Sepsis

Complex MONDO:1040015 Pathograph 15 Show in embeddings browser infectious disease

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. It is a syndrome rather than a single etiology: many different pathogens and infection sites converge on a common host program in which innate immune activation, endothelial injury, and coagulation activation become mutually amplifying. The resulting microcirculatory failure and cellular bioenergetic failure produce dysfunction across multiple organ systems. A concurrent, and often protracted, immunosuppressive arm leaves survivors of the initial insult unable to clear the primary infection and vulnerable to secondary infection. Septic shock is the subset with profound circulatory, cellular, and metabolic abnormalities and substantially higher mortality.

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9
Pathophys.
11
Phenotypes
2
Hypotheses
2
Gaps
15
Pathograph
6
Medical Actions
2
Subtypes
1
Deep Research
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Subtypes

2
severity
Septic Shock
The subset of sepsis in which circulatory, cellular, and metabolic abnormalities are profound enough to substantially increase mortality, clinically identified by a vasopressor requirement to maintain mean arterial pressure of 65 mm Hg or greater together with a serum lactate above 2 mmol/L in the absence of hypovolemia. No MONDO term for human septic shock exists, so no subtype_term is bound.
Show evidence (2 references)
PMID:26903338 SUPPORT Human Clinical
"Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone."
The international consensus statement defines septic shock as a severity subset of sepsis, which is how it is modeled here.
PMID:26903338 SUPPORT Human Clinical
"Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia."
Supplies the operational clinical criteria quoted in the subtype description.
age group
Neonatal Sepsis MONDO:0700217
Sepsis in infants younger than 28 days, in whom immature innate and adaptive immunity, distinct pathogen spectra, and different presenting physiology warrant a separate subtype.
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Mechanistic Hypotheses

2
Thromboinflammatory Microcirculatory Failure Model
thromboinflammatory_microcirculatory_model CANONICAL
Evidence balance 2 support
Pathogen- and damage-associated molecular patterns drive dysregulated innate immune activation. Activated leukocytes, platelets, and endothelium engage in reciprocal amplification, degrading the endothelial glycocalyx, raising permeability, and activating coagulation while suppressing fibrinolysis. The resulting thromboinflammation obstructs and dysregulates the microcirculation, causing tissue hypoperfusion and organ dysfunction.
Pathograph links
Invasive Infection and Pattern Recognition -> Dysregulated Innate Immune Activation DIRECT Pattern recognition initiates the host response whose dysregulation, not the infection itself, defines sepsis.
Dysregulated Innate Immune Activation -> Endothelial Activation and Glycocalyx Degradation INDIRECT KNOWN INTERMEDIATES Inflammatory mediators and activated leukocytes drive the endothelium into a proinflammatory, proadhesive, procoagulant state.
Endothelial Activation and Glycocalyx Degradation -> Thromboinflammation and Sepsis-Induced Coagulopathy DIRECT The procoagulant endothelial surface, together with activated leukocytes and platelets, drives coagulation activation with suppressed fibrinolysis.
Endothelial Activation and Glycocalyx Degradation -> Microcirculatory Dysfunction and Tissue Hypoperfusion DIRECT Glycocalyx damage and loss of vascular tone regulation directly impair microcirculatory blood flow.
Thromboinflammation and Sepsis-Induced Coagulopathy -> Microcirculatory Dysfunction and Tissue Hypoperfusion DIRECT Microvascular fibrin deposition obstructs capillary flow and compounds the perfusion defect caused by endothelial dysfunction.
Microcirculatory Dysfunction and Tissue Hypoperfusion -> Multiple Organ Dysfunction DIRECT Sustained hypoperfusion of multiple vascular beds produces the organ dysfunction that defines sepsis.
Microcirculatory Dysfunction and Tissue Hypoperfusion -> Sepsis-Associated Acute Kidney Injury INDIRECT KNOWN INTERMEDIATES The kidney is among the earliest and most frequently injured organs, with microcirculatory dysfunction one of the proposed pathogenic routes.
Show evidence (2 references)
PMID:37221630 SUPPORT Other
"The pathophysiology of sepsis-associated DIC is multifactorial, and in addition to coagulation activation with suppressed fibrinolysis, multiple inflammatory responses are initiated by activated leukocytes, platelets, and vascular endothelial cells as part of thromboinflammation."
States the coupled coagulation-inflammation mechanism that this hypothesis group organizes the main causal graph around.
PMID:32101446 SUPPORT Other
"In addition, glycocalyx damage and vascular tone dysfunction impair microcirculatory blood flow, leading to organ injury and, potentially, life-threatening organ failure."
Links the endothelial arm of the model to microcirculatory failure and organ dysfunction.
Oxidative Stress and Mitochondrial Bioenergetic Failure Model
bioenergetic_failure_model ALTERNATIVE
Evidence balance 1 support
An alternative, non-exclusive account holds that organ dysfunction in sepsis is driven less by perfusion failure than by a cellular inability to use oxygen. Overwhelming reactive species production with failure of antioxidant systems produces mitochondrial injury, so that organs fail despite adequate delivery of oxygen. This is offered as a complementary rather than competing mechanism, and it predicts that restoring macrocirculatory flow alone will not reverse organ dysfunction.
The two hypothesis groups are curated as complementary. No evidence here establishes the relative contribution of microcirculatory versus bioenergetic failure to organ dysfunction in an individual patient, and the causal edges are annotated accordingly rather than ranked.
Pathograph links
Dysregulated Innate Immune Activation -> Mitochondrial Dysfunction and Bioenergetic Failure INDIRECT KNOWN INTERMEDIATES Reactive species generated by the inflammatory response overwhelm antioxidant capacity and injure mitochondria.
Mitochondrial Dysfunction and Bioenergetic Failure -> Multiple Organ Dysfunction DIRECT Energy depletion at the cellular level produces organ dysfunction independently of, and additively to, perfusion failure.
Show evidence (1 reference)
PMID:24690420 SUPPORT Other
"The loss of the redox balance, together with a systemic inflammatory response during sepsis, can lead to progressive and irreversible mitochondrial failure, energy depletion, hypoxia, septic shock, severe sepsis, multiple organ dysfunction and death of the patient."
States the redox/mitochondrial route to multiple organ dysfunction that defines this hypothesis group.
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Discussions and Knowledge Gaps

2
Does tumor-microenvironment-driven GRP78 dysregulation causally increase sepsis susceptibility, severity, or mortality in patients with cancer, over and above the recognized contributions of neutropenia, mucosal barrier injury, and immunosuppressive antineoplastic therapy?
KNOWLEDGE GAP OPEN disc_sepsis_grp78_cancer_susceptibility
Attached to
pathophysiology#Invasive Infection and Pattern Recognition pathophysiology#Sepsis-Induced Immunosuppression
Patients with a history of cancer carry a large excess risk of acquiring and dying from sepsis, and sepsis and cancer are independently known to share immune defects, which makes a cancer-specific susceptibility mechanism biologically plausible. A 2026 narrative review proposes GRP78/HSPA5 dysregulation as that mechanism, acting both as a pathogen entry cofactor and as a secreted immunosuppressive signal. The proposal is explicitly hypothesis-level: the review states that no clinical cohort study has established a causal link, and that its argument rests on in vitro work, animal models, and non-oncologic sepsis cohorts. It is therefore curated here as an open gap attached to the trigger and immunosuppression nodes, rather than as a curated causal edge, a GRP78 pathophysiology node, or a separate cancer-associated sepsis disease entry - any of which would assert more than the evidence supports.
Proposed experiments
Oncology-specific prospective cohort of circulating GRP78 and sepsis outcome
exp_sepsis_grp78_oncology_cohort
Measure circulating GRP78 at cancer diagnosis and at infection onset in a prospective oncology cohort, and test whether it predicts sepsis incidence, severity, and mortality after adjustment for neutropenia, mucositis, recent cytotoxic therapy, and tumor stage. This is the study the source review identifies as absent.
Opened in response to issue #6274. The scope question there offered four options; this discussion implements the conservative one. A conserved GRP78 sepsis mechanism module and a distinct Cancer-Associated Sepsis disease entry were both considered and deferred, because a module asserts a recurrent, evidenced mechanism and the source explicitly disclaims that evidence. If an oncology-specific cohort establishes the link, the natural home is a comorbidity entry over Sepsis and the relevant cancer entries.
Show evidence (3 references)
PMID:42429070 SUPPORT Other
"To date, no clinical cohort study has directly established a causal link between GRP78 dysregulation and sepsis incidence or mortality in patients with cancer."
The review's own statement that the causal link is unestablished is the primary justification for curating this as a KNOWLEDGE_GAP rather than as a mechanism.
PMID:16778259 SUPPORT Human Clinical
"Patients with a history of cancer are at increased risk for acquiring and subsequently dying from sepsis, compared to the general population, although incidence and fatality rates are decreasing over time."
Establishes that the excess sepsis risk in cancer is real, which is what makes the unexplained mechanistic residue worth tracking as a gap.
PMID:24232462 SUPPORT Other
"Surprisingly, cancer and sepsis share many immune defects, and the remarkable success of new immunotherapeutics in cancer has highlighted the potential for this new approach in sepsis."
Independent support that cancer and sepsis share immune-defect biology, which is the general premise the GRP78 hypothesis tries to make specific.
In an individual patient with sepsis, what determines the relative contribution of microcirculatory perfusion failure versus mitochondrial bioenergetic failure to organ dysfunction, and can the two be distinguished at the bedside well enough to select therapy?
KNOWLEDGE GAP OPEN disc_sepsis_microcirculatory_vs_bioenergetic
Attached to
pathophysiology#Microcirculatory Dysfunction and Tissue Hypoperfusion pathophysiology#Mitochondrial Dysfunction and Bioenergetic Failure
Both routes to multiple organ dysfunction are curated here with supporting evidence, and they are not mutually exclusive. Neither source quantifies the relative contribution, and there is no validated bedside measure that separates a perfusion-limited from an oxygen-utilization-limited patient. This matters therapeutically: resuscitation strategies target the former, and would not be expected to reverse the latter.
Show evidence (1 reference)
PMID:24690420 SUPPORT Other
"Knowledge of the molecular processes associated with the development of oxidative stress should facilitate the development of effective therapies and better prognosis for patients with sepsis and organ dysfunction."
The review frames effective bioenergetically-targeted therapy as a future prospect, which is the unresolved half of this question. The sentence supports the gap by implication rather than stating it.
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Pathophysiology

9
Invasive Infection and Pattern Recognition
A bacterial, viral, or fungal infection at any site - most often lung, abdomen, urinary tract, or bloodstream - releases pathogen-associated molecular patterns that engage host pattern-recognition receptors. Tissue injury at the site of infection adds damage-associated molecular patterns to the same sensing machinery. The identity of the pathogen is not what makes the syndrome; the host response to it is.
Thromboinflammatory Microcirculatory Failure Model
Toll-like receptor signaling pathway GO:0002224 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Toll-like receptor signaling pathway (GO:0002224). GO:0002224 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Dysregulated Innate Immune Activation Pattern recognition initiates the host response whose dysregulation, not the infection itself, defines sepsis. Thromboinflammatory Microcirculatory Failure Model
Show evidence (1 reference)
PMID:24232462 SUPPORT Other
"Sepsis - which is a severe life-threatening infection with organ dysfunction - initiates a complex interplay of host pro-inflammatory and anti-inflammatory processes."
Establishes infection as the initiating event of the host program modeled by the rest of this graph.
Dysregulated Innate Immune Activation
Innate immune cells mount a proinflammatory program with cytokine and chemokine release, complement activation, neutrophil recruitment, and reactive oxygen species production. In sepsis this response is not merely large but unbalanced: hyperinflammation and immune suppression run concurrently rather than sequentially, which is why the syndrome resists treatment framed as either simple inflammation or simple immunodeficiency.
Oxidative Stress and Mitochondrial Bioenergetic Failure Model Thromboinflammatory Microcirculatory Failure Model
Macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. Neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
Positive regulation of inflammatory response GO:0050729 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Positive regulation of inflammatory response (GO:0050729). GO:0050729 is a biological process from the Gene Ontology. ↑ INCREASED Reactive oxygen species metabolic process GO:0072593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Reactive oxygen species metabolic process (GO:0072593). GO:0072593 is a biological process from the Gene Ontology. ↑ INCREASED Neutrophil extracellular trap formation GO:0140645 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Neutrophil extracellular trap formation (GO:0140645). GO:0140645 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Endothelial Activation and Glycocalyx Degradation Inflammatory mediators and activated leukocytes drive the endothelium into a proinflammatory, proadhesive, procoagulant state. Thromboinflammatory Microcirculatory Failure Model
Sepsis-Induced Immunosuppression The anti-inflammatory arm of the same host program, running concurrently, produces a protracted immunosuppressed state in patients whose sepsis does not resolve.
Mitochondrial Dysfunction and Bioenergetic Failure Reactive species generated by the inflammatory response overwhelm antioxidant capacity and injure mitochondria. Oxidative Stress and Mitochondrial Bioenergetic Failure Model
Show evidence (2 references)
PMID:34758337 SUPPORT Other
"This recently implemented definition does not capture the heterogeneity or the underlying pathophysiology of the syndrome, which is characterized by concurrent unbalanced hyperinflammation and immune suppression."
Supports modeling the innate response as concurrently hyperinflammatory and immunosuppressive rather than as a single inflammatory phase.
PMID:34758337 SUPPORT Other
"NETosis during sepsis can be detrimental through various mechanisms, including induction of intravascular thrombosis and multiple organ failure"
Supports curating neutrophil extracellular trap formation on this node: the same neutrophil effector that traps bacteria becomes injurious in sepsis, and the review names intravascular thrombosis and organ failure as its consequences, which are the two nodes downstream of this one.
Endothelial Activation and Glycocalyx Degradation
The endothelium, acting as a nonconventional immune organ, switches to a proapoptotic, proinflammatory, proadhesive, and procoagulant phenotype. Shedding of the glycocalyx exposes adhesion molecules and procoagulant surface, increases permeability with interstitial fluid loss, and impairs vasomotor regulation.
Thromboinflammatory Microcirculatory Failure Model
Endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
Response to cytokine GO:0034097 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Response to cytokine (GO:0034097). GO:0034097 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Thromboinflammation and Sepsis-Induced Coagulopathy The procoagulant endothelial surface, together with activated leukocytes and platelets, drives coagulation activation with suppressed fibrinolysis. Thromboinflammatory Microcirculatory Failure Model
Microcirculatory Dysfunction and Tissue Hypoperfusion Glycocalyx damage and loss of vascular tone regulation directly impair microcirculatory blood flow. Thromboinflammatory Microcirculatory Failure Model
Show evidence (1 reference)
PMID:32101446 SUPPORT Other
"Endothelial cells (ECs) are vascular, nonconventional immune cells that play a major role in the systemic response after bacterial infection to limit its dissemination."
Supports treating the endothelium as an active immune participant rather than a passive barrier in this node.
Thromboinflammation and Sepsis-Induced Coagulopathy
Coagulation activation with suppressed fibrinolysis produces widespread microvascular fibrin deposition and platelet consumption. This ranges from the compensated sepsis-induced coagulopathy stage, detectable with platelet count, prothrombin time-INR, and SOFA score, to overt disseminated intravascular coagulation as an end-stage consumptive state.
Thromboinflammatory Microcirculatory Failure Model
Platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
Blood coagulation GO:0007596 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Blood coagulation (GO:0007596). GO:0007596 is a biological process from the Gene Ontology. ↑ INCREASED Fibrin clot formation GO:0072378 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Fibrin clot formation, annotated with blood coagulation, fibrin clot formation (GO:0072378). GO:0072378 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Microcirculatory Dysfunction and Tissue Hypoperfusion Microvascular fibrin deposition obstructs capillary flow and compounds the perfusion defect caused by endothelial dysfunction. Thromboinflammatory Microcirculatory Failure Model
Show evidence (3 references)
PMID:37221630 SUPPORT Other
"Accordingly, the ISTH introduced SIC criteria in 2019 that are easy to use and require only platelet count, prothrombin time-international normalized ratio, and Sequential Organ Failure Assessment Score."
Supports the compensated sepsis-induced coagulopathy stage described in this node and names its operational measures.
PMID:37221630 SUPPORT Other
"Activated monocytes express tissue factor (TF) and phosphatidylserine (PS) on the surface, which initiate coagulation cascades."
Names tissue-factor-initiated coagulation as the entry into the cascade, which is the step the thrombogenesis module node this entry conforms to describes generically and which sepsis specializes to monocyte tissue factor.
PMID:37221630 SUPPORT Other
"Among the coagulation factors, thrombin is a critical mediator that regulates inflammation and coagulation"
Identifies thrombin as the central mediator of this node, which is what makes it a conformer of the module's thrombin-driven fibrin formation node rather than only a generic coagulation abnormality.
Microcirculatory Dysfunction and Tissue Hypoperfusion
Loss of capillary density, heterogeneous flow, and increased permeability uncouple regional perfusion from systemic hemodynamics. Tissue oxygen delivery falls even when cardiac output and arterial pressure are restored, which is the physiological reason macrocirculatory resuscitation alone does not reliably reverse organ dysfunction.
Thromboinflammatory Microcirculatory Failure Model
Downstream
Multiple Organ Dysfunction Sustained hypoperfusion of multiple vascular beds produces the organ dysfunction that defines sepsis. Thromboinflammatory Microcirculatory Failure Model
Sepsis-Associated Acute Kidney Injury The kidney is among the earliest and most frequently injured organs, with microcirculatory dysfunction one of the proposed pathogenic routes. Thromboinflammatory Microcirculatory Failure Model
Mitochondrial Dysfunction and Bioenergetic Failure
Irreversible oxidative stress injures mitochondria, so that cells cannot generate ATP even where oxygen is delivered. This cytopathic-hypoxia arm is curated as an alternative, complementary route to organ dysfunction rather than as a step in the microcirculatory chain.
Oxidative Stress and Mitochondrial Bioenergetic Failure Model
Oxidative phosphorylation GO:0006119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Oxidative phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Multiple Organ Dysfunction Energy depletion at the cellular level produces organ dysfunction independently of, and additively to, perfusion failure. Oxidative Stress and Mitochondrial Bioenergetic Failure Model
Show evidence (1 reference)
PMID:24690420 SUPPORT Other
"The purpose of this review is to consider the state of oxidative stress, failure of the antioxidant systems and mitochondrial failure as the main physiopathological mechanisms leading to multiple organ dysfunction during sepsis."
States the review's framing of oxidative stress and mitochondrial failure as mechanisms of organ dysfunction, which is what this node captures.
Sepsis-Associated Acute Kidney Injury
Acute kidney injury develops in roughly two thirds of patients with septic shock and is often present before medical attention is sought, making it an early sepsis-defining event rather than a late complication. It is curated as a distinct node because its mechanism is only partly the shared perfusion defect.
Downstream
Multiple Organ Dysfunction Renal dysfunction is one component of, and a major contributor to mortality within, the multiple organ dysfunction that defines sepsis.
Show evidence (1 reference)
PMID:33752856 SUPPORT Other
"The pathophysiology of S-AKI remains incompletely understood, so most therapies remain reactive and nonspecific."
The source's explicit statement of incomplete mechanistic understanding is preserved rather than curated away.
Sepsis-Induced Immunosuppression
Patients whose sepsis does not resolve enter a protracted immunosuppressed state marked by failure to clear the primary infection, acquisition of secondary infections, and reactivation of latent viruses. This arm accounts for much of the late mortality and is the rationale for immune-stimulating rather than anti-inflammatory therapy in selected patients.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology.
Apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:24232462 SUPPORT Other
"The immunosuppressive phase of sepsis is multifactorial and features defects in both innate and adaptive immunity, including apoptotic depletion of immune effector cells, increased numbers of regulatory T cells, decreased expression of positive co-stimulatory molecules, increased expression of..."
Supports both the lymphocyte-apoptosis annotation and the multifactorial immune-defect description of this node.
Multiple Organ Dysfunction
Concurrent dysfunction across respiratory, renal, hepatic, coagulation, cardiovascular, and neurological systems, operationalized clinically as an increase in the Sequential Organ Failure Assessment score. Organ dysfunction is not a complication of sepsis but the element that distinguishes sepsis from uncomplicated infection.
Show evidence (1 reference)
PMID:29937192 SUPPORT Other
"Sepsis is now defined as infection with organ dysfunction. This definition codifies organ dysfunction using the Sequential Organ Failure Assessment score."
States that organ dysfunction is definitional for sepsis and names the instrument used to operationalize it.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Sepsis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

