Patients that are admitted to hospital due to sepsis or develop sepsis during hospital stay require very frequently intensive care unit (ICU) admission, especially if organ dysfunction is present.
There are significant differences in epidemiologic trends in sepsis between western countries and low-income and middle-income countries. Indeed, we can find differences between pathogens involved in sepsis from geographic areas in western countries when these are compared to Asia and Latin America.
This work attempts to review the modern epidemiology of sepsis in western countries, including risk factors and clinical characteristics of affected population.
Incidence of sepsis
The American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) published the first consensus definition of syndromes related to sepsis in 1992, defining the clinical criteria for systemic inflammatory response syndrome (SIRS), sepsis as SIRS in the presence of known or suspected infection, and severe sepsis and septic shock as the progression to organ dysfunction (1). Since then over the last two decades, the knowledge of epidemiology of sepsis has clearly improved. No prospective studies have been performed to analyse incidence of sepsis in general population. The recent publication of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) should provide greater clarity and consistency for future epidemiologic studies (2).
In the United States (US), most of epidemiologic studies have been based on large, administrative databases. Several studies have defined sepsis cases using combinations of diagnostic codes on hospital discharge records (National Hospital Discharge Survey) and the International Classification of Diseases (ICD), Ninth Revision, Clinical Modification (9-CM).
The first report of epidemiology of sepsis in the US was performed by the Center for Disease Control and Prevention in 1990, before the consensus definition, estimating and increase of septicemia codes from 76 to 176 per 100,000 people from 1979 through 1987 (3).
More than a decade later, several studies estimated the incidence and mortality in sepsis (4-7). Angus et al. (4) reported and incidence of severe sepsis of 300 per 100,000 population in seven states in 1995. Martin et al. (5) observed an increase in the incidence or severe sepsis from 83 to 240 per 100,000 population from 1979 to 2000. Gaieski et al. (8), by applying these various definitions to a single national dataset from 2004 to 2009, reported a wide variation according to the employed definition, with similar average annual increase of 13%. One of the reasons that may explain these differences is the choice of ICD-9-CM codes. Angus et al. (4) used 1,286 codes indicating the infectious process, while Martin et al. (5) employed only six to identify systemic infection.
Wilhelms et al. (9) compared three strategies based on the ICD, Ninth and Tenth Revision (4,5,10), to estimate incidence of severe sepsis in Sweden between 1987 and 2005. Authors found three almost separate cohorts of patients, with an incidence of severe sepsis in 2005 ranging from 130 to 430/100,000 population, concluding that the ICD code abstraction strategies for recording severe sepsis provides an unsatisfactory way of estimating the true incidence of this entity. The incidence increased over the years in the three cohorts.
In general, studies describing epidemiology of sepsis outside the US use clinical definitions and ICU observational cohort designs instead of administrative databases and definitions. Finfer et al. (11) found an incidence of severe sepsis of 11.8% in a study performed in 23 ICUs in Australia and New Zealand. Results were similar in a French study that included 206 UCIs, with a reported incidence of 14.6% (12). In the SOAP study (13), that included 198 European ICUs, the average incidence of severe sepsis was 30%, with a wide range between countries. In a retrospective study performed in ICUs from the United Kingdom an incidence of 27.1% was reported during the first 24 h after ICU admission (14). Annane et al. (15) reported an increase in the incidence of septic shock from 7 to 9.7 cases per 100 admissions from 1993 to 2000.
Incidence of sepsis has clearly increased, probably due to progressive aging of population, provided that several studies have demonstrated a relationship between age and incidence of sepsis (4,5,16) and a larger number of people with disease comorbidities. Another possible contribution may be an increasing recognition and more frequent and liberal uses of sepsis codes after hospital discharge. In this way, one recent study compared the 2003 to 2012 trends in severe sepsis between administrative definitions and objective clinical markers, including positive blood cultures, vasopressors, and/or lactic acid levels (17), demonstrating a large increase (54–706%) in the rates of sepsis according to administrative definitions without a comparable increase in bacteremia, shock or lactic acidosis according to objective clinical data. Moreover, another study showed an 11% and a 49% increase in infection codes and sepsis codes, respectively, from 2003 and 2009 (18).
Sepsis mortality changes according to organ dysfunction. In patients without organ dysfunction mortality is less than 20% (5,19). In patients with severe sepsis varies between 20% and 50% (5,11,12,20,21) and in patients with septic shock is frequently over 50% (13,15). Variations in the definitions of severe sepsis can explain differences in mortality rates (1,22,23).
