Sepsis: evolving concepts and challenges

Sepsis remains a major cause of morbidity and mortality worldwide, with increased burden in low- and middle-resource settings. The role of the inflammatory response in the pathogenesis of the syndrome has supported the modern concept of sepsis. Nevertheless, a definition of sepsis and the criteria for its recognition is a continuous process, which reflects the growing knowledge of its mechanisms and the success and failure of diagnostic and therapeutic interventions. Here we review the evolving concepts of sepsis, from the "systemic inflammatory response syndrome triggered by infection" (Sepsis-1) to "a severe, potentially fatal, organic dysfunction caused by an inadequate or dysregulated host response to infection" (Sepsis-3). We focused in the pathophysiology behind the concept and the criteria for recognition and diagnosis of sepsis. A major challenge in evaluating the host response in sepsis is to characterize what is protective and what is harmful, and we discuss that, at least in part, the apparent dysregulated host response may be an effort to adapt to a hostile environment. The new criteria for recognition and diagnosis of sepsis were derived from robust databases, restricted, however, to developed countries. Since then, the criteria have been supported in different clinical settings and in different economic and epidemiological contexts, but still raise discussion regarding their use for the identification versus the prognostication of the septic patient. Clinicians should not be restricted to definition criteria when evaluating patients with infection and should wisely use the broad array of information obtained by rigorous clinical observation.

Immunomodulating effects of the purified hev b 13 fraction on septic rats / Efeitos imunomoduladores da fração purificada hev b 13 em ratos com sepse

ABSTRACT Background: Sepsis is a potentially life-threatening complication of an infection that occurs when chemicals released into the bloodstream to fight the infection trigger inflammatory responses throughout the body, especially in the acute phase of the disease, producing excessive pro-inflammatory cytokines, leading to multiple organ injury and death. The Hev b 13 fraction has demonstrated biological activity capable of inducing IL-10 production and shrinking inflammatory disease lesions. Aim: To investigate the immunomodulating effects of the Hev b 13 fraction on septic rats. Methods: Acinetobacter baumannii was injected into the peritoneal cavity of the animals after sustaining a lesion in the pancreas, with the stomach as an entry point. After 10 h of infection, they were euthanized for blood and lung collection, followed by total and differential leukocyte count, determination of cytokine level and histopathological analysis. Results: Administering a single dose of the Hev b 13 fraction 2 h after sepsis induction significantly decreased total leukocyte count. Higher IL-10 and IL-4 and lower IL-6 production shrank the lung tissue lesions compared to the control groups. Conclusion: The Hev b 13 fraction exhibits an anti-inflammatory tendency, with potential for sepsis treatment.

RESUMO Racional: Sepse se correlaciona com a ruptura do complexo equilíbrio entre os mediadores inflamatórios, que principalmente na fase aguda da doença, produz exacerbadamente citocinas pró-inflamatórias levando a lesão de múltiplos órgãos e morte. A fração Hev b 13 tem demonstrado atividade biológica capaz de induzir a produção de IL-10 e regredir lesões de doenças inflamatórias. Objetivo: Investigar os efeitos imunomoduladores da fração Hev b 13 em ratos com sepse. Métodos: Foi injetado Acinetobacter baumannii na cavidade peritoneal dos animais após lesão no pâncreas e estômago como porta de entrada. Após 10 h de infecção, foi realizada eutanásia para coleta de sangue e pulmões, em seguida, contagem total e diferencial de leucócitos, dosagem de citocinas e histopatologia para análise. Resultados: A administração de dose única da fração Hev b 13, 2 h após a indução de sepse, diminuiu significativamente a contagem total de leucócitos. Associado a maior produção de IL-10 e IL-4, e menor de IL-6, atenuou as lesões nos tecidos pulmonares em comparação com os grupos controles. Conclusão: A fração Hev b 13 apresenta tendência anti-inflamatória, com potencialidades no tratamento da sepse.

Lymphocyte count as a sign of immunoparalysis and its correlation with nutritional status in pediatric intensive care patients with sepsis: A pilot study

OBJECTIVES: Developing malnutrition during hospitalization is well recognized worldwide, and children are at a relatively higher risk for malnutrition than adults. Malnutrition can lead to immune dysfunction, which is associated with a higher mortality rate due to sepsis, the most frequent cause of death in pediatric intensive care units (PICUs). The aim of this study was to investigate whether malnourished patients are more likely to have relative or absolute lymphopenia and, consequently, worse prognoses. METHODS: We enrolled 14 consecutive patients with sepsis whose legal representatives provided written informed consent. Patients were classified as normal or malnourished based on anthropometric measurements. As an additional evaluation of nutritional status, serum albumin and zinc were measured on the 1st and 7th days of hospitalization. Lymphocyte count was also measured on the 1st and 7th days. Clinicaltrials.gov: NCT02698683. RESULTS: Malnutrition prevalence rates were 33.3% and 42.8% based on weight and height, respectively. Laboratory analyses revealed a reduction of serum albumin in 100% of patients and reduction of zinc in 93.3% of patients. A total of 35% of patients had fewer than 500 lymphocytes/mm3 on their first day in the PICU. Lymphocyte counts and zinc concentrations significantly increased during hospitalization. CONCLUSIONS: Nutritional evaluations, including anthropometric measurements, were not correlated with lymphocyte counts. Lymphocyte counts concomitantly increased with zinc levels, suggesting that micronutrient supplementation benefits patients with sepsis.