11
Blood 2
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873), qualified as temporality acute. HP:0001873 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:37221630 SUPPORT Other
"Accordingly, the ISTH introduced SIC criteria in 2019 that are easy to use and require only platelet count, prothrombin time-international normalized ratio, and Sequential Organ Failure Assessment Score."
Confirms platelet count as a scored component of sepsis-induced coagulopathy, the basis for curating thrombocytopenia here.
Disseminated intravascular coagulation HP:0005521 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disseminated intravascular coagulation (HP:0005521), qualified as temporality acute. HP:0005521 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:37221630 SUPPORT Other
"Since then, DIC has been understood as the end-stage consumptive coagulopathy and not the therapeutic target."
States the end-stage consumptive framing used in this phenotype's description.
Cardiovascular 3
Hypotension HP:0002615 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotension (HP:0002615), qualified as temporality acute. HP:0002615 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:26903338 SUPPORT Human Clinical
"Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia."
Supports vasopressor-dependent hypotension as a defining clinical feature of the septic shock subset.
Shock HP:0031273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Shock (HP:0031273), qualified as temporality acute; severity severe. HP:0031273 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE Severity: SEVERE
Show evidence (1 reference)
PMID:26903338 SUPPORT Human Clinical
"This combination is associated with hospital mortality rates greater than 40%."
Supplies the mortality figure quoted in this phenotype's description.
Tachycardia HP:0001649 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tachycardia (HP:0001649), qualified as temporality acute. HP:0001649 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Genitourinary 2
Acute kidney injury HP:0001919 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute kidney injury (HP:0001919), qualified as temporality acute. HP:0001919 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:33752856 SUPPORT Human Clinical
"Acute kidney injury (AKI) develops in about two thirds of patients with septic shock,5,6 and in half of them, AKI develops before presenting to the emergency department."
Supplies both the frequency and the early-onset claim in this phenotype's description.
Oliguria HP:0100520 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oliguria (HP:0100520), qualified as temporality acute. HP:0100520 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:33752856 SUPPORT Other
"it is reasonable to define S-AKI as a clinical syndrome characterized by an abrupt deterioration of renal function manifested by an increase in sCr, oliguria, or both, in the presence of sepsis without other meaningful explaining factors."
Names oliguria as one of the two manifestations by which sepsis-associated acute kidney injury is defined. The review proposes this working definition in the absence of a consensus one, which is why it is cited for the manifestation rather than for a frequency.
Metabolism 1
Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945), qualified as temporality acute. HP:0001945 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Nervous System 1
Encephalopathy HP:0001298 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Encephalopathy (HP:0001298), qualified as temporality acute. HP:0001298 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:26903338 SUPPORT Human Clinical
"they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less."
Names altered mentation as a qSOFA criterion, which is what this phenotype records.
Respiratory 2
Tachypnea HP:0002789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tachypnea (HP:0002789), qualified as temporality acute. HP:0002789 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:26903338 SUPPORT Human Clinical
"they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less."
Names tachypnea at the stated threshold as a qSOFA criterion.
Sepsis-Induced Hypoxemic Respiratory Failure HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sepsis-induced hypoxemic respiratory failure, annotated with Respiratory failure (HP:0002878), qualified as temporality acute. HP:0002878 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:34599691 SUPPORT Other
"Acute hypoxemic respiratory failure can result from causes of sepsis such as pneumonia or non-pulmonary infections resulting in ARDS."
States that acute hypoxemic respiratory failure follows from sepsis by both the pulmonary and the non-pulmonary route, which is the claim this phenotype's description makes.
💊

Medical Actions

6
Immediate Antimicrobial Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anti-infective agent NCIT:C254 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anti-infective agent (NCIT:C254). NCIT:C254 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Prompt administration of appropriate antimicrobials is the intervention directed at the initiating infection. Guidelines recommend immediate administration for confirmed or very likely sepsis, and a rapid assessment of infectious versus non-infectious causes when sepsis is only possible and shock is absent.
Mechanism Target:
INHIBITS Invasive Infection and Pattern Recognition — Antimicrobial therapy reduces pathogen burden and therefore the PAMP load driving the host response, acting at the trigger node of the graph.
Show evidence (1 reference)
PMID:34599691 SUPPORT Other
"we recommend administering antimicrobials immediately, ideally within 1 h of recognition"
Recommendation 12 states the immediacy of antimicrobial administration directly, rather than leaving it to be inferred from sepsis being an emergency.
Source Control of the Infectious Focus
Action: source control interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is source control intervention, annotated with Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. Ontology label: Therapeutic Procedure NCIT:C49236
Platform: Surgery
Drainage of an abscess, debridement of infected necrotic tissue, or removal of an infected device is the second intervention directed at the initiating infection. The guideline recommends rapidly identifying or excluding an anatomical focus that requires emergent source control, and implementing it as soon as medically and logistically practical.
Mechanism Target:
INHIBITS Invasive Infection and Pattern Recognition — Removing or draining the focus eliminates the source of the pathogen- and damage-associated molecular patterns that drive the host response, acting on the same trigger node as antimicrobial therapy by a different route.
Show evidence (1 reference)
PMID:34599691 SUPPORT Other
"Clinical experience suggests that without adequate source control, many severe presentations will not stabilise or improve despite rapid resuscitation and provision of appropriate antimicrobials."
States that antimicrobials and resuscitation do not substitute for source control, which is why this intervention is curated as acting on the trigger node in its own right rather than as part of antimicrobial therapy.
Show evidence (1 reference)
PMID:34599691 SUPPORT Other
"Source control may include drainage of an abscess, debriding infected necrotic tissue, removal of a potentially infected device"
Enumerates the interventions this treatment covers, which is what the generic NCIT action term cannot express.
Crystalloid Fluid Resuscitation
Action: fluid therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is fluid therapy (NCIT:C116537). NCIT:C116537 is a clinical intervention from the NCI Thesaurus. Ontology label: Fluid Therapy NCIT:C116537
Platform: Other
Intravenous crystalloid is the first-line resuscitation fluid for sepsis-induced hypoperfusion or septic shock, with at least 30 mL/kg suggested within the first three hours. This addresses the macrocirculatory deficit and does not by itself correct microcirculatory or bioenergetic failure.
Mechanism Target:
INHIBITS Microcirculatory Dysfunction and Tissue Hypoperfusion — Volume expansion targets the hypoperfusion node, though the guideline grades the specific volume recommendation weakly.
Show evidence (2 references)
PMID:34599691 SUPPORT Other
"the use of crystalloids as first-line fluid for resuscitation in sepsis and septic shock"
States the guideline's first-line fluid choice recorded in this treatment.
PMID:34599691 SUPPORT Other
"For patients with sepsis induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of intravenous (IV) crystalloid fluid should be given within the first 3 h of resuscitation"
Supplies the volume and timing. The guideline itself grades this a weak recommendation on low-quality evidence.
Norepinephrine Vasopressor Support
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: norepinephrine CHEBI:33569 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses norepinephrine, annotated with noradrenaline (CHEBI:33569). CHEBI:33569 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Norepinephrine is the first-line vasopressor for septic shock, restoring mean arterial pressure when fluid resuscitation alone is insufficient.
Mechanism Target:
INHIBITS Microcirculatory Dysfunction and Tissue Hypoperfusion — Vasopressor support restores perfusion pressure across vascular beds whose tone regulation has been lost.
Show evidence (1 reference)
PMID:34599691 SUPPORT Other
"strong recommendation for norepinephrine as the first-line agent"
States the guideline panel's first-line vasopressor recommendation recorded here.
Vasopressin as Second-Line Vasopressor
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: vasopressin CHEBI:34543 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vasopressin, annotated with argipressin (CHEBI:34543). CHEBI:34543 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Peptide
For septic shock on norepinephrine with an inadequate mean arterial pressure, the guideline suggests adding vasopressin rather than escalating the norepinephrine dose. Unlike the catecholamines it is not titrated to response but given at a fixed dose, and it raises pressure through V1 receptors on vascular smooth muscle rather than through adrenergic receptors.
Mechanism Target:
INHIBITS Microcirculatory Dysfunction and Tissue Hypoperfusion — Vasopressin restores perfusion pressure by a non-adrenergic route, which is what makes it an addition to norepinephrine rather than a substitute for a higher dose of it.
Show evidence (1 reference)
PMID:34599691 SUPPORT Other
"binding of V1 receptors on vascular smooth muscle resulting in increased arterial blood pressure"
States the receptor mechanism by which this treatment acts on the perfusion node, and the one that distinguishes it from norepinephrine.
Show evidence (2 references)
PMID:34599691 SUPPORT Other
"For adults with septic shock on norepinephrine with inadequate MAP levels, we suggest adding vasopressin instead of escalating the dose of norepinephrine"
Recommendation 38, which states the escalation step this treatment records. The guideline grades it weak on moderate-quality evidence.
PMID:34599691 SUPPORT Other
"Unlike most vasopressors, vasopressin is not titrated to response, but it is usually administered at a fixed dose of 0.03 units/min for the treatment of septic shock."
Supports the fixed-dose administration described here, which is what separates it from the titrated catecholamines.
Low-Dose IV Hydrocortisone
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: hydrocortisone NCIT:C555 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses hydrocortisone, annotated with Therapeutic Hydrocortisone (NCIT:C555). NCIT:C555 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
For septic shock with an ongoing vasopressor requirement the guideline suggests IV corticosteroids, in practice hydrocortisone 200 mg/day in divided doses. This is the intervention aimed at the dysregulated inflammatory arm of the host response rather than at perfusion or at the pathogen. The evidence behind it is faster shock resolution and more vasopressor-free days, without a clear effect on mortality, and the optimal dose, timing, and duration remain unsettled.
Mechanism Target:
INHIBITS Dysregulated Innate Immune Activation — Glucocorticoid therapy is directed at the dysregulated inflammatory arm of the host response, and is the only intervention curated here that acts on that node. The cited evidence is clinical, being shock resolution and vasopressor-free days, and does not measure the activity of this node directly. The link therefore records where the drug is understood to act, not a demonstrated change in the node.
Show evidence (3 references)
PMID:34599691 SUPPORT Other
"The optimal dose, timing of initiation, and duration of corticosteroids remain uncertain; recent RCTs used 200 mg per day of IV hydrocortisone in divided doses"
Supplies both the dose recorded in this treatment and the guideline's own statement that dose, timing, and duration are unsettled.
PMID:34599691 SUPPORT Other
"A meta-analysis conducted for this guideline revision (Supplementary Appendix 5) found an increase vasopressor-free days (MD 1.5 days; 95% CI 0.8- 3.11 days)"
Gives the effect size the weak recommendation rests on. The guideline reports the same analysis finding increased neuromuscular weakness and no clear mortality effect, which is why the description does not claim a survival benefit.
PMID:34758337 SUPPORT Other
"a recent re-analysis of the aforementioned VANISH trial provided further evidence that corticosteroid exposure may be associated with increased mortality among adult septic shock endotype A patients"
Supports the heterogeneity caveat recorded in this treatment's notes. The average effect the guideline's recommendation rests on need not be the effect in a given transcriptomic endotype.
🔬

Biochemical Markers

1
Serum lactate (INCREASED)
Context: A serum lactate above 2 mmol/L in the absence of hypovolemia, together with a vasopressor requirement, is part of the clinical identification of septic shock. Lactate is a severity and perfusion marker, not a diagnostic test for sepsis.
Show evidence (1 reference)
PMID:26903338 SUPPORT Human Clinical
"Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia."
Supplies the threshold and the interpretive context recorded here.
🔬

Diagnosis

5
Organ dysfunction scoring (SOFA)
Sepsis is diagnosed by demonstrating organ dysfunction in a patient with suspected infection, and the Sequential Organ Failure Assessment score is the instrument that operationalizes it. An acute rise of 2 points or more is the Sepsis-3 threshold. The score is a characterization of the patient rather than a management tool, and its components require laboratory results, so it does not capture dysfunction the moment it begins.
organ dysfunction scoring NCIT:C124351 NCI Thesaurus (NCIT)
Markers: PaO2, platelet count, creatinine level, bilirubin level
Results: An acute increase of 2 or more SOFA points in a patient with suspected infection, graded by organ system.
Show evidence (4 references)
PMID:29937192 SUPPORT Other
"This definition codifies organ dysfunction using the Sequential Organ Failure Assessment score."
Names SOFA as the instrument by which the definitional element of sepsis is established.
PMID:26903338 SUPPORT Human Clinical
"The score grades abnormality by organ system and accounts for clinical interventions."
Describes what the score measures, which is the basis for the organ systems listed in the markers field.
PMID:26903338 SUPPORT Human Clinical
"However, laboratory variables, namely, PaO2, platelet count, creatinine level, and bilirubin level, are needed for full computation."
Names the four laboratory variables recorded in the markers field, and is the basis for the description's caveat that the score cannot capture dysfunction the moment it begins.
+ 1 more reference
Bedside screening (qSOFA and other screening tools)
qSOFA (respiratory rate 22/min or greater, altered mentation, systolic blood pressure 100 mm Hg or less) identifies infected patients more likely to have poor outcomes. It is curated here with its limitation attached: the 2021 guideline recommends against using it as a single screening tool because it is specific but not sensitive, and a positive qSOFA should raise suspicion rather than rule sepsis in or out.
bedside sepsis screening NCIT:C124351 NCI Thesaurus (NCIT)
Results: Two or more of the three qSOFA criteria in a patient with suspected infection.
Show evidence (3 references)
PMID:26903338 SUPPORT Human Clinical
"they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less."
Supplies the three criteria and the two-of-three threshold recorded here.
PMID:34599691 SUPPORT Other
"We recommend against using qSOFA compared to SIRS, NEWS, or MEWS as a single screening tool for sepsis or septic shock"
Recommendation 2, which is the limitation this entry records. It is the reason qSOFA is curated as a bedside alert rather than as the diagnostic test.
PMID:34599691 SUPPORT Other
"There is wide variation in diagnostic accuracy of these tools with most having poor predictive values"
Generalizes the limitation beyond qSOFA to the screening tools as a class, which is why no screening instrument is curated here as diagnostic.
Microbiologic cultures before antimicrobials
Blood and site-appropriate cultures taken before the first antimicrobial dose are what identify the organism and allow the empiric regimen to be narrowed. The guideline makes the ordering conditional rather than absolute, on the condition that obtaining them causes no substantial delay to antimicrobial therapy.
microbial culture procedure NCIT:C25300 NCI Thesaurus (NCIT)
Results: Isolation of a causative organism with susceptibility testing, or no growth.
Show evidence (1 reference)
PMID:34599691 SUPPORT Other
"routine microbiologic cultures (including blood) should be obtained before starting antimicrobial therapy in patients with suspected sepsis and septic shock"
States the practice and its ordering relative to antimicrobial therapy. The guideline attaches the delay qualifier in the same passage.
Serum lactate measurement
Lactate is measured in suspected sepsis as an adjunct that shifts the pre-test probability and marks severity. It is not a diagnostic test: the guideline states plainly that lactate alone can neither rule the diagnosis in nor out.
lactic acid measurement NCIT:C79450 NCI Thesaurus (NCIT)
Results: Elevated serum lactate, with cutoffs in the reported studies ranging from 1.6 to 2.5 mmol/L; above 2 mmol/L is part of the septic shock criteria.
Show evidence (2 references)
PMID:34599691 SUPPORT Other
"For adults suspected of having sepsis, we suggest measuring blood lactate"
Recommendation 3, the guideline statement that lactate should be measured in suspected sepsis.
PMID:34599691 SUPPORT Other
"However, lactate alone is neither sensitive nor specific enough to rule-in or rule-out the diagnosis on its own."
States the limitation that keeps this curated as an adjunctive measurement rather than a diagnostic test.
Continued search for an alternative diagnosis
There is no confirmatory test for sepsis, and a third or more of patients initially diagnosed with it turn out to have something else. The guideline therefore makes continued re-evaluation part of the diagnostic process rather than an afterthought, with empiric antimicrobials stopped when an alternative cause is demonstrated or strongly suspected.
differential diagnosis NCIT:C15220 NCI Thesaurus (NCIT)
Results: Either continued treatment as sepsis, or an alternative diagnosis with empiric antimicrobials discontinued.
Show evidence (3 references)
PMID:34599691 SUPPORT Other
"For adults with suspected sepsis or septic shock but unconfirmed infection, we recommend continuously re-evaluating and searching for alternative diagnoses and discontinuing empiric antimicrobials if an alternative cause of illness is demonstrated or strongly suspected"
Recommendation 11, which is the practice this entry records.
PMID:34599691 SUPPORT Other
"Since there is no "gold standard" test to diagnose sepsis, the bedside provider cannot have a differential diagnosis of sepsis alone in a patient with organ dysfunction."
States the absence of a confirmatory test, which is the reason this is a diagnostic step at all.
PMID:34599691 SUPPORT Other
"Indeed, a third or more of patients initially diagnosed with sepsis turn out to have non-infectious conditions"
Supplies the misdiagnosis figure quoted in this entry's description.
📊

