RESUMEN

OBJECTIVES: The current death certification system in the USA fails to accurately track deaths due to adverse medical events. The aim of this study was to demonstrate the under-reporting of deaths due to adverse medical events due to limitations in the current death certification/reporting system, and the benefits of using the term 'therapeutic complication' as the manner of death. STUDY DESIGN: Retrospective review and comparison of death certificates and vital statistical coding. METHODS: The manner of death is certified as a therapeutic complication when death is caused by predictable complications of appropriate therapy, and would not have occurred but for the medical intervention. Based on medical examiner records, complications that caused or contributed to deaths over a five-year period were examined retrospectively. These fatalities were compared with deaths coded as medical and surgical complications by the New York City Bureau of Vital Statistics. RESULTS: The Medical Examiner's Office certified 2471 deaths as therapeutic complications and 312 deaths as accidents occurring in healthcare facilities. In contrast, the New York City Bureau of Vital Statistics reported 188 deaths due to complications of medical and surgical care. CONCLUSIONS: Use of the term 'therapeutic complication' as the manner of death identified nearly 14 times more deaths than were reported by the New York City Bureau of Vital Statistics. If these therapeutic complications and medical accidents were considered as a 'disease', they would rank as the 10th leading cause of death in New York City, surpassing homicides and suicides in some years. Nationwide policy shifts that use the term 'therapeutic complication' would improve the capture and reporting of these deaths, thus allowing better identification of fatal adverse medical events in order to focus on and assess preventative strategies.

Asunto(s)

Enfermedad Iatrogénica/epidemiología , Complicaciones Intraoperatorias/mortalidad , Complicaciones Posoperatorias/mortalidad , Causas de Muerte , Certificado de Defunción , Humanos , Masculino , Ciudad de Nueva York/epidemiología , Estudios Retrospectivos , Estadísticas Vitales

RESUMEN

Tuberculosis (TB) is associated with excessive production and bioactivation of transforming growth factor bets (TGF-ß) in situ. Here, modification of expression of components of plasminogen/plasmin pathway in human monocytes (MN) by inhibitors of TGF-ß signalling was examined. Smad3 siRNA effectively inhibited TGF-ß-induced urokinase plasminogen activator receptor (uPAR). Agents known to interfere with TGF-ß signalling, including the Smad inhibitors SIS3 and erythromycin derivatives, and ALK5 receptor inhibitor (SB 431542) in inhibition of uPAR expression in response to Mycobacterium tuberculosis (MTB) were examined. Inhibition by SIS3 only inhibited uPAR mRNA significantly. SIS3 may prove to be an effective adjunct to TB therapy.

Asunto(s)

Leucocitos Mononucleares/inmunología , Mycobacterium tuberculosis/inmunología , Fagocitos/inmunología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Tuberculosis/inmunología , Benzamidas/farmacología , Dioxoles/farmacología , Humanos , Isoquinolinas/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Fagocitos/efectos de los fármacos , Activadores Plasminogénicos/genética , Activadores Plasminogénicos/inmunología , Inactivadores Plasminogénicos/genética , Inactivadores Plasminogénicos/inmunología , Piridinas/farmacología , Pirroles/farmacología , ARN Mensajero/química , ARN Mensajero/genética , ARN Interferente Pequeño/farmacología , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Proteína smad3/antagonistas & inhibidores , Proteína smad3/inmunología , Factor de Crecimiento Transformador beta/inmunología

RESUMEN

Pleural tuberculosis (TB) remains a common presentation of Mycobacterium tuberculosis (MTB) infection in HIV/TB dually infected subjects, and both cellular and acellular components of the pleural milieu promote HIV-1 replication; however, they remain uncharacterized. Using cytokine array of pleural fluid and real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunophenotype analysis, pleural fluid mononuclear cells (PFMC) were compared to systemic counterparts [i.e. plasma and peripheral blood mononuclear cells (PBMC)]. Significant increases in pleural fluid cytokines compared to plasma were limited to interleukin (IL)-6, IL-8, interferon (IFN)-γ and transforming growth factor (TGF)-ß, and did not include other T helper type 1 (Th1) (IL-2, IL-15), Th2 or Th17 cytokines. Patterns and levels of cytokines were indistinguishable between pleural fluid from HIV/TB and TB patients. Forkhead box P3 (FoxP3) mRNA in PFMC was increased significantly and correlated highly with levels of IL-6 and IL-8, less with TGF-ß, and not with IFN-γ. Among CD4 T cells, FoxP3-reactive CD25(hi) were increased in HIV/TB dually infected subjects compared to their PBMC, and up to 15% of FoxP3(+) CD25(hi) CD4 T cells were positive for IL-8 by intracellular staining. These data implicate a dominant effect of MTB infection (compared to HIV-1) at pleural sites of dual HIV/TB infection on the local infectious milieu, that include IL-6, IL-8, IFN-γ and TGF-ß and regulatory T cells (T(reg) ). A correlation in expansion of T(reg) with proinflammatory cytokines (IL-6 and IL-8) in pleural fluid was shown. T(reg) themselves may promote the inflammatory cytokine milieu through IL-8.

