Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis

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Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis

INTRODUCTION — Sepsis is a clinical syndrome that complicates severe infection. It is characterized by the cardinal signs of inflammation (vasodilation, leukocyte accumulation, increased microvascular permeability) occurring in tissues that are remote from the infection. Systemic inflammatory response syndrome (SIRS) is an identical clinical syndrome that complicates a noninfectious insult (eg, acute pancreatitis, pulmonary contusion). Current theories about the onset and progression of sepsis and SIRS focus on dysregulation of the inflammatory response, including the possibility that a massive and uncontrolled release of proinflammatory mediators initiates a chain of events that lead to widespread tissue injury. This response can lead to multiple organ dysfunction syndrome (MODS), which is the cause of the high mortality associated with these syndromes.

The definitions, epidemiology, risk factors, and outcomes of sepsis and SIRS are reviewed here. The pathophysiology and treatment of sepsis are discussed separately. (See "Pathophysiology of sepsis" and "Evaluation and management of severe sepsis and septic shock in adults".)

DEFINITIONS — Systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock were initially defined in 1991 by a consensus panel convened by the American College of Chest Physicians (ACCP) and Society of Critical Care Medicine (SCCM) [1]. These definitions were reconsidered in 2001 during an International Sepsis Definitions Conference that included representatives from the ACCP, SCCM, American Thoracic Society (ATS), European Society of Intensive Care Medicine (ESICM), and Surgical Infection Society (SIS), and again in 2012 by the SCCM and ESICM [2,3]. A practical modification of the definitions has been published, which provides exact hemodynamic definitions for sepsis and septic shock [4].

SIRS is a clinical syndrome that is a form of dysregulated inflammation. The term SIRS has routinely been associated with both infectious processes (sepsis) and noninfectious insults, such as an autoimmune disorder, pancreatitis, vasculitis, thromboembolism, burns, or surgery. SIRS was previously defined as two or more abnormalities in temperature, heart rate, respiration, or white blood cell count [2]. However, in practice, its clinical definition and pathophysiology are equivocal such that SIRS and early sepsis cannot be readily distinguished. Thus, when SIRS is suspected it should prompt an evaluation for a septic focus.

The definitions that we provide below are based upon these resources and represent a continuum of early infection through multiple organ dysfunction syndrome (MODS).

Infection — Infection is the invasion of normally sterile tissue by organisms.

Bacteremia — Bacteremia is the presence of viable bacteria in the blood.

Sepsis — Sepsis is the clinical syndrome that results from a dysregulated inflammatory response to an infection. Sepsis is defined as the presence (probable or documented) of infection together with systemic manifestations of infection. Diagnostic criteria for sepsis include infection (documented or suspected) and some of the following [2,3]:

●General variables
•Temperature >38.3 or <36ºC
•Heart rate >90 beats/min or more than two standard deviations above the normal value for age
•Tachypnea, respiratory rate >20 breaths/min
•Altered mental status
•Significant edema or positive fluid balance (>20 mL/kg over 24 hours)
•Hyperglycemia (plasma glucose >140 mg/dL or 7.7 mmol/L) in the absence of diabetes
●Inflammatory variables
•Leukocytosis (WBC count >12,000 microL–1) or leukopenia (WBC count <4000 microL–1)
•Normal WBC count with greater than 10 percent immature forms
•Plasma C-reactive protein more than two standard deviations above the normal value
•Plasma procalcitonin more than two standard deviations above the normal value
●Hemodynamic variables
•Arterial hypotension (systolic blood pressure SBP <90 mmHg, MAP <70 mmHg, or an SBP decrease >40 mmHg in adults or less than two standard deviations below normal for age)
●Organ dysfunction variables
•Arterial hypoxemia (arterial oxygen tension [PaO2]/fraction of inspired oxygen [FiO2] <300)
•Acute oliguria (urine output <0.5 mL/kg/hr for at least two hours despite adequate fluid resuscitation)
•Creatinine increase >0.5 mg/dL or 44.2 micromol/L
•Coagulation abnormalities (international normalized ratio [INR] >1.5 or activated partial thromboplastin time [aPTT] >60 seconds)
•Ileus (absent bowel sounds)
•Thrombocytopenia (platelet count <100,000 microL–1)
•Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70 micromol/L)
●Tissue perfusion variables
•Hyperlactatemia (>1 mmol/L)
•Decreased capillary refill or mottling
Severe sepsis — Severe sepsis refers to sepsis-induced tissue hypoperfusion or organ dysfunction with any of the following thought to be due to the infection [2,3]:

●Sepsis-induced hypotension
●Lactate above upper limits of laboratory normal
●Urine output <0.5 mL/kg/hr for more than two hours despite adequate fluid resuscitation
●Acute lung injury with PaO2/FIO2 <250 in the absence of pneumonia as infection source
●Acute lung injury with PaO2/FIO2 <200 in the presence of pneumonia as infection source
●Creatinine >2 mg/dL (176.8 micromol/L)
●Bilirubin >4 mg/dL (34.2 micromol/L)
●Platelet count <100,000 microL–1
●Coagulopathy (INR >1.5)
Sepsis-induced hypotension is defined as a systolic blood pressure (SBP) <90 mmHg or mean arterial pressure (MAP) <70 mmHg or a SBP decrease >40 mmHg or less than two standard deviations below normal for age in the absence of other causes of hypotension.

Sepsis-induced tissue hypoperfusion is defined as infection-induced hypotension, elevated lactate, or oliguria.

Septic shock — Septic shock is defined as sepsis-induced hypotension persisting despite adequate fluid resuscitation, which may be defined as infusion of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). Septic shock is a type of vasodilatory or distributive shock [2,3]. In other words, it results from a marked reduction in systemic vascular resistance, often associated with an increase in cardiac output. (See "Shock in adults: Types, presentation, and diagnostic approach".)

Multiple organ dysfunction syndrome — Multiple organ dysfunction syndrome (MODS) refers to progressive organ dysfunction in an acutely ill patient, such that homeostasis cannot be maintained without intervention. It is at the severe end of the severity of illness spectrum of both SIRS and sepsis. MODS can be classified as primary or secondary:

●Primary MODS is the result of a well-defined insult in which organ dysfunction occurs early and can be directly attributable to the insult itself (eg, renal failure due to rhabdomyolysis)
●Secondary MODS is organ failure that is not in direct response to the insult itself, but is a consequence of the host’s response (eg, acute respiratory distress syndrome in patients with pancreatitis)
There are no universally accepted criteria for individual organ dysfunction in MODS. However, progressive abnormalities of the following organ-specific parameters are commonly used to diagnose MODS and scoring systems are used to predict ICU mortality [5]:

●PaO2/FiO2 ratio
●Platelet count
●Serum bilirubin
●Serum creatinine (or urine output)
●Glasgow coma score
●Hypotension
RISK FACTORS — The population at risk of developing sepsis is large. At any given moment, approximately 50 percent of ICU patients have a nosocomial infection and, therefore, are at high risk for sepsis [6]. Other risk factors include the following [7-11]:

●Bacteremia – Patients with bacteremia often develop systemic consequences of infection. In a study of 270 blood cultures, 95 percent of positive blood cultures were associated with sepsis, severe sepsis, or septic shock [12].
●Advanced age (≥65 years) – The incidence of sepsis is disproportionately increased in older adult patients and age is an independent predictor of mortality due to sepsis. Moreover, older adult non-survivors tend to die earlier during hospitalization and older adult survivors more frequently require skilled nursing or rehabilitation after hospitalization [13].
●Immunosuppression – Comorbidities that depress host-defense (eg, neoplasms, renal failure, hepatic failure, AIDS, asplenism) and immunosuppressant medications are common among patients with sepsis, severe sepsis, or septic shock. (See "Clinical features and management of sepsis in the asplenic patient".)
●Diabetes and cancer – Diabetes and some cancers may alter the immune system, result in an elevated risk for developing sepsis, and increase the risk of nosocomial sepsis.
●Community acquired pneumonia – Severe sepsis and septic shock develop in approximately 48 and 5 percent, respectively, of patients with community-acquired pneumonia [14].
●Genetic factors – Both experimental and clinical studies have confirmed that genetic factors can increase the risk of infection. In few cases, monogenic defects underlie vulnerability to specific infection, but genetic factors are typically genetic polymorphisms. Genetic studies of susceptibility to infection have initially focused on defects of antibody production, or a lack of T cells, phagocytes, natural killer cells, or complement. Recently, genetic defects have been identified that impair recognition of pathogens by the innate immune system, increasing susceptibility to specific classes of microorganisms [15].
EPIDEMIOLOGY

Incidence — In the late 1970s, it was estimated that 164,000 cases of sepsis occurred in the United States (US) each year [16]. Since then, rates of sepsis in the US and elsewhere have dramatically increased as supported by the following studies [17-19]:

●One national database analysis of discharge records from hospitals in the United States estimated an annual rate of more than 1,665,000 cases of sepsis between 1979 and 2000 (figure 1) [17].
●Another retrospective population-based analysis reported increased rates of sepsis and septic shock from 13 to 78 cases per 100,000 between 1998 and 2009 [18].
The increased rate of sepsis is thought to be a consequence of advancing age, immunosuppression, and multidrug-resistant infection [19-23]. It is also likely to be due to the increased detection of early sepsis from aggressive sepsis education and awareness campaigns, although this hypothesis is unproven.

