RESUMEN
Cardiovascular diseases and thrombotic events became major clinical problems in the combined antiretroviral therapy (cART) era. Although the precise mechanisms behind these clinical problems have not been fully elucidated, a persistent pro-inflammatory state plays a central role. As platelets play important roles on both, thrombus formation and inflammatory/immune response, we aimed at investigating platelet function in HIV-infected subjects virologically controlled through cART. We evaluate parameters of activation, mitochondrial function and activation of apoptosis pathways in platelets from 30 HIV-infected individuals under stable cART and 36 healthy volunteers. Despite viral control achieved through cART, HIV-infected individuals exhibited increased platelet activation as indicated by P-selectin expression and platelet spreading when adhered on fibrinogen-coated surfaces. Platelets from HIV-infected subjects also exhibited mitochondrial dysfunction and activation of apoptosis pathways. Finally, thrombin stimuli induced lower levels of P-selectin translocation and RANTES secretion, but not TXA2 synthesis, in platelets from HIV-infected individuals compared to control; and labeling of platelet alpha granules showed reduced granule content in platelets from HIV-infected individuals when compared to healthy subjects. In summary, platelets derived from HIV-infected individuals under stable cART exhibit a phenotype of increased activation, activation of the intrinsic pathway of apoptosis and undermined granule secretion in response to thrombin.
Asunto(s)
Terapia Antirretroviral Altamente Activa/efectos adversos , Enfermedades Cardiovasculares/sangre , Infecciones por VIH/tratamiento farmacológico , Inflamación/sangre , Trombosis/sangre , Adulto , Apoptosis/efectos de los fármacos , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/patología , Quimiocina CCL5/genética , Femenino , VIH/patogenicidad , Infecciones por VIH/complicaciones , Infecciones por VIH/genética , Infecciones por VIH/virología , Voluntarios Sanos , Humanos , Inflamación/inducido químicamente , Inflamación/patología , Masculino , Mitocondrias/genética , Mitocondrias/patología , Monocitos , Selectina-P/genética , Activación Plaquetaria/efectos de los fármacos , Activación Plaquetaria/genética , Agregación Plaquetaria/efectos de los fármacos , Trombina/metabolismo , Trombosis/inducido químicamente , Trombosis/genética , Trombosis/virologíaRESUMEN
BACKGROUND: Tuberculosis is one of the leading causes of death from infectious diseases worldwide, mainly after the human immunodeficiency virus (HIV) epidemics. Patient with HIV-related illness are more likely to present with severe TB due to immunosuppression. Very few studies have explored HIV/TB co-infection in critically ill patients. The goal of this study was to analyze factors associated with long-term mortality in critically ill patient with HIV-related disease coinfected with TB. METHODS: We conducted a retrospective study in an infectious disease reference center in Brazil that included all patient with HIV-related illness admitted to the ICU with laboratory-confirmed tuberculosis from March 2007 until June 2012. Clinical and laboratory variables were analyzed based on six-month survival. RESULTS: Forty-four patients with HIV-related illness with a confirmed diagnosis of tuberculosis were analyzed. The six-month mortality was 52 % (23 patients). The main causes of admission were respiratory failure (41 %), severe sepsis/septic shock (32 %) and coma/torpor (14 %). The median time between HIV diagnosis and ICU admission was 5 (1-60) months, and 41 % of patients received their HIV infection diagnosis ≤ 30 days before admission. The median CD4 count was 72 (IQR: 23-136) cells/mm(3). The clinical presentation was pulmonary tuberculosis in 22 patients (50 %) and disseminated TB in 20 patients (45.5 %). No aspect of TB diagnosis or treatment was different between survivors and nonsurvivors. Neurological dysfunction was more prevalent among nonsurvivors (43 % vs. 14 %, p = 0.04). The nadir CD4 cell count lower than 50 cells/mm(3) was independently associated with Six-month mortality (hazard ratio 4.58 [1.64-12.74], p < 0.01), while HIV diagnosis less than three months after positive serology was protective (hazard ratio 0.27, CI 95 % [0.10-0.72], p = 0.01). CONCLUSION: The Six-month mortality of HIV critically ill patients with TB coinfection is high and strongly associated with the nadir CD4 cell count less than 50 cels/mm(3).
Asunto(s)
Coinfección/mortalidad , Enfermedad Crítica/mortalidad , Infecciones por VIH/mortalidad , Insuficiencia Respiratoria/mortalidad , Sepsis/mortalidad , Tuberculosis Pulmonar/mortalidad , Adulto , Brasil/epidemiología , Recuento de Linfocito CD4 , Coinfección/epidemiología , Comorbilidad , Enfermedad Crítica/epidemiología , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , Hospitalización , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Mortalidad , Puntuaciones en la Disfunción de Órganos , Modelos de Riesgos Proporcionales , Insuficiencia Respiratoria/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Sepsis/epidemiología , Factores de Tiempo , Tuberculosis/mortalidad , Tuberculosis Pulmonar/epidemiología , Adulto JovenRESUMEN
INTRODUCTION: In recent years, the incidence of sepsis has increased in critically ill HIV/AIDS patients, and the presence of severe sepsis emerged as a major determinant of outcomes in this population. The inflammatory response and deregulated cytokine production play key roles in the pathophysiology of sepsis; however, these mechanisms have not been fully characterized in HIV/AIDS septic patients. METHODS: We conducted a prospective cohort study that included HIV/AIDS and non-HIV patients with septic shock. We measured clinical parameters and biomarkers (C-reactive protein and cytokine levels) on the first day of septic shock and compared these parameters between HIV/AIDS and non-HIV patients. RESULTS: We included 30 HIV/AIDS septic shock patients and 30 non-HIV septic shock patients. The HIV/AIDS patients presented low CD4 cell counts (72 [7-268] cells/mm(3)), and 17 (57%) patients were on HAART before hospital admission. Both groups were similar according to the acute severity scores and hospital mortality. The IL-6, IL-10 and G-CSF levels were associated with hospital mortality in the HIV/AIDS septic group; however, the CRP levels and the surrogates of innate immune activation (cytokines) were similar among HIV/AIDS and non-HIV septic patients. Age (odds ratio 1.05, CI 95% 1.02-1.09, p=0.002) and the IL-6 levels (odds ratio 1.00, CI 95% 1.00-1.01, p=0.05) were independent risk factors for hospital mortality. CONCLUSIONS: IL-6, IL-10 and G-CSF are biomarkers that can be used to predict prognosis and outcomes in HIV/AIDS septic patients. Although HIV/AIDS patients are immunocompromised, an innate immune response can be activated in these patients, which is similar to that in the non-HIV septic population. In addition, age and the IL-6 levels are independent risk factors for hospital mortality irrespective of HIV/AIDS disease.