Sepsis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.B.B.S. [2] ; Aditya Ganti M.B.B.S. [3]; Parth Vikram Singh, MBBS[4]; Jason Le, B.S.[5]
Synonyms and keywords: sepsis syndrome; septic shock; septicemia
Sepsis pathophysiology
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The current model emphasizes simultaneous, competing pro-inflammatory and immunosuppressive responses rather than a simple sequential progression from systemic inflammation to immunoparalysis. The resulting endothelial injury, coagulation activation, microcirculatory dysfunction, and cellular metabolic failure contribute to organ dysfunction. [1][2]
Host recognition of infection
- Innate immune recognition begins when pattern recognition receptors (PRRs), including Toll-like receptors, detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).
- PAMPs include microbial products such as lipopolysaccharide, lipoteichoic acid, and microbial DNA. DAMPs released from injured host tissue include ATP, mitochondrial DNA, histones, HMGB1, and hyaluronan.
- PRR signaling activates downstream pathways including NF-kB and MAPK, promoting production of pro-inflammatory mediators such as TNF, IL-1beta, IL-6, IL-8, and IL-18. Inflammasome activation promotes IL-1beta and IL-18 release and pyroptosis. [3][4]
Pro-inflammatory and immunosuppressive responses
- Sepsis involves concurrent hyperinflammation and immunosuppression; these responses can coexist from early in the disease and their relative balance varies among patients and over time. [2][5]
- The hyperinflammatory response includes excessive cytokine production, complement activation, emergency myelopoiesis, neutrophil respiratory burst, and formation of neutrophil extracellular traps (NETs/NETosis). Severe macrophage activation may produce a macrophage activation-like syndrome (MALS) phenotype. [6]
- The immunosuppressive response includes lymphopenia from lymphocyte apoptosis and impaired lymphopoiesis, expansion of regulatory T cells and myeloid-derived suppressor cells, monocyte endotoxin tolerance with reduced monocyte HLA-DR (mHLA-DR), increased immune-checkpoint signaling including PD-1/PD-L1 and CTLA-4, and functional impairment of neutrophils. [2][6]
- Persistent lymphopenia and low mHLA-DR are associated with secondary or nosocomial infection, latent viral reactivation, and adverse outcomes. [2][5]
- Persistent immune dysfunction is partly mediated by epigenetic reprogramming, including altered histone modification, DNA methylation, and transcription-factor dynamics. [6]
Endothelial and glycocalyx dysfunction
- The vascular endothelium becomes pro-inflammatory, proadhesive, procoagulant, and proapoptotic during sepsis.
- PAMP/DAMP-driven endothelial activation promotes shedding of the endothelial glycocalyx, disrupting vascular barrier integrity and amplifying inflammation and coagulation.
- Glycocalyx loss exposes adhesion molecules, increases leukocyte and platelet adhesion, and promotes capillary leak and tissue edema.
- Endothelial injury also promotes shedding or dysfunction of thrombomodulin and endothelial protein C receptor (EPCR), impairing endogenous anticoagulant and cytoprotective pathways. [7]
- Dysregulation of the angiopoietin-2/Tie2 axis contributes to endothelial destabilization, vascular hyperpermeability, and capillary leak. Angiopoietin-2 is also a biomarker of endothelial injury and disease severity. [7]
- Circulating syndecan-1 reflects glycocalyx shedding, while soluble thrombomodulin reflects endothelial injury; higher levels correlate with greater organ dysfunction. [8][9]
- Increased vascular permeability produces intravascular volume loss, interstitial edema, and impaired tissue oxygen diffusion, contributing to distributive shock and organ dysfunction.
Coagulation and immunothrombosis
- Sepsis activates coagulation while impairing endogenous anticoagulant pathways. Tissue factor and plasminogen activator inhibitor-1 increase, while circulating antithrombin, tissue factor pathway inhibitor, and protein C system activity decrease.
