Sepsis natural history, complications and prognosis

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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]; Parth Vikram Singh, MBBS[3] Jason Le, B.S.[4]

Synonyms and keywords: sepsis syndrome; septic shock; septicemia

Natural History, Complications and Prognosis

Sepsis is an acute systemic illness that can progress from infection-associated organ dysfunction to septic shock, multiple organ dysfunction syndrome (MODS), and death. Survivors remain at increased risk of readmission, late mortality, cognitive and functional impairment, and persistent post-sepsis morbidity.[1]

Natural history

Untreated or inadequately controlled sepsis may progress to septic shock and MODS. Acute organ dysfunction can involve multiple systems, including the respiratory, cardiovascular, renal, central nervous, hematologic, and hepatic systems; the pattern and sequence of organ involvement vary among patients.[1][2]

A subset of patients progresses to septic shock, which carries substantially higher mortality than sepsis without shock. In a 2026 systematic review and meta-analysis, septic-shock mortality was approximately 30-50%, with pooled early hospital mortality of approximately 33.2%. Higher illness severity, acute kidney injury (AKI), respiratory source, elevated lactate, and other markers of organ dysfunction were associated with worse outcomes.[3]

Acute complications

Major acute complications include:

  • Acute respiratory distress syndrome (ARDS), resulting from inflammatory alveolar-capillary injury and non-cardiogenic pulmonary edema.[1]
  • Septic cardiomyopathy, typically characterized by reversible ventricular dysfunction and potentially coexisting with vasoplegia.[4]
  • Sepsis-associated acute kidney injury (SA-AKI), a common complication associated with increased mortality in septic shock.[5][3]
  • Disseminated intravascular coagulation (DIC), characterized by systemic coagulation activation, microvascular thrombosis, consumption of platelets and coagulation factors, and variable bleeding.[6]
  • Sepsis-associated encephalopathy, ranging from delirium to impaired consciousness without a focal structural neurologic deficit; its course is variable and some patients recover substantially.[7][8]
  • Critical illness polyneuropathy/myopathy, ileus, hepatic dysfunction, thrombocytopenia, and other complications of prolonged critical illness.[9]

SA-AKI occurs in approximately 40-50% of patients with sepsis; roughly one in four affected patients dies in hospital, and SA-AKI carries higher mortality than sepsis or AKI alone (adjusted HR approximately 1.59).[10]

DIC is associated with worse outcomes when severe. Evidence for anticoagulant strategies in unselected sepsis or sepsis-associated coagulopathy has not established a mortality benefit; detailed management belongs in the Medical Therapy microchapter.

Mortality and prognosis

Contemporary mortality estimates vary according to sepsis definition, case mix, severity, geography, and era. A systematic review and meta-analysis of studies from Europe, North America, and Australia (2009-2019) estimated pooled 30-day mortality of approximately 24.4% for sepsis and 34.7% for septic shock, rising to approximately 32.2% and 38.5%, respectively, at 90 days; reported rates ranged widely (approximately 15-57%) across individual studies.[11]

The 2026 septic-shock meta-analysis reported mortality of approximately 30-50%, with higher mortality associated with greater illness severity, older age, cirrhosis, malignancy, higher comorbidity burden, AKI, respiratory source, elevated lactate, mechanical ventilation, and norepinephrine use.[3]

Large contemporary cohorts suggest that in-hospital mortality has declined over time in some health systems, although the magnitude and timing of improvement vary by region and sepsis definition. Mortality estimates therefore should be interpreted in the context of study era, population, and case definition.[12][13]

Prognostic factors and scoring

High-certainty prognostic factors for early mortality in septic shock include:

  • Patient factors: older age, cirrhosis, malignancy, and greater comorbidity burden.
  • Severity and organ dysfunction: AKI and higher SOFA, APACHE II, and SAPS II scores.
  • Presentation: respiratory source and elevated lactate.
  • Critical-care requirements: mechanical ventilation and norepinephrine use.
  • Organism: fungal infection is associated with worse survival than bacterial infection in observational data.[3][14]

The SOFA score is widely used for risk stratification and has strong mortality discrimination. qSOFA has limited sensitivity and should not be used alone as a rule-out tool; combining clinical severity measures with lactate can improve prognostic discrimination.[15][16]

In septic shock, a 2026 meta-analysis reported an adjusted odds ratio of approximately 1.88 for mortality associated with AKI.[3]

Long-term outcomes after sepsis

Survival to hospital discharge does not represent complete recovery. Compared with matched non-sepsis hospitalized controls, severe sepsis is associated with increased long-term mortality and rehospitalization.[17]

Approximately 39% of adult sepsis survivors experience unplanned rehospitalization within 1 year, with recurrent infection among the most common causes.[18][19] In a French nationwide cohort, recurrent-sepsis readmission was associated with substantially increased 1-year mortality.[20]

Post-sepsis syndrome and post-intensive care morbidity

Sepsis survivors may develop persistent cognitive, physical, and psychological impairment overlapping with post-intensive care syndrome (PICS).