Prevalence

1
Worldwide
Annual Incidence 648.0 per 100,000 (515.0–833.0) >1 in 1,000 per year
Derived from the GBD 2017 estimate of 48.9 million (95% UI 38.9-62.9) incident sepsis cases worldwide against a 2017 world population of approximately 7.55 billion. The source reports absolute counts, not a rate; the per-100,000 figures are this derivation and should be re-derived rather than quoted as published.
Show evidence (1 reference)
PMID:31954465 SUPPORT Human Clinical
"In 2017, an estimated 48·9 million (95% uncertainty interval [UI] 38·9-62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1-12·0) sepsis-related deaths were reported"
The GBD analysis supplies the global incident-case count from which the normalized rate in this record is derived.
{ }

Source YAML

click to show 
name: Sepsis
creation_date: "2026-08-17T12:00:00Z"
category: Complex
categories:
- Infectious Disease
- Critical Illness
synonyms:
- Septicaemia
- Septicemia
description: >-
  Sepsis is life-threatening organ dysfunction caused by a dysregulated host
  response to infection. It is a syndrome rather than a single etiology: many
  different pathogens and infection sites converge on a common host program in
  which innate immune activation, endothelial injury, and coagulation activation
  become mutually amplifying. The resulting microcirculatory failure and
  cellular bioenergetic failure produce dysfunction across multiple organ
  systems. A concurrent, and often protracted, immunosuppressive arm leaves
  survivors of the initial insult unable to clear the primary infection and
  vulnerable to secondary infection. Septic shock is the subset with profound
  circulatory, cellular, and metabolic abnormalities and substantially higher
  mortality.
parents:
- infectious disease
disease_term:
  preferred_term: Sepsis
  term:
    id: MONDO:1040015
    label: infectious disease with sepsis
notes: >-
  Ontology gap recorded at curation time (2026-08-17): MONDO has no generic
  "sepsis" disease class. The nearest anchor reachable from MONDO:0000001 is
  MONDO:1040015 "infectious disease with sepsis", whose textual definition is
  the Sepsis-3 definition, so it is used here as the entry anchor. MONDO also
  has no human "septic shock" class - only MONDO:1014822 "septic shock,
  non-human animal" - which is why the septic shock subtype below carries no
  subtype_term. HP:0100806 "Sepsis" exists as a phenotype but is not a disease
  anchor. Both gaps are candidates for a MONDO new-term request. A third gap
  sits on the treatment side: NCIT has no clinical-action term for source
  control, so that treatment is bound to the generic Therapeutic Procedure
  term rather than to any one of its instances.
has_subtypes:
- name: Septic shock
  display_name: Septic Shock
  classification: severity
  description: >-
    The subset of sepsis in which circulatory, cellular, and metabolic
    abnormalities are profound enough to substantially increase mortality,
    clinically identified by a vasopressor requirement to maintain mean arterial
    pressure of 65 mm Hg or greater together with a serum lactate above
    2 mmol/L in the absence of hypovolemia. No MONDO term for human septic shock
    exists, so no subtype_term is bound.
  evidence:
  - reference: PMID:26903338
    reference_title: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Septic shock should be defined as a subset of sepsis in which particularly
      profound circulatory, cellular, and metabolic abnormalities are associated
      with a greater risk of mortality than with sepsis alone.
    explanation: >-
      The international consensus statement defines septic shock as a severity
      subset of sepsis, which is how it is modeled here.
  - reference: PMID:26903338
    reference_title: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with septic shock can be clinically identified by a vasopressor
      requirement to maintain a mean arterial pressure of 65 mm Hg or greater
      and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence
      of hypovolemia.
    explanation: >-
      Supplies the operational clinical criteria quoted in the subtype
      description.
- name: Neonatal sepsis
  display_name: Neonatal Sepsis
  classification: age_group
  subtype_term:
    preferred_term: neonatal sepsis
    term:
      id: MONDO:0700217
      label: neonatal sepsis
  description: >-
    Sepsis in infants younger than 28 days, in whom immature innate and adaptive
    immunity, distinct pathogen spectra, and different presenting physiology
    warrant a separate subtype.
  review_notes: >-
    Curated as a placeholder subtype from the MONDO class only. The
    neonatal-specific immunological and epidemiological mechanism has not yet
    been curated with dedicated evidence.
mechanistic_hypotheses:
- hypothesis_group_id: thromboinflammatory_microcirculatory_model
  hypothesis_label: Thromboinflammatory Microcirculatory Failure Model
  status: CANONICAL
  description: >-
    Pathogen- and damage-associated molecular patterns drive dysregulated innate
    immune activation. Activated leukocytes, platelets, and endothelium engage
    in reciprocal amplification, degrading the endothelial glycocalyx, raising
    permeability, and activating coagulation while suppressing fibrinolysis. The
    resulting thromboinflammation obstructs and dysregulates the
    microcirculation, causing tissue hypoperfusion and organ dysfunction.
  evidence:
  - reference: PMID:37221630
    reference_title: "The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pathophysiology of sepsis-associated DIC is multifactorial, and in
      addition to coagulation activation with suppressed fibrinolysis, multiple
      inflammatory responses are initiated by activated leukocytes, platelets,
      and vascular endothelial cells as part of thromboinflammation.
    explanation: >-
      States the coupled coagulation-inflammation mechanism that this hypothesis
      group organizes the main causal graph around.
  - reference: PMID:32101446
    reference_title: Endothelial Responses in Sepsis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In addition, glycocalyx damage and vascular tone dysfunction impair
      microcirculatory blood flow, leading to organ injury and, potentially,
      life-threatening organ failure.
    explanation: >-
      Links the endothelial arm of the model to microcirculatory failure and
      organ dysfunction.
- hypothesis_group_id: bioenergetic_failure_model
  hypothesis_label: Oxidative Stress and Mitochondrial Bioenergetic Failure Model
  status: ALTERNATIVE
  description: >-
    An alternative, non-exclusive account holds that organ dysfunction in sepsis
    is driven less by perfusion failure than by a cellular inability to use
    oxygen. Overwhelming reactive species production with failure of antioxidant
    systems produces mitochondrial injury, so that organs fail despite adequate
    delivery of oxygen. This is offered as a complementary rather than competing
    mechanism, and it predicts that restoring macrocirculatory flow alone will
    not reverse organ dysfunction.
  evidence:
  - reference: PMID:24690420
    reference_title: "Sepsis, mitochondrial failure and multiple organ dysfunction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The loss of the redox balance, together with a systemic inflammatory
      response during sepsis, can lead to progressive and irreversible
      mitochondrial failure, energy depletion, hypoxia, septic shock, severe
      sepsis, multiple organ dysfunction and death of the patient.
    explanation: >-
      States the redox/mitochondrial route to multiple organ dysfunction that
      defines this hypothesis group.
  notes: >-
    The two hypothesis groups are curated as complementary. No evidence here
    establishes the relative contribution of microcirculatory versus
    bioenergetic failure to organ dysfunction in an individual patient, and the
    causal edges are annotated accordingly rather than ranked.
prevalence:
- population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 648.0
  rate_low: 515.0
  rate_high: 833.0
  notes: >-
    Derived from the GBD 2017 estimate of 48.9 million (95% UI 38.9-62.9)
    incident sepsis cases worldwide against a 2017 world population of
    approximately 7.55 billion. The source reports absolute counts, not a rate;
    the per-100,000 figures are this derivation and should be re-derived rather
    than quoted as published.
  evidence:
  - reference: PMID:31954465
    reference_title: "Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 2017, an estimated 48·9 million (95% uncertainty interval [UI]
      38·9-62·9) incident cases of sepsis were recorded worldwide and 11·0
      million (10·1-12·0) sepsis-related deaths were reported
    explanation: >-
      The GBD analysis supplies the global incident-case count from which the
      normalized rate in this record is derived.
pathophysiology:
- name: Invasive Infection and Pattern Recognition
  description: >-
    A bacterial, viral, or fungal infection at any site - most often lung,
    abdomen, urinary tract, or bloodstream - releases pathogen-associated
    molecular patterns that engage host pattern-recognition receptors. Tissue
    injury at the site of infection adds damage-associated molecular patterns to
    the same sensing machinery. The identity of the pathogen is not what makes
    the syndrome; the host response to it is.
  role: trigger
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: Toll-like receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0002224
      label: toll-like receptor signaling pathway
  downstream:
  - target: Dysregulated Innate Immune Activation
    causal_link_type: DIRECT
    hypothesis_groups:
    - thromboinflammatory_microcirculatory_model
    description: >-
      Pattern recognition initiates the host response whose dysregulation, not
      the infection itself, defines sepsis.
    evidence:
    - reference: PMID:26903338
      reference_title: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sepsis should be defined as life-threatening organ dysfunction caused by
        a dysregulated host response to infection.
      explanation: >-
        The consensus definition places the dysregulated host response, not the
        pathogen, causally between infection and organ dysfunction.
  evidence:
  - reference: PMID:24232462
    reference_title: "Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Sepsis - which is a severe life-threatening infection with organ
      dysfunction - initiates a complex interplay of host pro-inflammatory and
      anti-inflammatory processes.
    explanation: >-
      Establishes infection as the initiating event of the host program modeled
      by the rest of this graph.
- name: Dysregulated Innate Immune Activation
  description: >-
    Innate immune cells mount a proinflammatory program with cytokine and
    chemokine release, complement activation, neutrophil recruitment, and
    reactive oxygen species production. In sepsis this response is not merely
    large but unbalanced: hyperinflammation and immune suppression run
    concurrently rather than sequentially, which is why the syndrome resists
    treatment framed as either simple inflammation or simple immunodeficiency.
  role: mediator
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: Positive regulation of inflammatory response
    modifier: INCREASED
    term:
      id: GO:0050729
      label: positive regulation of inflammatory response
  - preferred_term: Reactive oxygen species metabolic process
    modifier: INCREASED
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
  - preferred_term: Neutrophil extracellular trap formation
    modifier: INCREASED
    term:
      id: GO:0140645
      label: neutrophil extracellular trap formation
  downstream:
  - target: Endothelial Activation and Glycocalyx Degradation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - thromboinflammatory_microcirculatory_model
    description: >-
      Inflammatory mediators and activated leukocytes drive the endothelium into
      a proinflammatory, proadhesive, procoagulant state.
    evidence:
    - reference: PMID:32101446
      reference_title: Endothelial Responses in Sepsis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        During sepsis, ECs shift toward a proapoptotic, proinflammatory,
        proadhesive, and procoagulant phenotype.
      explanation: >-
        Directly states the endothelial phenotype switch that this edge asserts
        occurs downstream of innate immune activation.
  - target: Sepsis-Induced Immunosuppression
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The anti-inflammatory arm of the same host program, running concurrently,
      produces a protracted immunosuppressed state in patients whose sepsis does
      not resolve.
    evidence:
    - reference: PMID:24232462
      reference_title: "Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients with unresolved, prolonged sepsis enter a phase of
        immunosuppression that is characterized by a failure to eradicate the
        primary infection, the acquisition of lethal secondary infections and/or
        the reactivation of numerous latent viruses.
      explanation: >-
        Supports the immunosuppressive arm as a downstream consequence of the
        same dysregulated host response.
  - target: Mitochondrial Dysfunction and Bioenergetic Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - bioenergetic_failure_model
    description: >-
      Reactive species generated by the inflammatory response overwhelm
      antioxidant capacity and injure mitochondria.
    evidence:
    - reference: PMID:24690420
      reference_title: "Sepsis, mitochondrial failure and multiple organ dysfunction."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        One of the pivotal factors in these processes is the increase of
        reactive species accompanied by the failure of the antioxidant systems,
        leading to a state of irreversible oxidative stress and mitochondrial
        failure.
      explanation: >-
        States the oxidative route from the inflammatory response to
        mitochondrial failure that this edge represents.
  evidence:
  - reference: PMID:34758337
    reference_title: The immunology of sepsis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This recently implemented definition does not capture the heterogeneity or
      the underlying pathophysiology of the syndrome, which is characterized by
      concurrent unbalanced hyperinflammation and immune suppression.
    explanation: >-
      Supports modeling the innate response as concurrently hyperinflammatory
      and immunosuppressive rather than as a single inflammatory phase.
  - reference: PMID:34758337
    reference_title: The immunology of sepsis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      NETosis during sepsis can be detrimental through various mechanisms,
      including induction of intravascular thrombosis and multiple organ failure
    explanation: >-
      Supports curating neutrophil extracellular trap formation on this node:
      the same neutrophil effector that traps bacteria becomes injurious in
      sepsis, and the review names intravascular thrombosis and organ failure as
      its consequences, which are the two nodes downstream of this one.
- name: Endothelial Activation and Glycocalyx Degradation
  description: >-
    The endothelium, acting as a nonconventional immune organ, switches to a
    proapoptotic, proinflammatory, proadhesive, and procoagulant phenotype.
    Shedding of the glycocalyx exposes adhesion molecules and procoagulant
    surface, increases permeability with interstitial fluid loss, and impairs
    vasomotor regulation.
  role: mediator
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Response to cytokine
    modifier: INCREASED
    term:
      id: GO:0034097
      label: response to cytokine
  downstream:
  - target: Thromboinflammation and Sepsis-Induced Coagulopathy
    causal_link_type: DIRECT
    hypothesis_groups:
    - thromboinflammatory_microcirculatory_model
    description: >-
      The procoagulant endothelial surface, together with activated leukocytes
      and platelets, drives coagulation activation with suppressed fibrinolysis.
    evidence:
    - reference: PMID:37221630
      reference_title: "The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The pathophysiology of sepsis-associated DIC is multifactorial, and in
        addition to coagulation activation with suppressed fibrinolysis,
        multiple inflammatory responses are initiated by activated leukocytes,
        platelets, and vascular endothelial cells as part of thromboinflammation.
      explanation: >-
        Names endothelial cells among the drivers of the thromboinflammatory
        state this edge points to.
  - target: Microcirculatory Dysfunction and Tissue Hypoperfusion
    causal_link_type: DIRECT
    hypothesis_groups:
    - thromboinflammatory_microcirculatory_model
    description: >-
      Glycocalyx damage and loss of vascular tone regulation directly impair
      microcirculatory blood flow.
    evidence:
    - reference: PMID:32101446
      reference_title: Endothelial Responses in Sepsis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In addition, glycocalyx damage and vascular tone dysfunction impair
        microcirculatory blood flow, leading to organ injury and, potentially,
        life-threatening organ failure.
      explanation: >-
        Directly asserts the glycocalyx-to-microcirculation causal step modeled
        by this edge.
  evidence:
  - reference: PMID:32101446
    reference_title: Endothelial Responses in Sepsis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Endothelial cells (ECs) are vascular, nonconventional immune cells that
      play a major role in the systemic response after bacterial infection to
      limit its dissemination.
    explanation: >-
      Supports treating the endothelium as an active immune participant rather
      than a passive barrier in this node.
- name: Thromboinflammation and Sepsis-Induced Coagulopathy
  description: >-
    Coagulation activation with suppressed fibrinolysis produces widespread
    microvascular fibrin deposition and platelet consumption. This ranges from
    the compensated sepsis-induced coagulopathy stage, detectable with platelet
    count, prothrombin time-INR, and SOFA score, to overt disseminated
    intravascular coagulation as an end-stage consumptive state.
  conforms_to: "thrombogenesis#Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation"
  role: mediator
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: Blood coagulation
    modifier: INCREASED
    term:
      id: GO:0007596
      label: blood coagulation
  - preferred_term: Fibrin clot formation
    modifier: INCREASED
    term:
      id: GO:0072378
      label: blood coagulation, fibrin clot formation
  downstream:
  - target: Microcirculatory Dysfunction and Tissue Hypoperfusion
    causal_link_type: DIRECT
    hypothesis_groups:
    - thromboinflammatory_microcirculatory_model
    description: >-
      Microvascular fibrin deposition obstructs capillary flow and compounds the
      perfusion defect caused by endothelial dysfunction.
    evidence:
    - reference: PMID:37221630
      reference_title: "The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        However, DIC is not merely a decompensated coagulation disorder, but
        also includes early stages with systemic activation in coagulation.
      explanation: >-
        Supports systemic coagulation activation as an early, ongoing process
        rather than only a terminal event. The abstract does not quantify the
        flow-obstruction contribution, so the microcirculatory consequence is
        inferred rather than stated here.
  evidence:
  - reference: PMID:37221630
    reference_title: "The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Accordingly, the ISTH introduced SIC criteria in 2019 that are easy to
      use and require only platelet count, prothrombin time-international
      normalized ratio, and Sequential Organ Failure Assessment Score.
    explanation: >-
      Supports the compensated sepsis-induced coagulopathy stage described in
      this node and names its operational measures.
  - reference: PMID:37221630
    reference_title: "The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Activated monocytes express tissue factor (TF) and phosphatidylserine (PS)
      on the surface, which initiate coagulation cascades.
    explanation: >-
      Names tissue-factor-initiated coagulation as the entry into the cascade,
      which is the step the thrombogenesis module node this entry conforms to
      describes generically and which sepsis specializes to monocyte tissue
      factor.
  - reference: PMID:37221630
    reference_title: "The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Among the coagulation factors, thrombin is a critical mediator that
      regulates inflammation and coagulation
    explanation: >-
      Identifies thrombin as the central mediator of this node, which is what
      makes it a conformer of the module's thrombin-driven fibrin formation
      node rather than only a generic coagulation abnormality.
- name: Microcirculatory Dysfunction and Tissue Hypoperfusion
  description: >-
    Loss of capillary density, heterogeneous flow, and increased permeability
    uncouple regional perfusion from systemic hemodynamics. Tissue oxygen
    delivery falls even when cardiac output and arterial pressure are restored,
    which is the physiological reason macrocirculatory resuscitation alone does
    not reliably reverse organ dysfunction.
  role: mediator
  biological_scale: TISSUE
  downstream:
  - target: Multiple Organ Dysfunction
    causal_link_type: DIRECT
    hypothesis_groups:
    - thromboinflammatory_microcirculatory_model
    description: >-
      Sustained hypoperfusion of multiple vascular beds produces the organ
      dysfunction that defines sepsis.
    evidence:
    - reference: PMID:32101446
      reference_title: Endothelial Responses in Sepsis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In addition, glycocalyx damage and vascular tone dysfunction impair
        microcirculatory blood flow, leading to organ injury and, potentially,
        life-threatening organ failure.
      explanation: >-
        Explicitly carries microcirculatory impairment through to organ injury
        and organ failure.
  - target: Sepsis-Associated Acute Kidney Injury
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - thromboinflammatory_microcirculatory_model
    description: >-
      The kidney is among the earliest and most frequently injured organs, with
      microcirculatory dysfunction one of the proposed pathogenic routes.
    evidence:
    - reference: PMID:33752856
      reference_title: Sepsis-Associated Acute Kidney Injury.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Possible pathogenic mechanisms to explain S-AKI include microcirculatory
        dysfunction, a dysregulated inflammatory response, and cellular
        metabolic reprogramming.
      explanation: >-
        Names microcirculatory dysfunction as a pathogenic mechanism of
        sepsis-associated AKI; the source's own hedging is preserved in the node
        description.
- name: Mitochondrial Dysfunction and Bioenergetic Failure
  description: >-
    Irreversible oxidative stress injures mitochondria, so that cells cannot
    generate ATP even where oxygen is delivered. This cytopathic-hypoxia arm is
    curated as an alternative, complementary route to organ dysfunction rather
    than as a step in the microcirculatory chain.
  role: mediator
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  downstream:
  - target: Multiple Organ Dysfunction
    causal_link_type: DIRECT
    hypothesis_groups:
    - bioenergetic_failure_model
    description: >-
      Energy depletion at the cellular level produces organ dysfunction
      independently of, and additively to, perfusion failure.
    evidence:
    - reference: PMID:24690420
      reference_title: "Sepsis, mitochondrial failure and multiple organ dysfunction."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The loss of the redox balance, together with a systemic inflammatory
        response during sepsis, can lead to progressive and irreversible
        mitochondrial failure, energy depletion, hypoxia, septic shock, severe
        sepsis, multiple organ dysfunction and death of the patient.
      explanation: >-
        Directly asserts the mitochondrial-failure-to-multiple-organ-dysfunction
        step this edge represents.
  evidence:
  - reference: PMID:24690420
    reference_title: "Sepsis, mitochondrial failure and multiple organ dysfunction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The purpose of this review is to consider the state of oxidative stress,
      failure of the antioxidant systems and mitochondrial failure as the main
      physiopathological mechanisms leading to multiple organ dysfunction during
      sepsis.
    explanation: >-
      States the review's framing of oxidative stress and mitochondrial failure
      as mechanisms of organ dysfunction, which is what this node captures.
- name: Sepsis-Associated Acute Kidney Injury
  description: >-
    Acute kidney injury develops in roughly two thirds of patients with septic
    shock and is often present before medical attention is sought, making it an
    early sepsis-defining event rather than a late complication. It is curated
    as a distinct node because its mechanism is only partly the shared
    perfusion defect.
  role: outcome
  biological_scale: ORGANISM
  downstream:
  - target: Multiple Organ Dysfunction
    causal_link_type: DIRECT
    description: >-
      Renal dysfunction is one component of, and a major contributor to
      mortality within, the multiple organ dysfunction that defines sepsis.
    evidence:
    - reference: PMID:33752856
      reference_title: Sepsis-Associated Acute Kidney Injury.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sepsis-associated acute kidney injury (S-AKI) is a common and
        life-threatening complication in hospitalized and critically ill
        patients.
      explanation: >-
        Establishes S-AKI as a common, life-threatening organ-level complication
        of sepsis.
  evidence:
  - reference: PMID:33752856
    reference_title: Sepsis-Associated Acute Kidney Injury.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pathophysiology of S-AKI remains incompletely understood, so most
      therapies remain reactive and nonspecific.
    explanation: >-
      The source's explicit statement of incomplete mechanistic understanding is
      preserved rather than curated away.
- name: Sepsis-Induced Immunosuppression
  description: >-
    Patients whose sepsis does not resolve enter a protracted immunosuppressed
    state marked by failure to clear the primary infection, acquisition of
    secondary infections, and reactivation of latent viruses. This arm accounts
    for much of the late mortality and is the rationale for immune-stimulating
    rather than anti-inflammatory therapy in selected patients.
  role: outcome
  biological_scale: ORGANISM
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: Apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:24232462
    reference_title: "Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The immunosuppressive phase of sepsis is multifactorial and features
      defects in both innate and adaptive immunity, including apoptotic
      depletion of immune effector cells, increased numbers of regulatory T
      cells, decreased expression of positive co-stimulatory molecules,
      increased expression of negative co-stimulatory molecules, increased
      numbers of myeloid-derived suppressor cells and T cell exhaustion.
    explanation: >-
      Supports both the lymphocyte-apoptosis annotation and the multifactorial
      immune-defect description of this node.
- name: Multiple Organ Dysfunction
  description: >-
    Concurrent dysfunction across respiratory, renal, hepatic, coagulation,
    cardiovascular, and neurological systems, operationalized clinically as an
    increase in the Sequential Organ Failure Assessment score. Organ dysfunction
    is not a complication of sepsis but the element that distinguishes sepsis
    from uncomplicated infection.
  role: outcome
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:29937192
    reference_title: Sepsis and septic shock.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Sepsis is now defined as infection with organ dysfunction. This definition
      codifies organ dysfunction using the Sequential Organ Failure Assessment
      score.
    explanation: >-
      States that organ dysfunction is definitional for sepsis and names the
      instrument used to operationalize it.
phenotypes:
- category: Constitutional
  name: Fever
  description: >-
    Fever is the common presenting sign of the infection that initiates sepsis,
    though hypothermia occurs and neither is required for the diagnosis under
    Sepsis-3.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
    temporality: ACUTE
- category: Cardiovascular
  name: Hypotension
  description: >-
    Vasodilation, capillary leak, and myocardial depression lower arterial
    pressure; a vasopressor requirement to maintain a mean arterial pressure of
    at least 65 mm Hg is part of the clinical identification of septic shock.
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
    temporality: ACUTE
  evidence:
  - reference: PMID:26903338
    reference_title: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with septic shock can be clinically identified by a vasopressor
      requirement to maintain a mean arterial pressure of 65 mm Hg or greater
      and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence
      of hypovolemia.
    explanation: >-
      Supports vasopressor-dependent hypotension as a defining clinical feature
      of the septic shock subset.
- category: Cardiovascular
  name: Shock
  subtype: Septic shock
  description: >-
    Circulatory failure with profound cellular and metabolic derangement,
    associated with hospital mortality above 40%.
  phenotype_term:
    preferred_term: Shock
    term:
      id: HP:0031273
      label: Shock
    temporality: ACUTE
    severity: SEVERE
  evidence:
  - reference: PMID:26903338
    reference_title: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This combination is associated with hospital mortality rates greater than
      40%.
    explanation: >-
      Supplies the mortality figure quoted in this phenotype's description.
- category: Cardiovascular
  name: Tachycardia
  description: >-
    Compensatory tachycardia accompanies vasodilation and reduced effective
    circulating volume.
  phenotype_term:
    preferred_term: Tachycardia
    term:
      id: HP:0001649
      label: Tachycardia
    temporality: ACUTE
- category: Respiratory
  name: Tachypnea
  description: >-
    A respiratory rate of 22/min or greater is one of the three quickSOFA
    criteria used to identify patients with suspected infection who are more
    likely to have poor outcomes.
  phenotype_term:
    preferred_term: Tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
    temporality: ACUTE
  evidence:
  - reference: PMID:26903338
    reference_title: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      they have at least 2 of the following clinical criteria that together
      constitute a new bedside clinical score termed quickSOFA (qSOFA):