- Immunothrombosis links innate immunity and coagulation. NETs, platelets, complement, and fibrin promote microvascular thrombus formation, impairing microcirculatory perfusion and contributing to organ dysfunction. [7]
- Endothelial injury, glycocalyx loss, complement activation, and coagulation form a self-amplifying thromboinflammatory network in which inflammation promotes coagulation and coagulation proteases further amplify inflammatory signaling. [7]
- Sepsis-induced coagulopathy (SIC) represents an early, potentially reversible stage of sepsis-associated coagulation dysfunction that may progress to overt disseminated intravascular coagulation (DIC). [7]
- Severe DIC is associated with increased mortality. No anticoagulant strategy has demonstrated a mortality benefit in unselected sepsis or sepsis-associated coagulopathy in randomized trials; possible benefit of recombinant thrombomodulin appears limited to selected subgroups with severe coagulopathy. Management is addressed in the Medical Therapy microchapter. [10][11][12]
Microcirculatory, cardiovascular, metabolic, and cellular dysfunction
- Sepsis-associated shock reflects the combined effects of vasodilation, capillary leak, microvascular thrombosis, and myocardial dysfunction. The resulting oxygen-delivery/demand mismatch can persist despite preserved or increased cardiac output.
- Septic cardiomyopathy is a typically reversible depression of ventricular contractility mediated by circulating cytokines, mitochondrial dysfunction, and altered calcium handling. It can coexist with vasoplegia and contribute to impaired systemic oxygen delivery. [2]
- Microvascular heterogeneity, endothelial edema, interstitial edema, and microthrombi impair effective tissue perfusion and oxygen diffusion.
- Immune-cell metabolism is profoundly altered. Peripheral blood mononuclear cells in sepsis can develop reduced ATP production, reduced NAD+, and impaired oxygen consumption, contributing to sustained immune dysfunction. [6]
- Mitochondrial dysfunction and impaired cellular oxygen utilization contribute to metabolic failure and lactic acidosis. Cytopathic hypoxia may contribute to organ dysfunction even when global hemodynamic variables have improved. [2]
- These mechanisms help explain why severe organ dysfunction can occur without proportionate widespread histologic cell necrosis and why organ function may recover substantially when the dysregulated host response resolves. [2]
Organ injury
- Multiple organ systems are commonly involved, including the respiratory, cardiovascular, renal, central nervous, hematologic, and hepatic systems; the pattern and sequence vary by patient rather than following a fixed hierarchy. [6]
- The combined effects of endothelial barrier failure, vasoplegia, immunothrombosis, microcirculatory dysfunction, myocardial dysfunction, and cellular metabolic failure produce tissue dysfunction across multiple organs.
- Lactic acidosis, cellular metabolic dysfunction, tissue edema, and impaired microvascular oxygen delivery are manifestations of this integrated pathophysiology.
Molecular heterogeneity and endotypes
- Sepsis is biologically heterogeneous. Transcriptomic and immunologic profiling identifies distinct host-response states that differ in inflammatory activity, immune suppression, and prognosis.
- Molecular response signatures include SRS1/SRS2 and Mars1-Mars4. SRS1 is associated with substantially higher mortality than SRS2, while Mars1 and Mars3 represent biologically distinct immune states with different mortality risks. [13][5][14]
- Immunoassay-defined phenotypes include hyperinflammatory/MALS states characterized by markers such as ferritin and IL-6, whereas immunoparalysis is characterized by features such as low mHLA-DR and lymphopenia. suPAR is better regarded as a general severity/risk biomarker rather than a specific marker of MALS. [5]
- A 2025 consensus analysis identified four reproducible molecular clusters across diverse critical-illness cohorts, supporting shared biological patterns of immune dysregulation. [15]
- No single endotyping system is currently established for routine bedside use, and immune phenotypes may change during the course of illness. Endotype-guided immunomodulation remains investigational. [5][15]
Clinically relevant mechanistic implications
- Persistent lactate elevation may reflect ongoing microcirculatory or cellular metabolic dysfunction and should not be interpreted solely as evidence of inadequate macrocirculatory perfusion.
