ReviewReview

Virulence 5:1, 4–11; January 1, 2014; © 2014 Landes Bioscience

Epidemiology of severe sepsis

Florian B Mayr1,2,3, Sachin Yende1,2,*, and Derek C Angus1,2
1
The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center; University of Pittsburgh; Pittsburgh, PA USA;
2
Department of Critical Care Medicine; University of Pittsburgh, Pittsburgh, PA USA; 3Department of Medicine; University of Pittsburgh; Pittsburgh, PA USA

Keywords: severe sepsis, epidemiology, risk factors, infection, organ dysfunction

Severe sepsis is a leading cause of death in the United often occurs in the setting of infection, noninfectious conditions,
States and the most common cause of death among critically ill such as burns, acute pancreatitis, and trauma, can lead to SIRS.
patients in non-coronary intensive care units (ICU). Respiratory Sepsis was defined as the presence of the SIRS criteria and pre-
tract infections, particularly pneumonia, are the most common sumed or proven infection. Severe sepsis was defined as sepsis
site of infection, and associated with the highest mortality. The accompanied by acute organ dysfunction.
type of organism causing severe sepsis is an important deter- Although the 1991 Consensus Conference laid the frame-
minant of outcome, and gram-positive organisms as a cause work to define sepsis, it had important limitations. The “2 out
of sepsis have increased in frequency over time and are now of 4” criteria for SIRS were arbitrary and not specific to sepsis
more common than gram-negative infections. alone. The criteria did not include biochemical markers, such as
Recent studies suggest that acute infections worsen pre-
C-reactive protein, procalcitionin (PCT), or interleukin (IL)-6,
existing chronic diseases or result in new chronic diseases,
which are often elevated in sepsis.
leading to poor long-term outcomes in acute illness survivors.
People of older age, male gender, black race, and preexisting A 2001 Consensus Conference by the Society of Critical
chronic health conditions are particularly prone to develop Care Medicine/European Society of Intensive Care Medicine/
severe sepsis; hence prevention strategies should be targeted American College of Chest Physicians/American Thoracic
at these vulnerable populations in future studies. Society/Surgical Infection Society was convened to modify
these definitions.4 The criteria for sepsis were revised to include
infection and presence of any of the diagnostic criteria shown
in Table 2. These criteria were based on clinical and laboratory
Sepsis and severe sepsis (sepsis accompanied by acute organ parameters. The conference participants acknowledged that there
dysfunction) are leading causes of death in the United States and was no single parameter or a set of clinical or laboratory param-
the most common cause of death among critically ill patients in eters that are adequately sensitive or specific to diagnose sepsis.
non-coronary intensive care units (ICU).1 Recent data suggest Severe sepsis criteria remained unchanged and it was defined as
the annual cost of hospital care for patients with septicemia is sepsis with an organ dysfunction. Although there are several cri-
$14 billion in United States.2 Therefore, sepsis and severe sepsis teria to define organ dysfunction during sepsis, the use of the
are important public health problems. This article focuses on the Sepsis-related Organ Failure (SOFA) score by Vincent and col-
epidemiology of severe sepsis and discusses common etiologies, leagues5 was recommended to define organ dysfunction during
risk factors, and long-term outcomes. The information provided sepsis. A more explicit definition for septic shock was also pro-
is focused primarily on developed countries, and the epidemi- posed. Septic shock was defined as persistent hypotension with
ology of severe sepsis in resource-limited countries may differ systolic blood pressure <90 mmHg or mean arterial blood pres-
substantially. sure <70 mmHg, despite adequate fluid resuscitation.
Epidemiological studies of administrative data sets often
Definitions rely on imprecise definitions such as ICD-9CM codes for “sep-
ticemia” and “bacteremia” along with separate codes for organ
In 1991, the American College of Chest Physicians and Society dysfunction,6 which may underreport the diagnosis of sepsis.7
of Critical Care Medicine Consensus Conference proposed a Diagnosis of severe sepsis can be made more sensitive by com-
broad framework to define systemic inflammatory response syn- bining codes for various infections (e.g., pneumonia) and acute
drome (SIRS), sepsis, and severe sepsis (Table 1).3 This syndrome organ system dysfunctions.1
was envisioned as a continuum of worsening inflammation, start-
ing with SIRS, and evolving from sepsis to severe sepsis and septic Epidemiology
shock. The criteria for SIRS were based on temperature, heart
rate, respiratory rate, and white blood cell count. At least 2 of Incidence and mortality
these 4 criteria had to be met to define SIRS. Although SIRS In the United States, the incidence of severe sepsis is estimated
to be 300 cases per 100 000 population.1 Approximately half
*Correspondence to: Sachin Yende; Email: yendes@upmc.edu of these cases occur outside the ICU. A fourth of patients who
Submitted: 08/06/2013; Revised: 11/21/2013; Accepted: 11/27/2013 develop severe sepsis will die during their hospitalization. Septic
http://dx.doi.org/10.4161/viru.27372
shock is associated with the highest mortality, approaching 50%.

