Journal of Critical Care 41 (2017) 170176

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Journal of Critical Care

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The characteristics and impact of source of infection on sepsis-related

ICU outcomes
Niranjan Jeganathan, MD, MS a,, Stephen Yau, MD a, Neha Ahuja, MD a, Dara Otu, MD a, Brian Stein, MD b,
Louis Fogg, PhD c, Robert Balk, MD b
a
Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA
b
Division of Pulmonary and Critical Care Medicine, Rush University Medical Center, Rush Medical College, Chicago, IL, USA
c
College of Nursing, Rush Medical College, Chicago, IL, USA

a r t i c l e i n f o a b s t r a c t

Available online xxxx Background: Source of infection is an independent predictor of sepsis-related mortality. To date, studies have
failed to evaluate differences in septic patients based on the source of infection.
Keywords: Methods: Retrospective study of all patients with sepsis admitted to the ICU of a university hospital within a
Sepsis 12 month time period.
Source
Results: Sepsis due to intravascular device and multiple sources had the highest number of positive blood cultures
Microbiology
and microbiology whereas lung and abdominal sepsis had the least. The observed hospital mortality was highest
Organ dysfunction
Mortality
for sepsis due to multiple sources and unknown cause, and was lowest when due to abdominal, genitourinary
Outcomes (GU) or skin/soft tissue. Patients with sepsis due to lungs, unknown and multiple sources had the highest rates
of multi-organ failure, whereas those with sepsis due to GU and skin/soft tissue had the lowest rates. Those
with multisource sepsis had a signicantly higher median ICU length of stay and hospital cost.
Conclusion: There are signicant differences in patient characteristics, microbiology positivity, organs affected,
mortality, length of stay and cost based on the source of sepsis. These differences should be considered in future
studies to be able to deliver personalized care.
2017 Elsevier Inc. All rights reserved.

1. Introduction
Sepsis is dened by the 2016 Society of Critical Care Medicine and
the European Society of Intensive Care Medicine task force as life-
threatening organ dysfunction caused by a dysregulated host response
to infection [1]. Currently there are no strong biomarkers to identify
the presence of infection or to link an identied organism with sepsis.
Organ dysfunction dened using the Sequential Organ Failure Assess-
ment (SOFA) score is predictive of in-hospital mortality but is not diag-
nostic of sepsis or indicative of source of infection as the true cause of
organ dysfunction [2].
In practice most clinicians suspect sepsis based on the signs and
symptoms consistent with infection, and then rely on supporting radio-
logic and microbiologic data to predict the source of sepsis which then
drives the treatment approach. As the source of infection dictates the
Abbreviations: GU, genitourinary; IVD, intravascular device; SOFA, Sequential Organ
Failure Assessment; LOS, length of stay; DM, diabetes mellitus; CHF, congestive heart
failure; ICU, intensive care unit; ESRD, end stage renal disease; AKI, acute kidney injury;
OR, odds ratio; HR, hazard ratio.
Corresponding author at: Rush University Medical Center, Chicago, IL 60612, USA.
E-mail address: Niranjan_Jeganathan@Rush.edu (N. Jeganathan).
magnitude of sepsis, and since treatment decisions are made based on
the suspected source of infection, understanding the differences in sep-
sis progression and outcomes between the different sources of infection
is paramount to providing precise and appropriate treatment.
To date, the majority of sepsis-related studies have grouped all septic
patients together and therefore have failed to identify specic patient
populations that may actually benet from a particular intervention.
Only a few studies have considered differences in in-hospital mortality
between the different sources of infection [3,4]. They have shown that
the anatomic source of infection is a signicant predictor of mortality ir-
respective of differences in baseline characteristics, bacteremia or anti-
microbial appropriateness [3,4]. To date, no studies have reported
differences in the characteristics of septic patients based on the source
of infection. Studies have also failed to report the differences in microbi-
ology, organ dysfunction, length of stay (LOS) and cost in these patients
based on the infectious source. In our pilot study we attempt to close
this knowledge gap by comparing the characteristics, microbiology
and short-term outcomes in septic patients based on the source of infec-
tion. Understanding these differences could aid clinicians in better esti-
mating the risk their patients face, and could help guide clinical decision
making. For example, recognition of severity and type of organs affected
in association with a particular source could lead to more focused

