Synonyms and keywords: sepsis syndrome; septic shock; septicemia

Sepsis is a condition characterized by a whole-body inflammatory state caused by infection. Septic shock is a serious medical condition caused by decreased tissue perfusion and oxygen delivery as a result of infection and sepsis. It can cause multiple organ failure and death. Its most common victims are children, immunocompromised individuals, and the elderly. This is because their immune systems cannot cope with the infection as well as those of full-grown adults.^[1]

The immunological response that causes sepsis is a systemic inflammatory response causing widespread activation of inflammation and coagulation pathways. This may progress to dysfunction of the circulatory system and, even under optimal treatment, may result in the multiple organ dysfunction syndrome and eventually death. A subclass of distributive shock, shock refers specifically to decreased tissue perfusion resulting in end-organ dysfunction. Dysregulated immune response remains the cornerstone of pathophysiology, involving both excessive inflammation and subsequent immunosuppression. Cytokines TNFα, IL-1β, interferon γ, IL-6 released in a large scale inflammatory response results in massive vasodilation, increased capillary permeability, decreased systemic vascular resistance, and hypotension. Hypotension reduces tissue perfusion pressure and thus tissue hypoxia ensues. Excessive inflammation is now recognized to include cytokine storm, formation of neutrophil extracellular traps (NETs), and emergency myelopoiesis. In parallel, an immunosuppressive phase develops, characterized by lymphopenia, expansion of MS1 monocytes, and T-cell exhaustion.

Recent work has also highlighted metabolic failure as a key contributor to immunoparalysis, with impaired glycolysis and oxidative phosphorylation in immune cells leading to inadequate host defense. Finally, in an attempt to offset decreased blood pressure, ventricular dilatation and myocardial dysfunction will occur.

Microvascular injury further amplifies tissue damage. Endothelial glycocalyx shedding leads to barrier loss, microvascular thrombosis, and inflammation, while complement overactivation exacerbates endothelial and organ injury.

Heterogeneity is increasingly recognized: gene expression and molecular profiling are uncovering distinct subtypes of sepsis with different immune signatures and therapeutic responses, such as macrophage activation–like syndrome.^{[2][3][4][5][6][7]}

In rough order of severity, these are bacteremia or fungemia; septicemia; sepsis, severe sepsis or sepsis syndrome; septic shock; refractory septic shock; multiple organ dysfunction syndrome, and death.

The process of infection by bacteria or fungi can result in systemic signs and symptoms that are variously described. The condition develops as a response to certain microbial molecules which trigger the production and release of cellular mediators, such as tumor necrosis factors (TNF); these act to stimulate immune response.^[8][9][10]

Sepsis must be differentiated from other syndromes presnting with fever, hypotension such as the acute bacterial endocarditis, myocardial ring abscess, subacute bacterial endocarditis and bacterial meningitis.^[11][12][13]

The hospitalization rate of those with a principal diagnosis of septicemia or sepsis more than doubled from 2000 through 2008. During the same period, the hospitalization rate for those with septicemia or sepsis as a principal or as a secondary diagnosis increased by 70% from 221 to 377 for every 100,000 people. Reasons for these increases may include an aging population with more chronic illnesses, greater use of invasive procedures, immunosuppressive drugs, chemotherapy, transplantation, and increasing microbial resistance to antibiotics.^[14]

Globally, the burden of sepsis remains very high, with an estimated 48.9 million cases and 11 million deaths annually. Importantly, about 85% of these cases occur in low- and middle-income countries (LMICs), particularly in sub-Saharan Africa.^[15]

Factors responsible for increased risk of sepsis may include an aging population with more chronic illnesses; greater use of invasive procedures, immunosuppressive drugs, chemotherapy, and transplantation; and increasing microbial resistance to antibiotics. Other patients population at increased risk are ICU admits, immunocompromised, bacteremic, with community acquired pneumonia, and with genetic predisposition.^[16][14][14]

There are many complications associated with sepsis, especially because it is a systemic phenomenon. Sepsis is a severe condition, and the prognosis of the patient will depend greatly on the condition and overall health of the patient. Many factors, such as age, hosts immune response, site of infection, type of infection, appropriate antibiotic therapy, and restoration of circulation of perfusion contribute to the overall prognosis.^{[17][18] [19][20][21][22] [23]}

Symptoms of sepsis are often related to the underlying infectious process. When the infection crosses into the bloodstream the resulting symptoms of sepsis occur fever, chills, and rigors, confusion, anxiety, difficulty breathing, fatigue and malaise, nausea and vomiting.^[24][25][1]

