Sepsis risk factors
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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] Jason Le, B.S.[3]
Synonyms and keywords: sepsis syndrome; septic shock; septicemia
Sepsis Risk Factors
Risk factors for sepsis include host characteristics, chronic comorbidities, immunocompromise, recent healthcare exposure, invasive devices or procedures, and selected genetic and socioeconomic factors. Risk factors for developing sepsis should be distinguished from predictors of outcome after sepsis is established, which belong in the Natural History/Prognosis microchapter.
Established risk factors
Highest-yield risk factors
A 2026 systematic review and meta-analysis of 23 studies identified 18 independent risk factors and one protective factor for incident sepsis. Risk factors included age ≥60 years and increasing age, male sex, low body mass index (BMI ≤18.5), Black race, diabetes, chronic obstructive pulmonary disease (COPD), cancer, kidney disease, postoperative infection, ASA score >2, GCS <8, higher Injury Severity Score, loss of functional independence, corticosteroid use, mechanical ventilation, prior hospitalization, prior emergency surgery, and previous sepsis. Antibiotic use was the single protective factor identified in the meta-analysis; substantial heterogeneity was present for several pooled associations, including age, diabetes, postoperative infection, and mechanical ventilation.[1]
- Prior antibiotic exposure is reported as protective in one meta-analysis but as a risk marker (adjusted OR approximately 3.4) in a large pandemic-era case-control study, a discrepancy likely reflecting confounding by indication rather than a true protective or causal effect.[2]
Comorbidity burden
Risk is not uniform across comorbidities. In a Danish population-based case-control study, the strongest independent associations with hospitalization for community-acquired sepsis were immunosuppression (adjusted OR 4.41), respiratory disease (OR 3.58), and alcoholism-related conditions (OR 2.90), followed by neurological, gastrointestinal, cardiovascular, diabetes, cancer, and renal disease. Associations were strongest in younger patients; among adults aged ≥85 years, the adjusted odds of sepsis hospitalization were approximately 6-fold higher than in younger adults.[3]
A Swedish nationwide case-control study of ICU-treated community-acquired sepsis identified end-stage renal disease, moderate-to-severe liver disease, metastatic malignancy, substance abuse, and congestive heart failure among the strongest individual comorbidity and socioeconomic risk factors.[4]
Multiple comorbidities compound risk. The risk of progression from infection to sepsis increases as comorbidity burden increases, with particularly pronounced effects for intra-abdominal infection and community-acquired pneumonia.[5]
Age, frailty, and nutrition
Sepsis risk is U-shaped across the lifespan; among adults it rises substantially after age 60, with the oldest adults carrying the greatest risk.[3] Advanced age, malnutrition, and frailty may compound risk through impaired host reserve and immune dysfunction.[6]
Immunocompromise
Immunocompromise is a major and heterogeneous risk category. More than 20% of sepsis-related hospitalizations involve patients with cancer.[7]
- Neutropenia, particularly an absolute neutrophil count <500/µL, markedly increases bacterial and fungal infection risk. Functional neutropenia may occur despite a normal neutrophil count.[6][8]
- Hematologic malignancy is associated with substantial sepsis risk; 12%–27% of patients develop sepsis within 1 year of diagnosis, and severe sepsis is approximately 5-fold more frequent after hematopoietic stem-cell transplantation than in non-transplant inpatients.[7]
- B-cell-depleting and cellular therapies, including bispecific antibodies and CAR T-cell therapy, increase infection risk through B-cell aplasia, hypogammaglobulinemia, and impaired immune reconstitution; severe infections are concentrated particularly early after therapy.[7]
- Immunosuppressive medications associated with increased risk include corticosteroids, cytotoxic chemotherapy, purine analogues, mTOR and kinase inhibitors, and alemtuzumab.[1][7][9]
- Solid organ transplantation and HIV are associated with approximately 3.2-fold higher hazards of community-acquired pneumonia, an important infectious source of sepsis.[9]
Chronic kidney disease and hemodialysis
Sepsis incidence is markedly elevated in dialysis-dependent patients. In a USRDS analysis of 870,571 patients, 29.8% developed sepsis, corresponding to 12.66 episodes per 100 person-years.[10]
Vascular access type is an important modifiable risk factor. Compared with an arteriovenous fistula, sepsis risk was higher with an arteriovenous graft (HR 1.35) and highest with a catheter (HR 1.80).[10] Catheter-associated bloodstream infection risk is substantially higher with central venous catheters than with fistulas; estimates in the dialysis literature are approximately 8-fold higher in the cited review, although bloodstream-infection estimates should not be equated with the sepsis-specific HR of 1.80.[11][12]
Iatrogenic and device-related factors
Recent hospitalization, surgery, invasive procedures, mechanical ventilation, and indwelling vascular or urinary catheters increase sepsis risk.[1][11] Intravascular catheters can become colonized and develop biofilms that facilitate bloodstream infection.[11]
Other established or clinically relevant factors