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.

TLR-2 and TLR-4 expression in monocytes of newborns with late-onset sepsis, / Expressão do TLR-2 e do TLR-4 em monócitos de recém-nascidos a termo com sepse tardia

Objective: To analyze toll-like receptor (TLR)-2 and TLR-4 expression in monocytes of newborns with late-onset sepsis. Methods: This prospective study included 27 full-term newborns aged 8 to 29 days, with clinical and laboratory diagnosis of late-onset sepsis. Ten newborns (37%) had positive cultures. Cytokines were measured by cytometric bead array in peripheral blood, while TLR-2, TLR-4 expression, and median fluorescence intensity (MFI) were determined by immunophenotyping peripheral whole blood monocytes, and were analyzed with a BD FACSDiva flow cytometer (Becton, Dickinson and Company, USA). A comparison was performed with healthy adults. Results: Microorganisms were identified in 37% of these septic newborns, and all of them had high levels of pro-inflammatory cytokines (IL-8, IL-6, IL-1β) and anti-inflammatory cytokine (IL-10) corroborating the inflammatory/septic process. In monocytes, the frequency of TLR-4 expression was higher in infected newborns (p = 0.01). Conclusion: This study investigated the innate immune response in septic newborns. Septic newborns that relied almost exclusively on the innate immune system showed little in vivo response at monocyte activation, suggesting impaired immune response and increased susceptibility to infection. .

Objetivos: Analisar a expressão dos TLR-2 e TLR-4 em monócitos de recém-nascidos com sepse tardia. Métodos: Trata-se de um estudo prospectivo com 27 recém-nascidos a termo entre 8 e 29 dias de vida com diagnóstico clínico e laboratorial de sepse tardia dos quais dez (37%) apresentaram cultura positiva. As citocinas foram determinadas por teste de CBA em sangue periférico enquanto que a expressão e MFI (mediana de intensidade de fluorescência) dos TLR-2 e TLR-4 foi determinado por imunofenotipagem em monócitos de sangue periférico total através de análise pelo citômetro de fluxo BD FACSDiva. O grupo usado para comparação foi de adultos saudáveis. Resultados: Microrganismos foram identificados em 37% dos pacientes e estes juntamente com os pacientes com sepse clínica tiveram níveis elevados de citocinas pró-inflamatórias (IL-8, IL-6, IL-1β) e de citocina anti-inflamatória (IL-10) corroborando o processo inflamatório/infeccioso. No monócito, a frequência de expressão do TLR-4 foi mais elevada (p = 0,01). Conclusões: Este estudo analisou a resposta imune inata no recém-nascido com sepse. Recémnascidos sépticos que dependem quase exclusivamente do sistema imune inato apresentaram pouca resposta in vivo na ativação de monócitos o que sugere uma resposta imune deficiente e maior susceptibilidade à infecção. .

Evaluation of Toll-like, chemokine, and integrin receptors on monocytes and neutrophils from peripheral blood of septic patients and their correlation with clinical outcomes

Recognition of pathogens is performed by specific receptors in cells of the innate immune system, which may undergo modulation during the continuum of clinical manifestations of sepsis. Monocytes and neutrophils play a key role in host defense by sensing and destroying microorganisms. This study aimed to evaluate the expression of CD14 receptors on monocytes; CD66b and CXCR2 receptors on neutrophils; and TLR2, TLR4, TLR5, TLR9, and CD11b receptors on both cell types of septic patients. Seventy-seven septic patients (SP) and 40 healthy volunteers (HV) were included in the study, and blood samples were collected on day zero (D0) and after 7 days of therapy (D7). Evaluation of the cellular receptors was carried out by flow cytometry. Expression of CD14 on monocytes and of CD11b and CXCR2 on neutrophils from SP was lower than that from HV. Conversely, expression of TLR5 on monocytes and neutrophils was higher in SP compared with HV. Expression of TLR2 on the surface of neutrophils and that of TLR5 on monocytes and neutrophils of SP was lower at D7 than at D0. In addition, SP who survived showed reduced expression of TLR2 and TLR4 on the surface of neutrophils at D7 compared to D0. Expression of CXCR2 for surviving patients was higher at follow-up compared to baseline. We conclude that expression of recognition and cell signaling receptors is differentially regulated between SP and HV depending on the receptor being evaluated.

