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RESEARCH ARTICLE
Trends in Epidemiology and Microbiology of
Severe Sepsis and Septic Shock in Children
Mukul Sehgal, MD,a,b Hugh J. Ladd, MD,aBalagangadhar Totapally, MDa,c
ABSTRACT BACKGROUND AND OBJECTIVES: To explore the microbiologic etiology and trends in incidence
and survival of nonneonatal pediatric sepsis in the United States by using the 2006, 2009, and
2012 Kids’Inpatient Database.
METHODS: Children with sepsis were identified by using International Classification of Diseases,
Ninth Revision, Clinical Modification (ICD-9-CM) codes for severe sepsis and septic shock (ICD-9-CM
cohort) and by the modified Angus method, which incorporates ICD-9-CM codes for infection and
organ dysfunction (Angus cohort). Temporal trends in incidence and microbiologic etiology were
evaluated.
RESULTS: Among 8 830 057 discharges, 26 470 patients in the ICD-9-CM cohort were diagnosed
with severe sepsis and septic shock (29.97 per 10 000 discharges) and 89 505 patients in the Angus
cohort (101.34 per 10 000 discharges). The incidence of sepsis increased in both cohorts from
2006 to 2012 (P,.01). In the Angus cohort, the case-fatality rate was the highest for methicillin-
resistant Staphylococcus aureus (14.42%, P,.01) among Gram-positive organisms and for
Pseudomonas (21.49%; odds ratio: 2.58 [95% confidence interval: 1.88–3.54]; P,.01) among Gram-
negative organisms.
CONCLUSIONS: The incidence of sepsis has increased, and the sepsis case-fatality rate has
decreased, without a decrease in the overall sepsis-associated mortality rate among hospitalized
children. Also, bacterial and fungal organisms associated with the pediatric sepsis have changed over
these years. These findings are important for focusing the allocation of health care resources and
guiding the direction of future studies.
a
Division of Pediatric
Critical Care Medicine,
Nicklaus Children’s
Hospital, Miami, Florida;
b
Division of Pediatric
Critical Care Medicine,
University of South
Alabama Children and
Women’s Hospital, Mobile,
Alabama; and
c
Department of
Pediatrics, Herbert
Wertheim College of
Medicine, Florida
International University,
Miami, Florida
www.hospitalpediatrics.org
DOI:https://doi.org/10.1542/hpeds.2020-0174
Copyright © 2020 by the American Academy of Pediatrics
Address correspondence to Balagangadhar R. Totapally, MD, Division of Pediatric Critical Care Medicine, Nicklaus Children’s Hospital,
3100 SW 62nd Ave, Miami, FL 33165. E-mail: balagangadhar.totapally@nicklaushealth.org
HOSPITAL PEDIATRICS (ISSN Numbers: Print, 2154-1663; Online, 2154-1671).
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
Drs Sehgal and Ladd conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript;
Dr Totapally conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript
for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all
aspects of the work.
HOSPITAL PEDIATRICS Volume 10, Issue 12, December 2020 1021
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Sepsis is a leading cause of morbidity and
mortality in hospitalized children in the
United States.1,2 A global prospective study
(the Sepsis Prevalence, Outcomes, and
Therapy [SPROUT] study) revealed that
hospital mortality rate was 25% in pediatric
sepsis, which was higher than what was
previously estimated in retrospective
studies that used administrative databases.3
In the recent years, several studies have
revealed an increase in the incidence rate
but decrease in the mortality rate related to
severe sepsis and septic shock.4–7
In the past, the definition of sepsis was
vague without precise guidelines for
determining the diagnoses of sepsis and
septic shock. In 1992, a consensus
conference sponsored by the American
College of Chest Physicians and the Society
of Critical Care Medicine introduced
definitions for the terms “systemic
inflammatory response syndrome”and
“multiple organ dysfunction syndrome”as
they relate to infection.8In 2005, the
International Pediatric Sepsis Consensus
Conference published a modified systemic
inflammatory response syndrome criteria
and definitions for severe sepsis and septic
shock for the pediatric population.9In 2016,
the Third International Consensus
Definitions for Sepsis and Septic Shock
redefined sepsis definitions for adults.10
Sepsis is, now, defined as life-threatening
organ dysfunction caused by a dysregulated
host response to infection.10 No such
definition of dysregulated host response has
been adopted for pediatric patients,
although a consensus of doing that has
been growing.11 Organ dysfunction is
identified as an acute change in the
Sequential Organ Failure Assessment (SOFA)