4 Virulence Volume 5 Issue 1

Table 1. Criteria for SIRS, sepsis, severe sepsis, and septic shock based on Table 2. Criteria for sepsis based on 2001 SCCM/ACCP/ATS/ESCIM/SIS
the 1991 ACCP/SCCM Consensus Conference Consensus Conference
Term Criteria Term Criteria
2 out of the 4 following criteria: Documented (or suspected) infection with any one of
Sepsis
the following clinical or laboratory criteria
Temperature >38 °C or <36 °C
Fever, hypothermia, tachycardia, tachypnea, altered
Heart rate >90/min
General mental status, arterial hypotension, decreased urine
SIRS*
Hyperventilation evidenced by respiratory rate >20/min or parameters output, significant peripheral edema, or positive fluid
arterial CO2 lower than 32 mmHg balance
White blood cell count >12 000 cells/μL or lower than Leukocytosis, leukopenia, hyperglycemia, increased
4000 cells/μL Inflammatory C-reactive protein, procalcitonin, or creatinine,
parameters coagulation abnormalities, increased cardiac output,
Sepsis SIRS criteria with presumed or proven infection
reduced mixed venous oxygen saturation
Severe
Sepsis with organ dysfunction Hemodynamic Hypotension, elevated mixed venous oxygen
sepsis
parameters saturation, elevated cardiac index
Septic Sepsis with hypotension despite adequate fluid
Arterial hypoxemia, acute oliguria, increase in
shock resuscitation Organ
creatinine level, elevated international normalized
dysfunction
Note: *SIRS, systemic inflammatory response syndrome. ratio or activated partial thromboplastin time, ileus,
parameters
thrombocytopenia, hyperbilirubinemia
The cumulative burden of organ failure is the strongest predictor Tissue
Hyperlactatemia, decreased capillary refill,
of death, both in terms of the number of organs failing and the perfusion
or mottling
degree of organ dysfunction. parameters
In 2003, Martin and colleagues found an increase in septi-
cemia incidence and septicemia-related deaths over the past treated in an ICU. A discussion of the epidemiology of sepsis is
2 decades in United States.6,8 This trend is expected to continue therefore really one of “treated sepsis”.18 The threshold of eligibil-
due to aging of the population, increasing burden of chronic ity for treatment almost certainly differs by time and country,
health conditions, and increased use of immunosuppressive with different cultural approaches to end-of-life care, different
therapy, transplantation, chemotherapy, and invasive procedures. availability of acute hospital and ICU beds, varying levels of
National estimates of severe sepsis incidence are often based on universal health insurance, and other cultural and economic fac-
use of administrative data sets. Changes in coding practices, par- tors.19 For example, in Spain in 2003 only 32% of patients with
ticularly increased coding of organ dysfunction, may overesti- severe sepsis were admitted to the ICU20 compared with 51.1% in
mate the rate of increase.9 the United States.1 Furthermore, an unrepresentative sample of
Over the past 2 decades, the case-fatality has declined due to ICUs may bias the result. Most countries have only quantified the
advances in supportive care for the critically ill.10 For example, epidemiology of sepsis in their intensive care populations and the
since implementation of bundled care processes (e.g., Surviving estimates would be influenced by the availability of ICU beds in
Sepsis Campaign) and low tidal volume ventilation in patients each country. It has been postulated that the high ICU incidence
with acute respiratory distress syndrome (ARDS), mortality of sepsis in countries such as the UK (27.1%) and Brazil (27.3%)
among critically ill patients with severe sepsis has decreased over reflects a scarcity of ICU beds, as only the sickest patients can be
the past decade.11-15 admitted.18 There are 8.6 ICU beds per 100 000 population in
Point prevalence studies in the ICU are the simplest approach the UK compared with 38.4 and 30.5 per 100 000 in France and
to describing the epidemiology of sepsis. For example, 32.8% of the United States,21 where the mean ICU frequency of sepsis is
895 patients in 254 Mexican ICUs had sepsis on a single day 12.4% and 12.6%, respectively.
in 1995.16 Extrapolation of such data to population estimates Some of these problems are overcome using administrative
assumes all patients with sepsis will be in an ICU. Even in the databases that record data from an entire population or correctly
most advanced health care systems this is unlikely to be the weighted samples thereof. Such an approach relies on accurate
case.1 Prevalence studies have other limitations. For example, the coding of disease by personnel entering data for another purpose,
prevalence may increase if illness duration increases with better usually reimbursement. Problems of case definition are particu-
survival, even if incidence falls. Data from point prevalence stud- larly important when using administrative databases. For exam-
ies have been used to estimate population incidence,17 but with- ple, Gaieski et al. demonstrated an up to 3.5-fold difference in
out information on illness duration, these figures are difficult to the incidence and mortality of severe sepsis depending on the
interpret. method of database abstraction used.22
Prospective cohort studies in which incidence is directly
observed are potentially more accurate. A cohort study of suffi- Etiology and Site of Infection
cient duration may also overcome problems of seasonal variation.
However, cohort studies limited to ICU patients may underesti- Etiology
mate the incidence. Extrapolating ICU incidence to population Gram-positive organisms as a cause of sepsis have increased
incidence remains flawed because not all patients with sepsis are in frequency over time and are now almost as common as