Papel protector de las lipoproteínas de alta densidad en sepsis: aspectos básicos e implicancias clínicas / Protective role of high density lipoproteins in sepsis: basic issues and clinical implications

High density lipoproteins (HDL) are responsible of reverse cholesterol transport and play an important antiatherogenic role. In recent years, several studies suggest that HDL have additional functions, including a possible anti-inflammatory activity in infectious conditions. Furthermore, available evidence indicates that the presence of lipopolysaccharide (LPS) within the circulation during infectious states induced by gram-negative bacteria may be involved in the decrease in HDL cholesterol levels and changes in lipoprotein composition, which have been associated with a higher mortality due to sepsis in animal models and in humans. In this article, we review this subject and also discuss possible mechanisms that explain the positive impact achieved by native HDL, reconstituted HDL, or HDL apolipoprotein peptides on the inflammatory response and mortality in models of endotoxemia. In this regard, it has been proposed that one of the mechanisms by which HDL protect against sepsis may be mediated by its binding ability and/or neutralizing capacity on LPS, avoiding an excessive response of the immune system. Thus, increasing blood levels of HDL and/or parenteral HDL administration may represent a new anti-inflammatory tool for managing septic states in humans.

Las lipoproteínas de alta densidad (HDL) son responsables del transporte reverso de colesterol y ejercen un importante papel anti-aterogénico. En los últimos años, diversos estudios indican que las HDL también tendrían otras funciones críticas, incluyendo una posible actividad anti-inflamatoria durante estados infecciosos. Además, la evidencia disponible sugiere que la presencia de lipopolisacárido (LPS) en la circulación durante estados infecciosos inducidos por bacterias gramnegativas podría estar involucrado en la disminución del colesterol HDL y los cambios en composición de esta clase lipoproteínas, lo cual se asociaría con una mayor tasa de mortalidad por sepsis en modelos animales y en humanos. En este trabajo, se revisan los antecedentes mencionados y además se discuten posibles mecanismos que explican la disminución de la respuesta inflamatoria y de la mortalidad que se logran en modelos de endotoxemia tratados con HDL o preparaciones similares. En este sentido, se ha propuesto que uno de los mecanismos protectores de las HDL estaría mediado por su capacidad de unión y/o neutralización del LPS, evitando una respuesta exacerbada del sistema inmune. De esta manera, el aumento de los niveles sanguíneos de HDL y/o su administración parenteral podrían constituir nuevas herramientas anti-inflamatorias para el manejo de estados sépticos en humanos.

El corazón endocrino y el proceso inflamatorio / [The endocrine heart and inflammation].

The endocrine heart produces the polypeptide hormones Atrial Natriuretic Factor (ANF or ANP) and Brain Natriuretic Peptide (BNP). Through the peripheral actions of these hormones the heart contributes to the regulation of the cardiac preload and afterload. More recently, new functions for these hormones have been described including the modulation of the immune response. Plasma levels of BNP but not those of ANF, increase following an acute rejection episode of a cardiac allotransplant but return to levels pre-rejection with successful treatment. This observation constitutes the first observation leading to characterizing the interactions of BNP with the immune response. Several other pathologies with an inflammatory component are now known to be associated with an increase in the production of BNP. Such an increase is due to an increase in the transcriptional activity of the BNP gene induced by cytokines and related substances. In vitro investigations have shown that an increase in BNP directly modulates immunological activity. Inflammation and hemodynamic changes co-exist in several cardiovascular diseases and therefore it may be beneficial to measure circulating levels of both ANF and BNP as biomarkers of changes in intravascular volume and of changes in intravascular volume plus inflammation, respectively. Changes in plasma ANF, that are relatively larger than those of BNP, might be an indication of hemodynamic deterioration while important changes in circulating BNP could indicate a worsening of the inflammatory process.

Propionibacterium acnes-killed attenuates the inflammatory response and protects mice from sepsis by modulating inflammatory factors

BACKGROUND: Sepsis is a systemic inflammation associated with infection caused by pathogenic micro-organisms with high mortality rates. OBJECTIVE: In this study, we investigated the protective effect of Propionibacterium acnes-killed against polymicrobial sepsis induced by cecal ligation and puncture. METHODS: The mice were treated by intramuscular route in 1, 3, 5, and 7 days before the cecal ligation and puncture induction. The control group animals received vehicle (saline solution 0.9%) and the animals of the treated group received the P. acnes-killed (0.4 mg/animal). After anesthesia, midline laparotomy was performed with exposure of cecum followed by ligature and one transverse perforation of the same, with a 18 G needle, for induction of lethal sepsis. After surgery, the cecum of the animals was replaced into the peritoneal cavity, and it was closed with a 4.0 nylon suture. The survival of animals subjected to lethal sepsis was evaluated after cecal ligation and puncture induction. Six hours after the induction of sepsis, neutrophil migration, the number of bacteria, TNF-α, MCP-1, IL-6, and IL-10 were performed in the peritoneal lavage. RESULTS: Prophylactic treatment with P. acnes-killed increased the survival of the animals, followed by a significant decrease in the TNF-α, IL-10, and MCP-1 levels, 6 h after cecal ligation and puncture. Furthermore, P. acnes-killed administration reduced the number of bacteria in the peritoneal cavity with increased migration of leukocytes, especially neutrophils. CONCLUSION: P. acnes-killed promoted increased survival rate of animals with sepsis, in part attributed to its immunomodulatory properties against pathogenic microorganisms, as well as better control of infection by reducing bacterial counts.

