Effect of gene-gene and gene-environment interactions associated with antituberculosis drug-induced hepatotoxicity.

OBJECTIVES: This study evaluated the association between environmental factors and genetic variations in enzymes that metabolize antituberculosis (anti-TB) drugs [arylamine N-acetyltransferase 2, cytochrome P450 2E1 (CYP2E1), glutathione S-transferase theta 1 (GSTT1), and glutathione S-transferase mu 1] with antituberculosis drug-induced hepatotoxicity (ATDH). We also investigated the potential gene-gene and gene-environment interactions as well as their association with ATDH development in a population of hospitalized TB patients from Buenos Aires. PATIENTS AND METHODS: We investigated 364 TB patients who received anti-TB drugs. Physicians collected demographic and clinical data to identify environmental risk factors for ATDH development. Polymorphisms were detected using gene sequencing, PCR, and PCR-restriction fragment length polymorphisms. A binary logistic regression analysis was carried out to compare the results of TB patients with and without the development of hepatotoxicity. The multifactor dimensionality reduction method was used to examine genetic and environmental interactions in association with ATDH. RESULTS: This study suggests that the slow acetylator profile [odds ratio (OR): 3.02; 95% confidence interval (CI): 1.82-5.00; P<0.001], genotypes carrying the c2 variant (OR: 2.16; 95% CI: 1.33-3.51; P=0.002) or the A4 variant of CYP2E1 (OR: 2.13; 95% CI: 1.06-4.29; P=0.050), and female sex (OR: 1.94; 95% CI: 1.20-3.14; P=0.006) were independent predictor variables for ATDH. Patients carrying the slow acetylator profile and the c2 variant showed an increased risk (OR: 7.068; 95% CI: 3.34-14.95; P<0.001). We also identified a synergic interaction (epistasis) between GSTT1 and CYP2E1 associated with an increased risk for ATDH. A meaningful gene-environment interaction was associated with an increased risk of ATDH [testing balance accuracy=0.675 (P=0.001) and cross-validation consistency=10/10]. CONCLUSION: ATDH is a severe and prevalent adverse drug reaction and leads to drug discontinuation in 11% of TB patients. Our study created a prediction model that properly classified the 67.5% of TB patients in their risk of developing ATDH. The considerable number of TB patients in our country supports the use of pharmacogenetic testing and a comprehensive clinical history to identify patients with a high risk of suffering hepatotoxicity.

tagSNP rs1495741 as a useful molecular marker to predict antituberculosis drug-induced hepatotoxicity.

INTRODUCTION: It has been widely reported that the slow acetylator phenotype of N-acetyltransferase 2 (NAT2) is associated with the development of antituberculosis drug-induced hepatotoxicity (ATDH). The aim of this report was to evaluate the level of agreement and accuracy of two recently recommended markers, the two-single nucleotide polymorphisms (SNP) (C282T and T341C) and tagSNP of NAT2 (rs1495741) genotypes, to predict the seven-SNP-inferred NAT2 phenotype in Bolivian and Argentinian tuberculosis (TB)-patient populations. In addition, we analyzed the association of these markers with ATDH. METHODS: We examined 331 TB patients who had been treated with anti-TB drugs. TagSNP of NAT2 genotyping was determined using PCR-restriction fragment length polymorphisms. The seven SNPs of NAT2 were determined using sequencing. Concordance analysis was carried out using Kendall's tau-b coefficient (w) and the degree of agreement with Cohen's κ coefficient (κ). Receiver operating characteristic receiver operating characteristic curves were obtained to measure the specificity and sensitivity of the method. A binary logistic regression was performed to identify variables associated with the development of ATDH. RESULTS: Both predictors showed a remarkable concordance (>95.0%) and an almost perfect agreement (κ>0.945; P<0.0001) with the predicted acetylator profile. However, the sensitivity of the tagSNP genotypes to predict the NAT2 acetylator phenotype was lower in the Bolivian population (92.3%) compared with the Argentinian population (100.0%). CONCLUSION: A nearly perfect agreement between both predictors and the predicted acetylation profile was observed with very high levels of sensitivity (>97%) and specificity (>98.0%). Furthermore, and as expected, both the two-SNP (C282T, T341C) and tagSNP were found to be independent variables in predicting ATDH with the same strength as seven-SNP of NAT2.