Asunto(s)

Citocinas/metabolismo , Infecciones por VIH/complicaciones , Infecciones por VIH/inmunología , Cavidad Pleural/inmunología , Linfocitos T Reguladores/inmunología , Tuberculosis Pleural/complicaciones , Tuberculosis Pleural/inmunología , Adulto , Citocinas/sangre , Femenino , Factores de Transcripción Forkhead/genética , Proteínas de Fusión gag-pol/genética , Expresión Génica/genética , Infecciones por VIH/sangre , Infecciones por VIH/metabolismo , VIH-1/aislamiento & purificación , Humanos , Interferón gamma/sangre , Interferón gamma/metabolismo , Interleucina-6/sangre , Interleucina-6/metabolismo , Interleucina-8/sangre , Interleucina-8/metabolismo , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Plasma/virología , Cavidad Pleural/metabolismo , Cavidad Pleural/patología , Cavidad Pleural/virología , Derrame Pleural/inmunología , Derrame Pleural/metabolismo , Derrame Pleural/patología , Derrame Pleural/virología , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Tuberculosis Pleural/sangre , Tuberculosis Pleural/metabolismo , Carga Viral , Adulto Joven

RESUMEN

The impact of intestinal helminth infection on Mycobacterium tuberculosis (MTB)-specific immune responses during active tuberculosis (TB) is not known. We investigated the role of intestinal helminth infection in anti-MTB immunity by evaluating both cellular phenotype and cytokine profiles in patients with TB and patients with concomitant TB and intestinal helminth infection (TB + Helm) during TB therapy. Twenty-seven per cent of TB patients enrolled for the study were co-infected with at least one intestinal helminth. At baseline, absolute frequencies of leucocytes, monocytes and eosinophils from TB and TB + Helm patients differed from healthy subjects. Concomitant intestinal helminth infection in TB + Helm patients had a negative impact (P < 0.05) on absolute frequencies of CD3(+), CD4(+), CD8(+), natural killer (NK) T and CD4(+) CD25(high) T cell subsets when compared to either TB patients or healthy controls. Differences in CD4(+) T cell frequencies were accompanied by lower interferon (IFN)-gamma and elevated and sustained interleukin (IL)-10 levels in whole blood (WB) cultures from TB + Helm compared to TB patients. In addition to a depressed anti-MTB immunity, TB + Helm patients also presented with more severe radiological pulmonary disease, with a significant difference (P = 0.013) in the number of involved lung zones at the end of TB treatment. The above data may indicate that concomitant intestinal helminth infection in patients with newly diagnosed TB skews their cytokine profile toward a T helper 2 response, which could favour persistent MTB infection and a more protracted clinical course of the disease.

Asunto(s)

Antituberculosos/uso terapéutico , Helmintiasis/inmunología , Parasitosis Intestinales/inmunología , Mycobacterium tuberculosis , Tuberculosis/tratamiento farmacológico , Tuberculosis/inmunología , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Citometría de Flujo , Helmintiasis/microbiología , Humanos , Inmunofenotipificación , Interferón gamma/inmunología , Interleucina-10/inmunología , Interleucina-5/inmunología , Parasitosis Intestinales/microbiología , Leucocitos/inmunología , Masculino , Estadísticas no Paramétricas , Tuberculosis/parasitología

RESUMEN

Active tuberculosis (TB) is associated with prolonged suppression of Mycobacterium tuberculosis (MTB)-specific immune responses, but mechanisms involved are understood incompletely. We investigated a potential role for CD4+CD25+ regulatory T cells in depressed anti-MTB immunity by evaluating serially CD4 cell phenotype and interferon (IFN)-gamma production by mononuclear cells from patients with TB. At diagnosis, frequencies of CD4+CD25+ T cells were increased in blood from TB patients compared to healthy purified protein derivative (PPD)-positive controls (with a history of prior TB exposure), and remained elevated at completion of therapy (6 months). By contrast, expression of another activation marker, CD69, by CD4 T cells was increased at diagnosis, but declined rapidly to control levels with treatment. Among CD4+CD25+ T cells from TB patients at diagnosis those expressing high levels of CD25, probably representing regulatory T cells, were increased 2.9-fold when compared to control subjects, while MTB-stimulated IFN-gamma levels in whole blood supernatants were depressed. A role for CD4+CD25+ T cells in depressed IFN-gamma production during TB was substantiated in depletion experiments, where CD25+-depleted CD4 T cells produced increased amounts of IFN-gamma upon MTB stimulation compared to unseparated T cells. At follow-up, IFN-gamma production improved most significantly in blood from TB patients with high baseline frequencies of CD4+CD25+ T cells (more than threefold higher than controls for both total and CD25hi+ CD4 T cells), who also had a significant drop in frequencies of both total and 'regulatory' CD4+CD25+ T cells in response to treatment. Expansion of CD4+CD25+ regulatory T cells during active TB may play a role in depressed T cell IFN-gamma production.