Prediction of sepsis-related outcomes in neonates through systematic genotyping of polymorphisms in genes for innate immunity and inflammation: a narrative review and critical perspective / Previsao de desfechos relacionados a sepse em neonatos atraves da genotipagem sistematica de polimorfismos de genes da imunidade inata e inflamacao: uma revisao narrativa e perspectiva critica

CONTEXT AND OBJECTIVE: Neonatal sepsis is associated with premature birth and maternal infection. Large-scale studies seek to define markers that identify neonates at risk of developing sepsis. Here, we examine whether the scientific evidence supports systematic use of polymorphism genotyping in cytokine and innate immunity genes, to identify neonates at increased risk of sepsis. DESIGN AND SETTING: Narrative literature review conducted at Fernandes Figueira Institute, Brazil. METHODS: The literature was searched in PubMed, Embase (Excerpta Medica Database), Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde), SciELO (Scientific Electronic Library Online) and Cochrane Library. From > 400,000 references, 548 were retrieved based on inclusion/exclusion criteria; 22 were selected for detailed analysis after quality assessment. RESULTS: The studies retrieved addressed the impact of gene polymorphisms relating to immune mechanisms (most often TNF-a, LT-a, IL-6, IL-1β, IL-1ra, L-selectin, CD14 and MBL) or inflammatory mechanisms (ACE and angiotensin II receptors; secretory PLA2; and hemostatic factors). Despite initial reports suggesting positive associations between specific polymorphisms and increased risk of sepsis, the accumulated evidence has not confirmed that any of them have predictive power to justify systematic genotyping. CONCLUSIONS: Sepsis prediction through systematic genotyping needs to be reevaluated, based on studies that demonstrate the functional impact of gene polymorphisms and epidemiological differences among ethnically distinct populations. .

CONTEXTO E OBJETIVO: A sepse neonatal está associada ao parto prematuro e à infecção materna. Estudos em grande escala buscam marcadores que identifiquem neonatos em risco de desenvolver sepse. Examinamos aqui se a evidência científica apoia o uso sistemático de genotipagem dos polimorfismos em genes de citocinas e imunidade inata, para identificar neonatos com risco elevado de sepse. TIPO DE ESTUDO E LOCAL: Revis ão narrativa da literatura, Instituto Fernandes Figueira, Brasil. M ÉTODOS: Busca online da literatura foi feita no PubMed, Embase (Excerpta Medica Database), Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde), SciELO (Scientific Electronic Library Online) e Cochrane Library. De mais de 400.000 referências, 548 foram recuperadas com base nos critérios de inclusão/exclusão, e 22, selecionadas para análise detalhada após verificação da qualidade. RESULTADOS: Recuperamos estudos de impacto dos polimorfismos em genes relacionados com mecanismos imunes (mais frequentemente, TNF-a, LT-a, IL-6, IL-1 β, IL-1ra, L-selectin, CD14, e MBL) ou inflamatórios (ACE e receptores de angiotensina II; PLA2 secretória; fatores hemostáticos). Contrariando estudos que inicialmente sugeriram associação positiva entre polimorfismos específicos e risco aumentado de sepse, a evidência acumulada não confirmou, para qualquer deles, valor preditivo que justifique genotipagem sistemática para orientar antibioticoterapia. CONCLUSÕES: A previsão da sepse por meio de genotipagem sistemática precisa ser reavaliada, com base em estudos que demonstram o impacto funcional de polimorfismos gênicos e as diferenças epidemiológicas entre populações etnicamente distintas. .

Células con propiedades inmunoreguladoras y su impacto en la patogénesis de la sepsis / Cells with immunoregulatory properties and their impact in the pathogenesis of sepsis

Sepsis, defined as a systemic inflammatory response syndrome caused by an infection, is a significant cause of mortality worldwide. It is currently accepted that death associated to sepsis is due to an immune hyperactivation state involving the development of a broad proinflammatory response along with alterations in the coagulation system. It is now clear that besides the inflammatory events, the clinical course of sepsis is characterized by the development of an anti-inflammatory response that could lead to death in its attempt to balance the initial response. The purpose of this review is to summarize current mechanisms that explain the pathogenesis of sepsis, underlying the role that cells with immunoregulatory properties play during the course of this complex syndrome. A better understanding of these processes will contribute in the search of more successful therapeutic strategies.

El síndrome de respuesta sistémica consecuencia de una infección, denominado sepsis, constituye una causa significativa de muerte en el mundo. Históricamente se ha aceptado que la muerte por sepsis se debe a un estado de hiperactivación inmunológica, que implica el desarrollo de una vasta respuesta pro-inflamatoria acompañada de alteraciones en el sistema de coagulación. Ahora es claro que además de los sucesos inflamatorios, el curso clínico de la sepsis se caracteriza por el desarrollo de una respuesta anti-inflamatoria que busca contrarrestar la respuesta inicial, y es ésta finalmente en gran parte responsable de la muerte de los pacientes. El propósito de esta revisión es resumir los mecanismos actuales que explican la patogénesis de la sepsis, y específicamente el papel que desempeñan las subpoblaciones celulares con propiedades inmuno-reguladoras durante el curso de la enfermedad. El mejor entendimiento de estos procesos contribuirá a la búsqueda de estrategias terapéuticas más exitosas.