Body mass index
The relationship between BMI and sepsis risk appears non-linear. Observational meta-analysis identifies low BMI (≤18.5) as a risk factor, while multivariable Mendelian randomization supports high BMI as an independent causal risk factor; other cardiometabolic associations may attenuate after adjustment for BMI.[1][13]
Genetic predisposition
Sepsis susceptibility has a heritable component. Candidate-gene and genome-wide studies have implicated variants involving pattern-recognition receptors, cytokines, and coagulation pathways, including TLR4 variants; a field synopsis identified multiple susceptibility-associated variants across several genes.[14][15][16]
No genetic test is currently validated for clinical sepsis-risk stratification. Genetic susceptibility should therefore be regarded as a research-level risk modifier rather than an indication for routine genetic testing.[16][14]
Socioeconomic factors
Low income and low educational attainment have been associated with community-acquired sepsis risk, although the contributions of healthcare access, comorbidity clustering, and other mediators remain uncertain.[4]
Clinically actionable risk reduction
- Prioritize assessment of high-magnitude and potentially modifiable factors, particularly immunosuppression, ESRD/dialysis, dialysis catheter access, advanced liver disease, metastatic cancer, COPD, and substance use.[4][7]
- Minimize unnecessary catheter dependence in hemodialysis and remove unnecessary vascular or urinary devices promptly when clinically appropriate.[11][10]
- In high-risk oncology and transplant populations, use guideline-based antimicrobial or antiviral prophylaxis when indicated by the patient's malignancy, therapy, and anticipated immunosuppression. NCCN and ASCO/IDSA recommendations stratify prophylaxis according to clinical and treatment-related infection risk.[17][18]
- Treat a history of previous sepsis or recent hospitalization as an ongoing marker for heightened future sepsis risk.[1]
Areas of uncertainty
- Diabetes is consistently associated with sepsis, but effect sizes are heterogeneous and often modest; some excess risk may be mediated through complications such as renal disease and tissue injury.[1][4]
- Genetic susceptibility is biologically plausible and supported by heritability and association studies, but candidate-gene findings have limited reproducibility and GWAS findings are not currently actionable.[19][16]
- Autoimmune disease does not appear to confer a uniform genetically mediated sepsis risk. Mendelian-randomization evidence supports causal associations for rheumatoid arthritis and type 1 diabetes, and possibly celiac disease, while treatment-related immunosuppression may account for part of the observed clinical association.[20]
- Socioeconomic associations are reproducible in some populations, but the contributions of healthcare access, comorbidity clustering, and other mediators remain uncertain.[4]
- Estimates of catheter-associated bloodstream infection risk should be distinguished from sepsis-specific risk estimates; they are related outcomes but are not interchangeable.[11][12]
High-yield clinical pearls
- Immunosuppression and chronic respiratory disease may confer greater adjusted sepsis risk than diabetes or cancer alone in population-based data; this comparison is based on a single national cohort and should not be generalized across all populations.[3]
- Catheter-based hemodialysis access carries approximately 1.8-fold the sepsis risk of an arteriovenous fistula in a large US cohort; bloodstream-infection risk estimates are higher and represent a different outcome.[10][11]
- Prior sepsis predicts future sepsis and should be treated as an ongoing risk marker.[1]
- More than 20% of sepsis hospitalizations involve patients with cancer; neutropenia and functional immune impairment are important drivers.[7][6]
- Comorbidities compound risk; risk of progression from infection to sepsis increases as comorbidity burden increases.[5]
Common pitfalls
- Treating all comorbidities as equivalent rather than weighting risk according to the magnitude and consistency of association.
- Overlooking functional neutropenia in patients whose absolute neutrophil count is not markedly reduced.[6]
- Assuming normal or high BMI is protective; evidence supports a non-linear relationship in which both low BMI and high BMI may be associated with increased risk.[1][13]
- Confusing infectious sources such as pneumonia or bacteremia with host risk factors; source and etiology are addressed in the Causes microchapter.
- Ordering genetic testing solely for sepsis-risk stratification; no validated clinical genetic test currently exists.[16][14]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Qin C, Lin S, Pang L; et al. (2026). "Risk Factors for Sepsis: A Systematic Review and Meta-Analysis". Front Public Health. 14: 1790141. doi:10.3389/fpubh.2026.1790141. PMID 42433399 Check
|pmid=value (help). - ↑ Zhong X, Ashiru-Oredope D, Pate A; et al. (2023). "Clinical and Health Inequality Risk Factors for Non-Covid-Related Sepsis During the Global COVID-19 Pandemic: A National Case-Control and Cohort Study". EClinicalMedicine. 66: 102321. doi:10.1016/j.eclinm.2023.102321.
- ↑ 3.0 3.1 3.2 Henriksen DP, Pottegård A, Laursen CB; et al. (2015). "Risk Factors for Hospitalization Due to Community-Acquired Sepsis - A Population-Based Case-Control Study". PloS One. 10 (4): e0124838. doi:10.1371/journal.pone.0124838. PMID 25898024.