Impaired dendritic cell differentiation of CD16-positive monocytes in tuberculosis: role of p38 MAPK.

Tuberculosis (TB) is one of the world's most pernicious diseases mainly due to immune evasion strategies displayed by its causative agent Mycobacterium tuberculosis (Mtb). Blood monocytes (Mos) represent an important source of DCs during chronic infections; consequently, the alteration of their differentiation constitutes an escape mechanism leading to mycobacterial persistence. We evaluated whether the CD16(+)/CD16(-) Mo ratio could be associated with the impaired Mo differentiation into DCs found in TB patients. The phenotype and ability to stimulate Mtb-specific memory clones DCs from isolated Mo subsets were assessed. We found that CD16(-) Mos differentiated into CD1a(+) DC-SIGN(high) cells achieving an efficient recall response, while CD16(+) Mos differentiated into a CD1a(-) DC-SIGN(low) population characterized by a poor mycobacterial Ag-presenting capacity. The high and sustained phosphorylated p38 expression observed in CD16(+) Mos was involved in the altered DC profile given that its blockage restored DC phenotype and its activation impaired CD16(-) Mo differentiation. Furthermore, depletion of CD16(+) Mos indeed improved the differentiation of Mos from TB patients toward CD1a(+) DC-SIGN(high) DCs. Therefore, Mos from TB patients are less prone to differentiate into DCs due to their increased proportion of CD16(+) Mos, suggesting that during Mtb infection Mo subsets may have different fates after entering the lungs.

Human pleural B-cells regulate IFN-γ production by local T-cells and NK cells in a Mycobacterium tuberculosis-induced delayed hypersensitivity reaction.

DTH (delayed type hypersensitivity) reactions are secondary cellular immune responses that appear 24-72 h after antigen exposure. Tuberculous pleurisy is a common manifestation of extrapulmonary TB (tuberculosis) and is considered a human model of Th1-mediated DTH. In order to identify functional cross-talk among cellular populations sited in this inflammatory microenvironment, we analysed phenotypic and functional features of human B-cells isolated from the PF (pleural fluid) of TB patients. Freshly isolated PF-B-cells displayed a lower expression of CD20, CD1d and HLA-DR, and a higher expression of CD95, CD38, CD25, CXCR3 (CXC chemokine receptor 3) and CXCR4 (CXC chemokine receptor 4) than their PB (peripheral blood) counterparts, suggesting a non-classical in situ activation. Although memory PF-T-cell frequencies were increased, the frequencies of memory PF-B-cells were not. We demonstrated that, upon stimulation with γ-irradiated M. tuberculosis, mycobacterially secreted proteins or a lectin mitogen, PF-B-cells had a strong activation and produced IL-10 by a mechanism that was dependent on bystander activation of CD19(-) PF cells. Besides, within PF cells, B-cells diminished in vitro M. tuberculosis-induced IFN (interferon)-γ production by T-cells and NK (natural killer) cells in an IL-10-dependent manner. Finally, we found that the lower the frequency of B-cells, the higher the ratio of IFN-γ/IL-10 within PF. Thus our results suggest that B-cells can regulate a human DTH reaction induced by M. tuberculosis.

Sex, ethnicity, and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs.