The physical examination of sepsis shows findings of the causative system as well as some generalized features.^[26][27]

The international guideline committee for diagnosis of septic shock recommends obtaining appropriate cultures that may include at least two blood cultures, urine, cerebrospinal fluid, wounds, respiratory secretions, or other body fluid cultures before antimicrobial therapy is initiated. If such cultures do not cause significant delay in antibiotic administration, then other tests that may be done include blood gases, kidney function tests, platelet count, white blood cell count, blood differential, fibrin degradation products, and peripheral smear.^[28][1]

Improved detection using molecular tools (e.g., plasma metagenomics) is increasing pathogen identification rates. Transcriptome- and proteome-based diagnostic tools have also been approved, though their clinical impact is still untested.^[15]

Sepsis-3 remains the dominant definition for adults, whereas the Phoenix 2024 criteria are now recommended for pediatrics.^[15]

There are no specific chest X-ray findings associated with sepsis but may show the features consistent with the primary source of infection.

There are no specific CT findings associated with sepsis but may show the features consistent with the primary source of infection.

There are no specific MRI findings associated with sepsis but may show the features consistent with the primary source of infection.

There are no specific echocardiography or ultrasound finidngs associated with sepsis but may show the features consistent with the primary source of infection.

According to IDSA, “Surviving Sepsis Campaign” guidelines, the management protocol for sepsis include screening for high-risk patients; taking bacterial cultures soon after the patient arrived at the hospital; starting patients on broad-spectrum intravenous antibiotic therapy before the results of the cultures are obtained; identifying the source of infection and taking steps to control it (e.g., abscess drainage); administering intravenous fluids to correct a loss or decrease in blood volume; and maintaining glycemic (blood sugar) control.^{[14][29][30][31][32][33][34][34][35][36][37][38][39]}

Surgical intervention is not recommended for the management of sepsis itself but may be essential as part of source control (e.g., abscess drainage, removal of infected devices).

Prevent infections that can lead to sepsis by cleaning scrapes and wounds and getting regular vaccination against infections that cause sepsis can help in the prevention of sepsis.^{_Sepsis_|_CDC-40|[40]}

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Sepsis currently has differing definitions as shown in the table below. These definitions were compiled from the three following sources:

1) Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock (2016)

2) Center of Medicare and Medicaid Services (CMS) (2015/2016)

3) The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) from 2016

This table is based on the 2019 published table by the Wisconsin Chapter of American College of Emergency Physicians.

• Surviving Sepsis Campaign
• Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

Synonyms and keywords: sepsis syndrome; septic shock; septicemia

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]

• 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]

• 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]

• 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.

• 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]

• 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]

• 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.

• 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]

• 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.

Synonyms and keywords: sepsis; septic shock

Sepsis results from a dysregulated host response to an underlying infection. Etiology is best characterized by the anatomic source of infection, causative pathogen, host factors, and site of acquisition. Identifying the likely source and pathogen is clinically important because these factors guide diagnostic evaluation, antimicrobial selection, and source control. ^[1]

• A causative pathogen is identified in approximately 60-70% of sepsis cases. The proportion varies by diagnostic method and clinical setting; absence of a positive culture does not exclude infection or sepsis. ^[1]
• Respiratory tract, particularly pneumonia or lower respiratory tract infection, is the most common source overall (pulmonary 40-60% of cases), although the relative frequency of sources varies by cohort and care setting. ^[1]
• Other common anatomic sources include:
  • Intra-abdominal infection, including peritonitis, abscess, bowel perforation, and biliary infection.
  • Genitourinary infection, including pyelonephritis, complicated urinary tract infection, prostatitis, and urinary tract obstruction.
  • Bloodstream infection, including primary bacteremia or fungemia and device-associated infection.
  • Skin and soft tissue infection, including surgical-site infection, infected wounds, pressure injuries, and necrotizing soft tissue infection.
  • Less common but clinically important sources include central nervous system infection, endocarditis, bone/joint infection, and infected prosthetic material. ^[1]
• In a large U.S. multicenter cohort, the most frequent infection sites varied by cohort: in MIMIC-IV, genitourinary, respiratory, and bloodstream sources accounted for approximately 33%, 28%, and 19%, respectively. These data illustrate that source frequency is population- and setting-dependent. ^[2]
• Intra-abdominal, lower respiratory tract, and biliary tract infections have been associated with higher mortality among patients with sepsis. ^[3]
• When no source is apparent, deliberate reassessment should include the perineal/perianal region, indwelling devices and catheters, prosthetic material, spine/epidural space, and occult abscesses or necrotizing soft tissue infection. ^[4]