Factors associated with mortality through sepsis syndrome in children 31 days to 14 years of age: Hospital Universitario del Valle, Cali / Factores asociados con mortalidad por síndrome de sepsis en niños entre 31 días y 14 años de edad: Hospital Universitario del Valle, Cali

Objective: To determine factors associated with mortality by sepsis syndrome in children. Methods: We performed an analytical study of cases and controls, which included patients between 31 days and 14 years of age, treated at Hospital Universitario del Valle in Cali, Colombia, with sepsis syndrome between 1999 and 2003. Information was gathered from medical records and books. The outcome variable was the status on discharge from hospital (alive or dead). All the dead children were verified in the hospital records and all the living children were confirmed alive four weeks after discharge. The exposure control variables were age, gender, origin, socioeconomic status, educational level of mothers, family order of the child, classification and origin of sepsis, nutritional status, underlying disease, presence and type of immunosuppression, invasive procedures, duration of surgery, broad-spectrum antibiotics, as well as preoperative, hospital and intensive care stay. Results: We evaluated 110 cases and 110 controls, 79 with diagnosis of sepsis and 31 with septic shock. The cases had more days of evolution of the disease, higher proportion of family order of the child between third and fifth offspring, malnutrition, acquired immunosuppression, respiratory origin of sepsis, and shorter hospital stay and in intensive care. The logistic regression model showed that more days of disease progression (OR 1.05 CI 95% 1.01-1.10), and family order of the child (1.39 CI 95% 1.11-1.74), meant greater risk of dying from sepsis syndrome. Conclusions: It must be insisted to the community of the importance of consultation and early diagnosis of any infectious process for rapid identification of the bacteria, allowing the introduction of specific treatment and referral according to severity level.

Objetivo: Determinar los factores asociados con mortalidad por síndrome de sepsis en niños. Métodos: Se diseñó un estudio analítico de casos y controles, que incluyó pacientes de 31 días a 14 años de edad, atendidos entre 1999 y 2003 en el Hospital Universitario del Valle, Cali, con síndrome de sepsis. Se obtuvo información de las historias clínicas, de los libros de egreso y del anfiteatro. La variable desenlace fue el estado al egreso del hospital (vivo o muerto). Todos los niños muertos fueron verificados en los libros de defunciones del hospital y todos los vivos fueron confirmados cuatro semanas posteriores al egreso. Las variables de exposición de control fueron edad, género, procedencia, estrato socioeconómico, nivel educativo de las madres, orden familiar del menor, clasificación y origen de la sepsis, estado nutricional, enfermedad de base, presencia y tipo de inmunosupresión, procedimientos invasivos, duración de la cirugía, antibióticos de amplio espectro, estancia prequirúrgica hospitalaria y en cuidados intensivos. Resultados: Se evaluaron 110 casos y 110 controles, 79 con diagnóstico de sepsis y 31 con choque séptico. Los casos tuvieron más días de evolución de la enfermedad, mayor proporción de orden familiar del menor entre tercero y quinto, de desnutrición, inmunosupresión adquirida, origen respiratorio de la sepsis y menor estancia hospitalaria y en cuidados intensivos. El modelo de regresión logística mostró que a más días de evolución de la enfermedad (OR 1,05 IC 95% 1,01-1,10) y orden familiar del menor (1,39 IC 95% 1,11-1,74), era mayor el riesgo de morir por el síndrome de sepsis. Conclusiones: Insistir a la comunidad acerca de la importancia de la consulta y diagnóstico temprano de todo proceso infeccioso para la rápida identificación del germen, que permita la instauración del tratamiento específico y según severidad remisión a un nivel superior.

Antibiotic resistance among pathogens causing disease in Jamaican children with HIV/AIDS / Resistencia antibiótica entre los patógenos que causan enfermedades en los niños jamaicanos con VIH/SIDA

OBJECTIVE: There are limited data regarding the antimicrobial resistance patterns of pathogens in children with HIV/AIDS from developing countries. We aimed to determine the prevalence and antibiotic susceptibility patterns of bacterial pathogens causing urinary tract infections (UTIs) and sepsis in a cohort of 219 HIV-infected Jamaican children. METHODS: This cross-sectional study examined clinical and microbiological data for children enrolled in the Kingston Paediatric/Perinatal HIV/AIDS programme from September 1, 2002 to May 31, 2007. Cases were defined as physician-diagnosed, laboratory confirmed UTIs and sepsis based on Centers for Disease Control and Prevention (CDC) criteria. Only isolates from urine, blood and sterile sites were considered. RESULTS: Forty-four patients (20.1%) accounted for 74 episodes of UTIs and sepsis. Mean number of infections was 1.7 ± 1.3 per patient. There were 31 males (70.5%) and mean age at time of infection was 5.6 ± 4.7 years. Bacterial infections comprised cystitis (n = 52, 70.3%), bacterial pneumonia (n = 15, 20.3%), meningitis (n = 4, 5.4%), septicaemia (n = 2, 2.7%) and bone infection (n = 1, 1.4%). Among 52 UTIs, 39 were caused by a single organism. The most common UTI isolates included Escherichia coli (n = 21, 53.8%) and Enterobacter spp (n = 5, 12.8%). Among 22 cases of sepsis, isolates included Streptococcus pneumoniae (n = 8, 36.4%) and coagulase negative Staphylococcus (n = 6, 27.3%). All E coli isolates at two of three clinical sites were resistant to cotrimoxazole. There were 79.7% (n = 51) of infectious episodes with a cotrimoxazole-resistant organism occurring among those on cotrimoxazole prophylaxis. CONCLUSIONS: Escherichia coli was the most frequent bacterial isolate. Cotrimoxazole is a poor choice for empiric treatment of sepsis and UTIs in this clinical setting.

