2016 UpToDate Sepsis Syndromes in Adults: Epidemiology, Definitions, Clinical Presentation, Diagnosis, And Prognosis - UpToDate

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Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis Author: Remi Neviere, MD Section Editor: Polly E Parsons, MD Deputy Editor: Geraldine Finlay, MD

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Sep 2016. | This topic last updated: Sep 19, 2016. INTRODUCTION — Sepsis is a clinical syndrome that has physiologic, biologic, and biochemical abnormalities caused by a dysregulated inflammatory response to infection. Sepsis and the inflammatory response that ensues can lead to multiple organ dysfunction syndrome and death. The epidemiology, definitions, risk factors, clinical presentation, diagnosis, and outcomes of sepsis are reviewed here. The pathophysiology and treatment of sepsis are discussed separately. (See "Pathophysiology of sepsis" and "Evaluation and management of suspected sepsis and septic shock in adults".) EPIDEMIOLOGY Incidence — In the late 1970s, it was estimated that 164,000 cases of sepsis occurred in the United States (US) each year [1]. Since then, rates of sepsis in the US and elsewhere have dramatically increased as supported by the following studies [2-5]: ● One national database analysis of discharge records from hospitals in the US estimated an annual rate of more than 1,665,000 cases of sepsis between 1979 and 2000 [2]. ● 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 [3]. ● A retrospective analysis of an international database reported a global incidence of 437 per 100,000 person-years for sepsis and 270 per 100,000 person-years for severe sepsis between the years 1995 and 2015, although this rate was not reflective of contributions from low- and middle-income countries [6]. The increased rate of sepsis is thought to be a consequence of advancing age, immunosuppression, and multidrug-resistant infection [4,7-10]. 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 1) [1]. The incidence is also greatest during the winter, probably due to the increased prevalence of

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respiratory infections [11]. Older patients ≥65 years of age account for the majority (60 to 85 percent) of all episodes of sepsis; with an increasing aging population, it is likely that the incidence of sepsis will continue to increase in the future [1,4,12,13]. Pathogens — The contribution of various infectious organisms to the burden of sepsis has changed over time [14-17]. 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 [1,14]. Disease severity — The severity of disease appears to be increasing [18]. In one retrospective analysis, the proportion of patients with sepsis who also had at least one dysfunctional organ increased from 26 to 44 percent between 1993 and 2003 [19,20]. The most common manifestations of severe organ dysfunction were acute respiratory distress syndrome, acute renal failure, and disseminated intravascular coagulation [21]. However, it is unclear as to whether the rising incidence of severe sepsis and septic shock reflects the overall increased incidence of sepsis or altered definitions of sepsis over time. DEFINITIONS — Sepsis exists on a continuum of severity ranging from infection and bacteremia to sepsis and septic shock, which can lead to multiple organ dysfunction syndrome (MODS) and death. The definitions of sepsis and septic shock have rapidly evolved since the early 1990s [14,22-27]. The systemic inflammatory response syndrome (SIRS) is no longer included in the definition since it is not always caused by infection. The definitions for sepsis that we provide below reflect expert opinion from task forces generated by national societies including the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Importantly, such definitions are not diagnostic of sepsis since they do not comprehensively include specific criteria for the identification of infection. (See 'Diagnosis' below.) Early sepsis — Infection and bacteremia may be early forms of infection that can progress to sepsis. However, there is no formal definition of early sepsis. Nonetheless, despite the lack of definition, monitoring those suspected of having sepsis is critical for its prevention. Infection and bacteremia — All patients with infection or bacteremia are at risk of developing sepsis and represent early phases in the continuum of sepsis severity: ● Infection is defined as the invasion of normally sterile tissue by organisms resulting in infectious pathology. ● Bacteremia is the presence of viable bacteria in the blood. Identification of early sepsis — Societal guidelines place emphasis on the early identification of infected patients who may go on to develop sepsis as a way to decrease sepsis-associated mortality. The 2016 SCCM/ESICM task force have described an assessment score for patients outside the intensive care unit as a way to facilitate the identification of patients potentially at risk of dying from sepsis [25-27]. This score is a modified version of the Sequential (Sepsis-related) Organ Failure Assessment score (SOFA) called the quickSOFA (qSOFA). The qSOFA only has three components that are each allocated one point: respiratory rate ≥22/minute, altered mentation, and systolic blood pressure ≤100 mmHg. A score ≥2 is associated with poor outcomes