• Bacteria account for the majority of sepsis, with both gram-positive and gram-negative organisms represented. Fungi and viral causes are important in selected hosts and clinical settings. ^[1]
• Bacteria account for the large majority of sepsis; fungi account for roughly 5% of cases overall but are associated with high mortality (approximately 40-60%). ^[5]
• Common pathogens vary with the source and host and include Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus species, and other gram-negative and gram-positive organisms. ^[2]
• Among blood-culture-positive community-onset sepsis in a large U.S. multicenter cohort of 201 hospitals (2016-2020), gram-negative rods were isolated in 55% and gram-positive cocci in 47%; resistant organisms were relatively infrequent, including MRSA in 11%, ceftriaxone-resistant Enterobacterales/ESBL organisms in 7%, and carbapenem-resistant Enterobacterales in 1.3%. ^[6]
• Candida species are the predominant fungal pathogens in many hospitalized patients with sepsis. Other fungal causes include endemic fungi and Pneumocystis jirovecii in selected immunocompromised hosts. Viral sepsis is particularly important in specific populations and outbreaks; in a multicountry pediatric study, viral infection accounted for approximately 21% of sepsis cases. ^[1]
• Important parasitic and region-specific causes include malaria, dengue, invasive nontyphoidal Salmonella, Burkholderia pseudomallei (melioidosis), rickettsial infections, tuberculosis, and HIV-associated infections. ^[7][1]

• Culture-negative sepsis is common: a pathogen is not identified in approximately 30-40% of cases, and blood cultures alone are positive in only about 14% of community-onset sepsis. Absence of a cultured organism does not exclude infection and may limit microbiologic narrowing of antimicrobial therapy. ^[1][6]
• Molecular and other culture-independent diagnostic methods may increase pathogen detection, but the clinical utility of these approaches depends on the assay and clinical setting. ^[1]

• Community-acquired sepsis commonly arises from pneumonia, urinary tract infection, intra-abdominal infection, or skin and soft tissue infection.
• Common pathogens include Escherichia coli, Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae, with the pathogen distribution varying by infection source and host factors. ^[1][6]
• In blood-culture-positive community-onset sepsis, gram-negative rods and gram-positive cocci are both prominent, while MRSA, ESBL/ceftriaxone-resistant Enterobacterales, and CRE represent smaller but clinically important proportions. ^[6]

• Healthcare-associated and hospital-acquired sepsis commonly originates from pneumonia, bloodstream infection, intra-abdominal infection, urinary tract infection, and skin/soft tissue infection. ^[8]
• In hospital-onset sepsis, reported sources include pneumonia (approximately 39%, of which only about one-third are ventilator-associated), bloodstream infection (approximately 17%), intra-abdominal infection (approximately 14.5%), urinary tract infection (approximately 7%), and skin/soft tissue infection (approximately 6%). ^[8]
• Hospital-acquired bloodstream infections have a greater representation of fungi and multidrug-resistant organisms than most community-acquired infections, including MRSA, vancomycin-resistant enterococci, and resistant gram-negative organisms; fungi are a substantial fraction of hospital-acquired but nearly absent in community-acquired bloodstream infections. ^[9][8]

• Immunocompromised patients have altered susceptibility to infection because of neutropenia or impaired neutrophil function, mucocutaneous barrier disruption, cellular or humoral immune dysfunction, asplenia, indwelling devices, or immunosuppressive therapy. ^[10]
• In patients with hematologic malignancy, neutropenia, or severe cellular immune dysfunction, gram-negative bacteria, Candida species, molds, and selected viruses may be important causes depending on the underlying immune defect and exposures. ^[10]
• In febrile neutropenia and hematologic malignancy, gram-negative bacteria predominate (approximately 50-66%; commonly Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae), with a rising burden of multidrug-resistant gram-negative organisms and non-albicans Candida; mucositis-related translocation and indwelling catheters are important contributors. ^[11][12]

• Approximately 85% of global sepsis cases occur in low- and middle-income countries, where the pathogen spectrum and infection sources differ from those commonly encountered in high-income settings. ^[7][1]
• Important region-specific or exposure-associated causes include malaria, dengue, invasive nontyphoidal Salmonella, Burkholderia pseudomallei (melioidosis), rickettsioses, tuberculosis, and HIV-related infection. Travel, residence, environmental exposure, and local epidemiology should therefore modify the etiologic differential. ^[7][1]
• The Global Burden of Disease 2017 analysis estimated approximately 48.9 million sepsis cases and 11.0 million sepsis-associated deaths worldwide, with more than half of cases occurring in children. ^[7]

• Determine the likely source, pathogen class, host immune status, and site of acquisition concurrently rather than relying on a single positive culture or presumed source.
• A positive culture does not necessarily identify the anatomic source; conversely, a clinically important infectious focus may remain culture-negative.
• When no source is identified initially, reassess for occult abscess, infected devices or prosthetic material, perineal infection, spinal/epidural infection, endocarditis, and necrotizing soft tissue infection. ^[4]
• Etiologic assessment should incorporate recent healthcare exposure, antimicrobial exposure, immune status, travel or residence, and relevant environmental or animal exposures when these alter the plausible pathogen spectrum.