http://dx.doi.org/10.1016/j.jcrc.2017.05.019
0883-9441/ 2017 Elsevier Inc. All rights reserved.
 N. Jeganathan et al. / Journal of Critical Care 41 (2017) 170176
monitoring and interventions directed toward these organs. Most ICU
studies exclude patients with unknown site of infection and/or microbi-
ology [5]. Understanding the prevalence of microbiological positivity
could impact the utilization of diagnostic procedures and biomarkers
and lead to further studies to determine the benet of these in septic pa-
tients with unknown site of infection and/or negative microbiology. The
ability to predict LOS and cost differences could improve utilization of
resources and provide more accurate information to patients. Further-
more, knowledge of the role of infectious sources in progression of sep-
sis may also provide insight into pathophysiological processes. These
differences should be given important consideration when designing
future studies related to biomarkers, prognostic scores and treatment.
2. Materials and methods
2.1. Patients
This retrospective cohort study was approved by the Rush University
Medical Center institutional review board. Patients were identied
using the University Health Consortium database (UHC database is a
collection of patient-level discharge abstract data from academic health
centers and afliate community hospitals maintained to provide bench-
mark measures on the use of health care resources for the purpose of
comparative data analysis between academic institutions). Patients
were included if they had an ICD-9 discharge code for sepsis (ICD 9
codes 995.91, 995.92), age greater or equal to 18 years at time of admis-
sion, and were admitted to the Rush University Medical Center medical
or surgical ICU for at least 24 h from January 1, 2011 through December
31, 2011. For patients with more than one admission during this year,
only the rst admission was included. Patients were excluded from
the study if they had been transferred from an outside hospital or
acute care facility (Supplementary Table 1).
2.2. Data collection
Three of the authors reviewed the electronic database for patients
who met the above criteria. They screened the patient chart to deter-
mine whether sepsis criteria [6] were indeed fullled and that all inclu-
sion and exclusion criteria were met. Sepsis was dened as suspected
infection and two or more of the following conditions: temperature
N 38 C or b 36 C; heart rate N 90 beats per minute; respiratory rate
N 20 beats per minute; and white blood cell count N 12,000 cells/l,
b4000 cells/l, or N10% immature (band) forms. Data was collected
from review of the electronic medical record.
2.3. Assessment and data collection at baseline
Demographic and clinical characteristics were collected for all pa-
tients. Patients were classied as having healthcare-associated sepsis if
they were admitted from a nursing home or if the sepsis developed
post-surgery/intervention, or N48 h after hospitalization. If the sepsis
developed post-surgery/intervention or required surgery/procedure
for management and/or source control, it was categorized as surgical
sepsis. Comorbid conditions were identied as diabetes mellitus (DM),
congestive heart failure (CHF), cirrhosis, malignancy (solid or hemato-
logical), transplantation, immunosuppressive therapy (chemotherapy,
prednisone 10 mg/day) or severe obesity (BMI 35 kg/m2). We deter-
mined expected (predicted) mortality using the UHC mortality predic-
tion models. UHC uses logistic regression to generate expected
mortality by Medicare Severity Diagnosis-Related Groups having the
same admission diagnosis. Predictor variables included but were not
limited to age, sex, race, chronic comorbid conditions, other conditions
present on admission, and admission point of origin [7]. The cost was
obtained from the UHC database. The cost reported is an estimation of
total cost. The cost is calculated based on the charges sent with dis-
charge, application of cost-to-charge ratios from each member's