www.landesbioscience.com Virulence 5
Table 3. Types of organisms in culture-positive infected patients and asso- Table 4. Common sites of infection in patients with severe sepsis by sex
ciated risk of hospital mortality (modified from reference 32) and associated crude mortality rates (based on Mayr et al.)37
Frequency (%) OR (95% CI) Frequency (%) Mortality (%)
Site of infection
Gram-positive 46.8 Male Female Male Female
Staphylococcus aureus 20.5 0.8 (0.6–1.1) Respiratory 41.8 35.8 22.0 22.0
MRSA 10.2 1.3 (0.9–1.8) Bacteremia, site
21.0 20.0 33.5 34.9
unspecified
Enterococcus 10.9 1.6 (1.1–2.3)
Genitourinary 10.3 18.0 8.6 7.8
S. epidermidis 10.8 0.9 (0.7–1.1)
Abdominal 8.6 8.1 9.8 10.6
S. pneumoniae 4.1 0.8 (0.5–1.4)
Device-related 1.2 1.0 9.5 9.5
Other 6.4 0.9 (0.7–1.2)
Wound/soft tissue 9.0 7.5 9.4 11.7
Gram-negative 62.2
Central nervous system 0.7 0.5 17.3 17.5
Pseudomonas species 19.9 1.4 (1.2–1.6)
Endocarditis 0.9 0.5 23.8 28.1
Escherichia coli 16.0 0.9 (0.7–1.1)
Other/unspecified 6.7 8.6 7.6 6.5
Klebsiella species 12.7 1.0 (0.8–1.2)
Acinetobacter species 8.8 1.5 (1.2–2.0)
North America vs. 19.2% in Asia). The only organisms associ-
Enterobacter 7.0 1.2 (0.9–1.6) ated with hospital mortality in multivariable logistic regression
Other 17.0 0.9 (0.7–1.3) analysis were Enterococcus, Pseudomonas, and Acinetobacter spe-
Anaerobes 4.5 0.9 (0.7–1.3) cies.32 The microbiologic results of the EPIC II are summarized
in Table 3.
Other bacteria 1.5 1.1 (0.6–2.0)
A large metaanalysis of 510 studies reported that gram-nega-
Fungi tive bacteremia was associated with a higher mortality compared
Candida 17.0 1.1 (0.9–1.3) with gram-positive bactermia.33 The most common bloodstream
Aspergillus 1.4 1.7 (1.0–3.1) infections were due to coagulase-negative Staphylococcus and
E. coli, but these were associated with a relatively low mortality
Other 1.0 1.9 (1.0–3.8)
(20% and 19%, respectively) compared with Candida (43%) and
Parasites 0.7 1.3 (0.5–3.3) Acinetobacter (40%) species. Gram-positive pneumonia due to
Other organisms 3.9 0.9 (0.6–1.3) Staphylococcus aureus had a higher mortality (41%) than that due
OR, odds ratio; CI, confidence interval; MRSA, methicillin-resistant S. aureus
to the most common gram-positive (Streptococcus pneumoniae,
13%), but the gram-negative bacillus Pseudomonas aeruginosa,
gram-negative infections,6,23-25 likely due to greater use of invasive had the highest mortality of all (77%). This study demonstrated
procedures and the increasing proportion of hospital-acquired the interaction of organism and site of infection in determining
infection.26 More frequent use of broad-spectrum antibiotics in mortality, and called for this to be incorporated into the risk
increasingly sick patients who remain in the ICU for longer peri- stratification of clinical trials. However, approximately a third
ods of time has likely resulted in an increased bacterial resistance of patients with severe sepsis never have positive blood cultures.34
over time.27,28 Antibiotic resistance is problematic, prolonging Before ascribing causative risk to a particular organism, it is also
length of stay and duration of mechanical ventilation, although necessary to take into account the confounding effect of the con-
the effect on mortality is uncertain.29-31 International variations text in which the organism most commonly develops. For exam-
in the implementation of the two main strategies to control resis- ple, the association of Acinetobacter with high mortality probably
tance (the more rational use of antibiotics and the prevention of reflects the tendency of Acinetobacter to develop as a nosocomial
cross-infection between patients) may explain different rates in infection after a prolonged ICU course in patients with many co-
different countries.28 morbidities. These factors, rather than the organism’s virulence,
The type of organism causing severe sepsis is an important may explain the high associated mortality.
determinant of outcome. Although most recent studies have Site of infection
suggested an increasing incidence of gram-positive organisms, Respiratory tract infections, particularly pneumonia, are the
the latest European Prevalence of Infection in Intensive Care most common site of infection, and associated with the high-
(EPIC II) study reported more gram-negative organisms (62.2% est mortality.35 However, the relative importance of pneumonia
vs. 46.8%).32 Patterns of infecting organisms were similar to has decreased over time.26 Men and alcoholics are particularly
those in previous studies, with predominant organisms being prone to developing pneumonia,36 while genitourinary infections
Staphylococcus aureus (20.5%), Pseudomonas species (19.9%), are more common among women.1,35 Other common sources of
Enterobacteriacae (mainly E. coli, 16.0%), and fungi (19%). infection include abdominal, skin, and soft tissue, device-related,
Acinetobacter was involved in 9% of all infections, with signifi- central nervous system, and endocarditis.1,37 Common sites of
cant variation of infection rates across different regions (3.7% in infection in severe sepsis patients are summarized in Table 4.