Asunto(s)

Receptores de Interleucina-2/inmunología , Linfocitos T Reguladores/inmunología , Tuberculosis Pulmonar/inmunología , Adulto , Antígenos Bacterianos/inmunología , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Linfocitos T CD8-positivos/inmunología , Femenino , Humanos , Interferón gamma/inmunología , Interleucina-10/inmunología , Lectinas Tipo C , Pulmón/inmunología , Masculino , Monocitos/inmunología , Mycobacterium tuberculosis/inmunología , Fenotipo , Factor de Crecimiento Transformador beta/inmunología , Tuberculina/inmunología , Tuberculosis Pulmonar/microbiología , Factor de Necrosis Tumoral alfa/inmunología

RESUMEN

Biologically active transforming growth factor beta 1 (TGFbeta1) has been identified at sites of Mycobacterium tuberculosis (MTB) infection in the lung; however, the underlying mechanism(s) for its activation is not clear. Here using an enzyme-linked immunospot assay for TGFbeta1, we show that human blood monocytes (MN) and alveolar macrophages (AM) produce bioactive TGFbeta1 upon stimulation by MTB. However, only MTB-stimulated MN increased TGFbeta1 production on a per cell basis. The frequency of TGFbeta1-producing MN was reduced by an inhibitor of plasmin, bdellin, indicating a role for plasmin pathways in the bioactivation of cytokine. The expression of urokinase plasminogen activator receptor (uPAR) mRNA and both surface and soluble uPAR (CD87) was increased in MTB-activated MN. However, antibody neutralization of uPAR suppressed bioactive TGFbeta1 in MN alone. Thus, the more immature MN, which are continuously recruited to the lung during tuberculosis (TB), have a higher capacity to bioactivate TGFbeta1 by expression of components of the plasmin pathway. Excess production and bioactivation of TGFbeta1 at sites of MTB infection may undermine host immune responses during TB.

Asunto(s)

Leucocitos Mononucleares/metabolismo , Mycobacterium tuberculosis/fisiología , Fagocitos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Adulto , Células Cultivadas , Fibrinolisina/antagonistas & inhibidores , Fibrinolisina/fisiología , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/microbiología , Fagocitos/inmunología , Fagocitos/microbiología , Inhibidores de Proteasas/farmacología , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Factor de Crecimiento Transformador beta/biosíntesis , Factor de Crecimiento Transformador beta1

RESUMEN

This study examined the impact of the host inflammatory microenvironment associated with localized tuberculosis (TB) on human immunodeficiency virus type 1 (HIV-1) replication within lymphocytes and macrophages in vivo. Paired plasma and pleural fluid samples from HIV-1-infected individuals with pleural TB (n=9) were analyzed. Detection of host proteins incorporated into the HIV-1 envelope by immunomagnetic capture analysis provided insight into the phenotype of cells supporting HIV-1 replication. The results indicated that the 4.0-fold greater median HIV-1 load in pleural fluid, compared with median load in plasma (P<.01), was derived in part from viral replication within HLA-DR+ cells, CD26+ lymphocytes, and, importantly, CD14+ macrophages. Greatly increased local concentrations of proinflammatory cytokines and immune activation markers in the pleural space correlated with the virologic findings. In summary, HIV-1 replication was increased at sites of Mycobacterium tuberculosis coinfection within activated cells, including lymphocytes and CD14+ macrophages.

Asunto(s)

Infecciones Oportunistas Relacionadas con el SIDA/virología , VIH-1/fisiología , Macrófagos/virología , Linfocitos T/virología , Tuberculosis Pleural/virología , Replicación Viral , Infecciones Oportunistas Relacionadas con el SIDA/inmunología , Adulto , Compartimento Celular , Dipeptidil Peptidasa 4/metabolismo , Antígenos HLA-DR/metabolismo , Humanos , Receptores de Lipopolisacáridos/metabolismo , Derrame Pleural/inmunología , Derrame Pleural/virología , Tuberculosis Pleural/inmunología