      respiratory rate of 22/min or greater, altered mentation, or systolic
      blood pressure of 100 mm Hg or less.
    explanation: >-
      Names tachypnea at the stated threshold as a qSOFA criterion.
- category: Respiratory
  name: Sepsis-Induced Hypoxemic Respiratory Failure
  description: >-
    Acute hypoxemic respiratory failure is the respiratory arm of the organ
    dysfunction that defines sepsis, and the lung is the organ system the
    Multiple Organ Dysfunction node names first. It arises both from pulmonary
    sources of sepsis such as pneumonia and from non-pulmonary infection
    progressing to ARDS, and it is the organ dysfunction the Surviving Sepsis
    Campaign guideline addresses with the largest number of separate
    recommendations (oxygen targets, high-flow nasal oxygen, and tidal-volume
    strategy with and without ARDS).
  phenotype_term:
    preferred_term: Sepsis-induced hypoxemic respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
    temporality: ACUTE
  evidence:
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute hypoxemic respiratory failure can result from causes of sepsis such
      as pneumonia or non-pulmonary infections resulting in ARDS.
    explanation: >-
      States that acute hypoxemic respiratory failure follows from sepsis by
      both the pulmonary and the non-pulmonary route, which is the claim this
      phenotype's description makes.
- category: Neurological
  name: Encephalopathy
  description: >-
    Altered mentation is a qSOFA criterion and a common manifestation of sepsis;
    it reflects diffuse cerebral dysfunction rather than a focal lesion.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
    temporality: ACUTE
  evidence:
  - reference: PMID:26903338
    reference_title: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      they have at least 2 of the following clinical criteria that together
      constitute a new bedside clinical score termed quickSOFA (qSOFA):
      respiratory rate of 22/min or greater, altered mentation, or systolic
      blood pressure of 100 mm Hg or less.
    explanation: >-
      Names altered mentation as a qSOFA criterion, which is what this phenotype
      records.
- category: Renal
  name: Acute kidney injury
  description: >-
    Acute kidney injury develops in about two thirds of patients with septic
    shock and frequently precedes presentation.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
    temporality: ACUTE
  evidence:
  - reference: PMID:33752856
    reference_title: Sepsis-Associated Acute Kidney Injury.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute kidney injury (AKI) develops in about two thirds of patients with
      septic shock,5,6 and in half of them, AKI develops before presenting to
      the emergency department.
    explanation: >-
      Supplies both the frequency and the early-onset claim in this phenotype's
      description.
- category: Renal
  name: Oliguria
  description: >-
    Falling urine output is one of the two ways sepsis-associated acute kidney
    injury declares itself, alongside a rising serum creatinine, and it is the
    one visible at the bedside without a laboratory result.
  phenotype_term:
    preferred_term: Oliguria
    term:
      id: HP:0100520
      label: Oliguria
    temporality: ACUTE
  evidence:
  - reference: PMID:33752856
    reference_title: Sepsis-Associated Acute Kidney Injury.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      it is reasonable to define S-AKI as a clinical syndrome characterized by
      an abrupt deterioration of renal function manifested by an increase in
      sCr, oliguria, or both, in the presence of sepsis without other meaningful
      explaining factors.
    explanation: >-
      Names oliguria as one of the two manifestations by which sepsis-associated
      acute kidney injury is defined. The review proposes this working
      definition in the absence of a consensus one, which is why it is cited for
      the manifestation rather than for a frequency.
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Platelet consumption in thromboinflammation lowers the platelet count, which
    is one of the three components of the ISTH sepsis-induced coagulopathy
    score.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
    temporality: ACUTE
  evidence:
  - reference: PMID:37221630
    reference_title: "The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Accordingly, the ISTH introduced SIC criteria in 2019 that are easy to
      use and require only platelet count, prothrombin time-international
      normalized ratio, and Sequential Organ Failure Assessment Score.
    explanation: >-
      Confirms platelet count as a scored component of sepsis-induced
      coagulopathy, the basis for curating thrombocytopenia here.
- category: Hematologic
  name: Disseminated intravascular coagulation
  description: >-
    Overt DIC is the end-stage consumptive coagulopathy of sepsis; the earlier
    compensated stage is captured by the sepsis-induced coagulopathy criteria.
  phenotype_term:
    preferred_term: Disseminated intravascular coagulation
    term:
      id: HP:0005521
      label: Disseminated intravascular coagulation
    temporality: ACUTE
  evidence:
  - reference: PMID:37221630
    reference_title: "The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Since then, DIC has been understood as the end-stage consumptive
      coagulopathy and not the therapeutic target.
    explanation: >-
      States the end-stage consumptive framing used in this phenotype's
      description.
biochemical:
- name: Serum lactate
  presence: INCREASED
  context: >-
    A serum lactate above 2 mmol/L in the absence of hypovolemia, together with
    a vasopressor requirement, is part of the clinical identification of septic
    shock. Lactate is a severity and perfusion marker, not a diagnostic test for
    sepsis.
  biomarker_term:
    preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
  evidence:
  - reference: PMID:26903338
    reference_title: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with septic shock can be clinically identified by a vasopressor
      requirement to maintain a mean arterial pressure of 65 mm Hg or greater
      and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence
      of hypovolemia.
    explanation: >-
      Supplies the threshold and the interpretive context recorded here.
diagnosis:
- name: Organ dysfunction scoring (SOFA)
  description: >-
    Sepsis is diagnosed by demonstrating organ dysfunction in a patient with
    suspected infection, and the Sequential Organ Failure Assessment score is
    the instrument that operationalizes it. An acute rise of 2 points or more
    is the Sepsis-3 threshold. The score is a characterization of the patient
    rather than a management tool, and its components require laboratory
    results, so it does not capture dysfunction the moment it begins.
  diagnosis_term:
    preferred_term: organ dysfunction scoring
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: >-
    An acute increase of 2 or more SOFA points in a patient with suspected
    infection, graded by organ system.
  markers: PaO2, platelet count, creatinine level, bilirubin level
  evidence:
  - reference: PMID:29937192
    reference_title: Sepsis and septic shock.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This definition codifies organ dysfunction using the Sequential Organ
      Failure Assessment score.
    explanation: >-
      Names SOFA as the instrument by which the definitional element of sepsis
      is established.
  - reference: PMID:26903338
    reference_title: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The score grades abnormality by organ system and accounts for clinical
      interventions.
    explanation: >-
      Describes what the score measures, which is the basis for the organ
      systems listed in the markers field.
  - reference: PMID:26903338
    reference_title: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, laboratory variables, namely, PaO2, platelet count, creatinine
      level, and bilirubin level, are needed for full computation.
    explanation: >-
      Names the four laboratory variables recorded in the markers field, and is
      the basis for the description's caveat that the score cannot capture
      dysfunction the moment it begins.
  - reference: PMID:26903338
    reference_title: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A higher SOFA score is associated with an increased probability of
      mortality
    explanation: >-
      Supports the score's prognostic use, which is why it is the instrument the
      consensus definition chose.
- name: Bedside screening (qSOFA and other screening tools)
  description: >-
    qSOFA (respiratory rate 22/min or greater, altered mentation, systolic blood
    pressure 100 mm Hg or less) identifies infected patients more likely to
    have poor outcomes. It is curated here with its limitation attached: the
    2021 guideline recommends against using it as a single screening tool
    because it is specific but not sensitive, and a positive qSOFA should raise
    suspicion rather than rule sepsis in or out.
  diagnosis_term:
    preferred_term: bedside sepsis screening
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: >-
    Two or more of the three qSOFA criteria in a patient with suspected
    infection.
  evidence:
  - reference: PMID:26903338
    reference_title: The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      they have at least 2 of the following clinical criteria that together
      constitute a new bedside clinical score termed quickSOFA (qSOFA):
      respiratory rate of 22/min or greater, altered mentation, or systolic
      blood pressure of 100 mm Hg or less.
    explanation: >-
      Supplies the three criteria and the two-of-three threshold recorded here.
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We recommend against using qSOFA compared to SIRS, NEWS, or MEWS as a
      single screening tool for sepsis or septic shock
    explanation: >-
      Recommendation 2, which is the limitation this entry records. It is the
      reason qSOFA is curated as a bedside alert rather than as the diagnostic
      test.
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There is wide variation in diagnostic accuracy of these tools with most
      having poor predictive values
    explanation: >-
      Generalizes the limitation beyond qSOFA to the screening tools as a class,
      which is why no screening instrument is curated here as diagnostic.
- name: Microbiologic cultures before antimicrobials
  description: >-
    Blood and site-appropriate cultures taken before the first antimicrobial
    dose are what identify the organism and allow the empiric regimen to be
    narrowed. The guideline makes the ordering conditional rather than
    absolute, on the condition that obtaining them causes no substantial delay
    to antimicrobial therapy.
  diagnosis_term:
    preferred_term: microbial culture procedure
    term:
      id: NCIT:C25300
      label: Microbial Culture Procedure
  results: >-
    Isolation of a causative organism with susceptibility testing, or no growth.
  evidence:
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      routine microbiologic cultures (including blood) should be obtained
      before starting antimicrobial therapy in patients with suspected sepsis
      and septic shock
    explanation: >-
      States the practice and its ordering relative to antimicrobial therapy.
      The guideline attaches the delay qualifier in the same passage.
- name: Serum lactate measurement
  description: >-
    Lactate is measured in suspected sepsis as an adjunct that shifts the
    pre-test probability and marks severity. It is not a diagnostic test: the
    guideline states plainly that lactate alone can neither rule the diagnosis
    in nor out.
  diagnosis_term:
    preferred_term: lactic acid measurement
    term:
      id: NCIT:C79450
      label: Lactic Acid Measurement
  results: >-
    Elevated serum lactate, with cutoffs in the reported studies ranging from
    1.6 to 2.5 mmol/L; above 2 mmol/L is part of the septic shock criteria.
  evidence:
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For adults suspected of having sepsis, we suggest measuring blood lactate
    explanation: >-
      Recommendation 3, the guideline statement that lactate should be measured
      in suspected sepsis.
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, lactate alone is neither sensitive nor specific enough to
      rule-in or rule-out the diagnosis on its own.
    explanation: >-
      States the limitation that keeps this curated as an adjunctive
      measurement rather than a diagnostic test.
- name: Continued search for an alternative diagnosis
  description: >-
    There is no confirmatory test for sepsis, and a third or more of patients
    initially diagnosed with it turn out to have something else. The guideline
    therefore makes continued re-evaluation part of the diagnostic process
    rather than an afterthought, with empiric antimicrobials stopped when an
    alternative cause is demonstrated or strongly suspected.
  diagnosis_term:
    preferred_term: differential diagnosis
    term:
      id: NCIT:C15220
      label: Diagnosis Assessment
  results: >-
    Either continued treatment as sepsis, or an alternative diagnosis with
    empiric antimicrobials discontinued.
  evidence:
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For adults with suspected sepsis or septic shock but unconfirmed
      infection, we recommend continuously re-evaluating and searching for
      alternative diagnoses and discontinuing empiric antimicrobials if an
      alternative cause of illness is demonstrated or strongly suspected
    explanation: >-
      Recommendation 11, which is the practice this entry records.
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Since there is no "gold standard" test to diagnose sepsis, the bedside
      provider cannot have a differential diagnosis of sepsis alone in a patient
      with organ dysfunction.
    explanation: >-
      States the absence of a confirmatory test, which is the reason this is a
      diagnostic step at all.
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Indeed, a third or more of patients initially diagnosed with sepsis turn
      out to have non-infectious conditions
    explanation: >-
      Supplies the misdiagnosis figure quoted in this entry's description.
treatments:
- name: Immediate Antimicrobial Therapy
  description: >-
    Prompt administration of appropriate antimicrobials is the intervention
    directed at the initiating infection. Guidelines recommend immediate
    administration for confirmed or very likely sepsis, and a rapid assessment
    of infectious versus non-infectious causes when sepsis is only possible and
    shock is absent.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anti-infective agent
      term:
        id: NCIT:C254
        label: Anti-Infective Agent
  target_mechanisms:
  - target: Invasive Infection and Pattern Recognition
    treatment_effect: INHIBITS
    description: >-
      Antimicrobial therapy reduces pathogen burden and therefore the PAMP load
      driving the host response, acting at the trigger node of the graph.
  evidence:
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      we recommend administering antimicrobials immediately, ideally within
      1 h of recognition
    explanation: >-
      Recommendation 12 states the immediacy of antimicrobial administration
      directly, rather than leaving it to be inferred from sepsis being an
      emergency.
- name: Source Control of the Infectious Focus
  description: >-
    Drainage of an abscess, debridement of infected necrotic tissue, or removal
    of an infected device is the second intervention directed at the initiating
    infection. The guideline recommends rapidly identifying or excluding an
    anatomical focus that requires emergent source control, and implementing it
    as soon as medically and logistically practical.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: source control intervention
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Invasive Infection and Pattern Recognition
    treatment_effect: INHIBITS
    description: >-
      Removing or draining the focus eliminates the source of the pathogen- and
      damage-associated molecular patterns that drive the host response, acting
      on the same trigger node as antimicrobial therapy by a different route.
    evidence:
    - reference: PMID:34599691
      reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Clinical experience suggests that without adequate source control, many
        severe presentations will not stabilise or improve despite rapid
        resuscitation and provision of appropriate antimicrobials.
      explanation: >-
        States that antimicrobials and resuscitation do not substitute for
        source control, which is why this intervention is curated as acting on
        the trigger node in its own right rather than as part of antimicrobial
        therapy.
  evidence:
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Source control may include drainage of an abscess, debriding infected
      necrotic tissue, removal of a potentially infected device
    explanation: >-
      Enumerates the interventions this treatment covers, which is what the
      generic NCIT action term cannot express.
  notes: >-
    NCIT has no clinical-action term for source control as a concept, so the
    generic Therapeutic Procedure term is used. Its instances are heterogeneous
    by design - percutaneous drainage, open debridement, and device removal are
    all source control - and binding any one of them (for example Drainage,
    NCIT:C50434) would name a single instance as though it were the category.
    The guideline gives no recommended timeframe: it states that the supporting
    studies suggest 6 to 12 hours but that the data are too limited to
    recommend a window.
- name: Crystalloid Fluid Resuscitation
  description: >-
    Intravenous crystalloid is the first-line resuscitation fluid for
    sepsis-induced hypoperfusion or septic shock, with at least 30 mL/kg
    suggested within the first three hours. This addresses the macrocirculatory
    deficit and does not by itself correct microcirculatory or bioenergetic
    failure.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: fluid therapy
    term:
      id: NCIT:C116537
      label: Fluid Therapy
  target_mechanisms:
  - target: Microcirculatory Dysfunction and Tissue Hypoperfusion
    treatment_effect: INHIBITS
    description: >-
      Volume expansion targets the hypoperfusion node, though the guideline
      grades the specific volume recommendation weakly.
  evidence:
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the use of crystalloids as first-line fluid for resuscitation in sepsis
      and septic shock
    explanation: >-
      States the guideline's first-line fluid choice recorded in this treatment.
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For patients with sepsis induced hypoperfusion or septic shock we suggest
      that at least 30 mL/kg of intravenous (IV) crystalloid fluid should be
      given within the first 3 h of resuscitation
    explanation: >-
      Supplies the volume and timing. The guideline itself grades this a weak
      recommendation on low-quality evidence.
- name: Norepinephrine Vasopressor Support
  description: >-
    Norepinephrine is the first-line vasopressor for septic shock, restoring
    mean arterial pressure when fluid resuscitation alone is insufficient.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: norepinephrine
      term:
        id: CHEBI:33569
        label: noradrenaline
  target_mechanisms:
  - target: Microcirculatory Dysfunction and Tissue Hypoperfusion
    treatment_effect: INHIBITS
    description: >-
      Vasopressor support restores perfusion pressure across vascular beds
      whose tone regulation has been lost.
  evidence:
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      strong recommendation for norepinephrine as the first-line agent
    explanation: >-
      States the guideline panel's first-line vasopressor recommendation
      recorded here.
- name: Vasopressin as Second-Line Vasopressor
  description: >-
    For septic shock on norepinephrine with an inadequate mean arterial
    pressure, the guideline suggests adding vasopressin rather than escalating
    the norepinephrine dose. Unlike the catecholamines it is not titrated to
    response but given at a fixed dose, and it raises pressure through V1
    receptors on vascular smooth muscle rather than through adrenergic
    receptors.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vasopressin
      term:
        id: CHEBI:34543
        label: argipressin
  target_mechanisms:
  - target: Microcirculatory Dysfunction and Tissue Hypoperfusion
    treatment_effect: INHIBITS
    description: >-
      Vasopressin restores perfusion pressure by a non-adrenergic route, which
      is what makes it an addition to norepinephrine rather than a substitute
      for a higher dose of it.
    evidence:
    - reference: PMID:34599691
      reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        binding of V1 receptors on vascular smooth muscle resulting in increased
        arterial blood pressure
      explanation: >-
        States the receptor mechanism by which this treatment acts on the
        perfusion node, and the one that distinguishes it from norepinephrine.
  evidence:
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For adults with septic shock on norepinephrine with inadequate MAP levels,
      we suggest adding vasopressin instead of escalating the dose of
      norepinephrine
    explanation: >-
      Recommendation 38, which states the escalation step this treatment
      records. The guideline grades it weak on moderate-quality evidence.
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Unlike most vasopressors, vasopressin is not titrated to response, but it
      is usually administered at a fixed dose of 0.03 units/min for the
      treatment of septic shock.
    explanation: >-
      Supports the fixed-dose administration described here, which is what
      separates it from the titrated catecholamines.
- name: Low-Dose IV Hydrocortisone
  description: >-
    For septic shock with an ongoing vasopressor requirement the guideline
    suggests IV corticosteroids, in practice hydrocortisone 200 mg/day in
    divided doses. This is the intervention aimed at the dysregulated
    inflammatory arm of the host response rather than at perfusion or at the
    pathogen. The evidence behind it is faster shock resolution and more
    vasopressor-free days, without a clear effect on mortality, and the optimal
    dose, timing, and duration remain unsettled.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydrocortisone
      term:
        id: NCIT:C555
        label: Therapeutic Hydrocortisone
  target_mechanisms:
  - target: Dysregulated Innate Immune Activation
    treatment_effect: INHIBITS
    description: >-
      Glucocorticoid therapy is directed at the dysregulated inflammatory arm of
      the host response, and is the only intervention curated here that acts on
      that node. The cited evidence is clinical, being shock resolution and
      vasopressor-free days, and does not measure the activity of this node
      directly. The link therefore records where the drug is understood to act,
      not a demonstrated change in the node.
  evidence:
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The optimal dose, timing of initiation, and duration of corticosteroids
      remain uncertain; recent RCTs used 200 mg per day of IV hydrocortisone in
      divided doses
    explanation: >-
      Supplies both the dose recorded in this treatment and the guideline's own
      statement that dose, timing, and duration are unsettled.
  - reference: PMID:34599691
    reference_title: "Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A meta-analysis conducted for this guideline revision (Supplementary
      Appendix 5) found an increase vasopressor-free days (MD 1.5 days; 95% CI
      0.8- 3.11 days)
    explanation: >-
      Gives the effect size the weak recommendation rests on. The guideline
      reports the same analysis finding increased neuromuscular weakness and no
      clear mortality effect, which is why the description does not claim a
      survival benefit.
  - reference: PMID:34758337
    reference_title: The immunology of sepsis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      a recent re-analysis of the aforementioned VANISH trial provided further
      evidence that corticosteroid exposure may be associated with increased
      mortality among adult septic shock endotype A patients
    explanation: >-
      Supports the heterogeneity caveat recorded in this treatment's notes. The
      average effect the guideline's recommendation rests on need not be the
      effect in a given transcriptomic endotype.
  notes: >-
    The benefit is not uniform across patients. Transcriptomic septic shock
    endotypes differ in their response, and a re-analysis of the VANISH trial
    associated corticosteroid exposure with increased mortality in one of them.
    This is curated as an open caveat on a guideline-recommended therapy, not as
    a contraindication: the endotypes are research instruments derived from
    leukocyte transcriptomes and are not measured at the bedside, so there is no
    way to act on the finding in an individual patient.
discussions:
- discussion_id: disc_sepsis_grp78_cancer_susceptibility
  prompt: >-
    Does tumor-microenvironment-driven GRP78 dysregulation causally increase
    sepsis susceptibility, severity, or mortality in patients with cancer, over
    and above the recognized contributions of neutropenia, mucosal barrier
    injury, and immunosuppressive antineoplastic therapy?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Invasive Infection and Pattern Recognition
  - pathophysiology#Sepsis-Induced Immunosuppression
  rationale: >-
    Patients with a history of cancer carry a large excess risk of acquiring and
    dying from sepsis, and sepsis and cancer are independently known to share
    immune defects, which makes a cancer-specific susceptibility mechanism
    biologically plausible. A 2026 narrative review proposes GRP78/HSPA5
    dysregulation as that mechanism, acting both as a pathogen entry cofactor
    and as a secreted immunosuppressive signal. The proposal is explicitly
    hypothesis-level: the review states that no clinical cohort study has
    established a causal link, and that its argument rests on in vitro work,
    animal models, and non-oncologic sepsis cohorts. It is therefore curated
    here as an open gap attached to the trigger and immunosuppression nodes,
    rather than as a curated causal edge, a GRP78 pathophysiology node, or a
    separate cancer-associated sepsis disease entry - any of which would assert
    more than the evidence supports.
  proposed_experiments:
  - experiment_id: exp_sepsis_grp78_oncology_cohort
    name: Oncology-specific prospective cohort of circulating GRP78 and sepsis outcome
    description: >-
      Measure circulating GRP78 at cancer diagnosis and at infection onset in a
      prospective oncology cohort, and test whether it predicts sepsis
      incidence, severity, and mortality after adjustment for neutropenia,
      mucositis, recent cytotoxic therapy, and tumor stage. This is the study
      the source review identifies as absent.
  evidence:
  - reference: PMID:42429070
    reference_title: "GRP78 dysregulation: A proposed molecular mechanism linking the tumor microenvironment to sepsis susceptibility in patients with cancer (Review)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To date, no clinical cohort study has directly established a causal link
      between GRP78 dysregulation and sepsis incidence or mortality in patients
      with cancer.
    explanation: >-
      The review's own statement that the causal link is unestablished is the
      primary justification for curating this as a KNOWLEDGE_GAP rather than as
      a mechanism.
  - reference: PMID:16778259
    reference_title: The epidemiology of sepsis in patients with malignancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with a history of cancer are at increased risk for acquiring and
      subsequently dying from sepsis, compared to the general population,
      although incidence and fatality rates are decreasing over time.
    explanation: >-
      Establishes that the excess sepsis risk in cancer is real, which is what
      makes the unexplained mechanistic residue worth tracking as a gap.
  - reference: PMID:24232462
    reference_title: "Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Surprisingly, cancer and sepsis share many immune defects, and the
      remarkable success of new immunotherapeutics in cancer has highlighted the
      potential for this new approach in sepsis.
    explanation: >-
      Independent support that cancer and sepsis share immune-defect biology,
      which is the general premise the GRP78 hypothesis tries to make specific.
  notes: >-
    Opened in response to issue #6274. The scope question there offered four
    options; this discussion implements the conservative one. A conserved
    GRP78 sepsis mechanism module and a distinct Cancer-Associated Sepsis
    disease entry were both considered and deferred, because a module asserts
    a recurrent, evidenced mechanism and the source explicitly disclaims that
    evidence. If an oncology-specific cohort establishes the link, the natural
    home is a comorbidity entry over Sepsis and the relevant cancer entries.
- discussion_id: disc_sepsis_microcirculatory_vs_bioenergetic
  prompt: >-
    In an individual patient with sepsis, what determines the relative
    contribution of microcirculatory perfusion failure versus mitochondrial
    bioenergetic failure to organ dysfunction, and can the two be distinguished
    at the bedside well enough to select therapy?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Microcirculatory Dysfunction and Tissue Hypoperfusion
  - pathophysiology#Mitochondrial Dysfunction and Bioenergetic Failure
  rationale: >-
    Both routes to multiple organ dysfunction are curated here with supporting
    evidence, and they are not mutually exclusive. Neither source quantifies the
    relative contribution, and there is no validated bedside measure that
    separates a perfusion-limited from an oxygen-utilization-limited patient.
    This matters therapeutically: resuscitation strategies target the former,
    and would not be expected to reverse the latter.
  evidence:
  - reference: PMID:24690420
    reference_title: "Sepsis, mitochondrial failure and multiple organ dysfunction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Knowledge of the molecular processes associated with the development of
      oxidative stress should facilitate the development of effective therapies
      and better prognosis for patients with sepsis and organ dysfunction.
    explanation: >-
      The review frames effective bioenergetically-targeted therapy as a future
      prospect, which is the unresolved half of this question. The sentence
      supports the gap by implication rather than stating it.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Review round 2: three central treatments, diagnosis section, thrombogenesis conformance · 2026-09-17T21:41:07Z · View source