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due to sepsis. However, the ability of qSOFA to predict death from sepsis requires prospective evaluation before it can be routinely used for this purpose. Importantly, this qSOFA score is different from the full SOFA score which is part of the 2016 SCCM/ESICM definition of sepsis, the details of which are described separately. (See "Predictive scoring systems in the intensive care unit", section on 'Sequential (sepsis-related) Organ Failure Assessment (SOFA)' and 'Sepsis' below.) Sepsis — A 2016 SCCM/EISCM task force has defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection: ● Organ dysfunction – Organ dysfunction is defined by the 2016 SCCM/ESICM task force as an increase of two or more points in the SOFA score. The validity of this score was derived from critically-ill patients with suspected sepsis by interrogating over a million intensive care unit (ICU) electronic health record encounters from ICUs both inside and outside the United States [25-27]. ICU patients were suspected as having infection if body fluids were cultured and they received antibiotics. Predictive scores (SOFA, systemic inflammatory response syndrome [SIRS], and logistic Organ Dysfunction System [LODS]) were compared for their ability to predict mortality. Among critically ill patients with suspected sepsis, the predictive validity of the SOFA score for in-hospital mortality was superior to that for the SIRS criteria (area under the receiver operating characteristic curve 0.74 versus 0.64). Patients who fulfill these criteria have a predicted mortality of ≥10 percent. Although the predictive capacity of SOFA and LODS were similar, SOFA is considered easier to calculate, and was therefore recommended by the task force. Importantly, the SOFA score is an organ dysfunction score. It is not diagnostic of sepsis nor does it identify those whose organ dysfunction is truly due to infection but rather helps identify patients who potentially have a high risk of dying from infection. In addition, it does not determine individual treatment strategies nor does it predict mortality based upon demographics (eg, age) or underlying condition (eg, stem cell transplant recipient versus postoperative patient). SOFA and other predictive scores are discussed separately. (See "Predictive scoring systems in the intensive care unit", section on 'Sequential (sepsis-related) Organ Failure Assessment (SOFA)'.) ● Infection – There are no clear guidelines to help the clinician identify the presence of infection or to causally link an identified organism with sepsis. In our experience, for this component of the diagnosis, the clinician is reliant upon clinical suspicion derived from the signs and symptoms of infection as well as supporting radiologic and microbiologic data and response to therapy. (See 'Clinical presentation' below and 'Diagnosis' below.) The term severe sepsis, which originally referred to sepsis that was associated with tissue hypoperfusion (eg, elevated lactate, oliguria) or organ dysfunction (eg, elevated creatinine, coagulopathy) [14,23], is no longer used since the 2016 sepsis and septic shock definitions include patients with evidence of tissue hypoperfusion and organ dysfunction. Septic shock — Septic shock is a type of vasodilatory or distributive shock. Septic shock is defined as sepsis that has circulatory, cellular, and metabolic abnormalities that are associated with a greater risk of mortality than sepsis alone [25]. Clinically, this includes patients who fulfill the criteria for sepsis (see 'Sepsis' above) who, despite adequate fluid resuscitation, require vasopressors to maintain a mean arterial pressure (MAP) ≥65 mmHg and have a lactate >2

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mmol/L (>18 mg/dL). Per predictions from the SOFA score, patients who fulfill these criteria for septic shock have a higher mortality than those who do not (≥40 versus ≥10 percent). (See "Predictive scoring systems in the intensive care unit", section on 'Sequential (sepsis-related) Organ Failure Assessment (SOFA)'.) Others — Multiple organ dysfunction syndrome (MODS) and systemic inflammatory response syndrome (SIRS) are terms frequently used in practice that need to be distinguished from sepsis. 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 infectious (sepsis, septic shock) and noninfectious conditions (eg, SIRS from pancreatitis). 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 are also used in scoring systems (eg, SOFA or LODS) to predict ICU mortality [28-30] (see "Predictive scoring systems in the intensive care unit"): ● Respiratory – Partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio ● Hematology – Platelet count ● Liver – Serum bilirubin ● Renal – Serum creatinine (or urine output) ● Brain – Glasgow coma score ● Cardiovascular – Hypotension and vasopressor requirement In general, the greater the number of organ failures, the higher the mortality, with the greatest risk being associated with respiratory failure requiring mechanical ventilation. (See "Acute respiratory distress syndrome: Prognosis and outcomes in adults".) Systemic inflammatory response syndrome — The use of systemic inflammatory response syndrome (SIRS) criteria to identify those with sepsis has fallen out of favor since it is considered by many experts that SIRS criteria are present in many hospitalized patients who do not develop infection, and their ability to predict death is poor when compared with other scores such as the SOFA score [27,31,32]. SIRS is considered a clinical syndrome that is a form of dysregulated inflammation. It was previously defined as two or more abnormalities in temperature, heart rate, respiration, or white blood cell count [23]. SIRS may occur in several conditions related, or not, to infection. Noninfectious conditions classically associated with SIRS include autoimmune disorders, pancreatitis, vasculitis, thromboembolism, burns, or surgery. RISK FACTORS — The importance of identifying risk factors for sepsis was highlighted in one

