Intravenous peramivir for treatment of influenza in hospitalized patients.

BACKGROUND: Influenza causes over 200,000 hospitalizations a year in the United States, but few antiviral treatment studies have focused on patients hospitalized with influenza. This open-label, randomized study was initiated during the 2009 H1N1 pandemic to help assess the antiviral activity, safety and tolerability of 5-10 days treatment with two different dosing regimens of the intravenous neuraminidase inhibitor, peramivir, in hospitalized subjects with influenza. METHODS: Quantitative virology was done on nasopharyngeal swab specimens from subjects ≥6 years of age to measure change from baseline in tissue culture infective dose (primary end point) and quantitative viral RNA levels by real-time PCR. Clinical end points included time to clinical resolution, a composite end point of four vital signs and oxygen saturation. RESULTS: A total of 234 hospitalized patients were randomized to peramivir 300 mg twice daily or 600 mg once daily; 127 had laboratory confirmed influenza. In those with detectable virus at baseline, viral titres declined without differences between regimens. There were no significant differences in clinical or virological end points between treatment arms, and apparent differences were explained by baseline disease severity differences in the groups. Peramivir was generally safe and well tolerated for treated patients hospitalized with pandemic influenza with outcomes similar to those described in the literature. CONCLUSIONS: This open-label trial of intravenous peramivir in subjects hospitalized predominantly with 2009 influenza A (H1N1) demonstrated that once- or twice-daily administration was associated with decreases in viral shedding and clinical improvement. ClinicalTrials.gov number NCT00957996.

Bacille Calmette-Guérin infection and disease with fatal outcome associated with a point mutation in the interleukin-12/interleukin-23 receptor beta-1 chain in two Mexican families.

Patients with Mendelian susceptibility to mycobacterial diseases (MSMD) mainly suffer from Mycobacterium and Salmonella infections, which are due to mutations in genes controlling the interleukin (IL)-12/IL-23-dependent IFN-γ production. We performed a molecular diagnosis in two Mexican patients with persistent mycobacterial infections. Patients 1 (P1) and 2 (P2) from two unrelated, non-consanguineous families from two villages near Mexico City developed bacille Calmette-Guérin (BCG) disease secondary to vaccination; patients and their families were studied at the immunological level for production and response to IFN-γ. The ß1 subunit of the IL-12 receptor (encoded by the IL12RB1 gene) was not expressed in cells from P1 or P2, or in two siblings of P1. Sequencing of the IL12RB1 gene showed the same point mutation 1791+2 T>G, homozygous in patients and heterozygous in parents. P1 and P2 died at the ages of 4 and 16 years, respectively, with disseminated and uncontrolled BCG disease and with Candida albicans infections in spite of multiple anti-mycobacterial drug treatments. One of P2's siblings also died following disseminated mycobacterial infection secondary to BCG vaccination. These are the first cases in Mexico of patients with BCG disease traced to a mutation in the IL12RB1 gene, with a fatal outcome. Doctors must be alert to the adverse reactions to BCG vaccination and to persistent Mycobacterium infections, and in such cases should investigate possible mutations in the genes of the IL-12/IL-23-IFN-γ axis.

Mycobacterium bovis BCG substrains confer different levels of protection against Mycobacterium tuberculosis infection in a BALB/c model of progressive pulmonary tuberculosis.

Mycobacterium bovis BCG is the only available vaccine against tuberculosis. Reasons for why diverse BCG substrains induce different levels of protection in clinical trials remain unclear. The aim of this study was to compare the effectiveness of 10 BCG substrains in a mouse model of pulmonary tuberculosis. BALB/c mice were subcutaneously vaccinated and 2 months later were challenged with Mycobacterium tuberculosis H37Rv by intratracheal injection. Two and 4 months after challenge, delayed-type hypersensitivity (DTH) response, lung tissue affected by pneumonia, CFU, T-cell counts, and cytokine expression (interleukin-2 [IL-2], IL-4, IL-10, and gamma interferon) were determined. A differential protective effect of the diverse BCG substrains was found. BCG Phipps led to the largest and most persistent reduction of CFU counts and of the area of pneumonia at 2 and 4 months after challenge. This protection was accompanied by reduced IL-10-producing T cells. Contemporary BCG substrains induce a wide range of protection in this animal model. These data can help in the selection of the best vaccine for human immunization and for the development of novel recombinant BCG-based vaccine.

Papel de las células epiteliales en la respuesta inmune del pulmón / Immunological role of epithelial cells of the lung

El sistema respiratorio se encuentra en contacto con agentes patógenos; sin embargo, gracias a la respuesta inmune innata de éste, sólo en raras ocasiones se produce la enfermedad. Las células epiteliales del tracto respiratorio desempeñan 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. Asimismo, son capaces de secretar citocinas, péptidos antimicrobianos y otras moléculas proinflamatorias, las cuales evitan el establecimiento de patógenos.