Different studies have demonstrated a decrease in mortality related to sepsis over years.
Compliance with Surviving Sepsis Campaign bundles may contribute to the decrease in mortality (27). With data from the Surviving Sepsis Campaign crude mortality rates were different between Europe and the US (41.1% vs. 28.3%). Nevertheless, when adjusted for disease severity, this difference disappeared (32.3% vs. 31.3%) (28), probably due to the effect of ICU bed availability.
In a recent retrospective study performed in 171 ICUs from Australia and New Zealand the authors demostrated a decrease in hospital mortality from 35% to 18.4% between 2000 and 2012 (20). This differences remained even after adjustments for disease severity.
Possible reasons for this decrease in mortality are improvements in diagnostic procedures, earlier and broader-spectrum antibiotic treatment, or more aggressive supportive therapy (27,29). In spite of the reduction in mortality, the absolute number of patients that die as a result of sepsis is increasing, on account of the raise in incidence (5). Concurrently to the decrease in mortality, average hospital stay of patients with sepsis has decreased over years. In the US, average stay was reduced in 5 days between 1979 to 2000 (5).
Factors associated to sepsis
No cohort studies investigating prehospital risk factors have been performed, so risk factors have been based on administrative data and on hospital longitudinal studies.
Risk of sepsis is increased in infants, is reduced in the rest of childhood and is increased again beyond 50–60 years of age (bimodal distribution) (4,30-32). In the study performed by Martin et al. (5) the mean age of patients with sepsis increased from 57.4 years in the period 1979–1984 to 60.8 years in the 1995–2000 period. The same author reported that patients 65 years and older constituted 12% of the population but nearly 65% of sepsis cases. A multivariate analysis that was adjusted for comorbid conditions found that patients with sepsis that were aged 65 years or more had a mortality 2.3 times higher (32). The aging of the population probably explains the increasing incidence of sepsis in industrialized countries.
Most of studies show a greater incidence of sepsis in male sex, ranging from 54% to 66% (10,11,13,14,21,25,26,30-32), what remains unexplained but may imply the effect of sexual hormones on immunity and on the cardiovascular response (33).
Probability of sepsis is 2-fold greater in the US black race (5,34,35) when compared with whites. Besides, sepsis has worse outcomes in this population (5,34). Possible reasons include different access to healthcare, immunizations, poverty, certain comorbid conditions and substance use disorders (35-37). However, these differences trend to persist after controlling many of these factors, suggesting the existence of genetic variables (36,38).
More than 50% of patients with severe sepsis present at least one comorbid illness (4,12,26). Likewise, comorbid illnesses independently increase mortality in this population (20). Diabetes mellitus, congestive heart failure, chronic pulmonary disease, immunosuppression, liver disease, cancer and chronic renal failure have been associated with sepsis (26,32,34,39,40). Alcohol consumption increases the risk of sepsis too (41).
The season is important in respiratory infections. Respiratory sepsis, but not other causes of sepsis, are more frequent in winter (42).
A study that included more than 1,000 people who had been adopted from de 1920s to the 1940s in Denmark showed and increased risk of death due to infection before the age of 50 if a biological parent died of an infectious cause (RR, 5.8; 95% CI: 2.4–13.7) (43).
Polymorphisms in toll-like receptor 4 (TLR4) and TLR1 seem to be associated with increased susceptibility to Gram-negative infections, bacteremia, candidemia and invasive aspergillosis (44-49). Recently, variants in SVEP1 (which encodes a cell adhesion molecule) and in FER gene (a cytosolic protein thought to be involved in leukocyte recruitment) have been implicated in increased 28-day mortality in sepsis and in increased survival in patients with pneumonia, respectively (50,51).
Source of infection
Respiratory tract infections are the most common source of sepsis. In most studies performed in ICU patients the rate of respiratory infection is over 50% (4,11,13,21,52). Respiratory infections are more frequent both in ICU patients and in patients outside the ICU (13,21). Abdominal infections are relatively more often in acquired infection outside the ICU.
Respiratory infection rates (as a cause for severe sepsis) seem to be increasing, whereas urinary source is decreasing in frequency (14).
In the Extended Prevalence of Infection in Intensive Care (EPIC II) study 70% of infected patients had positive microbiology (52).
From 1979 to 2000 in the US, Gram-positive bacterial infections rates increased an average of 26% per year, being the predominant class of organisms associated to severe sepsis since 1987 (5). In 2000, Gram-positive bacteria were implicated in 52% of cases, whereas Gram-negative and fungal organisms constituted 38% and 5% of cases, respectively. Fungal infections increased 207% during this period.