score consequent to an infection.12
In 2001, Angus et al13 developed criteria to
identify patients with severe sepsis using
the International Classification of Diseases,
Ninth Revision, Clinical Modification (ICD-9-
CM) codes, which defined severe sepsis as
presence of bacterial or fungal infection
and at least 1 organ dysfunction, whereas
the ICD-9-CM cohort was defined as a set of
explicit ICD-9-CM codes for severe sepsis
(995.92) and septic shock (785.52).14
Although billing codes for the sepsis
definition provided moderate reliability
(consistency of a measure) in comparison
to SOFA scores with high reliability, the
billing codes did have higher content validity
(reflects clinician judgement) when
compared to SOFA scores.15 There are few
studies in which researchers have
investigated the microbiologic etiologies
responsible for severe sepsis in
children.4,16,17 In the current study, the
incidence of sepsis was compared between
the 2 cohorts in the hospitalized pediatric
patients by using the 2006, 2009, and
2012 Kids’Inpatient Databases (KIDs).
Patients were identified by using explicit
ICD-9-CM codes for severe sepsis and
septic shock (ICD-9-CM cohort) and by the
modified Angus criteria (Angus cohort). We,
then, compared the trends in incidence of
sepsis from 2006 to 2012 using these 2
criteria. Finally, we described the underlying
microbiologic etiology and associated
sepsis case-fatality rate in these children.
METHODS
A retrospective cross-sectional database
study was conducted by using the 2006,
2009, and 2012 KID from Healthcare Cost
and Utilization Project of the Agency for
Healthcare Research and Quality. The KID is
the largest publicly available all-payer
pediatric inpatient care database in the
United States, containing data from 2 to
3 million pediatric hospital discharges,
excluding neonates, each year.18 We used
2 methods to identify pediatric patients with
sepsis; this was based on methodology used
by Balamuth et al,19 which formed the
foundation of this study’s analysis. In ICD-9-
CM cohort, all patients from 1 month old to
20 years old with diagnoses of severe sepsis
and septic shock (ICD-9-CM codes
995.92 and 785.52, respectively) were
included in the analysis. The incidence,
sepsis case-fatality rate, length of stay
(LOS), and associated comorbidities were
determined in this cohort. In the Angus
cohort, the method described by Angus
et al13 was used to identify patients with
sepsis in the 2006, 2009, and 2012 KID with
diagnoses of bacterial and fungal infections,
along with the diagnoses indicating acute
organ dysfunction. Clinical Classifications
Software (CCS) 2015 version was used to
identify pediatric sepsis by using modified
Angus criteria (Supplemental Tables 5–7).20
Total hospital charges were adjusted for
inflation to the year 2012, by using the
Consumer Price Index inflation calculator
from the US Department of Labor Bureau of
Labor Statistics.21 The Institutional Review
Board at Nicklaus Children’s Hospital
determined this study to be exempt.
STATISTICAL ANALYSIS
The overall incidence of sepsis was
presented as cases per 10 000 discharges,
whereas the incidence of sepsis caused by
specific microorganisms was calculated in
the Angus cohort and presented as
percentages. x
2
for trend analysis was used
to analyze trends in incidence of sepsis in
both cohorts and for each individual
microbiologic etiology. Epi Info StatCalc
(Centers for Disease Control and Prevention,
Atlanta, GA) was used for trend analysis to
compare the changes in incidence and
sepsis case-fatality rate from 2006 to 2012.
Children were grouped by age into 4 groups:
infant (1 month to 1 year), toddler
(2–5 years), school-aged (6–12 years), and
adolescent (13–20 years). x
2
was used to
compare categorical variables, and the
Kruskal-Wallis test was used for comparing
continuous variables. The odds ratio (OR) of
the sepsis case-fatality rate (Table 1) was
calculated by using Pearson’sx
2
, which
used the reference value as odds of sepsis
case-fatality rate from all causes of sepsis
in comparison to that of a particular
microorganism. In the ICD-9-CM cohort,
trend analysis was done for the proportion
of patients coded for septic shock, All
Patients Refined Diagnosis Related Group
(APR DRG) severity of illness (SOI) category
4 (extreme category), use of mechanical
ventilation (invasive or noninvasive) or
vasopressors, and discharge from
children’s hospitals. Binary regression
analysis was performed in the ICD-9-CM
cohort to determine the effect of calendar
year of admission on the case-fatality rate
adjusting for other variables, which
revealed a significant linear trend. For
regression analysis, we have recoded APR
DRG SOI into 3 categories, category 4
(extreme), category 3 (major), and others
(minor and moderate). Data were analyzed
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by using SPSS version 17 (SPSS Inc, Chicago,
IL). Sample weighting was used to present
national estimates.