Sepsis and septic shock can closely resemble non-infectious inflammatory syndromes and other forms of shock. In critically ill adults, diagnostic reasoning should therefore proceed in parallel: identify a plausible infectious source and organ dysfunction while actively testing whether the physiology is better explained by cardiogenic, hypovolemic/hemorrhagic, obstructive, endocrine, toxic, or hyperinflammatory disease. No single biomarker reliably establishes or excludes sepsis.

The first bedside question is whether the patient has a predominantly distributive, cardiogenic, hypovolemic/hemorrhagic, or obstructive physiology. These mechanisms may coexist, particularly in critically ill patients.

When the shock mechanism is unclear from the history and physical examination, bedside cardiac ultrasound is a preferred initial tool for evaluating cardiac function and distinguishing major shock phenotypes. The Society of Critical Care Medicine recommends bedside cardiac ultrasound in hemodynamically unstable patients (Grade 1B). Point-of-care ultrasound has limited ability to separate early septic shock from hypovolemic shock, so ultrasound findings should be integrated with the clinical picture rather than interpreted as a standalone etiologic test.^[1][2][3]

Advanced hemodynamic monitoring may be considered in complex or mixed shock states when non-invasive assessment remains inconclusive.

Several conditions can produce fever, tachycardia, leukocytosis, hypotension, elevated lactate, organ dysfunction, or markedly elevated inflammatory markers without infection being the primary driver.

A non-infectious inflammatory trigger does not exclude concomitant infection. Diagnostic reassessment should therefore remain dynamic, particularly when the clinical trajectory is inconsistent with the presumed diagnosis.

Secondary hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), and related cytokine-storm states can closely resemble severe sepsis or septic shock. Important clues include persistent fever, cytopenias affecting multiple lineages, extreme or rapidly rising ferritin, hypertriglyceridemia, hypofibrinogenemia, liver injury, coagulopathy, splenomegaly, and progressive multiorgan dysfunction.

Ferritin is useful as a signal of hyperinflammation but is not specific for HLH. Interpretation should incorporate the overall phenotype and, when appropriate, a formal HLH framework such as HLH-2004 criteria or HScore.

The HScore provides a validated adult probability framework incorporating known immunosuppression, temperature, organomegaly, cytopenias, ferritin, triglycerides, fibrinogen, AST, and hemophagocytosis. In the original derivation cohort, an HScore of approximately 169 provided high diagnostic sensitivity and specificity; subsequent critically ill adult cohorts have reproduced a similar operating range, although performance varies with population and disease prevalence.^[4][5][6][7]

For point-of-care use, the HScore calculator can provide an interactive probability estimate. The score should be used as an adjunct rather than as a substitute for clinical judgment or the broader HLH diagnostic framework.

A threshold of greater than 7% CD38^high/HLA-DR⁺ cells among CD8⁺ T cells had strong positive and negative predictive value for distinguishing HLH from early sepsis.^[8] This threshold is sensitive for T-cell–driven hyperinflammation but is not specific for HLH: values exceeding 7% also occur in MIS-C, MAS, and other immune-dysregulation disorders, whereas the amplitude of activation is highest in primary and EBV-associated HLH. It is not yet universally validated for adults.^[9]

Ferritin and HScore can aid recognition; combining CRP with ferritin may improve discrimination of HLH from other cytokine-storm syndromes.^[10][11]

The ferritin trajectory may be more informative than an isolated value. Extreme hyperferritinemia should prompt consideration of HLH/MAS and other hyperinflammatory syndromes, while recognizing that severe infection itself can produce very high ferritin concentrations.