Second follow-up to the ai4c-reviewer CHANGES_REQUESTED reviews on PR #8736 (2026-08-17 and 2026-09-15). Closes the one remaining blocker and every outstanding suggestion. Rebase first. The branch was 143 commits behind origin/main; rebased onto 2faf382875 with no conflicts. The post-rebase diff against origin/main is the Sepsis files plus the two single cache rows (MONDO:0700217 in cache/mondo/terms.csv and in the diseaseorsubtypeterm enum cache). Blocker (reviewer item 2): the three central treatments. All three are added with target_mechanisms, and every quote was checked against references_cache/PMID_34599691.md before being written, using the repository's own snippet matcher rather than by eye. The reviewer's line references were good but several of the spans they name are hyphen-split across line wraps in the cached PDF text, and a hyphen-split span verifies only under the audit's relaxed pass, which the gating validator does not run. Spans were re-cut to hyphen-clean sentences and each one verifies strictly: - Source Control of the Infectious Focus. treatment_term NCIT:C49236 Therapeutic Procedure, therapeutic_modality SURGERY, target_mechanisms -> Invasive Infection and Pattern Recognition (INHIBITS) with its own evidence item. NCIT has no clinical-action term for source control as a concept; its instances (percutaneous drainage, open debridement, device removal) are heterogeneous, and binding NCIT:C50434 Drainage would have named one instance as the category. The gap is recorded in the entry's top-level notes alongside the two MONDO gaps and in the treatment's own notes. - Low-Dose IV Hydrocortisone. NCIT:C15986 Pharmacotherapy + therapeutic_agent NCIT:C555 Therapeutic Hydrocortisone, target_mechanisms -> Dysregulated Innate Immune Activation (INHIBITS). That node previously had no incoming treatment edge. The link description states plainly that the cited evidence is clinical (shock resolution, vasopressor-free days) and does not measure the node, so the link records where the drug is understood to act rather than a demonstrated change. A third evidence item (PMID:34758337) carries the VANISH re-analysis associating corticosteroid exposure with increased mortality in one transcriptomic endotype; it is curated as an open caveat in the treatment's notes, not as a contraindication, since the endotypes are research instruments. - Vasopressin as Second-Line Vasopressor. NCIT:C15986 + therapeutic_agent CHEBI:34543 argipressin, therapeutic_modality PEPTIDE, target_mechanisms -> Microcirculatory Dysfunction and Tissue Hypoperfusion (INHIBITS) with the V1-receptor mechanism sentence as link evidence. Treatments were reordered to follow the clinical sequence (antimicrobials, source control, fluids, norepinephrine, vasopressin, hydrocortisone). Reviewer suggestions, all taken except one: - Crystalloid Fluid Resuscitation: treatment_term NCIT:C49236 -> NCIT:C116537 Fluid Therapy. - Immediate Antimicrobial Therapy: therapeutic_agent NCIT:C254 Anti-Infective Agent added. The paired suggestion of NCIT:C15620 Antibiotic Therapy as the action term was NOT taken: the guideline recommendation and this entry both cover antibacterial, antifungal and antiviral therapy, so Antibiotic Therapy would narrow the claim. Anti-Infective Agent carries the specificity without that narrowing. - conforms_to: thrombogenesis#Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation on Thromboinflammation and Sepsis-Induced Coagulopathy. The node was specialized to match the module node it now claims: GO:0072378 fibrin clot formation added alongside GO:0007596, and two evidence items added from the cached DIC review full text (monocyte tissue factor initiating the cascade; thrombin as the critical mediator). The module's conformance boundary requires a platelet-assisted, thrombin-generated fibrin thrombus, which is what those two items establish for sepsis. - diagnosis: section added, five entries: SOFA organ-dysfunction scoring, bedside screening (qSOFA, curated with the 2021 guideline's recommendation AGAINST its use as a single screening tool), microbiologic cultures before antimicrobials, serum lactate measurement (curated with the guideline's statement that lactate alone cannot rule the diagnosis in or out), and continued search for an alternative diagnosis (there is no gold-standard test, and a third or more of patients turn out to have something else). - datasets: [] removed. The omitted key says the same thing. - Compound node names: NOT changed. The reviewer said they would not force a split and neither would I. Endothelial activation and glycocalyx degradation are one measured event in the cited source, and splitting them would create a node with no evidence of its own. Deep-research report reconciliation (left open by the previous session): the falcon report's NET-formation suggestion is taken, as GO:0140645 neutrophil extracellular trap formation on Dysregulated Innate Immune Activation with evidence from PMID:34758337; the report gives the identifier as GO:0140725 in two places (lines 1042 and 1196), and GO:0140725 is 'free heme detoxification'. The correct term is GO:0140645 neutrophil extracellular trap formation, which is already in the local label and enum caches. This is the invented-ontology-identifier failure mode CLAUDE.md section 2a describes, and it is exactly what the previous session's warning covered: `just validate-research-terms` could not complete on this report because OLS timed out, so none of its identifiers were term-checked. The five HP identifiers the report names as phenotype gaps (HP:0002045, HP:0100520, HP:0002904, HP:0031258, HP:0012418) were each checked against the local cache or live OLS, and all five are correct; only the GO identifier was wrong. Hypoxemia (HP:0012418) is not added separately because the respiratory failure phenotype already curated here rests on the guideline's acute hypoxemic respiratory failure sentence. Oliguria (HP:0100520) added as a Renal phenotype from the S-AKI review's definition sentence. Hypothermia (HP:0002045) and delirium (HP:0031258) were NOT added: no cached reference in this branch mentions either, and hyperbilirubinemia (HP:0002904) was NOT added because the only cached mention is the Sepsis-3 statement of which laboratory variables SOFA computation needs, which is a statement about the score rather than an observation of the phenotype. Validated after the edits: `just validate kb/disorders/Sepsis.yaml` passed (schema + terms + references), Snippets checked: 67/67 verified; `just count-verified-snippets` 67/67; `just check-duplicate-keys`, `check-entity-refs`, `check-causal-targets`, `check-enum-values`, `check-qualifier-terms` OK; `check-folded-hyphens`, `check-snippet-grading`, `check-snippet-length`, `check-title-snippets`, `check-reference-titles` OK with no new occurrences; pytest tests/test_data.py -k "Sepsis or subtype or attaches or target or conforms or unique or duplicate or discussion or treatment or history or diagnosis" 20 passed. Evidence items went 42 -> 67. `just validate-disorders kb/disorders/Sepsis.yaml`, the CI-equivalent batched pass, also passed at 67/67. `just validate-history-all` reported no issues over 10,691 records. `just check-groupings --strict` fails on this branch and fails identically on origin/main with the same advisory NOT_SATISFIED output; no line of it names Sepsis. Still not done, and named rather than left silent: no progression, histopathology or datasets sections; no clinical_trials; no sepsis mechanism module; the neonatal sepsis subtype remains a placeholder; Hospital-Acquired_Acute_Kidney_Injury is still not cross-linked to this entry.