RESULTS
Demographic Characteristics
There were 8 830 057 nonneonatal pediatric
patient discharges from the US hospitals
during the years 2006, 2009, and 2012. In
total, 26 470 patients were diagnosed with
severe sepsis or septic shock (29.97 per
10 000 discharges) according to ICD-9-CM
criteria and 89 505 patients (101.34 per
10 000 discharges) according to the
modified Angus criteria. There were
18 258 patients who qualified in both the
ICD-9-CM and Angus cohorts. The age
distribution was significantly different in the
ICD-9-CM cohort compared with the Angus
cohort (Table 2). The relative proportion of
infants and toddlers was greater in the
Angus cohort, whereas there was a greater
proportion of adolescents in the ICD-9-CM
cohort. The sex distribution was similar in
both cohorts. Racial distribution was
similar in both cohorts, when compared to
other hospital discharges.
Incidence and Outcomes
Although the incidence of sepsis by using
either definition increased during the study
period (P,.01), the sepsis case-fatality
rate decreased during the same period
(P,.01; Fig 1). The overall case-fatality rate
during the 3 years was 16.5% in the ICD-9-
CM cohort and 7.8% in the Angus cohort.
However, the sepsis-associated mortality
rate (per 10 000 discharges) remained
unchanged in the ICD-9-CM cohort (P5
.55 for trend) and increased in the Angus
cohort (P,.001 for trend; Table 2). In the
Angus cohort, the age-specific sepsis case-
fatality rate was highest among infants,
compared with the other age groups (10.2%
in infants, 7.6% in toddlers, 8.0% in school-
aged children, and 7.0% in adolescents; P,
.01; Fig 2) When the SOI was compared by
using the APR DRG, we found that ICD-9-CM
cohort was more likely to have extreme loss
of function compared with the Angus cohort
(OR: 4.28 [95% confidence interval (CI):
4.10–4.47]; P,.001). In the ICD-9-CM cohort,
trend analyses revealed that there was an
increase in the coding of septic shock but a
decrease in the proportion of APR DRG SOI
4 and use of mechanical ventilation or
vasopressors from 2006 to 2012 (Table 1).
There was an increase in total charges
(adjusted for inflation to 2012) from 2006 to
2012 in both cohorts (P,.01; Kruskal-
Wallis test; Table 2). The LOS for
nonsurvivors was higher in comparison
with those who survived (12 days
[interquartile range (IQR) 3–36] vs 11 days
[IQR 5–25]; P,.01) and nonsurvivors had
higher total charges compared with
survivors ($186 790 IQR [65 679–496 026] vs
$97 178 [IQR 35 239–253 721]; P,.01).
Among nonsurvivors, 7.9% of patients
died on the day of admission, 12.2% on
day 1, and 53.3% within 10 days of
admission (Fig 3).
Bacteriology: Prevalence
Among the bacterial etiologies we
investigated, the prevalence decreased
for all except infections with Escherichia
coli (6.4%–7.3%, P5.02). The ICD-CM
code for methicillin-resistant
Staphylococcus aureus (MRSA) (ICD-9-CM
code 038.12) was not available until 2008,
and, therefore, its prevalence could not
be determined for 2006.22 In the Angus
cohort, MRSA prevalence decreased from
2009 to 2012 (1.3%–1.1%; P5.02),
additionally the “other”Gram-negative
sepsis (ICD-9-CM code 38.49) had the
highest prevalence (7.55%), followed by
Streptococcal sepsis (7.11%), and E coli
sepsis (5.7%; Table 3).
Bacteriology: Case-Fatality Rate
Overall, there was a decrease in sepsis
case-fatality rate due to most bacterial
organisms during the study period; the
only exception was sepsis caused by
meningococcus, in which the case-fatality
rate increased from 15.54% to 16.17%
(P5.01). The median LOS for patients with
meningococcal sepsis who did not survive
was much lower compared with the
patients who died of other causes of sepsis
(1 day [IQR 0–3 days] vs 12 days [IQR
3–35 days]; P,.01). The case-fatality rate
of sepsis due to Pseudomonas (21.49%) was
the highest when compared to the other
bacterial pathogens among the patients in
the Angus cohort for all 3 years (Table 3).