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epidemiologic study that reported that risk factors for septic shock were the fifth leading cause of years of productive life lost due to premature mortality [33]. Risk factors for sepsis include the following [34-43]: ● Intensive care unit admission – Approximately 50 percent of intensive care unit (ICU) patients have a nosocomial infection and are, therefore, intrinsically at high risk for sepsis [44]. ● 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 [39]. ● 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 [40]. ● 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 hospitalized with communityacquired pneumonia [41]. ● Previous hospitalization – Hospitalization is thought to induce an altered human microbiome, particularly in patients who are treated with antibiotics. Previous hospitalization has been associated with a three-fold increased risk of developing severe sepsis in the subsequent 90 days [42]. Patients with hospitalizations for infection-related conditions, especially Clostridium difficile infection, are at greatest risk. ● 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 [43]. CLINICAL PRESENTATION — Patients with suspected or documented sepsis typically present with hypotension, tachycardia, fever, and leukocytosis. As severity worsens, signs of shock (eg, cool skin and cyanosis) and organ dysfunction develop (eg, oliguria, acute kidney injury, altered mental status) [14,23]. Importantly, the presentation is nonspecific such that many other conditions (eg, pancreatitis, acute respiratory distress syndrome) may present similarly. Detailed discussion of the clinical features of shock are discussed separately. (See "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock", section on 'Clinical

