Associations between Single Nucleotide Polymorphisms of High Mobility Group Box 1 Protein and Clinical Outcomes in Korean Sepsis Patients

PURPOSE: High mobility group box 1 (HMGB1) plays a central role in the pathogenesis of sepsis and multiple organ dysfunction syndromes. We investigated the associations of a single nucleotide polymorphism (SNP; rs1045411) in HMGB1 with various clinical parameters, severity, and prognosis in patients with sepsis, severe sepsis, or septic shock. MATERIALS AND METHODS: We enrolled 212 adult patients followed for 28 days. All patients were genotyped for rs1045411, and the serum levels of HMGB1 and several cytokines were measured. RESULTS: The proportions of patients according to genotype were GG (71.2%), GA (26.4%), and AA (2.4%). Among patients with chronic lung disease comorbidity, patients with a variant A allele had higher positive blood culture rates and higher levels of various cytokines [interleukin (IL)-1beta, IL-6, IL-10, IL-17, and tumor necrosis factor-alpha] than those with the GG genotype. In the analysis of those with diabetes as a comorbidity, patients with a variant A allele had higher blood culture and Gram-negative culture rates than those with GG genotypes; these patients also had a higher levels of IL-17. In the analysis of those with sepsis caused by a respiratory tract infection, patients with a variant A allele had higher levels of IL-10 and IL-17 (all p<0.05). This polymorphism had no significant impact on patient survival. CONCLUSION: The variant A allele of rs1045411 appears to be associated with a more severe inflammatory response than the GG genotype under specific conditions.

Shock séptico en la Unidad de Cuidados Intensivos: terapéutica avanzada, inmunoparálisis y genómica. Estado del arte / Septic shock in ICU: Advanced therapeutics, immunoparalysis and genomics. State of the art

En las últimas décadas, se han incorporado nuevos y trascendentes conceptos para el tratamiento avanzado del paciente en shock séptico. Se debe considerar el uso de terapia inmune en grupos seleccionados de pacientes. Las terapias de sustitución renal de carácter continuo son bien toleradas y su empleo precoz evita sobrecargas de fluidos. El uso de hemofiltración de alto volumen puede jugar un papel en el paciente séptico hiperdinámico. La plasmaféresis es útil en el paciente con disfunción multiorgánica. El empleo de soporte extracorpóreo se debe considerar en quienes presentan shock séptico refractario. La inmunoparálisis se ha asociado con infecciones nosocomiales y mortalidad tardía. La información obtenida de los marcadores genéticos puede permitir la búsqueda de una medicina basada en la genómica

New and important concepts have emerged for the advanced management of the child with septic shock in the recent decades. Attending physicians in the Pediatric intensive care unit must be fully aware of them to improve patient care in the critical care unit. It should be considered the use of immune therapy only in selected groups of patients. Continuous renal replacement therapies are well tolerated and their early use prevents deleterious fluid overload. Removal of inflammatory mediators by using high volume hemofiltration may play a role in hyperdynamic septic patients. The use of plasmapheresis is recommended in patients with thrombocytopenia-associated multiple organ failure. Extracorporeal support use should be considered in those with refractory septic shock despite goals directed therapy. The immunoparalysis has been associated with nosocomial infections and late mortality. The information from genetic markers may allow early intervention and preventive genomics-based medicine

Inmunoglobulinas en sepsis y shock septico / Immunoglobulins in sepsis and septic shock

La eficacia clinica de las inmunoglobulinas poliespecificas o anticuerpos monoclonales para tratar pacientes con sepsis severa o shock septico es un motivo de controversia despues de haberse desarrollado numerosos ensayos clinicos. Solo algunos de ellos han podido demostrar un beneficio directo para reducir la mortalidad o este efecto es evidente tras un meta-analisis. La evidencia sostiene que las inmunoglobulinas G poliespecificas reducen la mortalidad en estos pacientes, siendo este efecto mayor para las inmunoglobulinas enriquecidas con IgM. Las mejores indicaciones son sepsis postquirurgicas o pacientes en shock septico precoz con altos títulos de endotoxinemia. Se recomienda tambien indicar inmunoglobulinas intravenosas en el tratamiento de pacientes con shock toxico estreptococcico, evidencia establecida a traves de estudios caso-control y un ensayo clinico randomizado que mostro una clara tendencia al beneficio. La evidencia no apoya a un impacto favorable en mortalidad para anticuerpos monoclonales dirigidos contra lipopolisacaridos bacterianos, otros antigenos bacterianos o contra FNT-alfa. Mas aun, la infusion de antagonistas del receptor recombinante de IL-1 o receptores solubles de FNT-alfa que pudieran atenuar la respuesta inflamatoria, no han demostrado utilidad despues de numerosos ensayos clinicos. Estas herramientas terapeuticas se caracterizan por un alto costo de adquisicion y aun no se han realizado analisis costo-efectividad

Células natural killer y el sistema inmune innato en la patología infecciosa / Natural killer cells and the innate immune system in infectious diseases

Natural killer (NK) cells form a unique third group of lymphocytes that differs from T and B cells in surface phenotype, target cell recognition and function. NK cells have two relevant functions, related to the innate immune response against pathogens microorganisms. One is cytotoxicity, mediated by the recognition and lysis of target cells such as virus and bacteria infected-cells. The second NK cell function is to produce cytokines, mainly IFN-g, that can modulate innate and specific immune responses. Cytotoxicity and cytokine secretion contribute to host resistance against microorganisms and both functions are significantly altered in infectious diseases

Superantígenos y su rol en las enfermedades infecciosas / The role of superantigens in infectious diseases