BACKGROUND AND AIM: Treatment with antituberculosis (TB) drugs produces liver damage in a large proportion of patients. Isoniazid, an antibacterial drug, is primarily responsible for this hepatotoxicity. Several polymorphisms of the N-acetyltransferase 2 (NAT-2) and cytochrome P450 2E1 enzymes, which are involved in the metabolism of isoniazid, may be directly associated with the development of hepatotoxicity. This study was designed to analyze the association between the NAT-2 and CYP2E1 polymorphisms with the development of anti-TB drug-induced hepatotoxicity (ATDH). METHODS: One hundred and seventy-five TB patients who had been treated with anti-TB drugs were studied. The allelic and genotypic frequency distributions of the NAT-2 and CYP2E1 enzymes were studied using polymerase chain reaction-restriction fragment length polymorphisms methodology. A binary logistic regression analysis was used to compare the results between TB patients with and without the development of hepatotoxicity. RESULTS: Having a slow acetylator status (odds ratio [OR] = 2.615; confidence interval [CI] = 1.264-5.411; P = 0.01), being female (OR = 2.734; CI = 1.325-5.639, P = 0.006), and having Bolivian ethnicity (OR = 2.711; CI = 1.307-6.625, P = 0.007) were found to be independent predictor variables for ATDH. CONCLUSIONS: This study showed that a patient's NAT-2 acetylator status, gender, and ethnic origin may be regarded as important risk factors for developing hepatotoxicity. Contrary to expectations, the CYP2E1 c1/c2 polymorphism did not show a significant association with hepatotoxicity in this study. Given the increases in TB cases and ATDH incidence levels, as well as the associated hospitalization costs, it may also be helpful to know patients' acetylator status prior to or at the beginning of the TB treatment regimen.

NK cells from tuberculous pleurisy express high ICAM-1 levels and exert stimulatory effect on local T cells.

Tuberculous pleurisy, one of the most common manifestations of extrapulmonary tuberculosis, is characterized by a T-cell-mediated hypersensitivity reaction along with a Th1 immune profile. In this study, we investigated functional cross-talk among T and NK cells in human tuberculous pleurisy. We found that endogenously activated pleural fluid-derived NK cells express high ICAM-1 levels and induce T-cell activation ex vivo through ICAM-1. Besides, upon in vitro stimulation with monokines and PAMP, resting peripheral blood NK cells increased ICAM-1 expression leading to cellular activation and Th1 polarization of autologous T cells. Furthermore, these effects were abolished by anti-ICAM-1 Ab. Hence, NK cells may contribute to the adaptive immune response by a direct cell-contact-dependent mechanism in the context of Mycobacterium tuberculosis infection.

Tigecycline in the treatment of ventilator-associated pneumonia: experience from the Latin American Tigecycline Use Registry.

OBJECTIVE: The aim of this study was to evaluate the clinical success rate of the patients with ventilator-associated pneumonia (VAP) treated with tigecycline. METHODS: Data from patients with established criteria of VAP were collected using a web-based reporting system from 16 February, 2006 to June 23, 2009. One hundred and seventeen patients coming from 10 ICUs from Argentina were studied. RESULTS: Overall, attending physician reported clinical success in 74 patients (63%; 95%CI 54.08-72.41%). Global mortality proportion was 33% (39/117 patients). Patients with APACHE II score at admission > or = 15 showed a clinical success rate significantly lower and a mortality rate significantly higher than those with APACHE II score at admission less than 15 (52.6% [30/57] vs 73.3% [44/60]; p 0.0332, and 45.6% [26/57]vs 21.7% [13/60]; p 0.0108). The etiology of VAP was established in 60 patients (51%). Acinetobacter spp. (59%; in 84% of cases carbapenems-resistant), and methicillin-resistant Staphylococcus aureus (22%) were the most common microorganisms isolated. Eleven patients (1.5%) had VAP with bacteremia (respiratory sample and blood cultures positive for the same pathogens). CONCLUSIONS: As initial evidence, our results suggest that tigecycline may be an acceptable alternative for therapy in patients with VAP. Nevertheless, only controlled clinical trials will provide the evidence to support approval for new indications.