Deep-research report (falcon), rebase onto main, PARTIAL migration · 2026-09-15T16:03:38Z · View source

Follow-up to the ai4c-reviewer CHANGES_REQUESTED review on PR #8736 (2026-08-17) and the pr-shepherd pass (2026-09-10). Deep-research artifact (reviewer item 1). Generated research/Sepsis-deep-research-falcon.md with the Edison Scientific falcon provider via `just research-disorder falcon Sepsis` (797 s, 48 citations). The run's built-in reference validation resolved 14/14 extracted references with no confabulation flagged; `just validate-research-reference` was re-run in place with deep-research-client 0.2.10 and added no off-topic flags. `just validate-research-terms` could not complete: EBI OLS timed out on two attempts (CHEBI:17650, GO:0070269), so the report's ontology identifiers are NOT term-checked and must be verified against OAK before any of them is copied into the entry. The report contains zero PMID strings by falcon design (DOIs supplied instead). The 14 DOI reference-cache files the validation pass fetched are committed alongside the report, as prior falcon PRs do. What the report says about the entry, without acting on it here: it independently names source control, vasopressin and IV hydrocortisone as the missing treatments (reviewer item 2), and lists phenotypes the entry does not curate: hypothermia (HP:0002045), oliguria (HP:0100520), hyperbilirubinemia (HP:0002904), delirium (HP:0031258), hypoxemia (HP:0012418). It suggests thrombogenesis-style coagulation/immunothrombosis and NET-formation (GO:0140725) mechanisms, and cell types beyond those curated. Reconciling the entry against the report is left as the follow-up; nothing from the report was added to kb/disorders/Sepsis.yaml in this session. Rebase. The branch was 1805 commits behind main and GitHub reported it CONFLICTING, so no CI ran. Rebased onto origin/main (57910dc19b). The two conflicts were both in regenerable files and were resolved by taking main's copy: cache/enums/diseaseorsubtypeterm_6d5891ec946f.csv (then re-derived by `just validate`, which re-seeded the entry's rows) and references_cache/PMID_26903338.md (add/add; main's copy kept, and all snippets citing it still verify). Post-rebase diff against origin/main is only the Sepsis files plus one cache/mondo/terms.csv row. Schema migration. On the rebased base, `just validate` rejected the entry: EvidenceItemSupportEnum no longer accepts PARTIAL. Four evidence items used it (Thromboinflammation -> Microcirculatory edge, PMID:37221630; crystalloid 30 mL/kg, PMID:34599691; GRP78 knowledge-gap discussion, PMID:42429070; bioenergetic knowledge-gap discussion, PMID:24690420). Each was regraded SUPPORT, following the schema's own migration note that former PARTIAL items become SUPPORT with `directness` left unset. `directness` was deliberately NOT set on those four, because the other 38 items in the entry carry no directness tag and a partial tagging would have to be interpreted; the hedge each PARTIAL carried was rewritten into the item's explanation instead. No snippet, reference or evidence_source changed. Validated after the edit: `just validate kb/disorders/Sepsis.yaml` passed (schema + terms + references, Snippets checked: 42/42 verified); `just count-verified-snippets` 42/42; `just check-duplicate-keys`, `just check-entity-refs`, `just check-causal-targets`, `just check-snippet-grading`, `just check-folded-hyphens`, `just check-title-snippets`, `just check-snippet-length` all OK with no new occurrences; `just validate-history-all` no issues; pytest tests/test_data.py -k "Sepsis or subtype or attaches or target or conforms or unique or duplicate or discussion or treatment or history" 20 passed. Still open after this session: reviewer item 2 (source control, hydrocortisone, vasopressin treatments with target_mechanisms), reconciliation of the entry against the falcon report, and the reviewer's suggestions (thrombogenesis conforms_to, diagnosis section).

Review round: fix claim-evidence mismatch, regrade human epidemiology, drop SIRS parent, add respiratory failure phenotype · 2026-09-10T14:00:14Z · View source

Review round on PR 8736, addressing four of the six blocking items from the ai4c-reviewer review. Item 4, the claim-evidence mismatch on the Antimicrobial Therapy treatment: the snippet Sepsis and septic shock are medical emergencies supports sepsis being an emergency, not the immediacy of antimicrobial administration, so it is replaced by Recommendation 12 from the same cached guideline, which states the immediacy directly. Item 5, evidence_source on human epidemiology: three items regraded from OTHER to HUMAN_CLINICAL, namely the two PMID:33752856 statements on sepsis-associated acute kidney injury frequency and on it being a common life-threatening complication, and the PMID:24232462 description of the clinical course of unresolved prolonged sepsis. The remaining OTHER items on those two references were left alone because they quote mechanistic hypothesis lists, statements of incomplete understanding, or cross-disease comparison rather than clinical observation, and the Surviving Sepsis Campaign consensus items are correctly OTHER. Item 6, the parents list: systemic inflammatory response syndrome removed, since Sepsis-3, which this entry adopts throughout, retired the SIRS framing. Item 3, respiratory organ dysfunction: added a Respiratory phenotype, Sepsis-Induced Hypoxemic Respiratory Failure, bound to HP:0002878 with temporality ACUTE and an exact quote from the cached guideline stating that acute hypoxemic respiratory failure follows from sepsis by both the pulmonary and the non-pulmonary route. Two blocking items were left for the entry author. Item 1, the missing deep-research artifact under research/, requires a deep-research provider run and cannot be produced by a shepherd pass. Item 2, the three missing treatments of source control, low-dose hydrocortisone and vasopressin, needs NCIT and CHEBI term selection plus a decision on which mechanism nodes each target_mechanisms link attaches to, and the guideline rationale prose it would be quoted from is hyphen-split across line wraps in the cached PDF text, so it needs a deliberate curation pass rather than a review-round edit. The branch also conflicts with main, in cache/enums/diseaseorsubtypeterm_6d5891ec946f.csv and references_cache/PMID_26903338.md; both are regenerable artifacts, and resolving them was outside this run one-branch-update budget. Validated with just validate, just validate-terms, just count-verified-snippets at 42 of 42, just check-duplicate-keys and just check-folded-hyphens.

Falcon ▸
Sepsis: Comprehensive Disease-Characteristics Report
Edison Scientific Literature 48 citations 2026-09-15T11:51:33.161847

Sepsis: Comprehensive Disease-Characteristics Report

Executive summary

Sepsis is an acute, life-threatening syndrome in which infection triggers a dysregulated host response and new organ dysfunction. It is not synonymous with infection, bacteremia, or systemic inflammatory response syndrome (SIRS). Under Sepsis-3, adult clinical operationalization is suspected/documented infection plus an acute increase in Sequential Organ Failure Assessment (SOFA) score of at least 2 points. Septic shock is the higher-risk subset requiring vasopressors to maintain mean arterial pressure (MAP) at least 65 mmHg and having lactate above 2 mmol/L despite adequate volume resuscitation. Reported mortality is approximately 15–25% for sepsis and 30–50% for septic shock, varying substantially by case mix and health-system capacity (hotchkiss2016sepsisandseptic pages 1-2).

Sepsis is a complex, heterogeneous syndrome rather than a Mendelian disease. Its biology comprises simultaneously evolving pathogen burden, innate inflammatory activation, endothelial and microvascular injury, coagulation/complement activation, metabolic dysfunction, and immune suppression. This heterogeneity explains why rapid antimicrobials, source control, and physiologic support remain more successful than non-stratified immunomodulation (hotchkiss2016sepsisandseptic pages 5-6, hotchkiss2016sepsisandseptic pages 9-10, sebastian2025sepsisandpostsepsis pages 8-10).

1. Disease information

Definition, names, and identifiers

Preferred name: sepsis. Synonyms/related terms: septicemia/septicaemia, blood poisoning, systemic infection, severe sepsis, septic shock, infection-associated organ dysfunction. “Septicemia” and “blood poisoning” are imprecise legacy terms; bacteremia may be absent, and “severe sepsis” is redundant under Sepsis-3.

Key suggested identifiers are:

  • MeSH: Sepsis, D018805.
  • ICD-10-CM: A40.- streptococcal sepsis; A41.- other sepsis; A41.9 unspecified-organism sepsis; R65.20 severe sepsis without shock; R65.21 severe sepsis with septic shock. Coding rules require the underlying infection/organism and acute organ dysfunction where applicable.
  • ICD-11: sepsis without versus with septic shock concepts should be verified against the implementation’s current release.
  • MONDO: retrieved disease-level mappings include MONDO:0005229, bacterial infectious disease with sepsis, and MONDO:1040015, infectious disease with sepsis. A general “sepsis” MONDO identifier should be release-verified rather than inferred from the Open Targets HPO-derived entry (OpenTargets Search: sepsis).
  • OMIM/Orphanet: not applicable as a single inherited or rare disease entity. Rare monogenic immunodeficiencies can predispose to invasive infection and sepsis, but are distinct diagnoses.

Sepsis knowledge comes from both individual-level data—EHR-derived vital signs, laboratory results, cultures, medications and outcomes—and aggregated resources, including registries, administrative claims, cohorts, trials, guidelines and ontologies. Definition and coding variation materially alter estimated incidence (ljungstrom2019incidencesofcommunity pages 12-13, hotchkiss2016sepsisandseptic pages 1-2).

2. Etiology, risk, and protective factors

Causal factors and infectious agents

The necessary upstream trigger is infection, most often pneumonia, urinary infection, intra-abdominal infection, bloodstream/device infection, or skin/soft-tissue infection. Bacteria predominate, but fungi, viruses and parasites can cause the syndrome. In one small cohort represented in a systematic-review evidence table, isolates were 48.7% Gram-negative, 31.6% Gram-positive and 14.5% fungal; this is illustrative rather than globally representative. Another cohort’s sources were urinary 30.4%, abdominal 26.6%, pulmonary 25.3%, other 6.3% and undetermined 11.4% (hodgsonUnknownyeararticletitlehealthrelated pages 15-16).

Typical agents include Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, streptococci, enterococci, anaerobes, Candida spp., influenza virus and SARS-CoV-2. Pathogen distribution depends on age, site, community versus hospital acquisition, geography, immune status and antimicrobial exposure. Culture negativity—reported in up to 30%—does not exclude sepsis (hotchkiss2016sepsisandseptic pages 12-13).

Host and environmental risk factors

Major risks include neonatal or advanced age, male sex in some older populations, frailty, diabetes, chronic kidney/liver/lung disease, cancer, immunosuppression, pregnancy/postpartum states, major surgery, trauma or burns, invasive devices, hospitalization, prior antimicrobials and resistant-organism exposure. In a Swedish population study, incidence increased more than forty-fold from the youngest to oldest groups; median age was 78 years, and men aged at least 85 had approximately 70% higher severe-sepsis incidence than women of similar age (ljungstrom2019incidencesofcommunity pages 12-13).

Environmental and health-system modifiers include sanitation, vaccination coverage, crowding, air pollution insofar as it increases respiratory disease, occupational injury, access to primary and obstetric care, delayed recognition, antimicrobial resistance, and limited laboratory/ICU capacity. Smoking, hazardous alcohol use, malnutrition, inactivity and obesity influence infection, cardiopulmonary reserve or recovery, but are neither necessary nor sufficient causes.

Protective factors are mainly infection prevention and physiological reserve: age-appropriate vaccination, hand hygiene, safe surgery/childbirth, catheter bundles, antimicrobial stewardship, prompt treatment of localized infection, nutrition, mobility and chronic-disease control. No validated common “protective allele” is used clinically.

Gene–environment interaction

Host genotype affects pathogen recognition and cytokine, leukocyte, endothelial and coagulation responses, but effect size depends on organism, infection site, ancestry, antimicrobial susceptibility, treatment timing and comorbidity. Examples include a TLR4 haplotype associated with acquisition in Han Chinese (OR 1.59), CD14 rs2569190 with septic shock (OR 1.72), TREM1 rs2234246 with shock (OR 3.10), and TREM1 rs5743661 with 30-day mortality after Gram-positive sepsis (OR 4.88); inconsistent replication prevents clinical use (giamarellosbourboulis2016theroleof pages 4-5). This context dependence is a genuine gene–environment interaction problem, not evidence of deterministic inheritance (sutherland2009benchtobedsidereviewassociation pages 1-2).

3. Phenotypes

Sepsis may occur at any age. Onset is usually acute over hours to days; severity and manifestations fluctuate with infection source, host reserve and treatment.

  • Constitutional signs: fever (HP:0001945), hypothermia (HP:0002045), chills, malaise and weakness. Temperature can be normal, especially in neonates, older or immunosuppressed patients.
  • Cardiovascular signs: tachycardia (HP:0001649), hypotension (HP:0002615), delayed capillary refill, mottling, vasoplegia and shock; myocardial depression may affect both ventricles, and mild troponin elevation is common but nonspecific (hotchkiss2016sepsisandseptic pages 9-10).
  • Respiratory: tachypnea (HP:0002789), hypoxemia (HP:0012418), pulmonary edema and ARDS. Alveolar-capillary injury lowers compliance and gas exchange. In the Swedish study, 78% of Sepsis-3 cases qualified through respiratory dysfunction alone, illustrating the sensitivity of epidemiology to oxygen-based SOFA classification (ljungstrom2019incidencesofcommunity pages 12-13, hotchkiss2016sepsisandseptic pages 9-10).
  • Neurologic/behavioral: altered consciousness, delirium (HP:0031258), agitation, somnolence and encephalopathy (HP:0001298). Long-term cognitive, anxiety, depressive and post-traumatic symptoms may persist.
  • Renal: oliguria (HP:0100520), rising creatinine, electrolyte/acid-base abnormalities and AKI.
  • Hematologic/coagulation: thrombocytopenia (HP:0001873), prolonged coagulation tests, microthrombosis, bleeding and disseminated intravascular coagulation (HP:0001928 broadly).
  • Hepatic/metabolic: hyperbilirubinemia (HP:0002904), cholestasis, hypoglycemia or hyperglycemia, metabolic acidosis and hyperlactatemia.
  • Gastrointestinal/musculoskeletal: ileus, feeding intolerance, catabolism, ICU-acquired weakness and lean-tissue loss.

Phenotype frequency cannot be represented by one universal percentage because cohorts use different definitions and infection sources. Severity ranges from reversible single-organ dysfunction to rapidly progressive multiorgan failure. Per-phenotype quality-of-life effects include impaired mobility/self-care from weakness, inability to work, cognitive and emotional disability after encephalopathy/delirium, and chronic dialysis or dyspnea after organ injury. In a 2023 German claims study of 7,370 previously employed working-age survivors, 69.2% returned to work by six months and 76.9% by 12 months; at one year, 9.8% remained on sick leave and 13.3% had retired early (DOI: https://doi.org/10.3389/fmed.2023.1187809; published May 2023) (fleischmannstruzek2023returntowork pages 8-8).

4. Genetic and molecular information

Disease architecture

There is no single causal sepsis gene, characteristic chromosomal abnormality, Mendelian inheritance, penetrance, anticipation, carrier frequency, founder mutation or germline-mosaicism framework. Sepsis susceptibility and outcomes are multifactorial and polygenic. Consequently, ClinVar-style “pathogenic/likely pathogenic” classification is generally inappropriate for common sepsis-associated variants; they are susceptibility or prognostic associations. Somatic clonal hematopoiesis genes such as TET2/SRSF2 are emerging disease modifiers, not causes of sepsis. Open Targets associations also prominently include adrenergic receptors and F8 because of therapeutic/clinical evidence; these should not be mislabeled causal genes (OpenTargets Search: sepsis).

Variant evidence

A GWAS of 832 septic-shock patients identified 139 death-associated SNPs at 5% FDR. Candidate loci included CYP11B2/PTPN11 for early death and FER, CISH, MAPKAPK3 for late death. The top regulatory candidate, rs143356980, lies near CISH in a monocyte/T-cell super-enhancer; CRISPR deletion and reporter assays supported enhancer function, with the T allele reducing activity relative to C. However, the reported very large multilocus early/late death-risk estimates require independent replication (DOI: https://doi.org/10.3390/ijms22115852; published May 2021) (rosier2021geneticpredispositionto pages 16-18, rosier2021geneticpredispositionto pages 1-2).

The FER rs4957796-C allele has an approximately 20% European frequency and was associated with lower mortality in pneumonia-related sepsis in one study but not replicated for 28-day mortality in another. TNF rs1800629 and TLR4 Asp299Gly/Thr399Ile are classic inconsistent candidate associations (rosier2021geneticpredispositionto pages 1-2, sutherland2009benchtobedsidereviewassociation pages 1-2).

Epigenetics and testing

Stimulus- and cell-specific chromatin accessibility, DNA methylation, histone modifications and trained immunity/tolerance can sustain immune reprogramming. CISH enhancer effects illustrate regulatory genetics, but not a diagnostic epigenetic lesion. Sepsis-related epigenomics remains investigational; cfDNA methylation is being tested as a tissue-of-origin and immune-injury biomarker (NCT06817408) (NCT06817408 chunk 1).

Routine WGS, WES, panels, CMA, karyotype, FISH, mtDNA or repeat-expansion testing is not recommended for sepsis itself. Genetic evaluation is appropriate only when recurrent/unusual infection suggests an underlying inborn error of immunity, metabolic disorder or other independent diagnosis. Current associations lack replication, ancestry generalizability and incremental clinical utility beyond age, comorbidity and physiological severity (sutherland2009benchtobedsidereviewassociation pages 1-2, sutherland2009benchtobedsidereviewassociation pages 6-7).