RESUMEN

Tuberculosis (TB) enhances HIV-1 replication and the progression to AIDS in dually infected patients. We employed pleural TB as a model to understand the interaction of the host with HIV-1 during active TB, at sites of Mycobacterium tuberculosis (MTB) infection. HIV-1 replication was enhanced both in the cellular (pleural compared with blood mononuclear cells) and acellular (pleural fluid compared with plasma) compartments of the pleural space. Several potential mechanisms for expansion of HIV-1 in situ were found, including augmentation in expression of tumor necrosis factor (TNF)-alpha and the HIV-1 noninhibitory beta-chemokine (MCP-1), low presence of HIV-1 inhibitory beta-chemokines (MIP-1 alpha, MIP-1 beta, and RANTES [regulated on activation, normal T expressed and secreted]), and upregulation in expression of the HIV-1 coreceptor, CCR5, by pleural fluid mononuclear cells. Thus, at sites of MTB infection, conditions are propitious both for transcriptional activation of HIV-1 in latently infected mononuclear cells, and facilitation of viral infection of newly recruited cells. These mechanisms may contribute to enhanced viral burden and dissemination during TB infection.

Asunto(s)

Infecciones Oportunistas Relacionadas con el SIDA/virología , VIH-1/fisiología , Tuberculosis Pleural/virología , Activación Viral , Replicación Viral , Infecciones Oportunistas Relacionadas con el SIDA/complicaciones , Secuencia de Bases , Quimiocinas/metabolismo , Cartilla de ADN , VIH-1/genética , Humanos , Monocitos/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tuberculosis Pleural/complicaciones , Factor de Necrosis Tumoral alfa/metabolismo , Carga Viral

RESUMEN

Tuberculosis (TB) is the most common opportunistic infection in human immunodeficiency virus type 1 (HIV-1)-infected patients globally and occurs throughout the course of HIV-1 disease. Here the production of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha by peripheral blood mononuclear cells (PBMC) of HIV-1-infected versus -uninfected patients with newly diagnosed pulmonary TB (PTB) was compared. Findings were correlated with cytokine profiles, clinical presentation, and expression of inducible nitric oxide (iNOS). Most HIV-1/PTB patients with a CD4 cell count of 200-500 cells/microL had high IFN-gamma production and radiographic evidence of atypical PTB. Low IFN-gamma production and radiographic evidence of reactivated PTB characterized both HIV-1/PTB patients with a CD4 cell count >or=500 cells/microL and HIV-1-uninfected patients. TNF-alpha levels were similar in all HIV-1/PTB patients, regardless of CD4 cell count. Induction of iNOS in PBMC was low and was associated with low IFN-gamma production. These data underscore the potential pathogenic role of macrophage-activating cytokines in TB in HIV-1-infected patients.

Asunto(s)

Infecciones Oportunistas Relacionadas con el SIDA/microbiología , Infecciones por VIH/inmunología , VIH-1 , Interferón gamma/biosíntesis , Leucocitos Mononucleares/inmunología , Tuberculosis Pulmonar/inmunología , Factor de Necrosis Tumoral alfa/biosíntesis , Adulto , Recuento de Linfocito CD4 , Infecciones por VIH/complicaciones , Humanos , Activación de Macrófagos , Persona de Mediana Edad , Óxido Nítrico/biosíntesis , Radiografía Torácica , Esputo/microbiología , Tuberculosis Pulmonar/complicaciones

RESUMEN

Pleural tuberculosis (TB) was employed as a model to study T cell apoptosis at sites of active Mycobacterium tuberculosis (MTB) infection in human immunodeficiency virus (HIV)-coinfected (HIV/TB) patients and patients infected with TB alone. Apoptosis in blood and in pleural fluid mononuclear cells and cytokine immunoreactivities in plasma and in pleural fluid were evaluated. T cells were expanded at the site of MTB infection, irrespective of HIV status. Apoptosis of CD4 and non-CD4 T cells in the pleural space occurred in both HIV/TB and TB. Interferon (IFN)-gamma levels were increased in pleural fluid, compared with plasma. Spontaneous apoptosis correlated with specific loss of MTB-reactive, IFN-gamma-producing pleural T cells. Immunoreactivities of molecules potentially involved in apoptosis, such as tumor necrosis factor-alpha, Fas-ligand, and Fas, were increased in pleural fluid, compared with plasma. These data suggest that continued exposure of immunoreactive cells to MTB at sites of infection may initiate a vicious cycle in which immune activation and loss of antigen-responsive T cells occur concomitantly, thus favoring persistence of MTB infection.