171
Medicare cost report as well as area wage indices. The UHC clinical da-
tabase has been previously used in a number of epidemiological studies
of sepsis [8,9].
2.4. Outcome measures
The endpoints were intensive care unit (ICU) mortality, hospital
mortality, ICU and hospital LOS, cost and the development of organ dys-
function. Patients were considered to have organ dysfunction if they
had a SOFA score of at least 3 during the rst 10 days of the ICU stay
[10]. Cardiovascular dysfunction was dened as the receipt of vasoac-
tive medication (dopamine in a dose N 5 g/kg/min or any dose of nor-
epinephrine, epinephrine, vasopressin, or phenylephrine). Pulmonary
dysfunction was dened as PaO2/FiO2 b 200 mm Hg with mechanical
ventilator support. Hematologic dysfunction was dened as platelet
count b 50 103/mm3. Hepatic dysfunction was dened as serum bili-
rubin N 6 mg/dL. Acute kidney injury (AKI) was dened as an increase
in serum creatinine N 200% from baseline based on KDIGO stage 2 and
higher [11,12] occurring within the rst 24 h of ICU admission. If base-
line creatinine (latest value from the previous six months excluding
the previous week) was unavailable, the lowest serum creatinine during
that hospitalization was considered as baseline for those with prior
renal disease and a serum creatinine N 2 mg/dl in those without prior
renal disease. Patients with history of thrombocytopenia, cirrhosis and
end stage renal disease (ESRD) were excluded in the respective organ
dysfunction analysis. ESRD patients were dened as chronically dialy-
sis-dependent prior to the ICU admission. The cause of death was classi-
ed by only one proximate cause (the predominant cause in each case).
The classications were septic shock, cardiovascular (arrhythmia, car-
diogenic, hypovolemic), respiratory (hypoxic respiratory failure), and
other (neurological or metabolic).
2.5. Microbiology
All patients had at least one set of blood cultures collected. A partic-
ular organ was considered to be the source of sepsis if there was
suspected (sufcient evidence to begin antibiotic therapy), clinically
documented (presentation compatible with infection and pus seen at
aspiration/puncture/surgery or signs at diagnostic imaging without mi-
crobiological documentation) or microbiologically documented infec-
tion (microbiology was considered to be positive if a pathogen was
identied from a tissue, blood, normally sterile body-uid culture, or a
central line/intravascular device and treated with antibiotics). In a
non-immunocompromised host, a single culture positive for gram-pos-
itive (G+) rods, coagulase-negative staphylococci or candida in a site
other than blood was considered to be a contaminant. In the immuno-
compromised patient (malignancy, post-transplantation, acquired im-
munodeciency syndrome or on immunosuppressive therapy) these
organisms were considered to be a pathogen if the patient was treated.
2.6. Statistical analysis
Analysis was performed using IBM SPSS statistics for Windows, Ver-
sion 19.0. (Armonk, NY: IBM Corp). Descriptive statistics are reported as
numbers and percentages. Categorical variables were compared using
the 2 test. Normally distributed quantitative parameter variables are
presented as means and standard deviations and compared using anal-
ysis of variance (ANOVA). Non-normally distributed parameters are
presented as medians and interquartile ranges (IQR, 2575th percen-
tile) and compared using the Mann-Whitney U test and Kruskal Wallis
test as appropriate. Logistic regression was used to adjust mortality for
differences in underlying patient characteristics. Cox regression was
used to determine effect on sepsis source on thirty day mortality adjust-
ed for covariates. In the rst step, univariate analyses were performed
for baseline factors (listed in Table 1), blood culture positivity and pre-
dicted mortality at admission. All variates with a p value 0.15 were
172 N. Jeganathan et al. / Journal of Critical Care 41 (2017) 170176