The incidence of sepsis varies among the different racial and ethnic groups, but appears to be highest among African-American males (figure 2) [16]. The incidence is also greatest during the winter, probably due to the increased prevalence of respiratory infections [24]. Older patients ≥65 years of age account for the majority (60 to 85 percent) of all episodes of severe sepsis which, with an increasing aging population, is likely to increase in the future [16,19,25,26].

Pathogens — The contribution of various infectious organisms to the burden of sepsis has changed over time [3,27-29]. Gram positive bacteria are most frequently identified in patients with sepsis in the United States, although the number of cases of Gram negative sepsis remains substantial. The incidence of fungal sepsis has increased over the past decade, but remains lower than bacterial sepsis [3,16].

Disease severity — The severity of disease appears to be increasing [30]. In one retrospective analysis, the proportion of patients with sepsis who also had at least one dysfunctional organ (ie, severe sepsis) increased from 26 to 44 percent over a ten-year period [31,32]. The most common manifestations of severe organ dysfunction were acute respiratory distress syndrome, acute renal failure, and disseminated intravascular coagulation [33].

MORTALITY AND PROGNOSIS — Sepsis has a high mortality rate. Estimates range from 10 to 52 percent [16,19,31,34-42]. Mortality rates increase stepwise according to the disease severity of sepsis. In one study, the mortality rates of SIRS, sepsis, severe sepsis, and septic shock were 7, 16, 20, and 46 percent, respectively [33]. Mortality appears to be lower in younger patients (<44 years) without comorbidities (<10 percent) [19].

Several studies have reported decreasing mortality rates over time [16,19,31,38,43,44]. As an example, a 12-year study of 101,064 patients with severe sepsis and septic shock from 171 ICUs in Australia and New Zealand reported a 50 percent risk reduction (from 35 to 18 percent) in in-hospital mortality from 2000 to 2012 [19]. This persisted after adjusting for multiple variables including underlying disease severity, comorbidities, age, and the rise in incidence of sepsis over time. This suggested that the reduction in mortality observed in this study was less likely due to the increased detection of early sepsis and possibly due to improved therapeutic strategies for sepsis. However, despite improved compliance with practice guidelines for the treatment of sepsis (also known as sepsis bundles) there is conflicting evidence as to whether sepsis bundles truly improve mortality [18,38,40,45-47].

Following discharge from the hospital, sepsis carries an increased risk of death as well as an increased risk of further sepsis and recurrent hospital admissions. Most deaths occur within the first six months but the risk remains elevated at one-year [48-52]. Patients who survive sepsis are more likely to be admitted to acute care and/or long term care facilities in the first year after the initial hospitalization, and also appear to have a persistent decrement in their quality of life [37,50-52].

PROGNOSTIC FACTORS — Clinical characteristics that impact the severity of sepsis and, therefore, the outcome include the host’s response to infection, the site and type of infection, and the timing and type of antimicrobial therapy.

Host response — Anomalies in the host's inflammatory response may indicate increased susceptibility to severe disease and mortality. As examples, consider the failure to develop a fever (or hypothermia) and leukopenia [53-55]. Failure to develop a fever (defined as a temperature below 35.5ºC) was more common among non-survivors of sepsis than survivors (17 versus 5 percent) in one study of 519 patients with sepsis [53]. Leukopenia (a white blood cell count less than 4000/mm3) was similarly more frequent among non-survivors than survivors (15 versus 7 percent) in study of 612 patients with Gram negative sepsis [55].

A patient’s comorbidities and functional health status are also important determinants of outcome in sepsis [53]. Risk factors for mortality include new-onset atrial fibrillation [56], an age above 40 years [25], and comorbidities such as AIDS [57], liver disease [58], cancer [59], alcohol dependence [58], and/or immune suppression [57,60]. Age is probably a risk factor for mortality because of its association with comorbid illnesses, impaired immunologic responses, malnutrition, increased exposure to potentially resistant pathogens in nursing homes, and increased utilization of medical devices, such as indwelling catheters and central venous lines [16,25,61].

Site of infection — The site of infection in patients with sepsis may be an important determinant of outcome, with sepsis from a urinary tract infection generally being associated with the lowest mortality rates [53,62]. One study found that mortality from sepsis was 50 to 55 percent when the source of infection was unknown, gastrointestinal, or pulmonary, compared to only 30 percent when the source of infection was the urinary tract [62]. Another retrospective, multicenter cohort study of nearly 8000 patients with septic shock reported similar results with the highest mortality in those with sepsis from ischemic bowel (78 percent) and the lowest rates in those with obstructive uropathy-associated urinary tract infection (26 percent) [42].