Incidence of sepsis in western countries seems to be increasing over years, whereas mortality associated is clearly decreasing. However absolute mortality is growing on account of the raise in incidence. The progressive aging of population and improvements in ICU care may partially explain these results, although liberal use of sepsis codification may play a role too, by recording more number of patients with sepsis and with less severity.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644-55. [Crossref] [PubMed]
- Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801-10. [Crossref] [PubMed]
- Centers for Disease Control (CDC). Increase in National Hospital Discharge Survey rates for septicemia--United States, 1979-1987. MMWR Morb Mortal Wkly Rep 1990;39:31-4. [PubMed]
- Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303-10. [Crossref] [PubMed]
- Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546-54. [Crossref] [PubMed]
- Dombrovskiy VY, Martin AA, Sunderram J, et al. Facing the challenge: decreasing case fatality rates in severe sepsis despite increasing hospitalizations. Crit Care Med 2005;33:2555-62. [Crossref] [PubMed]
- Melamed A, Sorvillo FJ. The burden of sepsis-associated mortality in the United States from 1999 to 2005: an analysis of multiple-cause-of-death data. Crit Care 2009;13:R28. [Crossref] [PubMed]
- Gaieski DF, Edwards JM, Kallan MJ, et al. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 2013;41:1167-74. [Crossref] [PubMed]
- Wilhelms SB, Huss FR, Granath G, et al. Assessment of incidence of severe sepsis in Sweden using different ways of abstracting International Classification of Diseases codes: difficulties with methods and interpretation of results. Crit Care Med 2010;38:1442-9. [Crossref] [PubMed]
- Flaatten H. Epidemiology of sepsis in Norway in 1999. Crit Care 2004;8:R180-4. [Crossref] [PubMed]
- Finfer S, Bellomo R, Lipman J, et al. Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units. Intensive Care Med 2004;30:589-96. [Crossref] [PubMed]
- Brun-Buisson C, Meshaka P, Pinton P, et al. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med 2004;30:580-8. [Crossref] [PubMed]
- Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006;34:344-53. [Crossref] [PubMed]
- Padkin A, Goldfrad C, Brady AR, et al. Epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Crit Care Med 2003;31:2332-8. [Crossref] [PubMed]
- Annane D, Aegerter P, Jars-Guincestre MC, et al. Current epidemiology of septic shock: the CUB-Réa Network. Am J Respir Crit Care Med 2003;168:165-72. [Crossref] [PubMed]
- Harrison DA, Welch CA, Eddleston JM. The epidemiology of severe sepsis in England, Wales and Northern Ireland, 1996 to 2004: secondary analysis of a high quality clinical database, the ICNARC Case Mix Programme Database. Crit Care 2006;10:R42. [Crossref] [PubMed]
- Rhee C, Murphy MV, Li L, et al. Comparison of trends in sepsis incidence and coding using administrative claims versus objective clinical data. Clin Infect Dis 2015;60:88-95. [Crossref] [PubMed]
- Walkey AJ, Wiener RS. Trends in infection source and mortality among patients with septic shock. Am J Respir Crit Care Med 2014;190:709-10. [Crossref] [PubMed]
- Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA 1995;273:117-23. [Crossref] [PubMed]
- Kaukonen KM, Bailey M, Suzuki S, et al. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA 2014;311:1308-16. [Crossref] [PubMed]
- Esteban A, Frutos-Vivar F, Ferguson ND, et al. Sepsis incidence and outcome: contrasting the intensive care unit with the hospital ward. Crit Care Med 2007;35:1284-9. [Crossref] [PubMed]
- Zhao H, Heard SO, Mullen MT, et al. An evaluation of the diagnostic accuracy of the 1991 American College of Chest Physicians/Society of Critical Care Medicine and the 2001 Society of Critical Care Medicine/European Society of Intensive Care Medicine/American College of Chest Physicians/American Thoracic Society/Surgical Infection Society sepsis definition. Crit Care Med 2012;40:1700-6. [Crossref] [PubMed]
- Vincent JL, Opal SM, Marshall JC, et al. Sepsis definitions: time for change. Lancet 2013;381:774-5. [Crossref] [PubMed]
- Zimmerman JE, Kramer AA, Knaus WA. Changes in hospital mortality for United States intensive care unit admissions from 1988 to 2012. Crit Care 2013;17:R81. [Crossref] [PubMed]