  • Cognitive impairment: sepsis in older adults is associated with increased moderate-to-severe cognitive impairment and accelerated long-term cognitive decline.[1][21]
  • Physical and functional impairment: survivors may acquire new limitations in activities of daily living and may not return to their previous level of independence or employment.[1][22]
  • Persistent morbidity: long-term physical, cognitive, and psychological deficits may persist for years after the acute illness.[23]
  • Persistent inflammatory and immunosuppressive abnormalities have been described in a substantial proportion of survivors and may contribute to late morbidity and mortality.[24]

Aftercare and follow-up

The 2021 Surviving Sepsis Campaign guideline recommends assessment and follow-up for physical, cognitive, and emotional problems after discharge, although it could not specify the optimal timing of follow-up.[25]

The 2026 Surviving Sepsis Campaign guideline carries forward assessment and follow-up for physical, cognitive, and emotional problems after discharge as a good-practice statement and conditionally suggests offering post-critical illness follow-up services (low certainty).[26]

The optimal timing and content of follow-up remain uncertain. Structured transitional-care programs are an evolving area of investigation and are addressed primarily in the Secondary Prevention microchapter.

Clinical pearls

  • Septic shock carries approximately 30-50% mortality; prognosis is influenced by illness severity, organ dysfunction, source, host factors, and treatment requirements.[3]
  • AKI is both common and prognostically important; SA-AKI occurs in approximately 40-50% of patients with sepsis and is associated with increased mortality.[10][3]
  • Survival to discharge is not equivalent to recovery. Readmission, recurrent infection, cognitive impairment, functional decline, and late mortality remain important after sepsis.[18][1]
  • Post-sepsis follow-up should address cognitive, physical, and psychological sequelae, consistent with current Surviving Sepsis Campaign guidance.[26]