Table 1
Patient characteristics - results are expressed as mean (standard deviation)a or count (percentage)b.

Lung GU Abdomen Skin/Soft tissue (n = 18) IVD (n = 26) Unknown Multiple p-Value
(n = 51) (n = 45) (n = 46) (n = 29) (n = 31)

Age (years)a 65.5 (15.9) 63.5 (15.5) 60.5 (15.3) 56.4 (14.5) 51.5 (17.7) 53.6 (15.2) 58.1 (14.9) b0.01
Male genderb 22 (43.1) 15 (33.3) 24 (52.2) 12 (66.7) 15 (57.7) 13 (44.8) 18 (58.1) ns
Raceb
African American 20 (39.2) 22 (48.9) 18 (39.1) 8 (44.4) 12 (46.2) 15 (51.7) 11 (35.5) ns
Caucasian 22 (43.1) 11 (24.4) 18 (39.1) 7 (38.9) 6 (23.1) 12 (41.4) 11 (35.5)
Hispanic 6 (11.8) 11 (24.4) 9 (19.6) 2 (11.1) 7 (26.9) 0 7 (22.6)
Other 3 (5.9) 1 (2.2) 1 (2.2) 1 (5.6) 1 (3.8) 2 (6.9) 2 (6.5)
Comorbiditiesb
DM 14 (27.5) 23 (51.1) 11 (23.9) 9 (50.0) 7 (26.9) 6 (20.7) 13 (41.9) ns
CHF 10 (19.6) 6 (13.3) 7 (15.2) 2 (11.1) 6 (23.1) 2 (6.9) 11 (35.5) 0.01
ESRD 6 (11.8) 6 (13.3) 7 (15.2) 2 (11.1) 8 (30.8) 6 (20.7) 4 (12.9) ns
Malignancy 22 (43.1) 15 (33.3) 22 (47.8) 3 (16.7) 9 (34.6) 16 (55.2) 15 (48.4) ns
Severe obesity 10 (19.6) 5 (11.1) 5 (10.9) 4 (22.2) 7 (26.9) 8 (27.6) 6 (19.4) ns
Transplant 9 (17.6) 8 (17.8) 6 (13.0) 0 2 (7.7) 5 (17.2) 11 (35.5) 0.08
Cirrhosis 3 (5.9) 2 (4.4) 4 (8.7) 0 0 4 (13.8) 7 (22.6) 0.05
Immunosuppression 17 (33.3) 17 (37.8) 7 (15.2) 1 (5.6) 11 (42.3) 13 (44.8) 18 (58.1) b0.01
Healthcareb associated sepsis 22 (43.1) 13 (28.9) 18 (39.1) 3 (16.7) 17 (65.4) 13 (44.8) 24 (77.4) b0.01
Surgical sepsisb 10 (19.6) 9 (20.0) 21 (45.7) 8 (44.4) 1 (3.8) 5 (17.2) 13 (41.9) b0.01
Mortalityb
ICU 13 (25.5) 3 (6.7) 7 (15.2) 0 7 (26.9) 10 (34.5) 12 (38.7) 0.04
Hospital 14 (27.5) 3 (6.7) 7 (15.2) 0 8 (30.7) 11 (37.9) 13 (41.9)

GU genitourinary, Soft tissue (muscle and bone), IVD intravascular device (including central venous catheters), CHF - congestive heart failure, DM diabetes mellitus, ESRD end stage
renal disease, ns - not signicant.

selected to be entered into the multivariable analyses. GU and other race
were used as the reference for anatomic source of infection and race re-
spectively. p 0.05 was considered statistically signicant.
3. Results
3.1. Patient characteristics
There were 248 patients with sepsis who met the inclusion and ex-
clusion criteria. The patients were divided based on the anatomical
source of sepsis (Fig. 1). Patient characteristics are presented in Table
1. The top three sources of sepsis were lung, genitourinary (GU) and
abdomen. There was one patient with neuro sepsis and one patient
with cardiac sepsis (not included in the analysis). Patients with the
most common sources of sepsis were older and were similar in age com-
pared to patients with intravascular device (IVD, including central ve-
nous catheters) related sepsis and unknown sepsis. Sex and race did
not show a statistically signicant difference between the groups. Statis-
tically signicant differences were not found between the groups with
the following comorbidities DM, malignancy, obesity and prior trans-
plant. However, there were signicant differences noted in the preva-
lence of CHF, cirrhosis and immunosuppression between the groups.
Patients with IVD-related sepsis and multiple sources of sepsis had the
highest prevalence of CHF and those with unknown sepsis had the

Fig. 1. Flowchart of the enrolled cohort. GU genitourinary, GI gastrointestinal, Soft tissue (muscle and bone), IVD intravascular device (including central venous catheters).
 N. Jeganathan et al. / Journal of Critical Care 41 (2017) 170176 173

lowest prevalence of CHF. A higher incidence of cirrhosis and immuno- Table 2

suppression was present in those with multiple source of sepsis or un- Multivariable logistic regression hospital mortality.