The case-fatality rate of all Staphylococcal
infections (methicillin-sensitive S aureus,
MRSA, and other staph species) was 12.8%
(OR: 1.78 [95% CI: 1.61–1.96]).
Fungal Infections
The overall prevalence of fungal infection
was 5.04% during the study period. The
prevalence did not change significantly from
2006 to 2012, but the case-fatality rate
decreased significantly (19.6%–11.6%; P,
.01; Fig 4). Among fungal infections, candida
was the most commonly associated
organism with severe sepsis (3.77%),
followed by Aspergillus (0.27%; Table 4).
Invasive aspergillosis had the highest case-
fatality rate among all microbiologic
organism found in the study (28.2%;
P,.01).
Children’s Hospitals
Overall, 30% of children in ICD-9-CM cohort
and 31.8% in Angus cohort were discharged
from children’s hospitals. The overall
incidence of sepsis with ICD-9-CM criteria in
children’s hospitals was 50.8 (40.4 in 2006 to
59.5 in 2012) per 10 000 discharges and with
Angus criteria was 183.9 (157.3 in 2006 to
205.8 in 2012) per 10 000 discharges. There
was an increase in the trend of discharge
from children’s hospitals in the ICD-9-CM
cohort during the study period (Table 1).
The case-fatality rate was not significantly
different in those discharged from
children’s hospital in comparison to
nonchildren’s hospitals in the ICD-9-CM
cohort (16.4% vs 15.9%; OR: 1.04 [95% CI:
TABLE 1 The Trend of SOI Indicators and Discharges From Children’s Hospitals in the ICD-9-CM
Cohort From 2006 to 2012
Variable 2006 2009 2012 Total Significance for Trend
APR DRG SOI 4, % 87.6 86.5 76.0 82.8 ,.001
Septic shock ICD-9-CM code, % 67.9 72.8 72.6 71.4 ,.001
Mechanical ventilation or vasopressor use, % 56.5 55.5 49.2 53.4 ,.001
Children’s hospital discharges, % 27.4 29.9 31.9 30.0 ,.001
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0.97–1.12]) but was higher in the Angus
cohort (8.4% vs 7.6%; OR: 1.12 [95% CI:
1.06–1.18]).
Mortality: Regression Analysis
In the ICD-9-CM cohort, a binary regression
analysis was performed, with mortality as
an independent variable and calendar year
of admission, septic shock, APR DRG SOI,
use of mechanical ventilation or
vasopressors, and discharge from
children’s hospitals as dependent factors.
Compared to 2006, the case-fatality rate
from sepsis was lower in 2009 (OR:
0.860 [95% CI 0.792–0.935]) and 2012 (OR:
0.716 [95% CI: 0.657–0.781]).
DISCUSSION
This study is focused on sepsis in the
nonneonatal pediatric population. The
disease process, etiology, pathogenesis, and
outcomes of sepsis in these patients differ
substantially from neonates.23 The KID
provides a large sample size and includes
data from 4200 US community hospitals,
and national estimates gave us an
opportunity to evaluate .8 million
nonneonatal hospital discharges.18 This is a
larger sample size compared to the Public
Health Information System (PHIS), which
includes data from 45 children’s hospitals.24
Studies have revealed that mortality rates
and other parameters, like medical
complexity and LOS, differ between large
teaching hospitals and smaller hospitals.25
Incidence
There was an increase in the incidence and
decrease in the case-fatality rate from
severe sepsis and septic shock during the
study period by using both the ICD-9-CM and
modified Angus criteria. As expected, the
incidence of sepsis was higher by using
the modified Angus criteria compared to
the ICD-9-CM criteria because the modified
Angus method is a more sensitive method of
identifying the patients with sepsis.26
However, the sepsis case-fatality rate was
higher when ICD-9-CM specific codes for
severe sepsis and septic shock were used to
identify sepsis. This suggests higher
specificity but lower sensitivity in identifying
patients with severe illness. The increase in
the incidence and decrease in the sepsis
case-fatality rate is similar to the other
published pediatric sepsis studies.6,19 The
increased incidence of sepsis may be due to
a true increase in sepsis incidence or due to
changes in coding and/or documentation
practices or a combination of both. The
increased incidence may be attributed to
sicker patients being hospitalized, increased
survival of patients with complex conditions,
and improved sepsis detection. A recent
study revealed increased prevalence of in-
hospital cardiac arrests, suggesting an
increased proportion of higher acuity
patients being admitted to the US
hospitals.27 However, the unchanged sepsis-
associated mortality rate (per 10 000 total
discharges) in the ICD-9-CM cohort and
FIGURE 1 Sepsis case-fatality rate and incidence trends in ICD-9-CM cohort and Angus cohort.