The respiratory tract is one of the main systems which is in perennial contact with a wide variety of pathogenic microorganisms; however, infection is seldom produced due to its innate immune response. Respiratory tract epithelial cells play a very important role to avoid colonization of the lung by infectious agents, because they recognize microbial molecules through very specialized receptors, such as toll-like receptors; moreover, these cells posses a broad variety of molecules which are related to local immunity. Respiratory tract epithelial cells produce chemokines, antimicrobial peptides and other proinflammatory molecules that prevent the establishment of pathogenic microorganisms.

Mecanismos moleculares de la respuesta inmune en la tuberculosis pulmonar humana / Molecular mechanisms of the immune response in human pulmonary tuberculosis

La tuberculosis pulmonar humana es una enfermedad infecciosa causada por M. tuberculosis; el control de la infección requiere el desarrollo de una respuesta inmune protectora. Este tipo de respuesta inmunológica incluye la participación de los macró-fagos alveolares, linfocitos T (CD4+,CD8+, NK y yδ) y la producción de citocinas como: 1L-2, IFN-γ, IL-12, IL-18 y TNF-α. Asimismo, de quimiocinas como: RANTES, MCP-1, MlP-lα e 11-8 que tienen un papel muy importante en la migración de las diferentes subpoblaciones celulares al sitio de infección para la formación del granuloma. El objetivo de este trabajo es ofrecer un panorama de los mecanismos inmunológicos involucrados en la respuesta inmune celular en la tuberculosis pulmonar humana.

Human pulmonary tuberculosis is an infectious disease caused by M. tuberculosis; the protective immune response plays a central role in the control and progression of this disease. The immune response includes the participation of alveolar macrophages, lymphocytes (subsets CD4+, CD8+, NK and yδ) and cytokine production such as IL-2, IFN-γ, IL-12, IL-18 and TNF-α. Moreover, chemokines like RANTES, MCP-1, MIP-lα and IL-8 play an important role in the chemotaxis of different cell populations at the infection site for the formation of granulomas. This paper provides an overview of the immune mechanisms involved in the cellular immune response in human pulmonary tuberculosis.

Response of IFN-gamma and IgG to ESAT-6 and 38 kDa recombinant proteins and their peptides from Mycobacterium tuberculosis in tuberculosis patients and asymptomatic household contacts may indicate possible early-stage infection in the latter.

BACKGROUND: The ESAT-6 antigen from Mycobacterium tuberculosis evokes a protective immune response in murine models and is widely recognized by tuberculosis patients (TB) and healthy household contacts (HHC). However, little is known about human immune response to this antigen in populations from areas of high endemicity. This study aimed to determine the capacity of T-cells from a group of TB patients and HHC for cell proliferation and production of cytokines type Th1 or Th2 (IL-4, IL-10, and IFN-gamma) and to identify total IgG reactivity to the recombinant protein rESAT-6 and five overlapping synthetic peptides as well as to r38 kDa and two peptides. METHODS: T-cells from nine TB patients and nine HHC were stimulated with rESAT-6 and five overlapping synthetic peptides, previously selected from a set of 21 peptides and each of 16 amino acids in length (P1, P4, P6, P8, and P20). Similar experiments were carried out with r38 kDa and two peptides of 20 amino acids in length (38G and 38K). Cytokines in supernatants and total IgG from serum were determined by ELISA. RESULTS: Stimulation index (SI) was highest in HHC to rESAT-6 and peptides P1, P8, and P20. Differences in response to 38 kDa and 38G peptide between TB patients and HHC were not demonstrated. Cytokines from T-cell cultures were tested with a resulting SI=3.0. IFN-gamma was produced predominantly in HHC to rESAT-6, P8, and P20, while in TB patients production of IL-10 was detected in relation to r38 kDa. IL-4 was detected in minimal amounts in both groups. IgG from TB patients was predominantly recognized in connection with rESAT-6 and the P4 peptide, with an important response against r38 kDa detected in HHC. CONCLUSIONS: ESAT-6 recognition by HHC could indicate that these responses represent possible early-stage infections.

[Tuberculosis: a current problem]. / Tuberculosis: un problema de actualidad.

Tuberculosis is a public health problem. If the current trends continue, is expected to arrive to 10.2 million of new cases in 2005. There are three studies accomplished in 1995 in Mexican patients. The results show important difficulty in the application and the follow-up of the program of control of the tuberculosis, what has caused accumulation of chronic cases, moderate rate of primary resistance and alarming levels of primary and secondary multiresistance (23%). Mechanism of protective immunity against mycobacterium tuberculosis (MTB) in humans have not been clarified. Different subpopulations of lymphocytes CD4, CD8 and other populations as well as macrophages, and monocytes, have an important role. In industrialized countries, the managing of the MDRTB is based on the use of individualized treatments with second line drugs according to susceptibility test, however the foregoing has not been possible to apply it middle or low income countries. WHO has launches the initiative "DOTS plus" that consist in the administration of a standarized regimen on the basis of epidemiology of resistance in the country or region.