OBJETIVO: Los datos existentes en relación con los patrones de resistencia antimicrobiana en los ninos con VIH/SIDA de los países en vías de desarrollo, son limitados. Nuestro objetivo fue determinar la prevalencia y los patrones de susceptibilidad antibiótica de los patógenos bacterianos que causan infecciones de las vías urinarias (IVU) y sepsis en una cohorte de 219 ninos jamaicanos infectados con VIH. MÉTODOS: Este estudio transversal examinó datos clínicos y microbiológicos de ninos enrolados en el programa KPAIDS del 1ero. de septiembre de 2002 al 31 de mayo de 2007. Los casos se definieron como IVU y sepsis de diagnóstico médico, confirmada en el laboratorio, a partir de criterios de los Centros de Control y Prevención de Enfermedades (CCE). Solamente se tuvieron en cuenta aislados de orina, sangre y sitios estériles. RESULTADOS: Cuarenta y cuatro pacientes (20.1%) dieron lugar a 74 episodios de IVU y sepsis. El número promedio de infecciones fue 1.7 ± 1.3 por paciente. Hubo 31 varones (70.5%) y la edad promedio en el momento de la infección fue 5.6 ± 4.7 anos. Las infecciones bacterianas abarcaron: cistitis (n = 52, 70.3%), pulmonía bacteriana (n = 15, 20.3%), meningitis (n = 4, 5.4%), septicemia (n = 2, 2.7%) e infección ósea (n = 1, 1.4%). De las 52 IVU, 39 fueron causadas por un solo microorganismo. Los aislados más comunes de IVU incluyeron Escherichia coli (n = 21, 53.8%) y Enterobacter spp (n = 5, 12.8%). De los 22 casos de sepsis, los aislados incluyeron Streptococcus pneumoniae (n = 8, 36.4%) y Staphylococcus coagulasa negativo (n = 6, 27.3%). Todos los aislados de E coli en dos o tres sitios clínicos eran resistentes al cotrimoxazol. Se produjeron 79.7% (n = 51) episodios infecciosos con un organismo resistente al cotrimoxazol entre los pacientes que se hallaban bajo profilaxis con cotrimoxazol. CONCLUSIONES: Escherichia coli fue el aislado bacteriano más frecuente. El cotrimoxazol es una opción pobre para el tratamiento empírico de sepsis e IVU en esta situación clínica.

Immune cells and oxidative stress in the endotoxin tolerance mouse model

Sepsis is a systemic inflammatory response that can lead to tissue damage and death. In order to increase our understanding of sepsis, experimental models are needed that produce relevant immune and inflammatory responses during a septic event. We describe a lipopolysaccharide tolerance mouse model to characterize the cellular and molecular alterations of immune cells during sepsis. The model presents a typical lipopolysaccharide tolerance pattern in which tolerance is related to decreased production and secretion of cytokines after a subsequent exposure to a lethal dose of lipopolysaccharide. The initial lipopolysaccharide exposure also altered the expression patterns of cytokines and was followed by an 8- and a 1.5-fold increase in the T helper 1 and 2 cell subpopulations. Behavioral data indicate a decrease in spontaneous activity and an increase in body temperature following exposure to lipopolysaccharide. In contrast, tolerant animals maintained production of reactive oxygen species and nitric oxide when terminally challenged by cecal ligation and puncture (CLP). Survival study after CLP showed protection in tolerant compared to naive animals. Spleen mass increased in tolerant animals followed by increases of B lymphocytes and subpopulation Th1 cells. An increase in the number of stem cells was found in spleen and bone marrow. We also showed that administration of spleen or bone marrow cells from tolerant to naive animals transfers the acquired resistance status. In conclusion, lipopolysaccharide tolerance is a natural reprogramming of the immune system that increases the number of immune cells, particularly T helper 1 cells, and does not reduce oxidative stress.