Exogenous antigens are presented to T lymphocytes through mechanisms that ensure high recognition specificity. Recently described superantigens in contrast to conventional antigens are particles that follow a different processing and presentation route not binding to a specific region of T lymphocyte receptors. These particles bind to a large number of T lymphocytes, generating a disproportionate and non-specific immune response. Two types of superantigens have been described. Endogenous superantigens, transported in the host genoma, have been involved in clonal depletion and immunological tolerance phenomena. Exogenous superantigens, mainly bacterial toxins, have been involved in several diseases. There is evidence that these antigens participate in diseases such as Kawasaki disease, toxic shock caused by Staphylococcus aureus, rheumatoid arthritis, HIV infection and Streptococcus pyogenes infections

Inflammatory ctokines and nitric oxide in children with sepsis and septic shock

The objectives of the present study were to study the role played by plasma pro-inflammatory cytokine interleukin-6 [IL-6]; anti-inflammatory cytokine interleukin-10 [IL-10] and nitric oxide [NO] in the pathogenesis of pediatric sepsis and sepsis-related cardiovascular dysfunction; multiple organ dysfunctions and non-survival. Twenty-five patients with sepsis and 20 matched controls were enrolled. Patients were subdivided into three groups according to the severity of sepsis illness; uncomplicated sepsis[n,5]; sepsis syndrome[n,10] and septic shock [n,10]. The following daily measures were done during the three study days period: i] Determination of plasma levels of IL-6; IL-10 and NO metabolites, nitrite plus nitrate [NO[2]/NO[3]]; ii] Echocardiographic evaluation of cardiovascular functions by determining cardiac index[CI], left ventricular ejection fraction[LVEF] and end-diastolic volume index[EDVI] and iii] Determination of Organ Dysfunction Index [ODI] score. Follow-up for hospital mortality was also recorded. Results of the study showed that [I] In uncomplicated sepsis: Throughout the three sepsis days, plasma IL-6 showed significant increased levels that correlated positively with a simultaneous significant increased levels of IL-10; whereas plasma NO[2]/NO[3] levels were comparable with controls. ODI score was nil and no mortality reported [II] Throughout the three study days in sepsis syndrome group and early in septic shock: plasma IL-6 levels were significantly increased Vs uncomplicated sepsis group, accompanied by significantly reduced levels of IL-10; significant increased levels of NO[2]/NO[3] and significant rise of ODI score. Plasma IL-6 correlated positively with plasma NO[2]/NO[3] and both parameters correlated positively with ODI scores[III] Late in septic shock: plasma NO[2]/NO[3] levels were significantly increased Vs sepsis syndrome and early septic shock patients. This was accompanied with significantly reduced IL-6 and significantly increased IL-10 levels. In addition, significant drop of LVEF; significant rise of EDVI; significant rise of ODI score and 60% mortality were noted. Plasma NO[2]/NO[3] showed the only significant correlation with the severity of hypotension as well as with echocardiographic indices of cardiovascular dysfunction. Plasma IL-6, IL-10 and NO[2]/NO[3] correlated positively with ODI score. Admission plasma IL-6; IL-10 late in septic shock and plasma NO[2]/NO[3] at any time of septic shock showed significantly elevated levels in non-survivors Vs survivors. In i] The data of the current study suggested activation of proinflammatory cytokine - nitric oxide pathway in children with sepsis syndrome and septic shock that correlated significantly with the associated cardiovascular dysfunctions, multiple organ dysfunctions and non-survival. ii] Proinflammatory cytokines - nitric oxide activation probably plays a pivotal role in the pathogenesis of pediatric sepsis and may strengthen the argument for cytokines - NO modulation as a treatment for critically-ill children with sepsis; iii] Also the current data highlight the role of IL-10 in down regulating proinflammatory cytokines - nitric oxide activation in uncomplicated sepsis and opened the door for future therapeutic trials of IL-10 therapy in pediatric sepsis

Defectos inmunológicos en el shock séptico: deficiencia de células natural killer y de linfocitos T / Immunological defects in septic shock: deficiency of natural killer cells and T-lymphocytes

It is well fnown that an immunosuppresive rsponse occuts after acute trauma. Some cellular mediators participate in the pathogenesis of septic shock. However, the exact role of the lymphocyte subsets and natural killer (NK) activity in this condition is not clear. We studied NK cytolytic activity through a 51Cr liberation assay using K-562 target cells in 20 patients with initial septic shock (10 men and 10 females, mean age 41 years old). Lymphocyte subsets CD3 (T3), CD4 (T4), CD8 (T8), CD16 (Leu-11) and CD56 (Leu-19) wetre also studied by indirect immunofluorescence. Compared to tesults obtained in 20 healthy volunteers, patient's NK activity was decreased (4.6 ñ 3.9 vs 26.1 ñ 10, p < 0.025), CD16 was lower (10%/187 vs 15%/280 per ul) and CD56 was also lower (6%/120 vs 12%/224 per ul), p < 0,05. T lymphocyte subsers were also decreased: CD3 cells (1100 vs 1352 per ul) and CD4 cells (634 vs 873 per ul), p < 0.05. Thus, a severe decrease in NK cells and NK cell function as well as decreases in CD3 and CD4 lymphocyte subsets are present in the initial stages of septic shock. The predictive value of these findings is currently under study

Immunological aspects in various forms of shock

Se presenta un repaso sobre los aspectos inmunológicos en tres formas del síndrome clínico de shock: anafiláctico, séptico y cardiogénico. Se hace una discusión de la participación de los derivados del ácido araquidónico, de la activación del sistema de complemento y de los efectos de los mediadores producidos por diferentes células que explican el origen de varias de las manifestaciones clínicas de estas tres entidades