Asunto(s)

Infecciones Oportunistas Relacionadas con el SIDA/inmunología , Apoptosis/inmunología , Interferón gamma/biosíntesis , Mycobacterium tuberculosis/inmunología , Linfocitos T/inmunología , Tuberculosis Pleural/inmunología , Infecciones Oportunistas Relacionadas con el SIDA/sangre , Infecciones Oportunistas Relacionadas con el SIDA/virología , Adolescente , Adulto , Recuento de Linfocito CD4 , Células Cultivadas , Citocinas , Proteína Ligando Fas , Femenino , Humanos , Interferón gamma/inmunología , Leucocitos Mononucleares , Masculino , Glicoproteínas de Membrana/análisis , Persona de Mediana Edad , Mycobacterium tuberculosis/virología , Linfocitos T/citología , Tuberculosis Pleural/sangre , Tuberculosis Pleural/virología , Factor de Necrosis Tumoral alfa/análisis , Uganda

RESUMEN

Active TB in HIV-1-infected subjects is associated with increased HIV-1-related immunodeficiency and mortality. We assessed plasma viral load in HIV-1-infected patients with pulmonary TB (HIV/TB) and non-TB symptomatic HIV-1-infected patients (HIV). HIV-1 load was higher in HIV/TB compared with HIV at higher CD4 counts (> 500/microl) (P < 0.01), but not at lower CD4 counts (< 500/microl). We also evaluated the status of HIV-1 gene expression in peripheral blood mononuclear cells (PBMC) and serum from HIV/TB and CD4-matched healthy HIV-infected patients (HIV/C) by reverse transcriptase-polymerase chain reaction over a range of CD4 (> 900/microl to < 200/microl). HIV-1 RNA in serum and PBMC correlated to one another, and both were markedly higher in HIV/TB compared with HIV/C with higher CD4 counts. Also, during a longitudinal study of anti-tuberculous chemoprophylaxis in HIV-1-infected patients, 10 subjects who developed TB had serologies before, at the time, and after the diagnosis of TB. These HIV/TB patients had an increase in viral load (average 2.5-fold) at the time of diagnosis of TB (P < 0.05). Overall, these data indicate that the transcriptional activity of HIV-1 is enhanced in HIV-1-infected patients with active TB, especially during early HIV-1 disease. As TB often is an early HIV-1 opportunistic infection, it may particularly favour early viral replication and dissemination, and therefore contribute to progression of HIV-1 disease.

Asunto(s)

Infecciones por VIH/virología , VIH-1/fisiología , Tuberculosis Pulmonar/virología , Infecciones Oportunistas Relacionadas con el SIDA/microbiología , Infecciones Oportunistas Relacionadas con el SIDA/virología , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/complicaciones , Infecciones por VIH/inmunología , Humanos , Tuberculosis Pulmonar/complicaciones , Tuberculosis Pulmonar/microbiología , Carga Viral

RESUMEN

Conjunctival and facial petechiae, although nonspecific findings, are considered hallmarks of asphyxial deaths. Consensus in the literature suggests that their pathogenesis is related to the combined effects of increased cephalic venous pressure and hypoxic damage to endothelial cells. Despite the common knowledge that they are neither predictable findings in all asphyxial deaths nor rare in natural, nonasphyxial deaths, the belief persists that petechiae are corroborative evidence of asphyxia. We suggest that a clear, physiologically based understanding of the pathogenesis of petechiae of the head is critical for their appropriate interpretation. We present a review of the literature and the basis of our conclusion that conjunctival and facial petechiae are the product of purely mechanical vascular phenomena, unrelated to asphyxia or hypoxia.

Asunto(s)

Asfixia/diagnóstico , Púrpura/etiología , Autopsia , Causas de Muerte , Conjuntiva/patología , Medicina Legal , Humanos

RESUMEN

Correlates of protective immunity to Mycobacterium tuberculosis in humans are desirable for identifying protective antigens, demonstrating the immunogenicity of a vaccine candidate and its potential efficacy, and permitting optimization of the dose, vehicle, adjuvant, and schedule of immunization. Potential correlates can be proposed on the basis of animal models and ex vivo/in vitro studies in humans. Most critical is their validation; ultimate validation will require correlation with protection in a phase III efficacy trial of an effective vaccine. Other approaches, however, can allow selection of the most promising correlates for inclusion in phase I and II and, ultimately, phase III vaccine trials. Current data from experimental models and studies of patients with pulmonary tuberculosis and their household contacts indicate that Mycobacterium tuberculosis-stimulated whole-blood production of interferon-gamma, although imperfect, is the best available correlate. Nonetheless, further refinement of this assay and additional studies of more complex assays that model M. tuberculosis killing and cytotoxic T lymphocyte activity are warranted. During planning of a vaccine trial, the best available correlates of immunity can be selected for inclusion.