Salmonelose septicêmica prolongada associada à esquistossomose: evolução do conhecimento e mecanismos imunopatogênicos: [revisão] / Schistosoma-associated chronic septicemic salmonellosis: evolution of knowledge and immunopathogenic mechanisms: [review]

A salmonelose septicêmica prolongada é uma entidade clinicamente individualizada caracterizada por febre prolongada com hepatoesplenomegalia que ocorre em indivíduos esquistossomóticos coinfectados com salmonelas. Os mecanismos imunopatogênicos são vários e dependem das peculiaridades das interações entre as salmonelas e várias espécies do gênero Schistosoma. As modificações ocasionadas no sistema imunitário pela infecção parasitária são responsáveis pela evolução do quadro da doença. Nesta revisão, analisamos a evolução do conhecimento sobre a entidade e discutimos os possíveis mecanismos imunofisiopatogênicos que concorrem para seu desenvolvimento.

Chronic septicemic salmonellosis is an individualized clinical entity characterized by prolonged fever with enlargement of the liver and spleen that occurs in Schistosoma-infected individuals who are coinfected with Salmonella. Several immunopathogenic mechanisms are involved, and they depend on the peculiarities of the interactions between Salmonella and various species of the genus Schistosoma. The modifications to the immune system that are caused by parasite infection are responsible for the evolution of the disease. In this review, we analyze the evolution of the knowledge on this entity and discuss the possible immuno-physiopathogenic mechanisms that contribute towards its development.

Antiphospholipid antibodies and multiple organ failure in critically ill cancer patients

OBJECTIVES: To describe the clinical outcomes and thrombotic events in a series of critically ill cancer patients positive for antiphospholipid (aPL) antibodies. DESIGN: Retrospective case series study. SETTING: Medical-surgical oncologic intensive care unit (ICU). PATIENTS AND PARTICIPANTS: Eighteen patients with SIRS/sepsis and multiple organ failure (MOF) and positive for aPL antibodies, included over a 10-month period. INTERVENTIONS: None MEASUREMENTS AND RESULTS: aPL antibodies and coagulation parameters were measured up to 48 hours after the occurrence of acrocyanosis or arterial/venous thrombotic events. When current criteria for the diagnosis of aPL syndrome were applied, 16 patients met the criteria for "probable" and two patients had a definite diagnosis of APL syndrome in its catastrophic form (CAPS). Acrocyanosis, arterial events and venous thrombosis were present in eighteen, nine and five patients, respectively. Sepsis, cancer and major surgery were the main precipitating factors. All patients developed MOF during the ICU stay, with a hospital mortality rate of 72 percent (13/18). Five patients were discharged from the hospital. There were three survivors at 90 days of follow-up. New measurements of lupus anticoagulant (LAC) antibodies were performed in these three survivors and one patient still tested positive for these antibodies. CONCLUSIONS: In this small series of patients, we observed a high frequency of auto-antibodies and micro- and macro-vascular thrombotic events in critically ill cancer patients. The coexistence of sepsis or SIRS and aPL antibodies was often associated with MOF and death. More studies are necessary to determine the pathophysiological significance of antiphospholipid antibodies in severely ill cancer patients.

Oxidative stress in sepsis in children.

BACKGROUND & OBJECTIVE: Information on oxidative damage during sepsis in children is not available, we undertook this study to assess the levels of certain antioxidants in blood of children with sepsis. METHODS: Study group had 38 children with sepsis (<5 yr) and 39 age-and sex-matched controls admitted to a tertiary care hospital. Red cell glutathione (GSH), superoxide dismutase (SOD) and thiobarbituric acid reactive substance (TBARS) and plasma vitamin C were estimated by standard techniques. RESULTS: There was no significant change in erythrocyte GSH, SOD and TBARS levels in sepsis when compared to controls. This may be due to the adaptive response of the body to combat the oxidative stress. However, plasma vitamin C levels were significantly reduced in patients aged one year one month to five years which may be due to active phagocytosis and due to its role as a free radical scavenger. INTERPRETATION & CONCLUSION: Our findings show that children affected by sepsis probably adapt to the free radical toxicity induced by this condition. Further studies need to be done on a larger sample to confirm the findings.

Effect of post-natal castration on sepsis mortality in rats

PURPOSE: To investigate the influence of castration in early periods of development on survival to experimental acute sepsis. METHODS: Four groups of 10 (ten) Wistar rats were used. The groups were comprised of males (M), females (F), males castrated on the fourth day of life (CM) and males castrated on the fourth day of life with testosterone replacement (CMR). Sepsis was induced by ligature and cecal perforation in adult life. RESULTS: The analysis of death within 24 hours following sepsis induction showed greater mortality between the M and the CMR groups as compared to the CM and F (p=0.0180) groups. Multiple correspondence analysis (MCA) indicates an association between the M and the CMR groups for death within 24 hours as well as a relationship between the F and the CM groups for the absence of death and death up to 24 hours following sepsis induction. Statistical analysis of the Kaplan-Meier survival curve through log-rank demonstrates a significant difference among the four groups (p=0.0055) and between the M and the F (p=0.0005) groups. CONCLUSION: Data suggest a better survival to sepsis within 24 hours for the F and CM groups, the presence or absence of testosterone in early periods of post-natal life being responsible for these findings.