Incidence increased and mortality decreased from 2006 to 2012 (P,.01; Epi Info).
FIGURE 2 Age-specific sepsis case-fatality rates in Angus cohort. The sepsis case-fatality rate in
infants (10.2%) was significantly higher than other groups. P,.01 compared with
other groups.
1024 SEHGAL et al
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increased sepsis-associated mortality rate
in the Angus cohort in the face of the
decreasing sepsis case-fatality rate may
suggest overdiagnosis. Similarly, patients in
the ICD-9-CM cohort were much sicker in
comparison with the Angus cohort, on the
basis of APR DRG SOI, which could again
point toward overdiagnosis of pediatric
sepsis by using the Angus criteria.28,29 The
increase in coding of septic shock but
decrease in the proportion of APR DRG SOI
4 and use of mechanical ventilation or
vasopressors from 2006 to 2012 (Table 1)
can be due to a change in coding and/or
documentation practice or due to early
recognition and rescue of sepsis episodes,
thereby decreasing SOI and critical
interventions, or, most likely, due to a
combination of both.
Over the study period, the gap in incidence
of severe sepsis between the 2 cohorts
seemed to decrease, which may indicate
better identification (or documentation)
over the time. We identified sepsis 3.4 times
more often using the modified Angus
criteria than we did using only the ICD-9-CM
codes for severe sepsis and septic shock. In
a recent study, researchers suggested a
need for improvement in the way we code
pediatric organ dysfunction by
incorporating age-specific organ
dysfunction thresholds, like the pediatric
SOFA score, Pediatric Logistic Organ
Dysfunction score, or Pediatric Multiple
Organ Dysfunction Score.30
When this study was compared to a similar
study by Hartman et al,4both studies
revealed an increase in the incidence of
sepsis, whereas culture-positive sepsis
organisms continue to decrease in
incidence. These trends could be explained
by the increase in the coding of sepsis in
the setting of organ dysfunction, for which
infection was suspected but not confirmed
by culture data (so called “culture-negative
sepsis”). Similarly, in other studies in
adults, researchers have found that coding
for sepsis has become more inclusive, with
increased application of these codes to
those without positive blood culture
results.31,32 The only exception to this trend
that was found in this study was the sepsis
FIGURE 3 LOS of nonsurvivors. Within 10 days of admission, 53.3% of the nonsurvivors died.
Most patients died on the first day (12.2%) of admission rather than the day of
admission (7.9%). For purpose of demonstration, only the first 20 days of the LOS are
depicted.
TABLE 3 The Incidence and Sepsis Case-Fatality Rate due to Various Bacterial Causes in the Angus Cohort
2006, OR (95% CI) 2009, OR (95% CI) 2012, OR (95% CI) Prevalence of Bacterial Isolationa, % Case-Fatality Ratea,%
Streptococcal sepsis 1.63 (1.33–1.99) 2.15 (1.78–2.60) 1.90 (1.53–2.36) 7.11 13.63
MSSA sepsis 1.54 (1.25–1.90) 1.53 (1.15–2.04) 1.69 (1.29–2.20) 5.12 11.98
MRSA sepsisb—2.46 (1.91–3.17) 1.75 (1.27–2.43) 1.24 14.42
Other Staphylococcus sepsis 2.00 (1.57–2.53) 1.26 (0.90–1.76) 2.20 (1.57–3.08) 2.47 13.46
Pneumococcal sepsis 1.23 (0.86–1.77) 1.00 (1.00–1.01) 1.88 (1.22–2.88) 2.72 10.64
Bacteroides fragilis sepsis 1.63 (0.81–3.30) 2.11 (1.20–3.74) 1.51 (0.73–3.14) 0.2 13.08
Hinfluenzae sepsis 1.16 (0.41–3.26) 1.08 (0.39–3.01) 0.85 (0.31–2.34) 0.39 3.48
E coli sepsis 1.88 (1.46–2.42) 1.55 (1.21–1.99) 1.05 (0.79–1.41) 5.7 10.93
Pseudomonas sepsis 3.79 (2.91–4.94) 3.39 (2.64–4.36) 2.58 (1.88–3.54) 2.64 21.49
Meningococcal sepsis 1.87 (1.20–2.93) 1.56 (0.88–2.79) 2.59 (1.36–4.95) 1.04 14.32
Serratia sepsis 1.71 (1.02–2.86) 1.49 (0.82–2.72) 0.94 (0.34–2.59) 0.57 10
Other Gram-negative sepsis 2.11 (1.75–2.54) 1.61 (1.32–1.96) 1.79 (1.44–2.21) 7.55 13.22
NOS Gram-negative sepsis 2.37 (1.69–3.33) 3.70 (2.68–5.10) 2.90 (2.02–4.16) 1.88 19.96
Bacteremia NOS 0.70 (0.60–0.82) 0.70 (0.60–0.82) 0.80 (0.68–0.96) 1.26 6.04
Data are presented as odds of sepsis case-fatality rate due to the listed causes of infection as compared with other causes of infection in Angus Cohort. Prevalence
is percentage of patients due to given cause of infection as compared all other causes of sepsis in Angus cohort. MSSA, methicillin-sensitive S aureus; NOS, not
otherwise specified; —, not applicable.