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manifestations'.) Symptoms and signs — The symptoms and signs of sepsis are nonspecific but may include the following: ● Symptoms and signs specific to an infectious source (eg, cough dyspnea may suggest pneumonia, pain and purulent exudate in a surgical wound may suggest an underlying abscess) ● Arterial hypotension (eg, systolic blood pressure [SBP] 38.3 or 90 beats/min or more than two standard deviations above the normal value for age ● Tachypnea, respiratory rate >20 breaths/min ● Altered mental status ● Ileus (absent bowel sounds; often an end-stage sign of hypoperfusion) ● Decreased capillary refill, cyanosis, or mottling (may indicate shock) Laboratory signs — Similarly, laboratory features are nonspecific and may be associated with abnormalities due to the underlying cause of sepsis or to tissue hypoperfusion or organ dysfunction from sepsis. They include the following: ● Leukocytosis (white blood cell [WBC] count >12,000 microL–1) or leukopenia (WBC count 140 mg/dL or 7.7 mmol/L) in the absence of diabetes ● Plasma C-reactive protein more than two standard deviations above the normal value ● Plasma procalcitonin more than two standard deviations above the normal value (not routinely performed in many centers) ● Arterial hypoxemia (arterial oxygen tension [PaO2]/fraction of inspired oxygen [FiO2] 1.5 or activated partial thromboplastin time [aPTT] >60 seconds) ● Thrombocytopenia (platelet count 4 mg/dL or 70 micromol/L) ● Hyperlactatemia (higher than the laboratory upper limit of normal) ● Adrenal insufficiency (eg, hyponatremia, hyperkalemia), and the euthyroid sick syndrome can also be found in sepsis Imaging — There are no radiologic signs that are specific to the identification of sepsis other than those associated with infection in a specific site (eg, pneumonia on chest radiography, fluid collection on computed tomography of the abdomen). Microbiology — The identification of an organism in culture in a patient who fulfills the definition of sepsis (see 'Sepsis' above) is highly supportive of the diagnosis of sepsis but is not necessary. The rationale behind its lack of inclusion in the diagnostic criteria for sepsis is that a culprit organism is frequently not identified in up to 50 percent of patients who present with sepsis nor is a positive culture required to make a decision regarding treatment with empiric antibiotics [45]. DIAGNOSIS — A limitation of the definitions above (see 'Definitions' above) is that they cannot identify patients whose organ dysfunction is truly secondary to an underlying infection. Thus, a constellation of clinical, laboratory, radiologic, physiologic, and microbiologic data is typically required for the diagnosis of sepsis and septic shock. The diagnosis is often made empirically at the bedside upon presentation, or retrospectively when followup data returns (eg, positive blood cultures in a patient with endocarditis) or a response to antibiotics is evident. Importantly, the identification of a culprit organism, although preferred, is not always feasible since in many patients no organism is ever identified. In some patients this may be because they have been partially treated with antibiotics before cultures are obtained. Although septic shock has a specific hemodynamic profile on pulmonary artery catheterization (PAC) (table 1), PACs are difficult to interpret and rarely placed in patients with suspected sepsis. (See "Pulmonary artery catheterization: Interpretation of hemodynamic values and waveforms in adults" and "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock", section on 'Pulmonary artery catheterization'.) The evaluation and diagnosis of shock is discussed separately. (See "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock".) PROGNOSIS In-hospital morbidity and mortality — Sepsis has a high mortality rate. Rates depend upon how the data are collected but estimates range from 10 to 52 percent [1,4,19,31,46-55]. Data derived from death certificates report that sepsis is responsible for 6 percent of all deaths while administrative claims data suggest higher rates [55]. Mortality rates increase linearly according to the disease severity of sepsis [31]. In one study, the mortality rates of SIRS, sepsis, severe sepsis, and septic shock were 7, 16, 20, and 46 percent, respectively [21]. In another study, the mortality associated with sepsis was ≥10 percent while that associated with septic shock was ≥40 percent [25]. Mortality appears to be lower in younger patients (2 mmol/L (>18 mg/dL). ● Risk factors for sepsis include intensive care unit (ICU) admission, a nosocomial infection, bacteremia, advanced age, immunosuppression, previous hospitalization (in particular hospitalization associated with infection), and community-acquired pneumonia. Genetic defects have also been identified that may increase susceptibility to specific classes of microorganisms. (See 'Risk factors' above.) ● Patients with suspected or documented sepsis typically present with hypotension, tachycardia, fever, and leukocytosis. As severity worsens, signs of shock (eg, cool skin and cyanosis) and organ dysfunction develop (eg, oliguria, acute kidney injury, altered mental status) [14,23]. Importantly, the presentation is nonspecific such that many other conditions (eg, pancreatitis, acute respiratory distress syndrome) may present similarly. (See 'Clinical presentation' above.) ● A constellation of clinical, laboratory, radiologic, physiologic, and microbiologic data is typically required for the diagnosis of sepsis and septic shock. The diagnosis is often made empirically at the bedside upon presentation, or retrospectively when follow-up data return or a response to antibiotics is evident. Importantly, the identification of a culprit organism, although preferred, is not always feasible since many patients have been partially treated with antibiotics before cultures are obtained. (See 'Diagnosis' above.) ● Sepsis has a high mortality rate that appears to be decreasing. Estimates range from 10 to 52 percent with rates increasing linearly according to the disease severity of sepsis. 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. 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 or late antibiotic coverage. (See 'Prognosis' above.) Use of UpToDate is subject to the Subscription and License Agreement.

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GRAPHICS Population-adjusted incidence of sepsis, according to race, 1979 - 2000

Points represent the annual incidence rate, and I bars the standard error. Data from: Martin, GS, Mannino, DM, Eaton, S, Moss, M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl Med 2003; 348:1546. Graphic 64115 Version 1.0

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Hemodynamic profiles of shock on pulmonary artery catheter in adults Physiologic variable

Preload

Pump function

Pulmonary capillary wedge pressure

Cardiac output*

Hypovolemic

↔ (early) or ↓ (late)

Cardiogenic

↑

Distributive

Clinical measurement

Afterload

Tissue perfusion

Systemic vascular resistance

Mixed venous oxyhemoglobin saturation ¶

↔ (early) or ↓ (late)

↑

>65% (early) or 65%

↑

↓

↑