Asunto(s)

Antígenos Bacterianos/inmunología , Interferón gamma/sangre , Mycobacterium tuberculosis/inmunología , Tuberculosis Pulmonar/prevención & control , Animales , Vacuna BCG/inmunología , Biomarcadores , Ensayos Clínicos como Asunto , Humanos , Linfocitos T Citotóxicos/inmunología , Tuberculosis Pulmonar/inmunología

RESUMEN

Adjunctive immunotherapy with heat-killed Mycobacterium vaccae was studied in a randomized, placebo-controlled trial of 120 non-human immunodeficiency virus-infected adults with newly diagnosed pulmonary tuberculosis. Patients were randomized to a single dose of M. vaccae or placebo 1 week after beginning chemotherapy and were followed up for 1 year. M. vaccae was safe and well tolerated. The rate of sputum culture conversion after 1 month of tuberculosis treatment was 35% in the M. vaccae group and only 14% in the placebo group (P=.01) but was comparable at 2 months and thereafter. Patients receiving M. vaccae had greater improvement on chest radiography at 6 months (91% vs. 77% for placebo recipients; P=.04) and 12 months (94% vs. 80%; P=.04) after initiation of tuberculosis treatment. These data provide evidence of an early increase in sputum culture conversion and greater radiographic improvement among patients who received M. vaccae. Further studies are warranted.

Asunto(s)

Mycobacterium/inmunología , Tuberculosis Pulmonar/terapia , Adulto , Femenino , Indicadores de Salud , Humanos , Masculino , Mycobacterium/clasificación , Radiografía Torácica , Esputo/microbiología , Uganda , Vacunas de Productos Inactivados

RESUMEN

Immunological and clinical profiles were evaluated in 2 groups: human immunodeficiency virus (HIV)-uninfected and HIV-infected patients, with newly diagnosed pulmonary tuberculosis (TB), and tuberculin-skin-test-reactive healthy control subjects. HIV-uninfected patients with TB were also followed up longitudinally during and after chemotherapy. At the time of diagnosis, purified protein derivative (PPD)-stimulated production of interferon (IFN)-gamma by peripheral blood mononuclear cells from TB patients was depressed, compared with that of healthy control subjects, whereas levels of transforming growth factor (TGF)-beta and interleukin (IL)-10 were increased. In longitudinal studies, PPD stimulated production of IL-10 and TGF-beta returned to baseline by 3 months, whereas IFN-gamma production remained depressed for at least 12 months. These data indicate that the immunosuppression of TB is not only immediate and apparently dependent (at least in part) on immunosuppressive cytokines early during the course of Mycobacterium TB infection but is also long lasting, presumably relating to a primary abnormality in T-cell function.

Asunto(s)

Citocinas/biosíntesis , Infecciones por VIH/complicaciones , Interferón gamma/biosíntesis , Mycobacterium tuberculosis/inmunología , Linfocitos T/inmunología , Tuberculosis Pulmonar/inmunología , Adolescente , Adulto , Anticuerpos Antibacterianos/sangre , Antituberculosos/uso terapéutico , Técnicas de Cocultivo , Citocinas/inmunología , Humanos , Interleucina-10/biosíntesis , Interleucina-10/inmunología , Estudios Longitudinales , Persona de Mediana Edad , Factor de Crecimiento Transformador beta/biosíntesis , Factor de Crecimiento Transformador beta/inmunología , Tuberculina/inmunología , Prueba de Tuberculina , Tuberculosis Pulmonar/complicaciones , Tuberculosis Pulmonar/tratamiento farmacológico

RESUMEN

Mycobacterium tuberculosis is associated with the activation of cytokine circuits both at sites of active tuberculosis in vivo and in cultures of mononuclear cells stimulated by M. tuberculosis or its components in vitro. Interactive stimulatory and/or inhibitory pathways are established between cytokines, which may result in potentiation or attenuation of the effects of each molecule on T-cell responses. Here we examined the interaction of transforming growth factor beta1 (TGF-beta1) and interleukin-10 (IL-10) in purified protein derivative (PPD)-stimulated human mononuclear cell cultures in vitro. TGF-beta1 induced monocyte IL-10 (but not tumor necrosis factor alpha) production (by 70-fold, P < 0.02) and mRNA expression in the absence but not in the presence of PPD. Both exogenous recombinant (r) IL-10 and rTGF-beta1 independently suppressed the production of PPD-induced gamma interferon (IFN-gamma) in mononuclear cells from PPD skin test-positive individuals. Synergistic suppression of IFN-gamma in cultures containing both rTGF-beta1 and rIL-10 was only seen when the responder cell population were peripheral blood mononuclear cells (PBMC) and not monocyte-depleted mononuclear cells and when PBMC were pretreated with rTGF-beta1 but not with rIL-10. Suppression of PPD-induced IFN-gamma in PBMC containing both rTGF-beta1 (1 ng/ml) and rIL-10 (100 pg/ml) was 1.5-fold higher (P < 0.05) than cultures containing TGF-beta1 alone and 5.7-fold higher (P < 0.004) than cultures containing IL-10 alone. Also, neutralization of endogenous TGF-beta1 and IL-10 together enhanced PPD-induced IFN-gamma in PBMC in a synergistic manner. Thus, TGF-beta1 and IL-10 together potentiate the downmodulatory effect on M. tuberculosis-induced T-cell production of IFN-gamma, and TGF-beta1 alone enhances IL-10 production. At sites of active M. tuberculosis infection, these interactions may be conducive to the suppression of mononuclear cell functions.