5. Environmental information

Sepsis is not directly caused by a toxin or radiation in the usual disease definition. Relevant exposures operate by increasing infection or reducing reserve: contaminated water/food, poor sanitation, healthcare-associated resistant organisms, wounds/trauma, invasive devices, occupational exposure to pathogens, malnutrition, smoke/air pollution and limited healthcare access. Antibiotic exposure selects resistant microbiota and changes empiric-treatment adequacy. LPS is a bacterial PAMP and experimental trigger, not usually a standalone environmental cause of human sepsis.

Lifestyle modification reduces background infection and comorbidity risk but cannot reliably prevent all sepsis. Smoking cessation, moderated alcohol use, physical activity, adequate protein/calorie intake, oral health, skin/foot care in diabetes, and adherence to chronic-disease therapy are reasonable population measures.

6. Mechanism and pathophysiology

Causal chain

  1. Trigger/upstream sensing: local or disseminated microbes release PAMPs; injured cells release DAMPs. TLRs, NOD-like receptors, dectins, RAGE and nucleic-acid sensors activate NF-κB, AP-1 and IRF3/7 (GO:0045087 innate immune response; GO:0002224 TLR signaling) (hotchkiss2016sepsisandseptic pages 5-6).
  2. Mediator amplification: macrophages, monocytes, dendritic cells, neutrophils and endothelium produce TNF, IL-1, IL-6, chemokines and interferons (GO:0019221). Complement C3a/C4a/C5a amplifies leukocyte recruitment and injury (GO:0006956) (vella2025cytokinesinsepsis pages 10-11).
  3. Barrier/coagulation failure: activated endothelium becomes adhesive, permeable and procoagulant; platelets, fibrin and neutrophils generate immunothrombi. Capillary leak causes edema, while microvascular flow heterogeneity and thrombosis impair oxygen/nutrient delivery (GO:0007596; GO:0030168) (hotchkiss2016sepsisandseptic pages 9-10).
  4. Cell/tissue injury: ROS, proteases, extracellular histones, complement, mitochondrial dysfunction, apoptosis and inflammatory cell death injure parenchyma. NETs capture organisms but expose histones/proteases that damage endothelium (GO:0140725) (vella2025cytokinesinsepsis pages 10-11).
  5. Organ manifestations: alveolar-capillary leak → hypoxemia/ARDS; vasodilation, leak and cardiodepression → hypotension; microvascular/metabolic tubular stress → AKI; BBB/neuroimmune dysfunction → delirium; cholestasis/hypoxia → bilirubin rise; platelet/coagulation consumption → thrombocytopenia/DIC (hotchkiss2016sepsisandseptic pages 9-10).
  6. Concurrent immune suppression: T/B/dendritic-cell apoptosis, lymphopenia, reduced monocyte MHC-II/HLA-DR, PD-1/PD-L1 signaling, regulatory/TH2 skewing and IL-10/TGF-β impair pathogen clearance and predispose to secondary infection. In human sepsis, stimulated lymphocyte pro-inflammatory/TH1 cytokine production was reported below 10% of non-septic controls; persistent lymphopenia predicts mortality (hotchkiss2016sepsisandseptic pages 5-6).
  7. Recovery or persistence: successful source control and organ support permit resolution; otherwise persistent inflammation, immunosuppression and catabolism produce chronic critical illness/post-sepsis syndrome.

Molecular profiling and advanced technologies

Bulk transcriptomics has defined immune-response endotypes. Pneumonia-associated SRS1 is relatively immunosuppressed and high-risk versus SRS2; an IFNγ/CXCL9-driven endotype may represent about 20% of cases and is now being therapeutically selected in EMBRACE. Eleven-gene host-response panels can distinguish sepsis from sterile inflammation in research settings, but endotypes are platform- and cohort-dependent (sebastian2025sepsisandpostsepsis pages 8-10).

Proteomics, metabolomics and lipidomics repeatedly implicate complement/coagulation, extracellular matrix, leukocyte migration, amino-acid depletion, mitochondrial/bioenergetic dysfunction and altered lipid mediators. A 2024 pilot proteomics study found 174 differentially expressed proteins and proposed plasma SPP1/osteopontin as a diagnostic/prognostic candidate, but its discovery sample—22 patients and 10 controls—is too small for implementation.

Single-cell RNA/ATAC and spatial methods increasingly resolve monocyte, neutrophil, lymphocyte and organ-parenchymal states hidden by bulk blood measurements. As of 2024, these approaches are primarily mechanistic and stratification tools, not standard diagnostics. Liquid-biopsy cfDNA epigenomics is being prospectively evaluated in 1,000 participants to infer tissue/cell injury and immune exhaustion (NCT06817408) (NCT06817408 chunk 1).

Suggested cell terms include neutrophil CL:0000775, monocyte CL:0000576, macrophage CL:0000235, dendritic cell CL:0000451, T cell CL:0000084, B cell CL:0000236, platelet CL:0000233 and endothelial cell CL:0000115. Relevant compartments are plasma membrane GO:0005886, extracellular region GO:0005576 and mitochondrion GO:0005739.

7. Anatomical structures affected

Sepsis is systemic and has no lateralization. Frequent primary sites are lung, urinary tract/kidney, abdomen, bloodstream/device, skin/soft tissue and CNS. Secondary injury affects lung (UBERON:0002048), kidney (UBERON:0002113), liver (UBERON:0002107), heart (UBERON:0000948), brain (UBERON:0000955), blood (UBERON:0000178), gastrointestinal barrier and skeletal muscle. The key cross-organ tissue is vascular endothelium, including glycocalyx and microcirculation. Relevant subcellular compartments include membrane PRR complexes, cytosolic inflammasomes, nucleus/chromatin, mitochondria, ER and lysosome/autophagy machinery.

8. Temporal development

Onset can be neonatal, pediatric, adult or geriatric. The usual pattern is acute, sometimes fulminant within hours. A practical trajectory is: localized infection → early systemic response and evolving organ dysfunction → established sepsis → septic shock/multiorgan dysfunction → recovery, death or chronic critical illness. These are trajectories, not formal cancer-like stages.

The crucial intervention window is at suspicion/recognition: obtain cultures without material delay, begin appropriate antimicrobials, control the source and restore perfusion. Progression rate is highly variable. Resolution may occur over days; organ recovery can take weeks to months. Recurrent infection, rehospitalization, weakness and neurocognitive/psychiatric sequelae can persist for years. Treatment-induced remission is better described as infection resolution and organ recovery; “spontaneous remission” is not a useful sepsis construct.

9. Inheritance and population epidemiology

Sepsis has multifactorial/polygenic susceptibility with variable, context-dependent expression—not AD, AR, X-linked or mitochondrial inheritance. There is no clinically defined penetrance, anticipation or carrier state.

A widely cited modeled global estimate for 2017 is approximately 48.9 million cases, incidence 677.5 per 100,000, and about 11 million deaths, roughly one in five deaths worldwide. Estimates include sepsis as an intermediate mechanism in many underlying diseases and are definition/model dependent. A prospective Swedish study found community-onset Sepsis-3 incidence of 838/100,000/year, versus 276/100,000/year for older severe-sepsis criteria; bacteremia occurred in 13% of suspected cases and had incidence 203/100,000/year (DOI: https://doi.org/10.1371/journal.pone.0225700; published December 2019) (ljungstrom2019incidencesofcommunity pages 12-13).

Burden is highest at the extremes of age and disproportionately affects low- and middle-income regions. Sex effects vary; male excess is often reported in older adults. Geographic variation reflects infectious-disease ecology, vaccination, maternal/neonatal care, antimicrobial resistance, coding, recognition and ICU access.

10. Diagnostics

Clinical criteria and differential diagnosis

Sepsis is a clinical syndrome, not confirmed by one assay. Identify suspected infection and acute organ dysfunction using history, examination, trends and SOFA components: respiratory oxygenation, platelets, bilirubin, MAP/vasopressors, Glasgow Coma Scale, creatinine/urine output. qSOFA—altered mentation, respiratory rate ≥22/min and systolic pressure ≤100 mmHg—is prognostic but insufficiently sensitive for screening. The 2021 SSC strongly recommends against qSOFA alone; SIRS, NEWS or MEWS may be used within structured programs. Performance-improvement programs were associated with lower mortality in 50 observational studies (OR 0.66, 95% CI 0.61–0.72), while randomized screening evidence did not itself show mortality benefit (RR 0.90, 95% CI 0.51–1.58) (evans2021survivingsepsiscampaign pages 1-2).

Obtain at least two blood-culture sets and source specimens before antimicrobials when this causes no harmful delay. CBC/differential, CMP, bilirubin, creatinine, coagulation tests, blood gas and serial lactate characterize organ dysfunction. Urinalysis/culture, respiratory testing, CSF, joint fluid or surgical specimens are source-dependent. Ultrasound, radiography, CT, MRI, echocardiography and ECG locate infection or assess organ failure; imaging should not delay stabilization.

Differentials include uncomplicated infection, noninfectious SIRS after trauma/surgery/pancreatitis, hemorrhagic/cardiogenic/obstructive shock, adrenal crisis, anaphylaxis, toxicologic syndromes, pulmonary embolism, cytokine-release/HLH-like states and thrombotic microangiopathy.

Biomarkers and omics

Lactate is useful for severity and resuscitation trends but is neither specific for sepsis nor a pure tissue-hypoxia marker. CRP and procalcitonin (PCT) support context-dependent probability and stewardship; PCT should not independently rule sepsis in/out. PCT-guided discontinuation can reduce antibiotic exposure, whereas initiation remains clinical (hotchkiss2016sepsisandseptic pages 12-13).

Presepsin, soluble TREM-1, IL-6, endothelial/glycocalyx markers, cell-free DNA, miRNAs and transcriptomic classifiers remain adjunctive/investigational. Monocyte distribution width (MDW) is automatically generated with some CBC analyzers; a 2,200-person prospective study is evaluating a cutoff of 20, but uses Sepsis-2 adjudication, limiting direct Sepsis-3 translation (NCT06267742) (NCT06267742 chunk 1).

There is no asymptomatic population or newborn “sepsis screening” test. Screening is continuous risk surveillance in symptomatic/high-risk patients. Genetic testing is not a routine diagnostic pathway.

11. Outcome and prognosis

Short-term prognosis is driven by age/frailty, comorbidities, source and pathogen, antimicrobial adequacy, lactate/shock, number and duration of failed organs and response to treatment. Approximate mortality is 15–25% in sepsis and 30–50% in septic shock (hotchkiss2016sepsisandseptic pages 1-2). In an oncologic ICU cohort, mortality was 37% overall and 68% for Sepsis-3 septic shock; SOFA outperformed qSOFA and SIRS for hospital-death discrimination.

A falling SOFA is favorable. In one derivation/validation analysis, less than a 25% fall by day 7 was associated with markedly increased death risk (OR 14.87), while day-7 ΔSOFA had AUROC 0.84 in the derivation cohort.

Survivors face new disability, cognitive impairment, depression/anxiety/PTSD, recurrent infection, cardiovascular events, kidney disease, muscle wasting and reduced HRQoL. Five- or ten-year “sepsis survival rates” are not stable disease constants because underlying illness and acute severity dominate. Rehabilitation, medication reconciliation and physical/cognitive/emotional follow-up are therefore part of sepsis care, not optional extras (fleischmannstruzek2023returntowork pages 8-8, hodgsonUnknownyeararticletitlehealthrelated pages 73-74).

12. Treatment and real-world implementation

Immediate algorithm

  1. Recognize sepsis as a medical emergency; measure lactate, obtain cultures and assess SOFA.
  2. Give empiric IV antimicrobials promptly—within 1 hour for septic shock/high-likelihood sepsis—chosen by source, local resistance, prior exposure, allergy, renal/hepatic function and PK/PD. Narrow when microbiology and clinical response permit. Risks include allergy, nephrotoxicity, C. difficile, microbiome injury and resistance (hotchkiss2016sepsisandseptic pages 12-13).
  3. Achieve source control—drain abscess, debride infected tissue, relieve obstruction or remove infected devices—as soon as practical.
  4. For hypoperfusion/shock, use crystalloid with repeated dynamic reassessment. The historical initial 30 mL/kg recommendation is weak, not a mandate; balanced crystalloids are generally favored over 0.9% saline. Avoid persistent positive balance and fluid-accumulation organ injury.
  5. Use norepinephrine first-line to target MAP near 65 mmHg; starting peripherally through an appropriate proximal vein is preferable to delaying for central access. Add vasopressin, then epinephrine when needed. Individualize MAP upward in selected chronic-hypertension patients.
  6. Consider IV hydrocortisone for ongoing vasopressor-dependent shock. It generally accelerates shock reversal; hyperglycemia, hypernatremia and neuromuscular weakness are relevant harms.

The 2021 SSC provides the authoritative adult framework (published October 2021; DOI: https://doi.org/10.1007/s00134-021-06506-y) (evans2021survivingsepsiscampaign pages 1-2). A 2023 expert summary emphasizes the changes: balanced fluid over saline, steroids for persistent vasopressor need, peripheral vasopressor initiation, and downgrade of fixed 30 mL/kg from strong to weak.

Organ support and supportive care

Use lung-protective ventilation for ARDS, conservative oxygen targets after stabilization, prone positioning for severe ARDS, sedation minimization and spontaneous awakening/breathing protocols. Apply standard indications for RRT rather than prophylactic early dialysis. Use restrictive RBC transfusion thresholds in stable adults, venous-thromboembolism and stress-ulcer prophylaxis when indicated, insulin protocols avoiding hypoglycemia, early enteral nutrition as tolerated, pressure-injury prevention and early mobilization. Surgery is etiologic only when required for source control.

No gene, cell, RNA or broadly targeted immunotherapy is approved specifically for routine sepsis. Activated protein C was withdrawn; routine high-dose steroids, IV vitamin C cocktails, immunoglobulin, polymyxin-B hemoperfusion, cytokine adsorption and checkpoint therapy are not standard outside selected indications/trials.

Precision and experimental therapy

Current development emphasizes treatable endotypes, not one universal immunomodulator. EMBRACE (NCT06694701; Phase 2, 75 participants, active-not-recruiting in the retrieved registry) selects IFNγ/CXCL9-high patients without monocyte-HLA-DR immunoparalysis for emapalumab, exemplifying biomarker-directed immunotherapy (NCT06694701 chunk 2). MODIFY (NCT05909683; Phase 3, 190 participants) evaluates PCT- and molecular-guided antibiotic decisions (NCT05909683 chunk 2). Additional active programs include:

  • NCT06817408, 1,000-person cfDNA epigenomics/tissue-injury cohort (NCT06817408 chunk 1).
  • NCT06267742, 2,200-person MDW diagnostic validation (NCT06267742 chunk 1).
  • NCT03929159, 150-person plasma/PBMC miRNA outcome cohort (NCT03929159 chunk 1).
  • NCT03226158, 160-child microbial cell-free DNA sequencing cohort for impending bloodstream infection (NCT03226158 chunk 1).

Suggested NCIt annotations include Anti-Infective Therapy, Source-Control Procedure/Drainage, Fluid Therapy, Norepinephrine Therapy, Vasopressor Therapy, Hydrocortisone, Mechanical Ventilation, Renal Replacement Therapy, Physical Therapy and Rehabilitation.

13. Prevention

Primary prevention: vaccination against influenza, COVID-19, pneumococcus, meningococcus, Haemophilus influenzae type b and other age/risk-appropriate infections; clean water/sanitation; maternal/neonatal infection prevention; hand hygiene; sterile procedural technique; catheter/ventilator/surgical-site bundles; wound and chronic-disease care; smoking cessation; nutrition; antimicrobial stewardship.

Secondary prevention: public/professional education about infection plus confusion, dyspnea, hypotension, oliguria or mottling; risk-based EHR surveillance; prompt evaluation, cultures, antimicrobials and source control. There is no recommended population biomarker or genetic screening program.

Tertiary prevention: minimize iatrogenic complications, de-escalate antimicrobials, prevent thrombosis/pressure injury/delirium, mobilize early, vaccinate before/after discharge as appropriate, and provide post-sepsis physical, cognitive, psychological and social follow-up. SSC added strong recommendations for discharge information, medication reconciliation, shared planning and referral for deficits.

14. Other species and natural disease

Naturally occurring sepsis occurs in companion and production animals, including dogs (NCBI Taxon 9615), cats (9685), horses (9796), cattle (9913), pigs (9823) and sheep (9940). Common settings include canine peritonitis/pyometra, equine colic and neonatal foal sepsis, bovine mastitis/metritis and neonatal calf sepsis. These are clinically and economically important, but pathogen distributions, hemodynamics and treatment constraints differ by species. Sepsis itself is not generally “transmitted” cross-species; zoonotic pathogens may cross species and then cause sepsis in the infected host.

No sepsis-specific breed ontology association or conserved causal gene is established. Orthologous TLR, cytokine, complement, coagulation and adrenergic pathways are conserved, enabling comparative research, but the retrieved evidence set did not support reliable breed-specific VBO annotations or veterinary incidence estimates.

15. Model organisms

CLP: surgical polymicrobial peritonitis in mouse/rat; reproduces leukopenia, thrombocytopenia, hypotension, cytokine elevation, organ dysfunction and later immune paralysis. It is widely considered the most comprehensive model but varies with ligation length, needle size, punctures, operator, fluids and antibiotics (kannan2024mousemodelsof pages 1-3, cai2023advancesinrodent pages 4-5).

Cecal slurry: standardized donor fecal material injected intraperitoneally; avoids surgery, is scalable and useful in neonatal mice, but varies by donor microbiome and batch (kannan2024mousemodelsof pages 11-12).

Live-pathogen models: E. coli, Pseudomonas, S. aureus, Klebsiella, pneumococcus, streptococci or Candida permit pathogen-specific immunity and antimicrobial testing. Artificial IV/IP routes can bypass the natural infection site; pneumonia models better reproduce local-to-systemic progression. Candida models reproduce kidney injury, shock, thrombocytopenia and PD-1/PD-L1 upregulation (cai2023advancesinrodent pages 2-4).

LPS/endotoxemia: rapid, reproducible TLR4 inflammation, but no replicating infection and incomplete biphasic human disease. Specific-pathogen-free mice require approximately 250–500-fold more LPS than humans for comparable responses (kannan2024mousemodelsof pages 11-12).

Two-hit models combine trauma/hemorrhage/ischemia with infection and may model clinical complexity, but protocols are poorly standardized. Humanized NSG mice recreate aspects of human immunity but have incomplete reconstitution. “Dirty” mice have adult-human-like immune experience and more severe CLP/LPS responses, improving some realism while reducing standardization (cai2023advancesinrodent pages 6-8, cai2023advancesinrodent pages 8-9).