6 Virulence Volume 5 Issue 1

 Risk Factors in technology using genome-wide scans, where up to 1 million
polymorphisms can be assayed in a single individual will allow
Risk factors for severe sepsis can broadly be divided into risk identification of novel genetic variants.
factors for infection and, contingent upon developing infection, Environmental risk factors
risk factors for organ dysfunction. Most of the risk factors of Severe sepsis is more common in colder months, both in
severe sepsis described in this paragraph relate to the infection the UK (35% higher in winter than in summer) 44 and US
risk, as risk factors that predispose someone with an infection to (17.7% higher in fall than in summer).45 The case fatality rate
developing acute organ dysfunction are less well understood.37 for sepsis is also higher in winter, despite similar severity of ill-
For example, age, male gender, black race, and increased ness. Respiratory infections have the greatest seasonal change,
burden of chronic health conditions are important risk factors with their highest incidence in colder months, whereas genito-
for severe sepsis. Moreover, a recent study reported an inverse urinary infections are significantly more frequent in summer.
relationship between socioeconomic status and the risk of blood This seasonal variation relates to climate and is reflected by
stream infection.38 The incidence of severe sepsis increases dis- the regional differences within the US: incidence variation is
proportionately in older adults, and more than half of severe sep- highest in the northeast and lowest in the south. Recent studies
sis cases occur in adults over 65 y of age.37 More than half of have also explored the relationship of light exposure and criti-
patients who develop severe sepsis also have at least one chronic cal illness. Consistent with the winter immunoenhancement
health condition. Severe sepsis is more likely to occur in indi- theory, a shorter exposure to sunlight (i.e., photoperiod) in the
viduals with chronic obstructive pulmonary disease, cancer, month before critical illness was associated with a reduced risk
chronic renal and liver disease, and diabetes. Other risk factors of death in a single center observational cohort study.46 However,
include residence in long-term care facilities, malnutrition, and once patients were in the ICU their exposure to natural light
use of immunosuppressive medications and prosthetic devices. was almost negligible and hence future studies are warranted
Finally, abnormalities in the immune response to infection, as whether manipulating light exposure, before or during ICU
described below, increase risk of infection and severe sepsis. admission, can enhance survival.
These abnormalities may be secondary to chronic diseases or age
(i.e., immunosenesence). Special Populations
Despite improved understanding of clinical risk factors influ-
encing susceptibility and outcomes of sepsis, why some subjects As mentioned above, increased burden of chronic health
develop severe sepsis and succumb to the infection while others conditions are important risk factors for severe sepsis. Many
do not, remains unclear. Thus genetic factors have been exam- comorbidities such as diabetes and chronic renal failure influ-