- Banta JE, Joshi KP, Beeson L, et al. Patient and hospital characteristics associated with inpatient severe sepsis mortality in California, 2005-2010. Crit Care Med 2012;40:2960-6. [Crossref] [PubMed]
- Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA 1995;274:968-74. [Crossref] [PubMed]
- Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med 2010;36:222-31. [Crossref] [PubMed]
- Levy MM, Artigas A, Phillips GS, et al. Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis 2012;12:919-24. [Crossref] [PubMed]
- Miller RR 3rd, Dong L, Nelson NC, et al. Multicenter implementation of a severe sepsis and septic shock treatment bundle. Am J Respir Crit Care Med 2013;188:77-82. [Crossref] [PubMed]
- Sundararajan V, Macisaac CM, Presneill JJ, et al. Epidemiology of sepsis in Victoria, Australia. Crit Care Med 2005;33:71-80. [Crossref] [PubMed]
- Dombrovskiy VY, Martin AA, Sunderram J, et al. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med 2007;35:1244-50. [Crossref] [PubMed]
- Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med 2006;34:15-21. [Crossref] [PubMed]
- Angele MK, Pratschke S, Hubbard WJ, et al. Gender differences in sepsis: cardiovascular and immunological aspects. Virulence 2014;5:12-9. [Crossref] [PubMed]
- Esper AM, Moss M, Lewis CA, et al. The role of infection and comorbidity: Factors that influence disparities in sepsis. Crit Care Med 2006;34:2576-82. [Crossref] [PubMed]
- Dombrovskiy VY, Martin AA, Sunderram J, et al. Occurrence and outcomes of sepsis: influence of race. Crit Care Med 2007;35:763-8. [Crossref] [PubMed]
- Mayr FB, Yende S, Linde-Zwirble WT, et al. Infection rate and acute organ dysfunction risk as explanations for racial differences in severe sepsis. JAMA 2010;303:2495-503. [Crossref] [PubMed]
- Barnato AE, Alexander SL, Linde-Zwirble WT, et al. Racial variation in the incidence, care, and outcomes of severe sepsis: analysis of population, patient, and hospital characteristics. Am J Respir Crit Care Med 2008;177:279-84. [Crossref] [PubMed]
- Ferwerda B, Alonso S, Banahan K, et al. Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock. Proc Natl Acad Sci U S A 2009;106:10272-7. [Crossref] [PubMed]
- Silva E, Pedro Mde A, Sogayar AC, et al. Brazilian Sepsis Epidemiological Study (BASES study). Crit Care 2004;8:R251-60. [Crossref] [PubMed]
- McBean M, Rajamani S. Increasing rates of hospitalization due to septicemia in the US elderly population, 1986-1997. J Infect Dis 2001;183:596-603. [Crossref] [PubMed]
- O'Brien JM Jr, Lu B, Ali NA, et al. Alcohol dependence is independently associated with sepsis, septic shock, and hospital mortality among adult intensive care unit patients. Crit Care Med 2007;35:345-50. [Crossref] [PubMed]
- Danai PA, Sinha S, Moss M, et al. Seasonal variation in the epidemiology of sepsis. Crit Care Med 2007;35:410-5. [Crossref] [PubMed]
- Sørensen TI, Nielsen GG, Andersen PK, et al. Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 1988;318:727-32. [Crossref] [PubMed]
- Agnese DM, Calvano JE, Hahm SJ, et al. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis 2002;186:1522-5. [Crossref] [PubMed]
- Lorenz E, Mira JP, Frees KL, et al. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 2002;162:1028-32. [Crossref] [PubMed]
- Van der Graaf CA, Netea MG, Morré SA, et al. Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw 2006;17:29-34. [PubMed]
- Plantinga TS, Johnson MD, Scott WK, et al. Toll-like receptor 1 polymorphisms increase susceptibility to candidemia. J Infect Dis 2012;205:934-43. [Crossref] [PubMed]
- Bochud PY, Chien JW, Marr KA, et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med 2008;359:1766-77. [Crossref] [PubMed]
- Henckaerts L, Nielsen KR, Steffensen R, et al. Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit. Crit Care Med 2009;37:192-201, e1-3.
- Nakada TA, Russell JA, Boyd JH, et al. Identification of a nonsynonymous polymorphism in the SVEP1 gene associated with altered clinical outcomes in septic shock. Crit Care Med 2015;43:101-8. [Crossref] [PubMed]
- Rautanen A, Mills TC, Gordon AC, et al. Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir Med 2015;3:53-60. [Crossref] [PubMed]
- Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009;302:2323-9. [Crossref] [PubMed]