known sepsis whereas a lower incidence of cirrhosis was seen in Covariables Odds ratio 95% condence interval p-Value
patients with sepsis due to skin/soft tissue and IVD. There was a lower Age 1.03 1.011.06 0.01
incidence of immunosuppression seen in those with sepsis due to Community 0.50 0.241.05 0.07
skin/soft tissue and abdominal source. Sepsis due to IVD or multiple Malignancy 0.95 0.422.15 ns
sources was healthcare-associated N 50% of the time. The percentage of Cirrhosis 1.35 0.424.36 ns
Immunosuppression 1.20 0.522.74 ns
surgical sepsis was highest and was over 40% when it was due to abdo-
Mortality predicted 96.27 10.79858.99 b0.01
men, skin/soft tissue and multiple sources. Lung 5.56 1.2824.21 0.02
Abdomen 2.96 0.6014.49 ns
3.2. Microbiology: Fig. 2 IVD 9.15 1.7448.07 b0.01
Unknown 10.44 2.1052.02 b0.01
Multiple 13.35 2.7464.93 b0.01
Blood cultures were positive in 37.9% of all patients. Sepsis due to
IVD or multiple sources resulted in a higher percentage of bacteremia GU was used as reference for the source of infection. GU genitourinary, IVD intravascu-
lar device (including central venous catheters), ns - not signicant.
(96.2% and 71%) whereas sepsis due to lung or abdomen resulted in a
lower percentage of bacteremia (15.7 and 15.2). The percentage of bac-
teremia due to GU, skin/soft tissue and unknown source was between with a statistically signicant association to mortality. Similarly, cox re-
30 and 40%. The microbiology was positive in 68.1% of all patients. gression was used to determine the effect of sepsis source on thirty day
When sepsis was due to GU, skin/soft tissue, IVD or multiple sources, mortality adjusted for covariates. Univariate cox analysis identied age,
pertaining cultures or blood was positive 80100% of the time. When CHF, malignancy, predicted mortality and source of sepsis as factors
the source was lung or abdomen, a positive culture was found in 40 with p b 0.15 which were then included in the nal model (Supplemen-
50% of cases. tary Table 3). In the multivariate cox analysis (Table 3) the hazard ratio
(HR) for mortality for GU was statistically comparable to GI but lower
3.3. Mortality compared to lung (HR 3.31), IVD (HR 4.61) and unknown (HR 5.87)
similar to logistic regression analysis. However, contrary to logistic re-
The total overall mortality was 22.6%. There was not a statistically gression, multiple sources did not have a statistically signicant associ-
signicant difference in predicted hospital mortality between the ation to mortality when analyzed based on time in cox univariate or
groups based on the UHC mortality prediction model. The observed hos- multivariate regression.
pital mortality was highest for sepsis due to multiple sources and un-
known cause (approximately 40%). Sepsis due to lung or IVD source 3.4. Organ dysfunction: Table 4
resulted in approximately 30% mortality, whereas, when it was due to
other sources, it was 15% or less (abdomen 15%, GU 7%, skin/soft tissue There were 30.6% of patients without any organ failure, 29% with
0%). Of those who died, 92% of the deaths occurred in the ICU. The ob- single organ failure and 40.4% had multi-organ failure (2 organs). Pa-
served ICU and hospital mortalities based on source had similar trends. tients with sepsis due to lungs, unknown and multiple sources had
There was no signicant difference in the ultimate cause of mortality 5060% of patients with multi-organ failure. Patients with GU and
between the groups (not shown). A multivariable logistic regression skin/soft tissue had the lowest number of patients with multiple organ
was performed to adjust for differences and to determine predictors of failure. In abdomen and IVD-related sepsis, multi-organ failure was
mortality. First, a univariate analysis was performed to identify factors present in 34.8% and 42.3%, respectively.
with p value b 0.15 which was included in the nal model (Supplemen- Next, we evaluated the difference in frequency of organ dysfunction
tary Table 2). The nal model analyzed the following factors: age, place by organ system. Cardiovascular dysfunction was present in approxi-
of acquisition, malignancy, cirrhosis, immunosuppression, mortality ex- mately 52% of patients with unknown or multiple source related sepsis.
pected and source of sepsis. After adjusting for the predisposing factors, The lowest incidence of cardiovascular dysfunction was seen in sepsis
variation in hospital mortality across source of infection remained large- due to GU and skin/soft tissue (2022%). Cardiovascular dysfunction
ly unchanged compared to crude hospital mortality and was statistically in sepsis due to lungs, abdomen and IVD-related sources was present
signicant (Table 2). The odds ratio (OR) of mortality, compared to GU, in 33.3%, 30.4% and 44% of patients, respectively. Respiratory failure
was similar for abdominal source but signicantly increased for other was highest in sepsis due to lungs and multiple sources (56% and
sources (lung - OR 5.56, IVD OR 9.15, Unknown OR 10.44. Multiple 48.4%, respectively). The lowest incidence was in patients with sepsis
OR 13.35). Age and predicted mortality were the only other factors due to GU and skin/soft tissue (approximately 11%). AKI was present
in 50.7% of non-ESRD patients. There was no signicant difference in
the incidence of acute kidney injury between the groups. Hepatic dys-
function was noted in approximately 25% of patient with unknown

Table 3
Multivariable cox regression thirty day hospital mortality.

