Virulence
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Multimodal therapy for diseases like cancer has only become practicable following the development of staging systems like the TNM (tumor, nodes, metastases) system. Staging enables the identification of subgroups of patients with a disease who not only have a differing prognosis, but who are also more likely to benefit from a specific therapeutic modality. Critically ill patients represent a highly heterogeneous population for whom multiple therapeutic options are potentially available, each carrying not only the potential for differential benefit, but also the potential for differential harm. ⋯ However the creation of a valid, robust, and clinically useful system presents significant challenges arising from the complexity of the disease state, the lack of a clear phenotype, the confounding influence of the effects of therapy and of cultural and socio-economic factors, and the relatively low profile of acute illness with clinicians and the general public. This review summarizes the rationale for such a model of illness stratification and the results of preliminary cohort studies testing the concept. It further proposes two strategies for building a staging system, recognizing that this will be a demanding undertaking that will require decades of work.
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Review
The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer?
Sepsis remains the leading cause of death in most intensive care units. Advances in understanding the immune response to sepsis provide the opportunity to develop more effective therapies. The immune response in sepsis can be characterized by a cytokine-mediated hyper-inflammatory phase, which most patients survive, and a subsequent immune-suppressive phase. ⋯ Currently in clinical trial for sepsis are granulocyte macrophage colony stimulating factor and interferon gamma, immune-therapeutic agents that boost patient immunity. Immuno-adjuvants with promise in clinically relevant animal models of sepsis include anti-programmed cell death-1 and interleukin-7. The future of immune therapy in sepsis will necessitate identification of the immunologic phase using clinical and laboratory parameters as well as biomarkers of innate and adaptive immunity.
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The immune response to sepsis can be seen as a pattern recognition receptor-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital. Invasive infection triggers both pro-inflammatory and anti-inflammatory host responses, the magnitude of which depends on multiple factors, including pathogen virulence, site of infection, host genetics, and comorbidities. Toll-like receptors, the inflammasomes, and other pattern recognition receptors initiate the immune response after recognition of danger signals derived from microorganisms, so-called pathogen-associated molecular patterns or derived from the host, so-called danger-associated molecular patterns. Further dissection of the role of host-pathogen interactions, the cytokine response, the coagulation cascade, and their multidirectional interactions in sepsis should lead toward the development of new therapeutic strategies in sepsis.
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Review
The clinical impact of multidrug-resistant gram-negative bacilli in the management of septic shock.
Multi-antibiotic drug-resistant (MDR) gram-negative bacilli are becoming a major threat to the standard care of septic patients. Empiric antimicrobial drug regimens to cover likely bacterial pathogens have to be altered in keeping with the spread of MDR pathogens in the health care setting and in the community. ⋯ In some regions of Asia, South America, and Eastern Europe in particular, MDR pathogens have become a major concern, necessitating the use of potentially toxic and costly antibiotic combinations as initial antibiotic therapy for septic shock. In this brief review, we will focus on the emergence of MDR gram-negative pathogens, resistance mechanisms, and suggest some management and prevention strategies against MDR pathogens.
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An important role for bioenergetic dysfunction is increasingly emerging to potentially explain the paradox of clinical and biochemical organ failure in sepsis yet minimal cell death, maintained tissue oxygenation and recovery in survivors. Associations are well-recognized between the degree of mitochondrial dysfunction and outcomes. ⋯ This is particularly pertinent in light of the multiple trial failures related to immunomodulatory therapies. This overview will provide insights into mitochondrial biology, the relevance to sepsis, and therapeutic opportunities that possibly emerge.