aPrevalence and case-fatality rate represents all 3 y (2006, 2009, and 2012).
bThe MRSA sepsis ICD-9-CM code was introduced after 2008 and, therefore, was not calculated for the 2006 database.
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due to E coli, in which incidence increased
from 5.7% to 6.2% (P5.02). In this study,
we also found that Streptococcal sepsis had
the highest incidence among the patients
who had a positive culture result recorded
(7.11%; Table 1); similarly, other studies had
found that in nonneonatal pediatric patients
with bacteremia, Streptococcal pneumoniae
was the most commonly identified
organism, followed by Neisseria
meningitidis.33,34
Sepsis Case-Fatality Rate
The sepsis case-fatality rate was almost
double in the ICD-9-CM cohort compared
with Angus cohort, which could be due to
more specific codes for severe sepsis and
septic shock used for this cohort, thus
representing a much sicker population in
the former. Although there was a
decreasing trend in the case-fatality rate
from severe sepsis during the study period,
the sepsis-associated mortality rate per all
discharges either remained flat or
increased (Table 2). Therefore, the increase
in sepsis incidence can point toward
misattribution or overdiagnosis of sepsis
due to an emphasis on early recognition of
sepsis or a real increase in sepsis due to an
increase in complex medical conditions and
SOI among hospitalized patients. As
previously mentioned, the Angus cohort
identified 3.4 times as many patients with
sepsis than the ICD-9-CM cohort. Therefore,
we used the Angus cohort to calculate the
case-fatality rate because we felt that it was
a complete representation of pediatric
sepsis. In fact, a 2014 study by Iwashyna
et al26 on adult patients, revealed that the
Angus cohort had higher sensitivity (50.3%
vs 9.2%) in identification of sepsis, although
they had a lower positive predictive value
(70.7% vs 100%) in comparison to ICD-9-CM
diagnosis codes. This could again be due to
overestimation of sepsis by using
administrative data. Similarly, identifying
microbiologic etiology by using ICD-9-CM
codes had its own inherent limitations and
sensitivities, ranging from 23% to 78%,
according to various studies.22,35,36 Sepsis
from Gram-negative organisms had a higher
case-fatality rate, compared to sepsis from
Gram-positive organisms. The case-fatality
rate declined for all bacterial etiologies of
sepsis that were identified in the study
except for meningococcemia. The incidence
of meningococcal sepsis decreased
significantly because of the introduction of
the meningococcal vaccine for adolescents
in 2005.37,38 However, the case-fatality rate
for meningococcal sepsis increased from
2006 to 2012. Interestingly, those patients
who died of meningococcemia had a short
LOS, indicating that they died relatively
quickly after admission. It appears that
the current strategies for early
recognition and management of sepsis
have not made an impact on the early
case-fatality rate from meningococcemia.
This may indicate that these strategies
are inadequate in patients presenting
with meningococcemia or that the
serotype of N meningitidis leading to
an increased case-fatality rate is not
covered by current vaccination.
Regression analysis revealed that after
adjusting for SOI, use of critical
interventions, and discharge from children’s
hospitals, the case-fatality rate was lower in
2009 and 2012 compared to that in 2006.
Although there may be a component of
increased coding as a reason for an
increased incidence of sepsis, the finding of
reduction in case-fatality rate still persisted
after adjusting for some of the variables.
Various factors have played a role in
reducing the sepsis case-fatality rate. The
Surviving Sepsis Campaign began in 2001,
with a goal of reducing mortality from
sepsis in adults by 25%. Guidelines specific
to pediatric sepsis were introduced in 2008,
and, later, a pediatric specific algorithm and
recommendations were developed in 2020,
as a part of the Surviving Sepsis
Campaign.39–41 Current guidelines are
focused on early recognition of sepsis and
the use of age-specific therapies to attain
time-sensitive goals.