The serum H-ferritin-to-total-ferritin ratio is an emerging biomarker under investigation in critically ill patients with hyperferritinemia and may provide additional discrimination among HLH, MAS-like states, sepsis, and other critical illness phenotypes; it should not yet be treated as a standalone diagnostic test.^[12]

Procalcitonin (PCT) can support clinical assessment but should not be interpreted as a binary test for infection. PCT may be elevated in some malignancies and does not reliably distinguish gram-positive from gram-negative infection or neutropenic from non-neutropenic patients.^[13]

PCT cannot reliably differentiate sepsis from non-infectious SIRS in critically ill adults (pooled AUC approximately 0.78).^[14] Other meta-analyses report higher discrimination, with estimates approaching 0.84–0.85 in some populations, illustrating heterogeneity by study design, population, reference standard, and timing of measurement.^[15][16]

PCT may also rise in non-infectious states, including trauma, surgery, malignancy, and other systemic inflammatory conditions. Consequently, an elevated PCT should increase neither diagnostic certainty nor antimicrobial commitment in isolation.

The Surviving Sepsis Campaign 2021 issued a weak recommendation against using procalcitonin plus clinical evaluation, versus clinical evaluation alone, to decide when to start antimicrobials.^[17]

Other biomarkers, including CRP, presepsin, cytokines, and host-response signatures, may provide complementary information but remain insufficiently specific to replace clinical assessment, microbiologic evaluation, and source-directed investigation.

• No single biomarker separates sepsis from its mimics. Ferritin, CRP, PCT, lactate and cytokines reflect overlapping inflammatory or physiologic pathways.
• A high PCT does not prove bacterial infection. Non-infectious inflammation and other critical illnesses can increase PCT.
• A low or modest PCT does not exclude infection. Timing, localized infection, immunologic state and pathogen type influence concentrations.
• Extreme ferritin is not synonymous with HLH. Severe infection, liver injury, MAS and other inflammatory disorders can produce marked hyperferritinemia.
• HScore is an adjunct, not a replacement for diagnostic judgment. Scores near the commonly used cutoff should be interpreted in clinical context.
• CD38^high/HLA-DR⁺ CD8⁺ T-cell activation is not HLH-specific. The >7% threshold can identify hyperinflammation but also occurs in other immune-dysregulation syndromes.
• POCUS does not always identify the cause of shock. Early septic and hypovolemic shock can have overlapping ultrasound findings.
• Mixed shock is common. Sepsis may coexist with myocardial dysfunction, hemorrhage, pulmonary embolism, adrenal insufficiency, or other contributors.
• Culture-negative sepsis remains possible. Negative cultures do not independently establish a non-infectious diagnosis when the clinical phenotype remains compatible with infection.
• MIS-A belongs in the adult differential. MIS-C is a pediatric syndrome and should not be presented as an adult diagnosis.

A useful bedside sequence is:

1. Confirm the physiology. Determine whether hypotension and organ dysfunction are present and assess the dominant shock phenotype.
2. Search for infection. Obtain a focused history and examination, blood cultures and other cultures as indicated, and source-directed imaging/testing.
3. Actively test major shock mimics. Consider cardiogenic, hemorrhagic/hypovolemic, obstructive, endocrine, toxic, and anaphylactic causes.
4. Look for hyperinflammation when the phenotype is disproportionate. Persistent fever, multilineage cytopenias, rapidly rising or extreme ferritin, hypofibrinogenemia, hypertriglyceridemia, hepatitis, and splenomegaly should prompt consideration of secondary HLH/MAS.
5. Use HScore when appropriate. An HScore around 169 is a useful probability threshold, but the score should be interpreted with the clinical context and evolving trajectory.
6. Use biomarkers as supporting evidence only. PCT, CRP, ferritin and emerging immune biomarkers should not independently establish or exclude infection.
7. Reassess serially. Diagnostic confidence should change when the patient’s trajectory, microbiology, imaging, or response to initial management conflicts with the working diagnosis.

Shabrish S, Desai M, Saxena V, Kelkar M, Madkaikar M. IFN-g:IL-10 Ratio: A Putative Predictive Biomarker to Discriminate HLH From Severe Viral Infections. Journal of Clinical Immunology. 2019;39(2):135–137. doi:10.1007/s10875-019-00601-y.^[18]

Chaturvedi V, Marsh RA, Zoref-Lorenz A, et al. T-Cell Activation Profiles Distinguish Hemophagocytic Lymphohistiocytosis and Early Sepsis. Blood. 2021;137(17):2337–2346. doi:10.1182/blood.2020009499.