Asunto(s)

Interleucina-10/biosíntesis , Mycobacterium tuberculosis/inmunología , Factor de Crecimiento Transformador beta/farmacología , Animales , Humanos , Interferón gamma/biosíntesis , Interleucina-10/farmacología , Ratas , Receptores de Interleucina/análisis , Receptores de Interleucina-10 , Tuberculina/inmunología , Factor de Necrosis Tumoral alfa/biosíntesis

RESUMEN

Several lines of evidence suggest that host genetic factors controlling the immune response influence infection by Mycobacterium tuberculosis. The proinflammatory cytokine interleukin (IL)-1beta and its antagonist, IL-1Ra (IL-1 receptor agonist), are strongly induced by M. tuberculosis and are encoded by polymorphic genes. The induction of both IL-1Ra mRNA and secreted protein by M. tuberculosis in IL-1Ra allele A2-positive (IL-1Ra A2(+)) healthy subjects was 1.9-fold higher than in IL-1Ra A2(-) subjects. The M. tuberculosis-induced expression of mRNA for IL-1beta was higher in subjects of the IL-1beta (+3953) A1(+) haplotype (P = 0.04). The molar ratio of IL-1Ra/IL-1beta induced by M. tuberculosis was markedly higher in IL-1Ra A2(+) individuals (P < 0.05), with minor overlap between the groups, reflecting linkage between the IL-1Ra A2 and IL-1beta (+3953) A2 alleles. In M. tuberculosis-stimulated peripheral blood mononuclear cells, the addition of IL-4 increased IL-1Ra secretion, whereas interferon gamma increased and IL-10 decreased IL-1beta production, indicative of a differential influence on the IL-1Ra/IL-1beta ratio by cytokines. In a study of 114 healthy purified protein derivative-reactive subjects and 89 patients with tuberculosis, the frequency of allelic variants at two positions (-511 and +3953) in the IL-1beta and IL-1Ra genes did not differ between the groups. However, the proinflammatory IL-1Ra A2(-)/IL-1beta (+3953) A1(+) haplotype was unevenly distributed, being more common in patients with tuberculous pleurisy (92%) in comparison with healthy M. tuberculosis-sensitized control subjects or patients with other disease forms (57%, P = 0.028 and 56%, P = 0. 024, respectively). Furthermore, the IL-1Ra A2(+) haplotype was associated with a reduced Mantoux response to purified protein derivative of M. tuberculosis: 60% of tuberculin-nonreactive patients were of this type. Thus, the polymorphism at the IL-1 locus influences the cytokine response and may be a determinant of delayed-type hypersensitivity and disease expression in human tuberculosis.

Asunto(s)

Interleucina-1/genética , Mycobacterium tuberculosis/inmunología , Polimorfismo Genético , Receptores de Interleucina-1/antagonistas & inhibidores , Sialoglicoproteínas/genética , División Celular/genética , División Celular/inmunología , Genotipo , Haplotipos/genética , Humanos , Hipersensibilidad Tardía/genética , Hipersensibilidad Tardía/inmunología , Proteína Antagonista del Receptor de Interleucina 1 , Interleucina-1/antagonistas & inhibidores , Interleucina-10/farmacología , Interleucina-4/farmacología , Interleucina-6/farmacología , Leucocitos/inmunología , Leucocitos/metabolismo , Mycobacterium tuberculosis/genética , ARN Mensajero/genética , Tuberculina/inmunología , Tuberculosis/genética , Tuberculosis/inmunología

RESUMEN

Pulmonary tuberculosis is a major cause of morbidity and mortality worldwide, resulting in the greatest number of deaths due to any one single infectious agent. This trend is due, at least in part, to increasing numbers of individuals co-infected with HIV and Mycobacterium tuberculosis (MTB). Concerted efforts between the World Health Organization and other agencies, therefore, are underway to improve tuberculosis control worldwide. These include basic research in tuberculosis diagnostics and vaccine development, institution of preventive therapy in individuals dually infected with HIV and MTB, and directly observed short-course antituberculous therapy in developing countries with a high prevalence of MTB infection. Further, newer, longer-acting antituberculous therapeutic agents such as rifapentine, which allow twice-weekly dosing in the continuation phase of anti-MTB therapy, have recently been released and are undergoing clinical trials. This review provides a synopsis of recent developments in these areas and serves as a reference source for interested readers.

