Sepsis causes

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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; septic shock

Sepsis Causes

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.

Sources of infection

• 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.
• 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.
• 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.
• 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.
• Intra-abdominal, lower respiratory tract, and biliary tract infections have been associated with higher mortality among patients with sepsis.
• 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.

Causative pathogens

• 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.
• 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%).
• 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.
• 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%.
• 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.
• Important parasitic and region-specific causes include malaria, dengue, invasive nontyphoidal Salmonella, Burkholderia pseudomallei (melioidosis), rickettsial infections, tuberculosis, and HIV-associated infections.

Culture-negative sepsis

• 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.
• 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.

Causes by site of acquisition

Community-acquired sepsis

• 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.
• 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.

Healthcare-associated and hospital-acquired sepsis

• Healthcare-associated and hospital-acquired sepsis commonly originates from pneumonia, bloodstream infection, intra-abdominal infection, urinary tract infection, and skin/soft tissue infection.
• 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%).
• 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.

Causes in special populations

Immunocompromised hosts

• 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.
• 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.
• 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.

Geographic variation

• 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.
• 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.
• 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.

Clinically relevant etiologic considerations

• 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.
• 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.