- ↑ 4.0 4.1 4.2 4.3 4.4 Lindström AC, Eriksson M, Mårtensson J, Oldner A, Larsson E (2021). "Nationwide case–control study of risk factors and outcomes for community-acquired sepsis". Sci Rep. 11 (1): 15118. doi:10.1038/s41598-021-94558-x.
- ↑ 5.0 5.1 Sinapidis D, Kosmas V, Vittoros V; et al. (2018). "Progression into sepsis: an individualized process varying by the interaction of comorbidities with the underlying infection". BMC Infect Dis. 18 (1): 242. doi:10.1186/s12879-018-3156-z.
- ↑ 6.0 6.1 6.2 6.3 Nates JL, Pène F, Darmon M; et al. (2024). "Septic shock in the immunocompromised cancer patient: a narrative review". Crit Care. 28 (1): 285. doi:10.1186/s13054-024-05073-0.
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 Deinhardt-Emmer S, Chousterman BG, Schefold JC; et al. (2025). "Sepsis in Patients Who Are Immunocompromised: Diagnostic Challenges and Future Therapies". Lancet Respir Med. 13 (7): 623–637. doi:10.1016/S2213-2600(25)00124-9. PMID 40409328 Check
|pmid=value (help). - ↑ Hong G, Ju H, Oh DK; et al. (2025). "Clinical characteristics and prognostic factors of sepsis in patients with malignancy". Sci Rep. 15 (1): 7078. doi:10.1038/s41598-025-87457-y.
- ↑ 9.0 9.1 Reichel F, Tesch F, Berger S; et al. (2024). "Epidemiology and risk factors of community-acquired pneumonia in patients with different causes of immunosuppression". Infection. 52 (6): 2475–2486. doi:10.1007/s15010-024-02314-w.
- ↑ 10.0 10.1 10.2 10.3 Locham S, Naazie I, Canner J; et al. (2021). "Incidence and Risk Factors of Sepsis in Hemodialysis Patients in the United States". J Vasc Surg. 73 (3): 1016–1021.e3. doi:10.1016/j.jvs.2020.06.126. PMID 32707386 Check
|pmid=value (help). - ↑ 11.0 11.1 11.2 11.3 11.4 11.5 Bello AK, Okpechi IG, Osman MA; et al. (2022). "Epidemiology of haemodialysis outcomes". Nat Rev Nephrol. 18 (6): 378–395. doi:10.1038/s41581-022-00542-7.
- ↑ 12.0 12.1 Guo H, Zhang L, He H, Wang L (2024). "Risk factors for catheter-associated bloodstream infection in hemodialysis patients: A meta-analysis". PloS One. 19 (3): e0299715. doi:10.1371/journal.pone.0299715. PMC 10971780 Check
|pmc=value (help). - ↑ 13.0 13.1 Zhang Z, Chen L, Zhang H; et al. (2024). "Genetic correlations and causal relationships between cardio-metabolic traits and sepsis". Sci Rep. 14 (1): 5718. doi:10.1038/s41598-024-56467-7.
- ↑ 14.0 14.1 14.2 Engoren M, Jewell ES, Douville N; et al. (2022). "Genetic variants associated with sepsis". PloS One. 17 (3): e0265052. doi:10.1371/journal.pone.0265052. PMC 8916629 Check
|pmc=value (help). - ↑ Liu R, Mo YY, Wang HL; et al. (2016). "The relationship between toll like receptor 4 gene rs4986790 and rs4986791 polymorphisms and sepsis susceptibility: A meta-analysis". Sci Rep. 6: 38947. doi:10.1038/srep38947.
- ↑ 16.0 16.1 16.2 16.3 Lu H, Wen D, Wang X; et al. (2019). "Host genetic variants in sepsis risk: a field synopsis and meta-analysis". Crit Care. 23 (1): 26. doi:10.1186/s13054-019-2313-0.
- ↑ "Prevention and Treatment of Cancer-Related Infections" (PDF). National Comprehensive Cancer Network. 2026-03-11.
- ↑ Taplitz RA, Kennedy EB, Bow EJ; et al. (2018). "Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update". J Clin Oncol. doi:10.1200/JCO.18.00374.
- ↑ Rubio I, Osuchowski MF, Shankar-Hari M; et al. (2019). "Current Gaps in Sepsis Immunology: New Opportunities for Translational Research". Lancet Infect Dis. 19 (12): e422–e436. doi:10.1016/S1473-3099(19)30567-5. PMID 31630991.
- ↑ Li H, Pan X, Zhang S; et al. (2023). "Association of autoimmune diseases with the occurrence and 28-day mortality of sepsis: an observational and Mendelian randomization study". Crit Care. 27 (1): 476. doi:10.1186/s13054-023-04763-5.