Asunto(s)

Brotes de Enfermedades/prevención & control , Tuberculosis Pulmonar/epidemiología , Antituberculosos/uso terapéutico , Resistencia a Múltiples Medicamentos , Femenino , Humanos , Incidencia , Masculino , Factores de Riesgo , Tasa de Supervivencia , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/tratamiento farmacológico , Organización Mundial de la Salud

RESUMEN

Mycobacterium tuberculosis (MTB)-induced T cell responses are depressed in peripheral blood mononuclear cells of persons with newly diagnosed pulmonary tuberculosis (TB), and levels of interferon (IFN)-gamma remain low even after completion of antituberculous therapy. Loss of MTB-reactive T cells through apoptotic mechanisms could account for this prolonged T cell hyporesponsiveness. T cell apoptosis was studied in TB patients and healthy control subjects. Both spontaneous and MTB-induced apoptosis (in CD4 and non-CD4 T cells) from TB patients was increased when compared with healthy control subjects, whereas coculture with control antigen (candida) had no effect on T cell apoptosis in either group of study subjects. An inverse correlation existed between increased MTB-induced T cell apoptosis and IFN-gamma and interleukin (IL)-2 immunoreactivities. Successful antituberculous chemotherapy resulted in a 50% reduction in both spontaneous and MTB-induced apoptosis, which coincided with 3- and 8-fold increases in levels of MTB-stimulated IL-2 and IFN-gamma, respectively. These data indicate that apoptotic pathways are operant during active MTB infection and may contribute to deletion of MTB-reactive T cells and the immunopathogenesis of this disease.

Asunto(s)

Apoptosis , Linfocitos T/inmunología , Tuberculosis Pulmonar/inmunología , Recuento de Linfocito CD4 , Epítopos , Humanos , Interferón gamma/análisis , Interferón gamma/biosíntesis , Interleucina-2/análisis , Interleucina-2/biosíntesis , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/patología

RESUMEN

STUDY OBJECTIVE: To determine the HIV seroprevalence rates in relation to the demographic characteristics of victims, cause of death, and toxicology findings in a sample of victims of violence and accidents who presented to emergency departments before death. METHODS: This descriptive survey of a complete 3-year sample of homicides and accidents was conducted in 5 boroughs of New York City (population 7,322,564). Persons 15 years of age and older injured by intentional violence or accidents (excluding drug overdoses, falls from short heights, and suicides) who presented to hospitals, died, and were sent to the medical examiner were included. Standard methods were used to test plasma and serum samples for HIV and cocaine or its metabolite. Chi2 Tests compared HIV seroprevalence across groups according to demographic characteristics and toxicology findings. Logistic regression analysis was done for those variables found to be significant with chi2 tests. All statistical tests were conducted with 2-tailed alpha levels of .05. RESULTS: Among the 1,242 subjects in the sample, 90 (7.2%) had positive findings. Male patients (8%) had higher rates than female patients (3.4%). HIV rates were highest among patients 35 to 44 years of age (20.8%), followed by the 45- to 54-year age group (9.6%) and 25- to 34-year age group (8.1%). Victims of homicide (8.2%) and accidents other than motor vehicle crashes (10.5%) had higher rates than victims of motor vehicle crashes (4%). Patients with positive results for cocaine (16.3%) were more likely than those with negative result (5.8%) to be HIV positive. There were no statistically significant differences by race, except that no Asians were HIV positive. Logistic regression analysis found that only age and positive cocaine results, not sex and race, were related to increased risk of HIV infection. CONCLUSION: We found the rate of HIV infection among victims of fatal trauma was significant, especially in those with evidence of cocaine use. The HIV infection rate approximates the high end of the range of HIV rates found in studies before 1990. It further emphasizes the need for use of universal precautions in the care of trauma patients.

Asunto(s)

Seroprevalencia de VIH , Heridas y Lesiones/mortalidad , Accidentes/mortalidad , Accidentes de Tránsito/mortalidad , Adolescente , Adulto , Factores de Edad , Anciano , Causas de Muerte , Distribución de Chi-Cuadrado , Cocaína/sangre , Servicios Médicos de Urgencia , Femenino , VIH/aislamiento & purificación , Homicidio/estadística & datos numéricos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Ciudad de Nueva York/epidemiología , Intoxicación/mortalidad , Grupos Raciales , Factores de Riesgo , Factores Sexuales , Precauciones Universales , Violencia/estadística & datos numéricos