The Emperor Has no Clothes? Searching for Dysregulation in Sepsis

Alcock, Joe

doi:10.20944/preprints201807.0486.v1

Cited by 3 publications

(3 citation statements)

References 35 publications

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“…The framework that we have provided here, supports the notion that Asian and African monkeys models for particular Gram‐negative bacterial infections in humans have significant limitations. It also helps illustrate why clinical approaches to lessening bystander damage during severe infection by limiting human LPS detection—a common approach in sepsis drug trials over the 1980s–2000s—should be expected to be deleterious 26,182 . An appreciation of how such traits are the outcome of the human evolutionary experience can further our understanding of not just our species' story, but how best to address infection and one of our most common causes of mortality.…”

Section: Discussionmentioning

confidence: 99%

Sepsis and the evolution of human increased sensitivity to lipopolysaccharide

Brinkworth

Valizadegan

2021

Evolutionary Anthropology

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Among mammals, humans are exquisitely sensitive to lipopolysaccharide (LPS), an environmentally pervasive bacterial cell membrane component. Very small doses of LPS trigger powerful immune responses in humans and can even initiate symptoms of sepsis. Close evolutionary relatives such as African and Asian monkeys require doses that are an order of magnitude higher to do the same. Why humans have evolved such an energetically expensive antimicrobial strategy is a question that biological anthropologists are positioned to help address. Here we compare LPS sensitivity in primate/mammalian models and propose that human high sensitivity to LPS is adaptive, linked to multiple immune tactics against pathogens, and part of multi‐faceted anti‐microbial strategy that strongly overlaps with that of other mammals. We support a notion that LPS sensitivity in humans has been driven by microorganisms that constitutively live on us, and has been informed by human behavioral changes over our species' evolution (e.g., meat eating, agricultural practices, and smoking).

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Section: Discussionmentioning

confidence: 99%

Sepsis and the evolution of human increased sensitivity to lipopolysaccharide

Brinkworth

Valizadegan

2021

Evolutionary Anthropology

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“…Both above studies comprised less than 50% sepsis patients. However, patients with sepsis have worse clinical outcomes and might have distinct immune profiles compared to those without [ 14 , 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Insufficient Nutrition and Mortality Risk in Septic Patients Admitted to ICU with a Focus on Immune Dysfunction

et al. 2019

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Immune dysfunction is seen both in sepsis patients and in those with malnutrition. This study aimed to determine whether insufficient nutrition and immune dysfunction have a synergistic effect on mortality in critically ill septic patients. We conducted a prospective observational study from adult sepsis patients admitted to intensive care units (ICUs) between August 2013 and June 2016. Baseline characteristics including age, gender, body mass index, NUTRIC, Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were recorded. Immune dysfunction, defined by human leukocyte antigen DR (HLA-DR) expression, was tested at days 1, 3, and 7 of ICU admission. The study included 151 patients with sepsis who were admitted to the ICU. The 28-day survivors had higher day 7 caloric intakes (89% vs 73%, p = 0.042) and higher day 1-HLA-DR expression (88.4 vs. 79.1, p = 0.045). The cut-off points of day 7 caloric intake and day 1-HLA-DR determined by operating characteristic curves were 65.1% and 87.2%, respectively. Immune dysfunction was defined as patients with day 1-HLA-DR < 87.2%. Insufficient nutrition had no influence on survival outcomes in patients with immune dysfunction. However, patients with insufficient nutrition had poor prognosis when they were immune competent. Insufficient nutrition and immune dysfunction did not have a synergistic effect on mortality in critically ill septic patients.

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“…При критических состояниях отмечается комбинация факторов системного повреждения инфекционной и неинфекционной природы, на которые ответ организма не является полностью ни адаптивным, ни, напротив, неадаптивным [47]. Поэтому некоторые авторы в принципе ставят под сомнение определение сепсиса как дисрегуляции реакции хозяина [7]. Кроме того, определение «дисрегулируемый, или дисфункциональный, ответ на инфекцию» подразумевает отсутствие типового подхода и то, что в дальнейшем нужно будет вводить в научный оборот формулировки «дисрегуляция ответа на травму, отравления, кровопотерю, гипоксию, на аллергены при анафилактическом шоке и т. д.».…”

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Sepsis-3: new edition — old problems. analysis from the perspective of general pathology

Гусев¹,

Zotova²,

Черешнев³

2021

Russian Journal of Infection and Immunity

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Sepsis-3 Guidelines defines sepsis as an organ dysfunction caused by dysregulated host response to infection. To record organ dysfunction, the SOFA/quick SOFA scales were recommended. In fact, in medical practice, sepsis is considered nothing more than a critical infection that requires intensive care. Therefore, sepsis is pathogenetically a nonhomogeneous condition manifested by diverse nosologies and syndromes. Unlike the previous two editions, Sepsis-1 and Sepsis-2 Guidelines, the formal criteria provided in the Sepsis-3 are closer to the de facto position, describe more specific, but less sensitive features to predict mortality. However, the initial, latent manifestations of critical conditions, which can be relatively effectively controlled by intensive therapy, remain outside the Sepsis-3 criteria. Not all signs of multiple organ dysfunctions (according to the Sepsis-3 criteria) will require intensive care. Hence, obviously the presence or absence of formal criteria of Sepsis-3 will not be always taken into account while verifying sepsis. The only relatively pathogenetically homogeneous definition in Sepsis-3 is “septic shock”. However, it also does not fully consider the staging (according to the degree of compensation of hemodynamic disturbances) and the phasing (according to the severity of the proinflammatory response) of the dynamics of the shock condition. From our point of view, a positive result of the Sepsis-3 consensus would be in transition of the systemic inflammatory response syndrome (SIRS) from the main to additional (optional) verifying sepsis criteria. We also believe that the weak side of the Sepsis-3 Guidelines is in underestimated mechanisms of systemic inflammation as a general pathological process in the genesis of developing critical conditions of various origins. From the perspective of general pathology, sepsis is a combination of the three common fundamental pathological processes: classical (canonical) and systemic inflammation (SI), as well as chronic systemic low-grade inflammation (parainflammation), the latter can be considered as an unfavorable background for development of the former two processes. All three processes are characterized by any SIR signs and require to be differentiated on the basis of integral criteria, which reflect specific blocks of the SI complex process. The pathogenesis of the SARS-CoV-2 infection (COVID-19) is a relevant example underlying inevitability of such approach. The systemic microvascular vasculitis, and its main clinical manifestations such as systemic microcirculatory disorders in the form of shockogenic conditions is the SI pathogenetic basis. Apparently, one of the modalities for further evolution of critical care medicine will be coupled to development of a more multilayered but effective methods for assessing pathogenesis of critical states and more differentiated methods of pathogenetic therapy. Therefore, it will require to modernize a number of fundamental premises in our knowledge about pathobiology, pathophysiology, and general pathology.

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The Emperor Has no Clothes? Searching for Dysregulation in Sepsis

Cited by 3 publications

References 35 publications

Sepsis and the evolution of human increased sensitivity to lipopolysaccharide

Sepsis and the evolution of human increased sensitivity to lipopolysaccharide

Insufficient Nutrition and Mortality Risk in Septic Patients Admitted to ICU with a Focus on Immune Dysfunction

Sepsis-3: new edition — old problems. analysis from the perspective of general pathology

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