Covariables Hazard ratio 95% condence interval p-Value

Age 1.03 1.001.05 0.03

CHF 2.07 1.014.25 0.05
Malignancy 0.96 0.511.84 ns
Mortality predicted 27.46 5.55135.87 b0.01
Lung 3.31 1.0111.63 0.05
Abdomen 1.88 0.487.39 ns
IVD 4.61 1.1618.38 0.03
Unknown 5.87 1.5821.78 b0.01
Multiple 1.77 0.397.96 ns

Fig. 2. Relationship between source of infection and culture positivity expressed as GU was used as reference for the source of infection. GU genitourinary, CHF congestive
percentage, p b 0.001 for both blood and microbiology. GU genitourinary, soft tissue heart failure, IVD intravascular device, (including central venous catheters), ns - not
(muscle and bone), IVD intravascular device (including central venous catheters). signicant.
174 N. Jeganathan et al. / Journal of Critical Care 41 (2017) 170176

Table 4
Organ dysfunction - results are expressed as count (percentage).

Organ dysfunction Lung GU Abdomen Skin/Soft tissue IVD Unknown Multiple p-Value
(n = 51) (n = 45) (n = 46) (n = 18) (n = 26) (n = 29) (n = 31)

Cardiovascular 17 (33.3) 9 (20) 14 (30.4) 4 (22.2) 11 (44) 15 (51.7) 16 (51.6) 0.05

Respiratory 28 (56) 5 (11.4) 10 (21.7) 2 (11.8) 8 (30.8) 11 (37.9) 15 (48.4) b0.01
Kidney 25 (55.6) 17 (43.6) 19 (48.7) 5 (31.3) 10 (55.6) 12 (52.2) 17 (63) ns
Hepatic 1 (2) 0 6 (13) 0 0 7 (25) 7 (23.3) b0.01
Hematologic 9 (18.4) 2 (4.7) 6 (13.6) 0 5 (21.7) 7 (25) 10 (35.7) 0.02
Number of organs
0 13 (25.5) 23 (58.1) 11 (23.9) 10 (55.6) 7 (26.9) 7 (24.1) 4 (12.9) b0.01
2 16 (34.8) 3 (16.6) 11 (42.3) 16 (55.2) 18 (58.1)
27 (52.9) 9 (20)

GU genitourinary, Soft tissue (muscle and bone), IVD intravascular device (including central venous catheters), ns - not signicant. Patients with history of thrombocytopenia, cirrhosis
and end stage renal disease were excluded in the analysis of respective organs.