FIGURE 4 Incidence and sepsis case-fatality rate of fungal infections among patients with severe
sepsis.
TABLE 4 Fungal Infections Among Patients With Severe Sepsis in the Angus Cohort
Fungal Infection No. Patients Deceased Case-Fatality Rate, %
Candidiasis 3455 403 11.7a
Aspergillosis 887 250 28.2a
Coccidioidomycosis 82 9 11.0
Dermatophytosis 38 2 5.3
Histoplasmosis 22 2 9.1
Blastomycosis 25 3 12.0
aSepsis case-fatality rate dues to these fungal infections were found to be statistically significant when
compared to other causes of infection among patients with severe sepsis.
1026 SEHGAL et al
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Children’s Versus Nonchildren’s
Hospitals
Less than one-third of all children in both
cohorts in our study were discharged from
children’s hospitals. There was an increase
in the trend of discharges from children’s
hospitals during the study period. The case-
fatality rate was similar in children’s
hospital compared to nonchildren’s
hospitals in the ICD-9-CM cohort but was
significantly higher in the children’s hospital
(the absolute difference in case-fatality rate
was 0.8%) among those in the Angus cohort.
Balamuth et al19 have included data from
children’s hospitals during a 9-year period
from 2004 to 2012, whereas our study
included national data of children
discharged during 3 years in similar time
frame. The other key demographic
difference between the 2 studies is that we
have included children ,21 years of age but
excluded neonates, whereas the PHIS study
included all patients ,18 years of age,
including neonates. The case-fatality rate
was similar in the Angus cohort in our study
(8.4% vs 8.1%) compared to that in the study
by Balamuth et al,19 which used the PHIS
database. However, the overall case-fatality
rate is 16.4%, compared to 21.2% in the PHIS
database study in the ICD-9-CM cohort. The
PHIS database includes data from a limited
number of children’s hospitals, whereas the
KID data set includes data from all
children’s hospitals. The ratio of the Angus
to ICD-9-CM cohort in the Balmuth et al19
study is 7.1, whereas the ratio is 3.6 in our
study among discharges from children’s
hospitals. The age distribution and
characteristics of children’s hospitals may
have contributed to the differences in case-
fatality rates. The findings of increased
incidence and decreased case-fatality rate
of sepsis in hospitalized children is similar
in both studies. Similar trends are noted in
children’s hospitals, as reported in
Balamuth et al’s19 study, as well as in all
hospitals as in our study.
Resource Use
Sepsis continues to be a leading cause of
morbidity and mortality among pediatric
patients. Although the exact cost in the
pediatric population is unclear, sepsis in
adults has been found to account for 13% of
TABLE 2 Demographic Characteristic of Pediatric Sepsis
ICD-9-CM Code Cohort Angus Cohort
2006 (n57781) 2009 (n59178) 2012 (n59511) Total (26, 470) 2006 (n525 418) 2009 (n532 170) 2012 (n531 917) Total (n589 505)
Prevalence per 10 000 discharges 25.47a30.15a34.81a29.97a83.22a105.68a116.82a101.34a
Sepsis case-fatality rate, % 19.8a16.9a12.9a16.52a8.9a7.8a6.9a7.87a
Sepsis-associated mortality per 10 000 discharges 5.04 5.10 4.49 4.95 7.41a8.24a8.06a7.98a
Age, median (IQR) 11 (2–17) 12 (2–18) 13 (3–18) 12 (2–18) 9 (1–17) 10 (2–18) 10 (2–18) 10 (2–17)
Age groups, n(%)
Infants (1 mo–1 y) 1010 (13) 1210 (13.2) 1336 (14) 3556 (13.4)a4762 (18.7) 5108 (15.9) 5734 (18) 15 603 (17.3)a
Toddlers and preschoolers (2–5 y) 1289 (16.6) 1828 (19.9) 1746 (18.4) 4864 (18.3)a5821 (22.9) 7534 (23.4) 6943 (21.8) 20 298 (22.5)a
School-aged children (6–12 y) 1137 (14.6) 1663 (18.1) 1620 (17) 4420 (16.7)a4168 (16.4) 5315 (16.5) 5145 (16.1) 14628 (16.3)a
Adolescents and young adults (13–20 y) 4345 (55.8) 4477 (48.8) 4809 (50.6) 13 630 (51.5)a10 667 (42) 14 213 (44.2) 14 095 (44.2) 38 974 (43.3)a
Female sex, % 46.5 49.2 50.1 48.6 48.7 50.1 48.8 49.2
LOS, d, median (IQR) 13 (6–27) 12 (5–26) 10 (5–22) 11 (5–25) 12 (5–26) 11 (5–25) 11 (5–24) 11 (5–25)
Total chargesa, $, median (IQR) 93 824
(39 675–2,15 841)
110 929
(45 622–274 962)
111 653
(46 608–292 745)
112 397
(46 976–277 537)
77 627
(29 032–190 337)
89 183
(32 452–237 707)
106 777
(37 571–287 297)
97 178
(35 239–253 721)
Race and/or ethnicity, %
White 49.3 49.0 48.0 48.9 49.3 48.7 48.7 48.9
Black 16.4 16.4 17.9 16.9 18.6 18.6 19.0 18.6
Hispanic 22.9 23.6 22.4 22.8 21.3 22.2 22.0 22
Others 11.4 11.1 11.8 11.4 10.8 10.4 10.2 10.5
aPrevalence values and mortality rates, when analyzed by using Epi Info trend analysis, revealed that the trends over 3 y had a statistically significant difference; the Pvalue was ,.05.