Approximately 50 percent of patients with severe sepsis are bacteremic at the time of diagnosis according to one study [63]. This is consistent with a study of 85,750 hospital admissions, which found that the incidence of positive blood cultures increased along a continuum, ranging from 17 percent of patients with sepsis to 69 percent with septic shock [64]. However, the presence or absence of a positive blood culture does not appear to influence the outcome, suggesting that prognosis is more closely related to the severity of sepsis than the severity of the underlying infection [64,65].

Type of infection — Sepsis due to nosocomial pathogens has a higher mortality than sepsis due to community-acquired pathogens [66,67]. Increased mortality is associated with bloodstream infections due to methicillin-resistant staphylococcus aureus (odds ratio 2.70, 95% CI 2.03-3.58), non-candidal fungus (odds ratio 2.66, 95% CI 1.27-5.58), candida (odds ratio 2.32 95% CI 1.21-4.45), methicillin-sensitive staphylococcus aureus (odds ratio 1.9, 95% CI 1.53-2.36), and pseudomonas (odds ratio 1.6, 95% CI 1.04-2.47), as well as polymicrobial infections (odds ratio 1.69, 95% CI 1.24-2.30) [66,68]. When bloodstream infections become severe (ie, severe sepsis or septic shock), the outcome is similar regardless of whether the pathogens are Gram-negative or Gram-positive bacteria [8,69].

Antimicrobial therapy — Studies have shown that appropriate antibiotic therapy (ie, antibiotics to which the pathogen is sensitive) has a beneficial impact on bacteremic sepsis [55,65]. In one report, for example, early institution of adequate antibiotic therapy was associated with a 50 percent reduction in the mortality rate compared to antibiotic therapy to which the infecting organisms were resistant [55]. In contrast, prior antibiotic therapy (ie, antibiotics within the past 90 days) may be associated with increased mortality, at least among patients with Gram negative sepsis [70]. This is probably because patients who have received prior antibiotic therapy are more likely to have higher rates of antibiotic resistance, making it less likely that appropriate antibiotic therapy will be chosen empirically.

Restoration of perfusion — Failure to aggressively try to restore perfusion early (ie, failure to initiate early goal-directed therapy) may also be associated with mortality [71]. This is discussed in detail separately. (See "Evaluation and management of severe sepsis and septic shock in adults", section on 'Interventions to restore perfusion'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient information: Sepsis in adults (The Basics)")
SUMMARY AND RECOMMENDATIONS

●Sepsis is the consequence of a dysregulated inflammatory response to an infectious insult. (See 'Introduction' above.)
●Sepsis exists on a continuum of severity: infection is the invasion of normally sterile tissue by organisms; bacteremia is the presence of viable bacteria in the blood; sepsis is defined as the presence (probable or documented) of infection together with systemic manifestations of infection; severe sepsis refers to sepsis plus sepsis-induced organ dysfunction; and septic shock is defined as sepsis-induced hypotension persisting despite adequate fluid resuscitation. (See 'Definitions' above.)
●Systemic inflammatory response syndrome (SIRS) is a syndrome that is the consequence of a dysregulated inflammatory response to an infectious or non-infectious insult. It can be due to and is often indistinguishable from early sepsis such that a source of sepsis should be sought when it is suspected. (See 'Definitions' above.)
●Multiple organ dysfunction syndrome refers to progressive deterioration of organ function in an acutely ill patient. It is the most severe end of the spectrum for both sepsis and SIRS. (See 'Multiple organ dysfunction syndrome' above.)
●Risk factors for sepsis include a nosocomial infection, bacteremia, advanced age, immunosuppression, and community-acquired pneumonia. Genetic defects have also been identified that may increase susceptibility to specific classes of microorganisms. (See 'Risk factors' above.)
●The incidence and severity of sepsis appear to be increasing, with Gram positive bacteria being the pathogens that are most commonly isolated from patients with sepsis. Mortality due to sepsis is high, but appears to have decreased. (See 'Epidemiology' above.)
●Poor prognostic factors include the inability to mount a fever, leukopenia, age >40 years, certain comorbidities (eg, AIDS, hepatic failure, cirrhosis, cancer, alcohol dependence, immunosuppression), a non-urinary source of infection, a nosocomial source of infection, and inappropriate antibiotic coverage. (See 'Prognostic factors' above.)