- The combination of vasoplegia and glycocalyx-mediated capillary leak explains the coexistence of hypotension and tissue edema.
- Persistent lymphopenia and low mHLA-DR indicate an immunosuppressed phenotype and increased risk of secondary infection.
- Thrombocytopenia with abnormalities of coagulation and fibrin degradation supports assessment for sepsis-associated coagulopathy or DIC.
- The biological heterogeneity of sepsis provides a mechanistic rationale for precision immunotherapy, but routine endotype-directed immunomodulation is not established.
References
- ↑ Singer M, Deutschman CS, Seymour CW, et al. (2016). "The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)". JAMA.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Meyer NJ, Prescott HC (2024). "Sepsis and Septic Shock". N Engl J Med. 391 (22): 2133–2146. doi:10.1056/NEJMra2403213. PMID 39774315 Check
|pmid=value (help). - ↑ Sauer A, Putensen C, Bode C. Immunomodulation by Tetracyclines in the Critically Ill. Critical Care. 2022.
- ↑ Leligdowicz A, Harhay MO, Calfee CS. Immune Modulation in Sepsis, ARDS, and Covid-19. N Engl J Med. 2022.
- ↑ 5.0 5.1 5.2 5.3 5.4 Kox M, Bauer M, Bos LDJ, et al. The immunology of sepsis: translating new insights into clinical practice. Nature Reviews Nephrology. 2026;22(1):30-49. doi:10.1038/s41581-025-01004-6.
- ↑ 6.0 6.1 6.2 6.3 6.4 Giamarellos-Bourboulis EJ, Aschenbrenner AC, Bauer M, et al. The pathophysiology of sepsis and precision-medicine-based immunotherapy. Nature Immunology. 2024;25(1):19-28. doi:10.1038/s41590-023-01660-5.
- ↑ 7.0 7.1 7.2 7.3 7.4 Iba T, Maier CL, Ferrer R, Nagakari K, Levy JH. Endotheliopathy Within the Thromboinflammatory Network of Sepsis-Induced Coagulopathy. Inflammation Research. 2026.
- ↑ Zhou G, Liu J, Zhang H, Wang X, Liu D. Elevated endothelial dysfunction-related biomarker levels indicate the severity and predict sepsis incidence. Scientific Reports. 2022.
- ↑ Joffre J, Hellman J. Oxidative Stress and Endothelial Dysfunction in Sepsis and Acute Inflammation. Antioxidants & Redox Signaling. 2021.
- ↑ Adelborg K, Larsen JB, Hvas AM. Disseminated intravascular coagulation: epidemiology, biomarkers, and management. Br J Haematol. 2021;192(5):803-818. doi:10.1111/bjh.17172.
- ↑ Wada T, Yamakawa K, Kabata D, et al. Age-related differences in the survival benefit of the administration of antithrombin, recombinant human thrombomodulin, or their combination in sepsis. Sci Rep. 2022;12:9304. doi:10.1038/s41598-022-13346-3.
- ↑ Yamakawa K, Levy JH, Iba T. Recombinant human soluble thrombomodulin in patients with sepsis-associated coagulopathy (SCARLET): an updated meta-analysis. Crit Care. 2019;23:302. doi:10.1186/s13054-019-2587-2.
- ↑ Leligdowicz A, Matthay MA. Heterogeneity in sepsis: new biological evidence with clinical applications. Crit Care. 2019;23:80. doi:10.1186/s13054-019-2372-2.
- ↑ Stevens J, Tezel O, Bonnefil V, Hapstack M, Atreya MR. Biological basis of critical illness subclasses: from the bedside to the bench and back again. Crit Care. 2024;28:186. doi:10.1186/s13054-024-04959-3.
- ↑ 15.0 15.1 Moore AR, Zheng H, Ganesan A, et al. A Consensus Immune Dysregulation Framework for Sepsis and Critical Illnesses. Nature Medicine. 2025.