[Tuberculosis treatment. A practical guide elaborated by the tuberculosis section, Argentine Association of Respiratory Medicine]. / Tratamiento de la tuberculosis. Guia practica elaborada por la seccion tuberculosis, Asociacion Argentina de Medicina Respiratoria.

Tuberculosis is a worldwide prevalent disease. The emergence of multidrug-resistant strains spurred the search for new drugs. There are several tuberculosis treatment guidelines, international and local in a programmatic approach. An Argentinean specialists panel draw practical guidelines based in clinical criteria and the local and international bibliography through consensus meetings, including issues as: antituberculosis drugs available in Argentina, initial and re-treatement modalities, special situations treatment, adverse reactions to antituberculosis drugs, current indications of surgical treatment and new drugs under study for the treatment of the disease.

The distribution of allelic and genotypic frequencies of N-Acetyltransferase-2 variants in an Argentine population.

INTRODUCTION: Arylamine N-acetyltransferase-2 (NAT-2) is a key human enzyme in drug detoxification and elimination. Mutations in NAT-2 affect the activity of anti-tuberculosis drugs and result in three different phenotypes: rapid (RA), intermediate (IA) and slow acetylators (SA). METHODOLOGY: The allelic, genotypic and phenotypic frequencies of NAT-2 were studied in 185 patients from Buenos Aires by restriction fragment length polymorphism. RESULTS: The following allele frequencies were obtained: *4 = 29.9%, *5 = 37.0, *6 = 25.6%, *7 = 8% and *14 = 1.3%. With regard to the phenotype, we observed that 53.6% of the population was SA, 35.7% was IA and 10.7% was RA. CONCLUSION: A high prevalence of SA might have an impact on anti-TB drug-induced hepatotoxicity.

Fístula anal de etiología tuberculosa. A propósito de un caso y breve revisión bibliográfica / Tubercular fistula in-ano. Report of a case and brief review

La fístula anal de etiología tuberculosa es una afección rara. Presentamos un caso en una paciente HIV (-), revisamos datos epidemiológicos y discutimos la fisiopatología, manifestaciones clínicas, nuevos desarrollos diagnósticos y brevemente su tratamiento.

Tubercular fistula in-ano is a rare condition. In addition to presenting a case in a HIV (-) patient, in this paper we review epidemiologic data, pathophysiology, clinical manifestations and new developments in diagnosis and their treatment is discussed briefly.

Paradoxical role of CD16+CCR2+CCR5+ monocytes in tuberculosis: efficient APC in pleural effusion but also mark disease severity in blood.

The role of CD16(-) and CD16(+) Mo subsets in human TB remains unknown. Our aim was to characterize Mo subsets from TB patients and to assess whether the inflammatory milieu from TB pleurisy modulate their phenotype and recruitment. We found an expansion of peripheral CD16(+) Mo that correlated with disease severity and with TNF-α plasma levels. Circulating Mo from TB patients are activated, showing a higher CD14, CD16, and CD11b expression and Mtb binding than HS. Both subsets coexpressed CCR2/CCR5, showing a potential ability to migrate to the inflammatory site. In tuberculous PF, the CD16(+) subset was the main Mo/MΦ population, accumulation that can be favored by the induction of CD16 expression in CD16(-) Mo triggered by soluble factors found in this inflammatory milieu. CD16(+) Mo in PF were characterized by a high density of receptors for Mtb recognition (DC-SIGN, MR, CD11b) and for lipid-antigens presentation (CD1b), allowing them to induce a successful, specific T cell proliferation response. Hence, in tuberculous PF, CD16(+) Mo constitute the main APC population; whereas in PB, their predominance is associated with the severity of pulmonary TB, suggesting a paradoxical role of the CD16(+) Mo subset that depends on the cellular localization.