OBJETIVO: Investigar a influência da castração em períodos precoces do desenvolvimento de ratos, na sobrevida a sepse aguda experimental quando adultos, desenvolveu-se este estudo. MÉTODOS: Utilizou-se quatro grupos de 10 ratos Wistar divididos entre machos (GM), fêmeas (GF), machos castrados no quarto dia de vida GMC) e machos castrados no quarto dia de vida com reposição de testosterona (GMCR). A sepse foi induzida por ligadura e perfuração cecal na vida adulta. RESULTADOS: A análise do óbito até 24 horas da indução da sepse mostrou maior mortalidade entre os GM e GMCR em relação aos grupos GMC e GF (p=0.0180). A análise de correspondência múltipla (ACM) indica uma associação entre si dos GM e GMCR para o óbito em 24 horas, assim como uma relação entre si dos GF e GMC para a ausência de óbito e o óbito até 24 horas. A análise estatística da curva de sobrevida de Kaplan-Meier pelo log-rank demonstra diferença significativa entre os quatro grupos (p=0,0055), e entre GM e GF (p=0,0005). CONCLUSÃO: Os dados sugerem uma maior sobrevida à sepse em 24 horas dos grupos GF e GMC, e a presença ou ausência de testosterona em períodos precoces da vida pós-natal seria responsável por este achado.

Gender and sex hormones influence the response to trauma and sepsis: potential therapeutic approaches

Several clinical and experimental studies have demonstrated gender dimorphism in immune and organ responsiveness and in the susceptibility to and morbidity from shock, trauma, and sepsis. In this respect, cell-mediated immune responses have been shown to be depressed in males following trauma-hemorrhage, whereas they were aintained/enhanced in proestrus females. Furthermore, sex hormones have been shown to be responsible for this gender-specific immune response following adverse circulatory conditions. More specifically, studies indicate that androgens produce immunodepression following trauma-hemorrhage in males. In contrast, female sex steroids appear to exhibit immunoprotective properties following trauma and severe blood loss. With regard to the underlying mechanisms, receptors for sex hormones have been identified on various immune cells suggesting direct effects of these hormones on the immune cells. Alternatively, indirect effects of sex hormones, ie, modulation of cardiovascular responses or androgen- and estrogen-synthesizing enzymes, might contribute to gender-specific immune responses. Recent studies indicate that sex hormones, eg, dehydroepiandrosterone (DHEA), also modulate the function of peripheral blood mononuclear cells in surgical patients. Thus, the immunomodulatory properties of sex hormones/receptor antagonists/sex steroid synthesizing enzymes following trauma-hemorrhage suggests novel therapeutic strategies for the treatment of immunodepression in surgical patients.

Uma série de estudos clínicos e experimentais demonstram a existência de dimorfismo sexual das respostas imunológicas e orgânicas, bem como da suscetibilidade e morbidade em relação ao choque, ao trauma e à sepse. Respostas imunes celularmente mediadas apresentam-se deprimidas em machos em resposta ao binômio trauma-hemorragia, mas conservados/enaltecidos em fêmeas em proestro. Adicionalmente demonstra-se que os hormônios sexuais são responsáveis por esta dicomotomia de resposta sexualmente específica, em condições cardiovasculares adversas. Estudos específicos indicam que os andrógenos produzem imunodepressão pós-trauma hemorragia em machos. Em contraste, esteróides sexuais femininos parecem exibir propriedades imunoprotetoras após episódios de trauma com ou sem perda importante de sangue. No terreno dos mecanismos subjacentes, foram identificados receptores para hormônios sexuais em várias células do sistema imunológico, sugerindo a existência de efeitos diretos destes hormônios sobre tais células. Alternativamente, observam efeitos indiretos de hormônios sexuais tais como modulação das respostas cardiovasculares das enzimas sintetizadores de andrógeno e estrógeno, que podem contribuir para as estas respostas sexualmente diferenciadas. Estudos recentes indicam que os hormônios sexuais, como por exemplo a dehidroepiandrosterona também modulam a função de células mononucleares da série branca em pacientes cirúrgicos. Assim, as propriedades imunomodulatórias de hormônios sexuais/antagonistas de receptores/enzimas sintetizadores de esteróides após a ocorrência de trauma ou de hemorragia sugerem o caminho para novas estratégias terapêuticas para o tratamento de imunodepressão em pacientes cirúrgicos.

Sepsis: emerging role of nitric oxide and selectins

Sepse – um estado de infecção bacteriana sistêmica – frequentemente leva à falência múltipla de órgãos e associa-se a altos índices de mortalidade, apesar de progressos recentes no manejo de pacientes em unidades de terapia intensiva. Muitos dos efeitos maléficos associados à sepse são atribuídos a uma resposta inflamatória patologicamente ampliada que leva a recrutamento neutrofílico e ativação das moléculas de adesão do grupo das selectinas, durante as fases iniciais do processo . O óxido nítrico e sua diversas isoformas também foram implicados nas diversas manifestações vasculares da sepse como participantes diretos da toxicidade celular. Esta revisão descreve o papel das selectinas e do óxido nítrico em situações clínicas e experimentais de sepse, bem como os respectivos efeitos de processos terapêuticos de bloqueio.