves participation of alveolar macrophages and T CD4+, CD8+ and T <FONT FACE=Symbol>gd</FONT> lymphocytes, and production of cytokines such as IL-2, IFN-gamma, IL-12, IL-18 and TNF-alpha, as well as chemokines such as RANTES, MCP-1, MIP-1alphaand IL-8 which play an important role in the migration of different cell subpopulations to the infection site for the formation of granulome. In addition, the role of "natural killer" (NK) cells, along with epitelial cells, is essential as part of the innate immune response

Resumen. En una población de niños Warao menores de 15 años con una tasa de prevalencia de tuberculosis (TBC) de 3190/100.000 se planteó como objetivo, estudiar ciertos parámetros de la respuesta inmunitaria en una población de 107 niños, de éstos, 32 presentaban TBC (27 PPD positivos y 5 PPD negativos) y 75 eran controles sin clínica de TBC (45 PPD positivos y 30 PPD negativos). Se evaluaron la inmunidad humoral, celular y algunos aspectos de la inmunidad innata. Entre los niños pacientes y controles, no se encontraron diferencias significativas en los componentes C3 y C4 del complemento. En cuanto a la inmunidad humoral, el grupo de pacientes presentó un alto porcentaje de niños con niveles totales de IgA e IgG elevados (13,8% y 79,3%, respectivamente) en comparación con los niños controles (0% y 69,2%). En el grupo control, un alto porcentaje de niños presentaron niveles totales de IgM e IgAs elevados (69,2% y 56,16%, respectivamente) en comparación con los pacientes (48,3% y 31,25%). El 100% de los niños presentó altos niveles séricos de IgE. Los estudios de la respuesta celular retardada mostraron que los niños de mayor edad presentaron las mayores medidas de induraciones. Los niños menores de 7 años presentaron similar reactividad positiva al PPD independientemente de la presencia o no de cicatriz de BCG. Un alto porcentaje de niños sin y con cicatriz (46,8% y 27,6% respectivamente) presentaron medidas de induraciones a la tuberculina de 0 mm. La reactividad a Candida mostró un 80% de niños con estados de anergia no específica. Sin embargo, el mayor porcentaje de niños con TBC estaba vacunado y presentaba positividad a la prueba de tuberculina. En conclusión, en los niños Warao se observó un aumento en los niveles de los componentes C3 y C4 del complemento y una hipergammaglobulinemia. Los resultados de los isotipos mostraron que, la disminución de IgAs podría ser un marcador de enfermedad activa, mientras que el aumento de IgM un marcador de infección reciente. La policlonalidad fue independiente de la reactividad al PPD.

Abstract. The present study was carried out in a Warao childhood population with extremely high tuberculosis (TB) rate of 3190/100,000 in 0-15 years old children. One hundred seven serum and saliva samples were tested, 32 from patients with active TB (27 positive and 5 negative for the tuberculin skin test, TST) and 75 apparently healthy contact children (45 positive and 30 negative for the TST). The innate, immunoglobulin and cellular responses were studied. The results showed that both, patients and controls, had a high percentage of children with increased levels of complement C3 and C4 components. A high percentage of children with increased total serum IgA and IgG (13.8% and 79.3% respectively) was observed in children with TB in comparison to control children (0% and 69.2%). A high percentage of control children had increased levels of IgM and sIgA (69.2% and 56.16%, respectively) in comparison to patients (48.3% and 31.25%). Both groups showed children with increased levels of IgE. The results concerning to the cellular immune response to PPD and the BCG vaccination status showed that there was a correlation between an increase in PPD reactivity and age. The PPD reactivity in children less than 7 years old was similar and also independent of the BCG vaccination status. A significant number of children without or with scars (46.8% and 27.6%, respectively) showed induration values of 0 mm to tuberculin skin test. The Candida reactivity showed a high percentage of children (80%) with anergy status. In conclusion, an increase in the levels of complement components C3 and C4 and hypergammaglobulinemia was observed in Warao children, and these results were independent from PPD reactivity and BCG vaccination. The isotype results showed that the decrease in sIgA could be and active disease marker, while the increase in IgM levels could represent a marker of recent disease.