Tuberculosis vulvar: Una rara localización / Vulvar Tuberculosis: A Rare Localization

La tuberculosis vulvar es una rara localización de la enfermedad, que debe incluirse en los diagnósticos diferenciales de lesiones ulcerosas o exofíticas dolorosas a ese nivel. Se presenta el caso de una mujer joven, VIH negativa, con grave compromiso del estado general debido a una tuberculosis diseminada con múltiples localizaciones: pulmonar, renal, genital, intestinal y peritoneal. La cepa de Mycobacterium tuberculosis aislada del esputo, orina y tracto genital fue pansensible y la paciente respondió al tratamiento con drogas de primera línea.

The vulvar tuberculosis is an uncommon localization of tuberculosis, which has to be included in the differential diagnosis of painful vulvar ulcerative or exophytic lesions. This report presents a case of an HIV negative young woman with severe compromise of her health status, due to disseminated tuberculosis with multiple localizations: pulmonary, renal, genital, intestinal and peritoneal manifestations. The strain of Mycobacterium tuberculosis isolated from sputum, urine and the genital tract was susceptible to all the antituberculosis medicaments and the patient responded to treatment with first-line drugs.

Mycobacterium tuberculosis-induced gamma interferon production by natural killer cells requires cross talk with antigen-presenting cells involving Toll-like receptors 2 and 4 and the mannose receptor in tuberculous pleurisy.

Tuberculous pleurisy allows the study of human cells at the site of active Mycobacterium tuberculosis infection. In this study, we found that among pleural fluid (PF) lymphocytes, natural killer (NK) cells are a major source of early gamma interferon (IFN-gamma) upon M. tuberculosis stimulation, leading us to investigate the mechanisms and molecules involved in this process. We show that the whole bacterium is the best inducer of IFN-gamma, although a high-molecular-weight fraction of culture filtrate proteins from M. tuberculosis H37Rv and the whole-cell lysate also induce its expression. The mannose receptor seems to mediate the inhibitory effect of mannosylated lipoarabinomannan, and Toll-like receptor 2 and 4 agonists activate NK cells but do not induce IFN-gamma like M. tuberculosis does. Antigen-presenting cells (APC) and NK cells bind M. tuberculosis, and although interleukin-12 is required, it is not sufficient to induce IFN-gamma expression, indicating that NK cell-APC contact takes place. Indeed, major histocompatibility complex class I, adhesion, and costimulatory molecules as well as NK receptors regulate IFN-gamma induction. The signaling pathway is partially inhibited by dexamethasone and sensitive to Ca2+ flux and cyclosporine. Inhibition of p38 and extracellular-regulated kinase mitogen-activated protein kinase pathways reduces the number of IFN-gamma+ NK cells. Phosphorylated p38 (p-p38) is detected in ex vivo PF-NK cells, and M. tuberculosis triggers p-p38 in PF-NK cells at the same time that binding between NK and M. tuberculosis reaches its maximum value. Thus, interplay between M. tuberculosis and NK cells/APC triggering IFN-gamma would be expected to play a beneficial role in tuberculous pleurisy by helping to maintain a type 1 profile.

Síndrome DRESS inducido por fármacos anti tuberculosis / DRESS syndrome induced by anti-tuberculosis drugs

Presentamos cuatro pacientes con tuberculosis pulmonar y reacciones adversas graves a los fármacos antituberculosis. Estos pacientes tuvieron farmacodermia, hepatitis, eosinofilia, fiebre y uno de ellos insuficiencia renal, constituyendo el Síndrome DRESS. Este síndromees una reacción grave de hipersensibilidad a diferentes fármacos. Suele ser producido por los anticonvulsivantes, las sulfonamidas, algunos fármacos antivirales, entre otros. Los fármacos anti tuberculosis también pueden producir este síndrome potencialmente fatal. Se destaca la importancia de la farmacovigilancia para su detección y tratamiento precoz.

We present four patients with pulmonary tuberculosis and severe adverse reactions to antituberculosis drugs. These patients had skin rash, hepatitis, eosinophilia, fever, and oneof them had renal failure; all these signs conform the diagnosis of DRESS syndrome. This syndrome is caused by a severe hypersensitivity reaction to different drugs. It is usually caused by anticonvulsants, sulfonamides, some antiviral drugs, among others drugs.Anti-tuberculosis drugs can also cause this potentially fatal syndrome. The importance of surveillance for early detection and treatment of adverse drug reactions is emphasized.