Debaugnies F, Goetzinger F, Wolff F, et al. Serum H-Ferritin-to-Ferritin Ratio as a Biomarker of Hemophagocytic Lymphohistiocytosis in Critically Ill Patients With Hyperferritinemia. American Journal of Hematology. 2026;101(3):648–653. doi:10.1002/ajh.70189.

van Berkel M, Kox M, Frenzel T, et al. Biomarkers for Antimicrobial Stewardship: A Reappraisal in COVID-19 Times? Critical Care. 2020;24(1):600. doi:10.1186/s13054-020-03291-w.^[19]

Lee S, Song J, Park DW, et al. Diagnostic and Prognostic Value of Presepsin and Procalcitonin in Non-Infectious Organ Failure, Sepsis, and Septic Shock: A Prospective Observational Study According to the Sepsis-3 Definitions. BMC Infectious Diseases. 2022;22(1):8. doi:10.1186/s12879-021-07012-8.^[20]

Conlon TW, Baker D, Bhombal S. Cardiac Point-of-Care Ultrasound: Practical Integration in the Pediatric and Neonatal Intensive Care Settings. European Journal of Pediatrics. 2024;183(4):1525–1541. doi:10.1007/s00431-023-05409-y.^[21]

Zieleskiewicz L, Lopez A, Hraiech S, et al. Bedside POCUS During Ward Emergencies Is Associated With Improved Diagnosis and Outcome: An Observational, Prospective, Controlled Study. Critical Care. 2021;25(1):34. doi:10.1186/s13054-021-03466-z.^[22]

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9. Tang BM, Eslick GD, Craig JC, McLean AS. Accuracy of Procalcitonin for Sepsis Diagnosis in Critically Ill Patients: Systematic Review and Meta-Analysis. Lancet Infect Dis. 2007;7(3):210–217. doi:10.1016/S1473-3099(07)70052-X.
10. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063–e1143. doi:10.1097/CCM.0000000000005337.
11. Maves RC, Enwezor CH. Uses of Procalcitonin as a Biomarker in Critical Care Medicine. Infect Dis Clin North Am. 2022;36(4):897–909. doi:10.1016/j.idc.2022.07.004.
12. Tan M, Lu Y, Jiang H, Zhang L. The Diagnostic Accuracy of Procalcitonin and C-Reactive Protein for Sepsis: A Systematic Review and Meta-Analysis. J Cell Biochem. 2019;120(4):5852–5859. doi:10.1002/jcb.27870.
13. Ghatak T, Pal A, Rochwerg B, et al. The Diagnostic Accuracy of Serum Procalcitonin for Sepsis in Critically Ill Adults. A Systematic Review and Diagnostic Meta-Analysis. J Crit Care. 2025;92:155402. doi:10.1016/j.jcrc.2025.155402.
14. Chairaj T, Mongkhon P, Leewongsakorn P, et al. Diagnostic Performance of Procalcitonin and Presepsin in Sepsis: A Systematic Review and Meta-Analysis. BMC Emerg Med. 2025;26(1):9. doi:10.1186/s12873-025-01433-3.
15. Levitov A, Frankel HL, Blaivas M, et al. Guidelines for the Appropriate Use of Bedside General and Cardiac Ultrasonography in the Evaluation of Critically Ill Patients—Part II: Cardiac Ultrasonography. Crit Care Med. 2016;44(6):1206–1227. doi:10.1097/CCM.0000000000001847.
16. Yoshida T, Yoshida T, Noma H, et al. Diagnostic accuracy of point-of-care ultrasound for shock: a systematic review and meta-analysis. Crit Care. 2023;27(1):200. doi:10.1186/s13054-023-04495-6.
17. Ramadan A, Abdallah T, Abdelsalam H, Mokhtar A, Razek AA. Accuracy of echocardiography and ultrasound protocol to identify shock etiology in emergency department. BMC Emerg Med. 2022;22(1):117. doi:10.1186/s12873-022-00678-6.
18. Shabrish S, Desai M, Saxena V, Kelkar M, Madkaikar M. IFN-g:IL-10 Ratio: A Putative Predictive Biomarker to Discriminate HLH From Severe Viral Infections. J Clin Immunol. 2019;39(2):135–137. doi:10.1007/s10875-019-00601-y.
19. Debaugnies F, Goetzinger F, Wolff F, et al. Serum H-Ferritin-to-Ferritin Ratio as a Biomarker of Hemophagocytic Lymphohistiocytosis in Critically Ill Patients With Hyperferritinemia. Am J Hematol. 2026;101(3):648–653. doi:10.1002/ajh.70189.
20. van Berkel M, Kox M, Frenzel T, et al. Biomarkers for Antimicrobial Stewardship: A Reappraisal in COVID-19 Times? Crit Care. 2020;24(1):600. doi:10.1186/s13054-020-03291-w.
21. Lee S, Song J, Park DW, et al. Diagnostic and Prognostic Value of Presepsin and Procalcitonin in Non-Infectious Organ Failure, Sepsis, and Septic Shock: A Prospective Observational Study According to the Sepsis-3 Definitions. BMC Infect Dis. 2022;22(1):8. doi:10.1186/s12879-021-07012-8.
22. Conlon TW, Baker D, Bhombal S. Cardiac Point-of-Care Ultrasound: Practical Integration in the Pediatric and Neonatal Intensive Care Settings. Eur J Pediatr. 2024;183(4):1525–1541. doi:10.1007/s00431-023-05409-y.
23. Zieleskiewicz L, Lopez A, Hraiech S, et al. Bedside POCUS During Ward Emergencies Is Associated With Improved Diagnosis and Outcome: An Observational, Prospective, Controlled Study. Crit Care. 2021;25(1):34. doi:10.1186/s13054-021-03466-z.