ined to explain variability in susceptibility and outcomes of infec- ence susceptibility to and outcome from severe sepsis.37 However,
tion. A study by Sorensen and colleagues39 suggests that genetic some patient populations deserve special mentioning.
factors may be more important in outcomes of infectious diseases Malignancy
compared with cardiovascular disease. In this study, adopted Cancer is one of the most common co-morbidities among
children whose biological parents died due to infectious causes patients with severe sepsis.47 Analysis of a subgroup of patients
had a 5.8-fold increased risk of dying due to infections. In com- with cancer in the 1979–2001 National Hospital Discharge
parison, the increased risk of death due to cardiovascular causes Survey found cancer of all types increased the risk of develop-
was 4.5-fold if their biological parents died of cardiovascular ing sepsis almost 10-fold. Malignancy increased the risk of sepsis
causes. Because sepsis is common and often fatal, the pattern of more than any other comorbidity, and the source of infection was
inheritance is unlikely to be Mendelian, where phenotypic differ- related to the type of cancer; for example lung cancer patients
ences are attributed to a single gene. Multiple genes may interact were particularly likely to develop pneumonia. Sepsis contrib-
with pathogens (environmental factors) and influence suscep- uted to 30% of all hospitalized cancer deaths. Cancer increased
tibility, response and outcome of sepsis. Some of the candidate the case fatality rate of sepsis by 55%. However this is declining
genes that have shown promising results in preliminary studies with time (cancer associated sepsis case fatality rates fell from
include tumor necrosis factor (TNF), plasminogen activator 44.7% in 1979 to 23.8% in 2001), perhaps due to safer chemo-
inhibitor (PAI)-1, Toll-like receptor (TLR)-1 and TLR-4, and therapy, or maybe just in parallel to the overall improvement in
the Mal functional variant required for downstream signaling of sepsis treatment. While the risk of developing severe sepsis was
TLR-2 and TLR-4.40-42 A single center study in Belgium reported 8.7 times higher in hematological malignancy compared with
an association of MASP2 and NOD2/TLR4 genotypes with sus- solid tumors, the in-hospital mortality from severe sepsis was
ceptibility to bacteremia and in-hospital mortality, respectively.43 similar in each group.
The relative contribution of clinical and genetic factors to Obesity
susceptibility and outcomes of severe sepsis remains unclear. Obesity is a fast growing epidemic worldwide and is associ-
Genetic factors may play an important role in younger individ- ated with other morbid conditions including diabetes, cardiovas-
uals but could be less important in older adults where chronic cular and respiratory diseases as well as cancer.48 The effects of
diseases may play a more important role. Furthermore, common obesity on severe sepsis susceptibility and outcomes are not well
variants may have a smaller attributable risk, while certain rare described, but there is accumulating evidence that obese patients
variants may lead to a higher attributable risk. Recent advances are more susceptible to infections and more likely to develop