bCharges are expressed as 2012 dollars.
HOSPITAL PEDIATRICS Volume 10, Issue 12, December 2020 1027
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the total US hospital costs ($24 billion in
2013), making it the highest among the
admissions for all disease states.42 As of
2003, the estimated cost of sepsis in
children in the US was $1.97 billion.16 In this
study, it was determined that the total
hospital charges for nonneonatal sepsis in
children were $8.38 billion in 2012. Although
the sepsis case-fatality rate had decreased,
it was found that the LOS in nonsurvivors
was 38% higher, with almost double the
charges, than those who survived, almost
similar to the study by Odetola et al.43
Similar correlations between mortality and
increased charges have been found in other
studies as well.6
Fungal Infections
Fungal infections continue to be an
important player in the pediatric sepsis
epidemiology.44 Candida sepsis is the
leading cause of fungal sepsis in our study
and other similar studies.45 Ever since the
introduction of amphotericin B and its use
as an antifungal agent since 1958, there has
been a decline in mortality due to invasive
fungemia.46,47 Although the case-fatality rate
of the fungal sepsis decreased in our study,
the overall prevalence of fungal infections
remained stable (∼5%) from 2006 to 2012.
Invasive aspergillosis had the highest case-
fatality rate (28.2%) among any other cause
of sepsis in the study. This may be due to
underlying serious illnesses, such as
immunosuppression and transplant. This
study revealed the case-fatality rate of
invasive candidiasis was 11.7%, compared
to the other studies, which had case-fatality
rates ranging from 10% to 28%.48–50 The
higher case-fatality rates in other studies
were probably due to a larger proportion of
neonatal population. The decreased case-
fatality rate in fungal sepsis can be
explained by the advent of newer antifungal
medications and early recognition of sepsis.
Limitations
There are many limitations to the study.
First, there is a lack of standardization of
sepsis codes because they vary from
1 institution to another. There are chances
that there may be errors while coding and
misinterpretation of the clinical status of
the patient. This may lead to over- or
underestimation of sepsis.
Secondly, sensitivity of only a few codes has
been validated and has variable results in
different studies. Therefore, chances are
that, in some cases, sepsis may not have
been identified when it was present.
Similarly, overestimation of sepsis, on the
basis of the recent studies revealing an
increase in sepsis coding, is also a
possibility.32
Lastly, as mentioned earlier, bacterial and
fungal infection ICD-9-CM code sensitivity
varies a lot, depending on the organism.
This may skew the results for certain
organisms.
CONCLUSIONS
In this study, we show that the incidence of
sepsis has increased, and the case-fatality
rate has decreased among children
hospitalized with sepsis in the United States.
Current strategies for early recognition and
management of sepsis have not made an
impact on the case-fatality rate of
meningococcemia. These findings are
important for focusing the allocation of
health care resources and guiding the
direction of future studies.
Acknowledgments
We thank Ricardo Meneses and Natasha
Strump for their help with data collection.
We also thank Taruna Sehgal, PhD, for
helping us with editing the article.
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2020;10;1021Hospital Pediatrics
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Trends in Epidemiology and Microbiology of Severe Sepsis and Septic Shock in
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