Synonyms and keywords: sepsis syndrome; septic shock; septicemia

• The most current systematic estimate from the Global Burden of Disease (GBD) 2021 analysis reported approximately 166 million sepsis cases and 21.4 million all-cause sepsis-related deaths in 2021, representing approximately 31.5% of all global deaths.^[1]
• For comparison, the GBD 2017 analysis estimated 48.9 million cases and 11.0 million deaths, accounting for approximately 19.7% of global deaths. The estimates should be interpreted according to the year and methodology and should not be averaged across analyses.^[2]
• Approximately 85% of the global sepsis burden occurs in low- and middle-income countries (LMICs); sub-Saharan Africa accounts for approximately 40% of cases worldwide. The pathogen spectrum and epidemiologic context differ substantially from those in high-income countries.^[3][2]
• GBD estimates are modeled population-level estimates derived from available mortality and health-system data and should therefore be interpreted with uncertainty, particularly in settings with sparse primary epidemiologic data.^[1][2]

• From 1990 through 2017, age-standardized sepsis incidence and mortality declined by approximately 37% and 52.8%, respectively.^[2][3]
• This long-term decline was interrupted in 2020-2021, with a substantial increase in sepsis-related mortality driven largely by the COVID-19 pandemic.^[1][4]
• In the United States, age-adjusted sepsis mortality was approximately 77.5 per 100,000 in 1999 and 76.1 per 100,000 in 2019, followed by an approximately 30% increase from 2019 to 2021.^[4]
• The effect of COVID-19 on sepsis epidemiology complicates comparisons between pre-pandemic and pandemic-era estimates.^[4]

• Sepsis incidence has a U-shaped (biphasic) age distribution: incidence is highest in children younger than 5 years, reaches a nadir during later childhood and adolescence, and rises exponentially beginning around age 60.^[3]
• Approximately 26% of the 11 million sepsis deaths estimated for 2017 occurred in children younger than 5 years.^[3]
• The absolute mortality burden is concentrated in older adults, particularly those aged 70 years and older, who had the highest sepsis-related mortality in 2021, with approximately 9.28 million deaths.^[1][5]
• In older U.S. hospitalization data, in-hospital death occurred in approximately 20% of sepsis hospitalizations among patients aged 65 years and older compared with approximately 13% among those younger than 65 years.^[3]

• Sex differences vary by outcome and data source. GBD 2017 reported slightly higher age-standardized incidence in females than males (716 vs 643 per 100,000).^[2]
• U.S. mortality analyses consistently report higher sepsis-related mortality in men than women, including approximately 57 versus 45.1 deaths per 100,000.^[6][4]

• In U.S. mortality data, sepsis-related mortality is higher among non-Hispanic Black, American Indian/Alaska Native, and Hispanic populations than among White populations, with Black patients bearing the highest absolute mortality throughout 1999-2022.^[6][4]
• Observed racial and ethnic differences in sepsis mortality should not be interpreted as intrinsic biologic differences. After adjustment for hospital characteristics, much of the Black-White and Hispanic-White in-hospital mortality gap narrows, implicating hospital-level factors and site of care as important contributors.^[7]

• In the United States, sepsis is present in approximately 1 in 3 patients who die in U.S. hospitals.^[8]
• In the United States, sepsis accounts for an estimated 1.7 million adult hospitalizations and approximately 270,000-350,000 associated deaths annually.^[9]
• Approximately 4.5%-6.7% of hospitalizations have been estimated to meet clinical/EHR-based sepsis criteria in contemporary surveillance studies; estimates vary substantially according to case definition and ascertainment method.^[10][11]