www.landesbioscience.com Virulence 7
serious complications of common infections.49 Recently, Arabi with emergency medicine services (EMS) receive out-of-hospital
et al. reported similar outcomes for obese and normal weight fluid resuscitation.60
patients with septic shock in an international multi-center study Sex and race
after adjusting for baseline characteristics and treatment inter- Women appear to be at lower risk of developing sepsis than
ventions.50 Interestingly, obese patients received less fluid resusci- men.1,61 Whether the greater male risk of developing severe sepsis
tation and lower doses of antimicrobial agents adjusted for body reflects an increased risk of developing infection or of progressing
weight compared with normal weight patients. The intricacies of to severe sepsis is not known, as are the underlying mechanisms
caring for morbidly obese critically ill patients have been nicely of these disparities. A combination of differences in chronic dis-
summarized by El-Solh.51 ease burden, particularly subclinical disease, social and environ-
Human immunodeficiency virus (HIV) mental factors, and genetic predisposition causing differences in
The epidemiology of sepsis in patients with HIV is changing the host immune response to infection likely contribute to the
significantly with advancements in highly active antiretroviral observed differences. For example, healthy female volunteers
therapy (HAART) and Pneumocystis jirovecii prophylaxis. Over showed a more pronounced pro-inflammatory response after
the past decade, the proportion of HIV-positive patients admitted endotoxin infusion compared with healthy men.62 In addition,
to the ICU has steadily increased, as has their overall survival.52 men tend to be treated more aggressively and undergo more inva-
Compared with the pre-HAART era, most HIV-positive patients sive procedures,63 whereas women more frequently have a “do not
who are hospitalized or admitted to the intensive care unit die resuscitate” order written.64 Another paper in this special issue
of non-AIDS-related illness, the most common being sepsis.53-55 by Angele et al. explores the role of estrogens and androgens that
Data from a recent single center study in the United States may account for the gender differences in sepsis outcomes.
found approximately 13.7% HIV-positive patients among all Epidemiological studies consistently report a higher incidence
ICU admissions, with an overall in-hospital mortality of 42%.54 of severe sepsis among black compared to white patients.65,66 The
Among HIV-positive patients, 194 acute infections were iden- higher severe sepsis rate is due to both a higher infection rate in
tified, of which the majority were nosocomial or healthcare- black patients and a higher risk of developing acute organ dys-
associated (57.7%). The remainder were AIDS-related (28.4%) function.37 These results are independent of sex, robust across
or community-acquired (13.9%). Similar to the “general” popu- different sources and etiologies of infections, and persist after
lation, sepsis in AIDS patients is increasingly due to multi-resis- adjusting for poverty level and hospital effect. The underlying
tant organisms.56 mechanisms of racial disparities in infection and severe sepsis
Children are poorly understood. Similar to gender differences, a combina-
The subject of pediatric sepsis is discussed in detail in this tion of differences in chronic disease burden, social and envi-
special issue on sepsis (see contribution by Randolph and ronmental factors, and the immune response to infection likely
McMulloh). contribute to the observed differences in infection and severe sep-
Analysis of a large administrative database using hospital dis- sis-related hospitalization rates. A higher prevalence of chronic
charge data from 7 US states recently reported an 81% increase kidney disease and diabetes among black patients hospitalized
in pediatric sepsis cases between 1995 and 2005, corresponding for infection may partly explain higher infection-related hospital-
with an increased prevalence from 0.56 to 0.89 per 1000 pediat- ization rates among black patients. Furthermore, the differences
ric population.57 This increase was largely driven by a dispropor- in co-morbidities did not explain higher risk of organ dysfunc-
tionate increase in severe sepsis in neonates, particularly those tion among those hospitalized for infection. Differences in host
with very low birth weight (9.7 vs. 4.5 per 1000 births). Of cases immune response may partly explain these differences,67,68 and
where a site of infections was identified, respiratory (48.9%) and recent studies suggesting polymorphisms in key proteins involved
primary bacteremia (18.1%) were the two most common. in the host response to infection suggest an increased susceptibil-
Out-of-hospital severe sepsis ity to severe infections and septic shock among people of African
The emphasis on early recognition and aggressive treatment of descent.41,42 In addition, the majority of black patients receive
sepsis was illustrated by the “early goal directed therapy” study, care for common infections, such as community-acquired pneu-
which showed that early aggressive resuscitation measures signifi- monia, at hospitals that provide overall poorer quality of care
cantly improved mortality.58 As a consequence, early fluid resus- regardless of race. Thus, policy interventions directed at hospitals
citation, vasopressor support and blood transfusion to improve that provide care to large number of black patients seem most
hemodynamics have been incorporated into treatment recom- promising to reduce racial disparities for CAP and severe sepsis.69
mendations. Nevertheless, a recent multicenter cohort study
showed that out-of-hospital interventions including fluid resus- Long-Term Outcomes
citation, monitoring, and serial vital signs occurred in less than
half of subjects.59 Hence, there is a need to address the role of out- The traditional focus of care in patients with infectious disease
of-hospital interventions in improving clinical outcomes in severe has been to reduce short-term mortality and clinical trials have
sepsis and recognition strategies for severe sepsis before hospital used 28-d or 90-d mortality as an endpoint. However, recent
arrival, as the limited data available suggest that only a third of studies suggest that infection may worsen long-term outcomes.70-73
patients with severe sepsis who are transported to the hospital While it is commonly perceived that serious infections occur in