Caracterización de la respuesta inmunológica humoral contra diversos componentes bacterianos de la Klebsiella rhinoscleromatis / Caracterization of humoral inmune response againts diverses bacterial components of Klebsiella rhinoscleromatis

El rinoescleroma es una infección crónica granulomatosa de las vías aéreas superiores, causada por la Klebsiella rhinoscleromatis. Esta es una bacteria intracelular obligada, oportunista, que infecta a individuos inmunocomprometidos, por esta razón, es endémica en áreas tropicales en poblaciones de muy bajo nivel socioeconómico. Para hacer el diagnóstico es necesario pensar en este padecimiento como posibilidad, ya que sus manifestaciones clínicas son muy polimorfas y por tanto,inespecíficas. En este trabajo se reportan los resultados de la evaluación de la respuesta humoral por la técnica de ELISA, en contra de la bacteria entera, así como polisacáridos y proteínas de membrana, en pacientes, parientes sanos y sujetos sanos no relacionados. Los títulos de anticuerpos contra las proteínas de membranas resultaron estadísticamente significativos. Esta prueba, además de ser una posible ayuda diagnóstica en la práctica diaria, es un primer intento para explorar la naturaleza de los antígenos reconocidos por los enfermos y por los sujetos sanos

Valoración del uso de inmunoensayos para el diagnóstico rápido de tuberculosis en población abierta / Evaluation of immunoassays use for the fast diagnosis of tuberculosis in open population

Se valoró la utilización de técnicas inmunológicas como métodos alternativos en el diagnóstico de tuberculosis pulmonar(TBP), realizando la búsqueda de antígenos de M. tuberculosis y anticuerpos dirigidos contra la misma bacteria en suero de pacientes con sospecha clínica de tuberculosis. El antígeno -lipoarabinomanana- (LAM) de M. tuberculosis, se detectó por coaglutinación e inmunoensayo en papel (DOT) utilizando suero hiperinmune de conejo y un anticuerpo monoclonal. Para la detección de anticuerpos se usaron dos sistemas de ELISA utilizando en ellos, como antígenos, un extracto soluble de M. tuberculosis y lipoarabinomanana purificada. Los resultados demostraron que la detección del antígeno en estos sistemas fue poco eficiente, para coaglutinación la sensibilidad fue 32 por ciento y la especificidad 81 por ciento, mientras que para DOT fueron 38 por ciento y 84 por ciento respectivamente. La detección por ELISA de anticuerpos utilizando extracto de M tuberculosis mostró una sensibilidad del 80 por ciento con especificidad del 60 por ciento. Con LAM la sensibilidad fue 50 por ciento con especificidad de 90 por ciento. Los resultados anteriores sugieren que el uso de inmunoensayos utilizando sueros de pacientes para la búsqueda de LAM y, para la detección de anticuerpos en contra de estos antígenos, no tiene suficiente especificidad y sensibilidad para ser de utilidad en el diagnóstico rutinario de tuberculosis en población abierta. Es necesario desarrollar métodos rápidos para el diagnóstico de TBP, especialmente en países en desarrollo en los que la prevalencia de TBP es mayor

Inmunogenética en tuberculosis pulmonar / Immunogenetics in pulmonar tuberculosis

La predisposición genética a la tuberculosis y enfermeades infecciosas crónicas similares, ha sido tema de numerosos estudios y controversias, debido a la diversidad de resultados obtenidos. En un estudio previo realizado en una población abierta de enfermos, determinando los antígenos de histocompatibilidad se describió una disminución importante en expresión de estos marcadores. También se describió un incremento en la beta 2 microglobulina, péptido asociado estructuralmente a estos antígenos. En este trabajo, se estudiaron 19 familias de tuberculosos (23 enfermos y 58 sanos) los antígenos HLA (incluyendo el locus DQ) y la beta 2 microglobulina, así como, las subpoblaciones de linfocitos T. Encontrando que la coincidencia en enfermos del alelo DQ1 e incremento de la beta 2 microglobulina sérica es altamente significativa (p<0.00001). Estos datos apoyan la existencia de una predisposición genética en la mayoría de los enfermos con tuberculosis.

Infecciones intraahospitalarias: vigilancia epidemiológica en el Instituto Nacional de Enfermedades Respiratorias / Interhospitalary infection: a survellance program in the National Institute of Respiratory Diseases

Las infecciones nosocomiales, por su repercusión en el pronóstico de pacientes, costo y eficiencia del hospital, constituyen un grave problema de salud. En este artículo, se presenta la información obtenida a través de un estudio propectivo de vigilancia epidemiológica durante un años, en el Instituto Nacional de Enfermedades Respiratorias. Los resultados mostraron una razón de 11.5% por 100 egresos, con 78.5% en la unidad de terapia intensiva. Los sitios más frecuentes de infección fueron tracto gastrointestinal, vías urinarias y vías respiratorias. Se comparan estos resultados con otros estudios efectuados en México