and multiple sources of sepsis. The presence of hepatic dysfunction in
patients with lung, GU, skin/soft tissue and IVD-related sepsis was
close to 0%. The highest percentage of hematologic dysfunction was
present in those with multiple sources of sepsis. Less than 5% of patients
with GU and skin/soft tissue sepsis developed hematologic dysfunction.
Lung, abdomen, IVD and unknown sepsis resulted in 18.4%, 13.6%, 21.7%
and 25% of hematologic dysfunction, respectively.
3.5. Other outcomes: Table 5
There was a signicant difference in the ICU length of stay between
patients. The highest LOS was for patients with multiple sources of sep-
sis with a median of 9 days. The median ICU LOS for the other groups
was between 2 and 4 days. However, the hospital LOS was not different
between the groups. The median cost was signicantly higher for pa-
tients with multiple source of sepsis ($96,839). The median cost for
the other groups ranged from $19,062 to $37,259.
4. Discussion
Sepsis is a profound dysregulated inammatory state driven by the
presence of infection. The septic process begins with a focus of infection.
Within that focus, the organism replicates and releases toxic products
which trigger pro-inammatory mediators which exceed the bound-
aries of the local environment, and lead to a more generalized response
resulting in tissue injury and organ dysfunction [13-15]. Studies in the
past have focused on the immunologic component of sepsis due to the
belief in the concept that the inammatory cascade, once triggered, pro-
gresses independent of the infectious trigger [16,17]. Perhaps due to this
fundamental misunderstanding, many attempts at immunomodulatory
therapies have failed to show improved outcomes in clinical trials [18].
The shortcoming of the immunologic concept is the failure to appreciate
the importance of the infectious process and the role of microbial load in
driving the disease process, including the development of organ dys-
function. The source of infection is an independent predictor of mortal-
ity after adjusting for differences in baseline and downstream responses
[4]. However, in our extensive search, we were not able to nd any de-
scriptive sepsis-related studies focused on differences between patients
based on the source of infection. In this pilot observational study, we
evaluated and compared the baseline characteristics, microbiology
and short-term outcomes of patients admitted to the ICU with sepsis
based on the source of infection.
There are numerous host-related factors such as advanced age
(N65 years), immunosuppression, diabetes and prior recent hospitaliza-
tion that have been shown to be associated with severe illness and in-
creased mortality in patients with sepsis [19,20]. We observed
signicant differences in age, comorbidities and prevalence of
healthcare/surgical sepsis between the groups. A higher prevalence of
cirrhosis and immunosuppression was observed in patients with multi-
ple sources of sepsis and unknown sepsis. However, the prevalence of
CHF was signicantly lower in those with unknown sepsis compared
to multiple source of sepsis. These interesting observations could lead
to further studies to understand the basis for these differences. Although
these factors are not modiable, understanding these differences and
risk factors is important in the development of prediction models and
personalized treatment.
Numerous studies have evaluated the impact of positive microbiolo-
gy on outcomes and have yielded conicting results. Some studies have
reported no difference in outcomes between culture-negative and cul-
ture-positive groups [3,21,22]. However, a recent study showed that
culture-negative patients have fewer comorbidities, shorter hospitaliza-
tions and lower mortality compared to culture-positive septic patients
[23]. Similarly, the importance of positive blood cultures and the impact
of gram positive versus gram negative sepsis have also yielded conict-
ing results [24-26]. A major cause for the discrepancy between studies is
perhaps the failure to account for the source of infection. Our reported
prevalence of bacteremia (37.9%) and positive microbiology (68.1%) is
consistent with the reported incidence of microbiology in other studies
[3,23]. To date, studies have not evaluated the prevalence of bacteremia
and microbiologic positivity based on the source of infection. We found
signicant differences in both positive blood cultures and microbiology
between the different sources of infection, and noted no correlation be-
tween the microbiologic positivity and mortality when evaluated ac-
cording to site of infection. For example the IVD group had much
higher incidence of positive blood culture than the unknown and multi-
ple source groups, but much lower mortality compared to both groups.
Similarly GU and skin/soft tissue had 8090% microbiologic positivity,
much higher than lung and abdominal sources, but the mortality for

Table 5
Outcomes - results are expressed as median (interquartile range).

Outcomes Lung GU (n = 45) Abdomen (n = Skin/soft tissue (n IVD (n = 26) Unknown (n = Multiple (n = 31) p-Value
(n = 51) 46) = 18) 29)

Length of stay
(days)
ICU 3 (27) 2 (14) 3 (26) 2 (1.753.25) 3.5 (16.75) 4 (28.5) 9 (316) b0.01
Hospital 8 (412) 7 (412) 9 (6.514) 10.5 (3.7516.75) 6.5 (313.25) 9 (413) 13 (6.524.5) ns
Cost $27,285 $19,062 $29,685 $30,988 $37,259 $30,269 $96,839 b0.01
(1377644,254) (1176829,296) (2032263,233) (1769259,289) (1711890,003) (1792671,221) ($41,124$214,819)