8 Virulence Volume 5 Issue 1

older subjects with chronic health conditions and that these con- Mechanisms underlying increased long-term mortality and
ditions contribute to higher mortality even after recovery from morbidity remain unclear. Unresolved immune response during
acute illness, several studies show that higher long-term mortality recovery may worsen long-term outcomes. For example, higher
is independent of baseline functional and health status.74 circulating levels of inflammatory and coagulation markers were
Adverse long-term outcomes are not limited to increased observed at hospital discharge when patients appeared to have
mortality risk. For example, elderly survivors of severe sepsis are clinically recovered from infection and increased subsequent
up to three times as likely to develop persistent cognitive and mortality.76
functional impairments compared with elderly controls not hos-
pitalized for sepsis.75 Acute infections may worsen pre-existing Conclusion
chronic diseases or new chronic diseases may emerge. The rela-
tionship between acute infection and chronic illness may be Sepsis and severe sepsis are leading causes of death in the
bidirectional. Whereas the increased burden of chronic health United States and the most common cause of death among criti-
conditions increase the risk of infection and sepsis, survivors of cally ill patients in non-coronary intensive care units. Recent
infection may develop a higher burden of chronic disease. For studies also suggest that acute infections worsen pre-existing
example, individuals with renal disease are at higher risk for seri- chronic diseases or result in new chronic diseases, hence leading
ous infection. The episode of serious infection can lead to renal to poor long-term outcomes in acute illness survivors. People of
failure and eventually lead to chronic dialysis. Similarly, it has older age, male gender, black race, and preexisting chronic health
been shown that infection with influenza is associated with conditions are particularly prone to develop severe sepsis, hence
increased risk of cardiovascular disease. These examples under- prevention strategies should be targeted at these vulnerable popu-
score the complex relationship between infection and underly- lations. The epidemiology of severe sepsis in developing countries
ing chronic disease, where co-morbid conditions are both a risk may differ significantly from developed countries, which war-
factor and are modified by the infectious event. The worsening rants greater attention in future studies.
of chronic illness following infection is in turn a risk factor for
subsequent acute illness, thereby initiating a spiral of events that Disclosure of Potential Conflicts of Interest
can ultimately lead to death. No potential conflicts of interest were disclosed.
8. Kumar G, Kumar N, Taneja A, Kaleekal T, Tarima 14. Urtecho J, Snapp M, Sperling M, Maltenfort M,
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