The central translational limitation is that young, inbred, SPF rodents exposed to a synchronized insult do not reproduce older, comorbid, genetically and microbiologically heterogeneous patients receiving antibiotics, surgery and ICU support. Accordingly, 2023–2024 experts recommend matching the model to the question, using both sexes/ages and supportive care, standardizing severity, and validating across multiple models before clinical translation (DOIs: https://doi.org/10.3390/ijms24119578, published May 2023; https://doi.org/10.1002/cpz1.997, published March 2024) (kannan2024mousemodelsof pages 1-3, cai2023advancesinrodent pages 1-2).

Ontology and knowledge-base mapping

The following compact mapping distinguishes verified identifiers from suggested terms needing current-release validation.

Domain Preferred concept / identifier Suggested ontology terms / codes Practical note
Disease Sepsis MeSH: Sepsis (D018805); ICD-10-CM: A41.9, Sepsis, unspecified organism; ICD-11 candidates: 1G40, sepsis without septic shock; 1G41, sepsis with septic shock; MONDO: general sepsis identifier requires release-level verification Sepsis is infection-associated, life-threatening organ dysfunction caused by a dysregulated host response; do not equate it with uncomplicated infection, bacteremia, or SIRS (hotchkiss2016sepsisandseptic pages 1-2, evans2021survivingsepsiscampaign pages 1-2).
Disease subtype Bacterial infectious disease with sepsis MONDO: MONDO:0005229 (verified in retrieved Open Targets mapping) A narrower concept than all-cause sepsis; sepsis may also be viral, fungal, or parasitic (OpenTargets Search: sepsis).
Disease subtype Infectious disease with sepsis MONDO: MONDO:1040015 (verified in retrieved Open Targets mapping) Broad infection-with-sepsis concept found in Open Targets; confirm intended hierarchy before production use (OpenTargets Search: sepsis).
Disease severity Septic shock ICD-10-CM: R65.21; ICD-11 candidate: 1G41; SNOMED CT: use current-release “Septic shock” concept Clinical subset with vasopressor-dependent hypotension and elevated lactate despite adequate volume resuscitation; substantially higher mortality than sepsis without shock (hotchkiss2016sepsisandseptic pages 1-2, vasques2018septicshock3vs pages 7-7).
Phenotype Fever or hypothermia HPO: Fever (HP:0001945); Hypothermia (HP:0002045) Variable and episodic acute signs; absence of fever does not exclude sepsis. Temperature responses depend on host age, severity, and environment (hotchkiss2016sepsisandseptic pages 1-2, bakoush2023…classification pages 8-10).
Phenotype Tachycardia and hypotension HPO: Tachycardia (HP:0001649); Hypotension (HP:0002615) Cardiovascular manifestations range from compensated tachycardia to vasoplegia, myocardial depression, and shock (hotchkiss2016sepsisandseptic pages 9-10).
Phenotype Tachypnea, hypoxemia, respiratory failure HPO: Tachypnea (HP:0002789); Hypoxemia (HP:0012418); Respiratory failure (term; verify current HPO identifier) Alveolar–capillary injury causes noncardiogenic edema, impaired compliance, and reduced gas exchange; respiratory dysfunction commonly contributes to SOFA-defined sepsis (ljungstrom2019incidencesofcommunity pages 12-13, hotchkiss2016sepsisandseptic pages 9-10).
Phenotype Altered consciousness, delirium, encephalopathy HPO: Delirium (HP:0031258); Encephalopathy (HP:0001298); Altered mental status (term; verify current HPO identifier) May be an early sign or sepsis-associated encephalopathy; exclude CNS infection, structural lesions, drugs, metabolic disease, and primary neurologic causes (hotchkiss2016sepsisandseptic pages 9-10).
Phenotype Oliguria and acute kidney injury HPO: Oliguria (HP:0100520); Acute kidney injury (term; verify current HPO identifier) Dynamic organ dysfunction assessed using urine output and creatinine; may require renal replacement therapy in severe cases (hotchkiss2016sepsisandseptic pages 9-10, NCT06817408 chunk 1).
Phenotype Thrombocytopenia and coagulopathy HPO: Thrombocytopenia (HP:0001873); Abnormality of coagulation (HP:0001928); Disseminated intravascular coagulation (term; verify current HPO identifier) Reflects platelet consumption, coagulation activation, endothelial injury, and—in severe disease—DIC (hotchkiss2016sepsisandseptic pages 9-10, bakoush2023…classification pages 8-10).
Phenotype Hyperbilirubinemia and hepatic dysfunction HPO: Hyperbilirubinemia (HP:0002904); Abnormal liver function (term; verify current HPO identifier) SOFA hepatic dysfunction is bilirubin-based; mechanisms include cholestasis, inflammation, hypoxia, and shock (hotchkiss2016sepsisandseptic pages 9-10).
Laboratory phenotype Hyperlactatemia HPO: Increased circulating lactate concentration (term; verify current HPO identifier); LOINC: use specimen/method-specific lactate code Lactate supports severity assessment and resuscitation monitoring but is neither sepsis-specific nor a pure measure of tissue hypoxia (vasques2018septicshock3vs pages 7-7, oczkowski2022survivingsepsiscampaign pages 7-8).
Organ Lung UBERON: lung (UBERON:0002048) Frequent infection source and target of secondary injury; manifestations include pneumonia, hypoxemia, and ARDS (ljungstrom2019incidencesofcommunity pages 12-13, hotchkiss2016sepsisandseptic pages 9-10).
Organ Kidney UBERON: kidney (UBERON:0002113) Sepsis-associated AKI involves microcirculatory, inflammatory, endothelial, and metabolic injury rather than hypoperfusion alone (hotchkiss2016sepsisandseptic pages 9-10).
Organ Liver UBERON: liver (UBERON:0002107) Hepatic dysfunction may present with cholestasis, hyperbilirubinemia, impaired clearance, or hypoxic hepatitis (hotchkiss2016sepsisandseptic pages 9-10).
Organ Heart UBERON: heart (UBERON:0000948) Sepsis-induced cardiomyopathy can affect both ventricles; mild troponin elevation is common but nonspecific (hotchkiss2016sepsisandseptic pages 9-10).
Organ Brain UBERON: brain (UBERON:0000955) Neuroinflammation, blood–brain-barrier dysfunction, microglial activation, and systemic metabolic disturbances contribute to encephalopathy and long-term cognitive deficits (hotchkiss2016sepsisandseptic pages 1-2, hotchkiss2016sepsisandseptic pages 9-10).
System/tissue Blood and vascular endothelium UBERON: blood (UBERON:0000178); vasculature (term; verify site-specific UBERON code) Endothelial activation converts an anticoagulant surface into a proadhesive, procoagulant interface and promotes capillary leak and immunothrombosis (hotchkiss2016sepsisandseptic pages 9-10).
Cell type Neutrophil CL: neutrophil (CL:0000775) Performs phagocytosis and NET formation; dysregulated NETs trap pathogens but can damage endothelium and amplify thrombosis and inflammation (vella2025cytokinesinsepsis pages 10-11, bakoush2023…classification pages 8-10).
Cell type Monocyte CL: monocyte (CL:0000576) Key pathogen-sensing and antigen-presenting cell; reduced monocyte HLA-DR is used experimentally to define sepsis-induced immunoparalysis (hotchkiss2016sepsisandseptic pages 5-6, NCT06694701 chunk 2).
Cell type Macrophage CL: macrophage (CL:0000235) Produces inflammatory cytokines after PRR activation; later polarization and uptake of apoptotic cells can increase IL-10 and TGF-β and suppress immunity (hotchkiss2016sepsisandseptic pages 5-6, vella2025cytokinesinsepsis pages 10-11).
Cell type Dendritic cell CL: dendritic cell (CL:0000451) Apoptotic depletion and impaired antigen presentation contribute to immunosuppression (hotchkiss2016sepsisandseptic pages 5-6).
Cell type T lymphocyte CL: T cell (CL:0000084) Lymphopenia, apoptosis, PD-1 expression, TH2/regulatory skewing, and functional exhaustion are associated with persistent immune dysfunction (hotchkiss2016sepsisandseptic pages 5-6).
Cell type B lymphocyte CL: B cell (CL:0000236) Sepsis-associated apoptosis reduces adaptive immune-cell numbers and may impair subsequent antimicrobial immunity (hotchkiss2016sepsisandseptic pages 5-6).
Cell type Platelet CL: platelet (CL:0000233) Platelets link coagulation to innate immunity through fibrin binding, P-selectin-mediated leukocyte recruitment, and microthrombus formation (hotchkiss2016sepsisandseptic pages 9-10).
Cell type Endothelial cell CL: endothelial cell (CL:0000115) Central effector of permeability, leukocyte adhesion, vasoplegia, coagulation activation, and microvascular organ injury (vella2025cytokinesinsepsis pages 10-11, hotchkiss2016sepsisandseptic pages 9-10).
Mechanism Pattern-recognition receptor signaling GO-BP: innate immune response (GO:0045087); inflammatory response (GO:0006954); Toll-like receptor signaling pathway (GO:0002224) PAMPs and DAMPs activate TLRs, NOD proteins, dectins, RAGE, and RNA sensors, converging on NF-κB, AP-1, and IRFs (hotchkiss2016sepsisandseptic pages 5-6).
Mechanism Cytokine production and signaling GO-BP: cytokine-mediated signaling pathway (GO:0019221); positive regulation of cytokine production (GO:0001819) TNF, IL-1, IL-6, chemokines, and interferons drive systemic inflammation, while IL-10 and TGF-β contribute to compensatory immunosuppression (hotchkiss2016sepsisandseptic pages 5-6, bakoush2023…classification pages 8-10).
Mechanism Complement activation GO-BP: complement activation (GO:0006956) C3a, C4a, and particularly C5a amplify inflammation, alter neutrophil function, and can promote immune-cell apoptosis (vella2025cytokinesinsepsis pages 10-11, hotchkiss2016sepsisandseptic pages 17-18).
Mechanism Coagulation and immunothrombosis GO-BP: blood coagulation (GO:0007596); platelet activation (GO:0030168) Inflammation, endothelial activation, platelets, fibrin, and leukocytes generate microvascular thrombi; excessive activation may progress to consumptive coagulopathy or DIC (hotchkiss2016sepsisandseptic pages 9-10, bakoush2023…classification pages 8-10).
Mechanism Programmed cell death GO-BP: apoptotic process (GO:0006915); pyroptosis (GO:0070269) Human autopsy and experimental evidence support lymphocyte and dendritic-cell apoptosis as drivers of immunosuppression; pyroptosis is a plausible inflammatory mechanism but requires evidence-specific annotation (hotchkiss2016sepsisandseptic pages 5-6).
Mechanism Neutrophil extracellular-trap formation GO-BP: neutrophil extracellular trap formation (GO:0140725) NETs support antimicrobial defense but expose histones and proteases that injure endothelium and amplify cytokine signaling (vella2025cytokinesinsepsis pages 10-11).
Mechanism Mitochondrial/metabolic dysfunction GO-BP: cellular response to oxidative stress (GO:0034599); cellular respiration (GO:0045333); GO-CC: mitochondrion (GO:0005739) Bioenergetic failure, oxidative stress, and metabolic reprogramming may cause organ dysfunction despite restored macrocirculation; many candidate signatures remain investigational (sebastian2025sepsisandpostsepsis pages 8-10, cai2023advancesinrodent pages 8-9).
Mechanism Immune suppression/exhaustion GO-BP: negative regulation of immune response (GO:0050777); regulation of T-cell apoptotic process (suggested term) PD-1/PD-L1 signaling, reduced MHC-II/HLA-DR, lymphocyte apoptosis, impaired cytokine production, and regulatory-cell expansion can coexist with inflammation (hotchkiss2016sepsisandseptic pages 5-6).
Subcellular site Plasma membrane and extracellular compartment GO-CC: plasma membrane (GO:0005886); extracellular region (GO:0005576) PRRs, adhesion molecules, complement, cytokines, coagulation proteins, and NET components act across these compartments (hotchkiss2016sepsisandseptic pages 5-6, vella2025cytokinesinsepsis pages 10-11, hotchkiss2016sepsisandseptic pages 9-10).
Chemical Lipopolysaccharide ChEBI: lipopolysaccharide (CHEBI:16412) Gram-negative PAMP and experimental endotoxemia trigger; LPS models are reproducible but do not reproduce live, heterogeneous human infection (kannan2024mousemodelsof pages 11-12, cai2023advancesinrodent pages 4-5).
Chemical/biomarker Lactate ChEBI: lactate (CHEBI:24996) Measure specimen-specific blood lactate clinically; elevation has multiple causes, including adrenergic glycolysis, impaired clearance, and hypoperfusion (vasques2018septicshock3vs pages 7-7, oczkowski2022survivingsepsiscampaign pages 7-8).
Chemical/intervention Norepinephrine ChEBI: noradrenaline (CHEBI:18357); NCIt suggested term: Norepinephrine Preferred first-line vasopressor in septic shock; receptor-target associations in Open Targets reflect therapeutic biology rather than causal sepsis genes (OpenTargets Search: sepsis, oczkowski2022survivingsepsiscampaign pages 7-8).
Chemical/intervention Vasopressin ChEBI: vasopressin (verify current ChEBI identifier); NCIt suggested term: Vasopressin Common adjunct to norepinephrine when escalating vasopressor support; not a pathogen-directed therapy (vasques2018septicshock3vs pages 7-7, oczkowski2022survivingsepsiscampaign pages 7-8).
Chemical/intervention Hydrocortisone ChEBI: hydrocortisone (CHEBI:17650); NCIt suggested term: Hydrocortisone Suggested for septic shock with an ongoing vasopressor requirement; annotate as adjunctive corticosteroid therapy, not general sepsis monotherapy (oczkowski2022survivingsepsiscampaign pages 7-8).
Intervention Broad-spectrum antimicrobial therapy NCIt suggested terms: Antibiotic Therapy; Anti-Infective Therapy; Antimicrobial Treatment Start promptly after appropriate cultures when this does not cause harmful delay; select empirically by source, resistance risk, prior exposure, and local ecology, then de-escalate when possible (hotchkiss2016sepsisandseptic pages 12-13).
Intervention Source control NCIt suggested terms: Surgical Procedure; Drainage Procedure; Device Removal Drain infected collections, debride necrotic tissue, relieve obstruction, or remove infected devices as soon as medically and logistically practical (hotchkiss2016sepsisandseptic pages 12-13).
Intervention Intravenous crystalloid resuscitation NCIt suggested terms: Fluid Therapy; Intravenous Infusion; Crystalloid Solution Initial resuscitation is individualized; balanced crystalloids are generally preferred, and repeated reassessment is needed to avoid fluid accumulation and organ edema (oczkowski2022survivingsepsiscampaign pages 7-8).
Intervention Vasopressor therapy NCIt suggested terms: Vasopressor Therapy; Norepinephrine Therapy Used to restore perfusion pressure when hypotension persists during/after initial fluid resuscitation; peripheral initiation may avoid harmful delay while central access is arranged (oczkowski2022survivingsepsiscampaign pages 7-8).
Intervention Mechanical ventilation / ARDS care NCIt suggested terms: Mechanical Ventilation; Lung Protective Ventilation Use lung-protective ventilation for sepsis-associated ARDS; ventilatory support treats organ failure but not the infectious trigger (hotchkiss2016sepsisandseptic pages 9-10, oczkowski2022survivingsepsiscampaign pages 7-8).
Intervention Renal replacement therapy NCIt suggested term: Renal Replacement Therapy Reserved for standard urgent indications or severe persistent AKI; trials evaluate need and timing as outcomes rather than establishing sepsis-specific dialysis criteria (oczkowski2022survivingsepsiscampaign pages 7-8, NCT06817408 chunk 1).
Intervention Post-sepsis rehabilitation and follow-up NCIt suggested terms: Rehabilitation; Physical Therapy; Occupational Therapy; Cognitive Assessment Assess physical, cognitive, emotional, medication, social, and economic needs after discharge; long-term disability and failure to return to work are common (fleischmannstruzek2023returntowork pages 8-8, hodgsonUnknownyeararticletitlehealthrelated pages 73-74).

Table: Compact knowledge-base mappings for sepsis disease concepts, phenotypes, anatomy, cells, mechanisms, chemicals, and interventions. Verified identifiers are distinguished from suggested terms or codes requiring release-level validation.

Evidence-quality and expert interpretation

The strongest evidence supports Sepsis-3/SOFA characterization, rapid infection treatment/source control and individualized organ support. Epidemiologic estimates are definition-sensitive. Biomarkers should augment rather than replace bedside judgment. Genetic, epigenetic, single-cell and multi-omics findings are biologically informative but mostly not clinically validated. The most credible precision-medicine direction is prospective enrichment of trials by reproducible immune/endothelial/metabolic endotypes rather than retrospective subgroup claims.

Direct abstract wording supporting the central concept includes: “sepsis [is] life-threatening organ dysfunction caused by a dysregulated host response to infection” in the SSC/Sepsis-3 framework (evans2021survivingsepsiscampaign pages 1-2). Recent model experts similarly emphasize that “human sepsis is a complex disease that manifests with a diverse range of phenotypes and inherent variability,” explaining why no single model or targeted drug captures the syndrome (kannan2024mousemodelsof pages 1-3).

Key cited publications and URLs

  • Hotchkiss RS et al. Sepsis and septic shock. Nature Reviews Disease Primers. Published June 30, 2016. https://doi.org/10.1038/nrdp.2016.45 (hotchkiss2016sepsisandseptic pages 1-2)
  • Evans L et al. Surviving Sepsis Campaign: International Guidelines 2021. Published October 2021. https://doi.org/10.1007/s00134-021-06506-y (evans2021survivingsepsiscampaign pages 1-2)
  • Ljungström L et al. Population incidence study. Published December 2019. https://doi.org/10.1371/journal.pone.0225700 (ljungstrom2019incidencesofcommunity pages 12-13)
  • Rosier F et al. CISH-enhancer GWAS/functional study. Published May 2021. https://doi.org/10.3390/ijms22115852 (rosier2021geneticpredispositionto pages 16-18)
  • Cai L et al. Rodent-model review. Published May 2023. https://doi.org/10.3390/ijms24119578 (cai2023advancesinrodent pages 4-5)
  • Kannan SK et al. Mouse-model protocols. Published March 2024. https://doi.org/10.1002/cpz1.997 (kannan2024mousemodelsof pages 1-3)
  • Fleischmann-Struzek C et al. Return-to-work outcomes. Published May 2023. https://doi.org/10.3389/fmed.2023.1187809 (fleischmannstruzek2023returntowork pages 8-8)

PMIDs were included where available in the retrieved records; many full-text excerpts supplied DOI but not PMID. The foundational Sepsis-3 consensus is Singer et al., JAMA 2016, DOI https://doi.org/10.1001/jama.2016.0287; PMID 26903338.

References

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References checked 14
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Unverifiable 0
References weighed for topical relevance 14
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