GU genitourinary, Soft tissue (muscle and bone), IVD intravascular device (including central venous catheters), ns - not signicant.
 N. Jeganathan et al. / Journal of Critical Care 41 (2017) 170176
GU and skin/soft tissue was much lower than for lungs and abdomen.
The positive microbiology is likely dependent on the source of infection.
Some infection sites are likely to be more culture negative than others
due to protection from anatomical barriers and natural defense mecha-
nisms to clear infection. Based on our study, when evaluated by the
source of infection, microbiology positivity had no association with
mortality.
The source of infection is an independent predictor of mortality [4].
In our study the highest mortality was noted for patients with multiple
sources of sepsis and unknown sepsis followed by IV device, lung, abdo-
men, GU and soft tissue infections in the order of decreasing mortality.
This is consistent with prior studies which have reported similarly
higher crude mortality for multiple source sepsis and unknown sepsis
and lower mortality for GU-related infections [3,4]. The mortality re-
ported for abdominal sepsis in our study is likely an underestimate
due to combining all patients with gastrointestinal tract-associated sep-
sis into one group. In a recently published large study, septic shock pa-
tients were subcategorized based on 20 anatomic sites. As shown in
this study, the mortality due to abdominal source varies by subcategory
with the highest mortality in those with ischemic bowel and the lowest
mortality in those with cholecystitis/cholangitis [4]. Future studies
should expand these subcategories and report more comprehensively
on the progression of sepsis using the framework laid out in our pilot
study including patient characteristics, microbiology, organ dysfunc-
tion, length of stay and cost. The differences noted, based on the source,
are likely due to protective barriers and defense mechanisms unique to
each organ. In addition, certain infectious sources such as urinary and
biliary tract are more easily recognized and rapidly treated. However,
when multiple sites are involved or the source of sepsis is unknown, it
may be more difcult to provide early and appropriate therapy.
To date, studies have not explored the impact of source of infection
on organ dysfunction. Organ dysfunction measured using the SOFA
score is an important component of the recent sepsis-3 denition
given that organ dysfunction is a strong predictor of mortality [1,2].
Therefore it is vital to understand the association between the source
of infection and organs affected in order to identify measures to prevent
additional organ failure. We found signicant differences in the number
of organs and the type of organs affected between the different sources
of sepsis. Fifty to 60% of patients with pulmonary, unknown and multi-
ple source of sepsis had 2 organ dysfunctions, and approximately 50%
of patient with GU or soft tissue infections had no organ dysfunction. As
expected, the number of organs affected correlated positively with ob-
served mortality between the different sources of sepsis.
Based on recent studies, patients hospitalized with sepsis have an
average length of stay of approximately 9 days which is 75% longer
than those hospitalized for other conditions [27,28]. We showed that
the length of stay in the ICU varies signicantly based on the source of
sepsis, with multisource sepsis resulting in 25 times as many days in
the ICU compared to the other sources. The mean hospital cost reported
for patients with severe sepsis is around $20,000 [28]. We observed a
signicant variability in the cost based on the source of sepsis. Similar
to the trend observed with the ICU length of stay, the cost was also 2
5 times higher for patients with multisource sepsis compared to the
other sources. Understanding these differences is crucial for healthcare
organizations to be able to identify areas which may need better utiliza-
tion of resources. This information could also help physicians provide
more accurate and specic information to families to guide them with
what to expect regarding patients expected length of stay and nancial
needs.
There are a number of limitations to our study. First, as a retrospec-
tive study we cannot attribute causality for the differences observed, al-
though this was not the goal of this study. It was conducted at a single
medical center which limits the generalizability of our results, and the
small sample size limits complex statistical analyses. Due to testing mul-
tiple variables independently it is possible that any p-value above 0.01
may well be attributable to random effects. However, we have multiple
175
variables that are signicant (p 0.05) in each table (Table 1 7/14 and
Table 3 5/6) which is far above the chance rate of 1/20. The cost com-
parisons have limited generalizability outside of U.S. hospitals. Addi-
tionally, patients were identied using ICD-9 codes for sepsis and,
therefore, those who were not coded as such may have been excluded.
In those that were coded as septic we veried this diagnosis via chart re-
view (we found 99.5% consistency). Even though a number of statisti-
cally signicant differences were noted, the small numbers limits the
ability to detect minor differences. We did not have information on
timing of antibiotics and interventions performed which may have
had a potential impact on outcomes. However, given the expertise of
our ED and ICU physicians in managing patients with sepsis, and
based on our internal audits which have shown a high compliance
with meeting sepsis treatment targets, we believe the observed differ-
ences are unlikely to be due to discrepancies in the treatment provided.
Despite these limitations, our pilot study provides a foundation for fu-
ture studies to better characterize the differences between the groups,
and more importantly, emphasize the need to consider these differ-
ences in designing basic and clinical studies evaluating biomarkers,
prognostic scores and therapies. These additional studies could result
in the development of a more personalized treatment approach based
on the source of sepsis.
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.jcrc.2017.05.019.
Author contributions
Dr. Jeganathan designed the study, analyzed the data and drafted the
manuscript.
Dr. Ahuja, Dr. Yau and Dr. Otu reviewed the electronic charts and col-
lected the data.
Dr. Stein assisted with data acquisition.
Dr. Fogg and Dr. Balk assisted with data analysis and editing
manuscript.
Prior publication
The authors attest that this manuscript is not under consideration
for publication elsewhere. No aspect of this manuscript has been pub-
lished elsewhere.
Financial disclosures
No source of funding to disclose.
Competing interests
No potential conicts of interest to disclose.
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