• Sepsis epidemiologic estimates depend strongly on the case definition and ascertainment method. Comparisons between studies should distinguish historical SIRS/severe sepsis definitions from current Sepsis-3 criteria and administrative coding from clinical or electronic-health-record surveillance.^[3][11]
• In a prospective Swedish population study, Sepsis-3 sepsis incidence was 838 per 100,000 persons per year, approximately three times the incidence of severe sepsis at 276 per 100,000 persons per year. The difference was attributed largely to the broader organ-dysfunction criteria used by Sepsis-3.^[12]
• Administrative coding may show increasing apparent sepsis incidence because of changes in recognition and coding practices; therefore, trends in coded cases should not automatically be interpreted as changes in true biological incidence.^[3][11]

• Sepsis incidence is substantially elevated in patients with immunocompromising and chronic medical conditions. More than 20% of U.S. adult sepsis hospitalizations occur in patients with cancer, and sepsis incidence is increased approximately 40-fold among patients receiving long-term hemodialysis.^[3]
• Validated epidemiologic risk factors include older age, male sex, low body mass index, Black race, diabetes, COPD, cancer, kidney disease, postoperative infection, mechanical ventilation, corticosteroid use, prior hospitalization, and prior sepsis.^[13]
• Detailed individual risk factors and their effect sizes are addressed in the Risk Factors microchapter.

• Approximately 85% of sepsis cases and a disproportionate share of sepsis deaths occur in LMICs.^[3][2]
• Sub-Saharan Africa accounts for approximately 40% of global sepsis cases. The infectious causes and pathogen spectrum in these settings differ substantially from those in high-income countries and include malaria, typhoid, dengue, HIV, and tuberculosis.^[3]
• Geographic differences in sepsis burden should be interpreted in the context of health-system capacity, access to care, underlying disease prevalence, infection epidemiology, and differences in surveillance quality.^[3]

• Interpret sepsis statistics according to the case definition and data source. Historical severe sepsis/SIRS-based estimates are not directly interchangeable with Sepsis-3 estimates, and administrative coding estimates are not equivalent to clinical/EHR surveillance estimates.^[3][12][11]
• Heightened epidemiologic risk occurs at the extremes of age and in patients with major chronic or immunocompromising conditions, including cancer, dialysis dependence, COPD, and diabetes.^[3][13]
• Older adults, particularly those aged 70 years and older, account for the largest absolute mortality burden.^[1][5]
• Hospital-level disparities contribute to observed racial differences in sepsis mortality and should be considered when interpreting disparities and designing quality-improvement interventions.^[7]
• The epidemiology of sepsis changed substantially during the COVID-19 pandemic, making direct comparisons between pre-pandemic and pandemic-era estimates potentially misleading.^[1][4]

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Synonyms and keywords: sepsis syndrome; septic shock; septicemia

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.

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]

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]

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 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]

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]

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]

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]

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]

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]

• 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]

• 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]

• 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]

• 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]

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Synonyms and keywords: sepsis syndrome; septic shock; septicemia

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]

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]

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.

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]

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]

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]

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]

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.

• 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]

• 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.

Synonyms and keywords: sepsis syndrome; septic shock; septicemia

Several entities have instituted mandatory reporting in their jurisdictions. These efforts are consistent with prior recommendations by the Academy of Medicine for mandatory reporting^[1].

Mandatory reporting of sepsis quality measures, “SEP-1” by Centers for Medicare and Medicaid Services was announced 08/2014 and implemented in 10/01/2015 as a value based purchase with the possibility of financial penalties^[8][9][2]. Variations in hospital mortality contributed to the rationale for SEP-1^[10]. As of 2017, 87% of eligible hospitals reported compliance measures with variation in rates of compliance^[11].

Concerns about the reporting is the complexity of determining compliance as the documentation for chart reviews if 120 pages and may require 2-3 hours per chart to review^[2]. The SEP-1 rule has been criticized for focusing on processes of care that are hard to measure rather than more easily measured rates and outcomes^[2]. As an example, abstractions of clinical charts usually disagree over determining “time zero”^[12].

Related is the voluntary Bundled Payments for Care Improvement (BPCI) initiative in 2013^[3]. After the first 9 months of the BPCI, 88 of 2918 eligible hospitals participated in BPCI for sepsis^[4]. No difference was found in the quality or costs of sepsis care^[4].

In 2013, the New York State Department of Health (NYSDOH) began mandatory state-wide reporting of quality measures (Rory’s Regulations)^[5][13][14]. This was in part due to the death in 2012 of Rory Staunton. Implementation was based on SEPSIS-2^[7]. Subsequent reduction in mortality was associated with increased compliance to process measures^[14]. The benefit may be specifically linked to speed of antibiotic administration; however, study of fluids examined when fluids were finished and not when fluids were started^[15].

In a controlled study, the improvement of care in New York exceeded the improvement in control states that were only under the influence of CMS pressure^[6].

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