Tratamiento de la tuberculosis: guia practica elaborada por la Seccion Tuberculosis, Asociacion Argentina de Medicina Respiratoria / Tuberculosis treatment: a practical guide elaborated by the Tuberculosis Section, Argentine Association of Respiratory Medicine

La tuberculosis es una enfermedad prevalente en todo el mundo. La emergencia de cepas multirresistentes del Mycobacterium tuberculosis ha incentivado la búsqueda de nuevos fármacos. Existen diversas guías de tratamiento de la enfermedad, internacionales y a nivel programático local. Un grupo de especialistas argentinos elaboró una guía práctica basada en criterios clínicos y en la bibliografía nacional e internacional sobre el tema a través de reuniones de consenso, abarcando tópicos como: fármacos antituberculosos disponibles en la Argentina, modalidades de tratamiento inicial y retratamiento, tratamiento en situaciones especiales, reacciones adversas a fármacos antituberculosos, indicaciones actuales de tratamiento quirúrgico y nuevos fármacos en estudio para el tratamiento de la enfermedad.

Tuberculosis is a worldwide prevalent disease. The emergence of multidrug-resistant strains spurred the search for new drugs. There are several tuberculosis treatment guidelines, international and local in a programmatic approach. An Argentinean specialists panel draw practical guidelines based in clinical criteria and the local and international bibliography through consensus meetings, including issues as: antituberculosis drugs available in Argentina, initial and re-treatement modalities, special situations treatment, adverse reactions to antituberculosis drugs, current indications of surgical treatment and new drugs under study for the treatment of the disease.

Evaluación y tratamiento de la enfermidad intersticial pulmonar en la Argentina / Evaluation and treatment of interstitial lung disease in Argentine

Para realizar un relevamiento de las disponibilidades y modalidades de estudio de la enfermedad intersticial en nuestro país la Sección Patología Intersticial de la Asociación de Medicina Respiratoria (AAMR) elaboró una encuesta referida a los métodos de diagnóstico y tratamiento utilizados habitualmente. Se recolectaron 115 respuestas (38.5%), 43% de las cuales correspondían a médicos que residían en el interior del país. El acceso a la utilización de la prueba de difusión de monóxido de carbono (DLCO) es limitado: 25.4% nunca tiene oportunidad de utilizarla y 35.6% sólo puede hacerlo ocasionalmente. El acceso a la tomografía computada de alta resolución es más frecuente, 85% la pueden utilizar frecuentemente (32.4%) o siempre (52.6%). La broncoscopia está disponible en 87.7% de los encuestados frecuentemente (21.9%) o siempre (65.8%). Sin embargo, sólo 20.2% realiza BAL y 13.1% biopsia transbronquial a todos los pacientes. Sólo 16.6% somete a la mayoría o a todos sus pacientes a biopsia quirúrgica. De los médicos que siempre disponen de DLCO 66.6% la aplican en todos los pacientes vs 7.1% de los que la disponen ocasionalmente (p = 0.0003). La disponibilidad de fibrobroncoscopia no influye en la decisión de usar BAL o biopsia transbronquial. La frecuencia de uso de biopsia quirúrgica o el uso regular de inmunosupresores no está influido por ninguna variable. Se concluye que la tendencia actual en nuestro medio es la sub-utilización de recursos diagnósticos. La mayor limitación al acceso es la de la DLCO. Un esfuerzo de las autoridades de salud para conseguir centralizar el estudio de estos pacientes podría permitir que la mayor parte de los mismos se diagnostiquen y traten adecuadamente según los estándares internacionales.