Common pitfalls

  • Using qSOFA as a standalone rule-out tool because of its limited sensitivity.[15][16]
  • Equating hospital discharge with complete recovery and failing to recognize the substantial risk of readmission and late morbidity.[18][1]
  • Focusing only on in-hospital mortality while overlooking post-sepsis cognitive, physical, and psychological outcomes.[1][23]
  • Misclassifying infectious foci such as endocarditis or osteomyelitis as complications rather than causes/sources of sepsis.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Meyer NJ, Prescott HC (2024). "Sepsis and Septic Shock". New England Journal of Medicine. 391 (22): 2133–2146. doi:10.1056/NEJMra2403213.
  2. ↑ Jacobi J (2022). "The Pathophysiology of Sepsis - 2021 Update: Part 2, Organ Dysfunction and Assessment". American Journal of Health-System Pharmacy. 79 (6): 424–436. doi:10.1093/ajhp/zxab393. PMID 34651652 Check |pmid= value (help).
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Jung RG, Gupta A, Stotts C; et al. (2026). "Prognostic Factors Associated With Mortality in Septic Shock: A Systematic Review and Meta-Analysis". The Lancet Respiratory Medicine. 14 (3): 225–232. doi:10.1016/S2213-2600(25)00397-2. PMID 41619747 Check |pmid= value (help).
  4. ↑ Shields AD, Plante LA, Pacheco LD, Louis JM (2023). "Society for Maternal-Fetal Medicine Consult Series #67: Maternal Sepsis". American Journal of Obstetrics and Gynecology. 229 (3): B2–B19. doi:10.1016/j.ajog.2023.05.019.
  5. ↑ Giamarellos-Bourboulis EJ, Aschenbrenner AC, Bauer M; et al. (2024). "The pathophysiology of sepsis and precision-medicine-based immunotherapy". Nature Immunology. 25 (1): 19–28. doi:10.1038/s41590-023-01660-5.
  6. ↑ Hotchkiss RS, Moldawer LL, Opal SM; et al. (2016). "Sepsis and septic shock". Nature Reviews Disease Primers. 2: 16045. doi:10.1038/nrdp.2016.45.
  7. ↑ Manabe T, Heneka MT (2022). "Cerebral dysfunctions caused by sepsis during ageing". Nature Reviews Immunology. 22 (7): 444–458. doi:10.1038/s41577-021-00643-7.
  8. ↑ Sekino N, Selim M, Shehadah A (2022). "Sepsis-associated brain injury: underlying mechanisms and potential therapeutic strategies for acute and long-term cognitive impairments". Journal of Neuroinflammation. 19 (1): 101. doi:10.1186/s12974-022-02464-4.
  9. ↑ Angus DC, van der Poll T (2013). "Severe Sepsis and Septic Shock". New England Journal of Medicine. 369 (9): 840–851. doi:10.1056/NEJMra1208623.
  10. ↑ 10.0 10.1 Takeuchi T, Flannery AH, Liu LJ; et al. (2025). "Epidemiology of Sepsis-Associated Acute Kidney Injury in the ICU With Contemporary Consensus Definitions". Critical Care. 29 (1): 128. doi:10.1186/s13054-025-05351-5.
  11. ↑ Bauer M, Gerlach H, Vogelmann T; et al. (2020). "Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019—results from a systematic review and meta-analysis". Critical Care. 24 (1): 239. doi:10.1186/s13054-020-02950-2.
  12. ↑ Poole AP, Chaba A, Bellomo R; et al. (2025). "Mortality Trends for Sepsis and Septic Shock Among Critically Ill Adults in Australia and New Zealand". Intensive Care Medicine. 51 (12): 2318–2328. doi:10.1007/s00134-025-08162-y.
  13. ↑ Imaeda T, Oami T, Yokoyama T; et al. (2025). "Epidemiology and outcomes of septic shock in Japan: a nationwide retrospective cohort study from a medical claims database by the Japan Sepsis Alliance (JaSA) study group". Critical Care. 29 (1): 309. doi:10.1186/s13054-025-05556-8.
  14. ↑ Guo Q, Qu P, Cui W; et al. (2023). "Organism type of infection is associated with prognosis in sepsis: an analysis from the MIMIC-IV database". BMC Infectious Diseases. 23 (1): 431. doi:10.1186/s12879-023-08387-6.
  15. ↑ 15.0 15.1 Lu J, Dong Z, Ye L, Gao Y, Zheng Z (2025). "Predictive value of SOFA, PCT, Lactate, qSOFA and their combinations for mortality in patients with sepsis: A systematic review and meta-analysis". PLOS ONE. 20 (9): e0332525. doi:10.1371/journal.pone.0332525.
  16. ↑ 16.0 16.1 Guarino M, Gambuti E, Alfano F; et al. (2021). "Predicting in-hospital mortality for sepsis: a comparison between qSOFA and modified qSOFA in a 2-year single-centre retrospective analysis". European Journal of Clinical Microbiology & Infectious Diseases. 40 (4): 825–831. doi:10.1007/s10096-020-04086-1.
  17. ↑ Farrah K, McIntyre L, Doig CJ; et al. (2021). "Sepsis-Associated Mortality, Resource Use, and Healthcare Costs: A Propensity-Matched Cohort Study". Critical Care Medicine. 49 (2): 215–227. doi:10.1097/CCM.0000000000004777.
  18. ↑ 18.0 18.1 18.2 Shankar-Hari M, Rubenfeld GD, Ferrando-Vivas P, Harrison DA, Rowan K (2020). "Development, Validation, and Clinical Utility Assessment of a Prognostic Score for 1-Year Unplanned Rehospitalization or Death of Adult Sepsis Survivors". JAMA Network Open. 3 (9): e2013580. doi:10.1001/jamanetworkopen.2020.13580.
  19. ↑ Shankar-Hari M, Saha R, Wilson J; et al. (2020). "Rate and Risk Factors for Rehospitalisation in Sepsis Survivors: Systematic Review and Meta-Analysis". Intensive Care Medicine. 46 (4): 619–636. doi:10.1007/s00134-019-05908-3.
  20. ↑ Pandolfi F, Brun-Buisson C, Guillemot D, Watier L (2022). "One-year hospital readmission for recurrent sepsis: associated risk factors and impact on 1-year mortality—a French nationwide study". Critical Care. 26 (1): 371. doi:10.1186/s13054-022-04212-9.
  21. ↑ Wang HE, Kabeto MM, Gray M; et al. (2021). "Trajectory of Cognitive Decline After Sepsis". Critical Care Medicine. 49 (7): 1083–1094. doi:10.1097/CCM.0000000000004897.
  22. ↑ Fleischmann-Struzek C, Born S, Kesselmeier M; et al. (2024). "Functional dependence following intensive care unit-treated sepsis: three-year follow-up results from the prospective Mid-German Sepsis Cohort (MSC)". The Lancet Regional Health - Europe. 46: 101066. doi:10.1016/j.lanepe.2024.101066.
  23. ↑ 23.0 23.1 Bircak-Kuchtova B, Rose N, Geis C; et al. (2025). "Effectiveness of targeted post-acute interventions and follow-up services for sepsis survivors: a systematic review". Critical Care. 29 (1): 351. doi:10.1186/s13054-025-05585-3.
  24. ↑ Kox M, Bauer M, Bos LDJ; et al. (2026). "The immunology of sepsis: translating new insights into clinical practice". Nature Reviews Nephrology. 22 (1): 30–49. doi:10.1038/s41581-025-01004-6.
  25. ↑ Evans L, Rhodes A, Alhazzani W; et al. (2021). "Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021". Critical Care Medicine. 49 (11): e1063–e1143. doi:10.1097/CCM.0000000000005337.
  26. ↑ 26.0 26.1 Prescott HC, Antonelli M, Alhazzani W; et al. (2026). "Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2026". Critical Care Medicine. 54 (4): 725–812. doi:10.1097/CCM.0000000000007075.
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