Tubeculosis generalizada por Mycobacterium Bovis en un paciente inmunocompetente (presentación de un caso y revisión de la bibliografía) / Generalized tuberculosis by Mycobacterium bovis in a immunocompetent patient (case report and bibliographic review)

El Mycobacterium bovis es una variedad del complejo M. tuberculosis que afecta principalmente al ganado vacuno. Raramente puede producir tuberculosis pulmonar y extrapulmonar en el hombre. Presentamos el caso de una paciente de 72 años, con serología negativa para HIV y sin otras evidencias de inmunosupresión que se internó por tuberculosis pulmonar miliar, ósea y cutánea por M. bovis. El diagnóstico se confirmó por el examen directo y cultivo del esputo y la biopsia de piel. Al ingreso presentaba severa afectación de su estado general, pero luego de tres meses de tratamiento antituberculoso su evolución clínica y radiológica fue favorable. Analizamos la incidencia, las características del bacilo y las vías de contagio. Este es un caso poco frecuente de tuberculosis generalizada por M. bovis en un paciente inmunocompetente

Enfermedades intersticiales del pulmón: incidencia, etiología y estrategia diagnóstica en un centro especializado / Interstitial lung diseases: incidence, etiology and diagnostic strategy in a specialized center

Las enfermedades intersticiales del pulmón (EIP) son un grupo muy amplio y heterogéneo de enfermedades que comprometen difusamente el parénquima pulmonar afectando predominantemente al intersticio. Con el objetivo de determinar la incidencia y etiologías de las EIP y conocer la estrategia empleada para llegar al diagnóstico, se revisaron retrospectivamente las historia clínicas (HC) de los pacientes que consultaron por primera vez durante el período 2/1/99 al 30/12/00. Se seleccionaron las que cumplían con uno o más de los criterios aceptados para su diagnóstico. Se evaluó cada método de diagnóstico empleado, clasificándolos en métodos no invasivos (MNI): HC, Rx, TAC de tórax, pruebas de laboratorio y de función pulmonar; y métodos invasivos (MI): lavado broncoalveolar (LBA), biopsia transbronquial (BTB) y biopsia quirúrgica (BQ). De las 4518 HC revisadas, 88 (1,94 por ciento) presentaron EIP. En 67 pacientes (76 por ciento) se llegó a un diagnóstico específico (DE). Las etiologías más frecuentes fueron: TB 16 (18 por ciento), silicosis 14 (16 por ciento), sarcoidosis 8 (9 por ciento) y FPI 6 (6,8 por ciento). Utilizando solamente MNI se obtuvo el diagnóstico en 31 de los 67 pacientes (46 por ciento). En el resto, 36 pacientes (54 por ciento), el diagnóstico se hizo por MNI y MI. El LBA se realizó en la mitad de los casos (44 pacientes). En 13 (30 por ciento) permitió hacer DE y en 31 (70 por ciento) no contribuyó al diagnóstico. La BTB fue realizada en 32 pacientes (36 por ciento). En 9 (28 por ciento) permitió hacer el diagnóstico y en 23 (72 por ciento) no fue útil para el mismo. La BQ se practicó en 5 pacientes (6 por ciento) obteniéndose diagnóstico en 4 (80 por ciento). De los 21 pacientes sin DE, a 10 se le realizaron MI y a pesar de ello, no se pudo obtener el diagnóstico. Conclusiones: La incidencia de EIP fue baja (2 por ciento) si se la compara con otras enfermedades del aparato respiratorio. Las causas más frecuentes fueron: TB y silicosis. Esto podría deberse a que en nuestro hospital se derivan pacientes con estas patologías. En casi la mitad de los pacientes, el DE se realizó sólo por MNI. El rendimiento del LBA y la BTB fue de alrededor de 30 por ciento. En cambio, el de la BQ fue 80 por ciento. En 24 por ciento de los pacientes no pudo obtenerse DE. Esto podría deberse a que la BQ se realizó en sólo 5 pacientes. Recomendamos realizar la BQ con más frecuencia.