the host response to sepsis and developmental impact

8/13/2019 The Host Response to Sepsis and Developmental Impact

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DOI: 10.1542/peds.2009-3301; originally published online April 26, 2010;2010;125;1031Pediatrics

Wheeler

James Wynn, Timothy T. Cornell, Hector R. Wong, Thomas P. Shanley and Derek S.The Host Response to Sepsis and Developmental Impact

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The Host Response to Sepsis and Developmental

Impact

This is the first in a series of 3 state-of-the-art review articles focusedon sepsis.

abstractInvasion of the human by a pathogen necessitates an immune re-

sponse to control and eradicate the microorganism. When this re-

sponse is inadequately regulated, systemic manifestations can result

in physiologic changes described as “sepsis.” Recognition, diagnosis,

and management of sepsis remain among the greatest challenges

shared by the fields of neonatology and pediatric critical care medi-

cine. Sepsis remains among the leading causes of death in both devel-

oped and underdeveloped countries and has an incidence that is pre-

dicted to increase each year. Despite these sobering statistics,

promising therapies derived from preclinical models have universally

failed to obviate the substantial mortality and morbidity associated

with sepsis. Thus, there remains a need for well-designed epidemio-

logic and mechanistic studies of neonatal and pediatric sepsis to im-

prove our understanding of the causes (both early and late) of deaths

attributed to the syndrome. In reviewing the definitions and epidemi-

ology, developmental influences, and regulation of the host response

to sepsis, it is anticipated that an improved understanding of this hostresponse will assist clinician-investigators in identifying improved

therapeutic strategies. Pediatrics 2010;125:1031–1041

AUTHORS: James Wynn, MD,a Timothy T. Cornell, MD,b

Hector R. Wong, MD,c Thomas P. Shanley, MD,b and Derek

S. Wheeler, MDc

a Division of Neonatology, Duke University Children’s Hospital,

Durham, North Carolina; b Division of Critical Care Medicine, C. S.

Mott Children’s Hospital, University of Michigan, Ann Arbor,

Michigan; and c Division of Critical Care Medicine, Cincinnati

Children’s Hospital Medical Center, Cincinnati, Ohio

KEY WORDS

sepsis, septic shock, developmental influence, hemodynamics,

coagulation cascade, immune function

ABBREVIATIONS

SIRS—systemic inflammatory response syndrome

VLBW—very low birth weight

EOS—early-onset sepsis

LOS—late-onset sepsis

SVR—systemic vascular resistance

ATP—adenosine triphosphate

DIC— disseminated intravascular coagulation

APC—activated protein C

IL—interleukin

TNF—tumor necrosis factor

Ig—immunoglobulin

www.pediatrics.org/cgi/doi/10.1542/peds.2009-3301

doi:10.1542/peds.2009-3301

Accepted for publication Mar 1, 2010

Address correspondence to Thomas P. Shanley, MD, C. S. Mott

Children’s Hospital, F-6892, 1500 E Medical Center Dr, Ann Arbor,

MI 48109. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2010 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have

no financial relationships relevant to this article to disclose.

Funded by the National Institutes of Health (NIH).

STATE-OF-THE-ART REVIEW ARTICLES

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“Sepsis,” which refers to the “decom-

position of animal or vegetable or-

ganic matter in the presence of bacte-

ria,”1 first appeared more than 2700

years ago in the poems of Homer. Hip-

pocrates also used the term “sepsis”

and believed that the decompositioncould release “dangerous principles”

that could cause “autointoxication.”2

Lewis Thomas3 furthered this concept

when he proposed that the clinical re-

sponses seen in sepsis were the result

of the host’s response to the infectious

agent. In 1991, an American College of

Chest Physicians/Society of Critical

Care Medicine consensus conference

was convened to create a framework

in which to define the systemic re-sponse to sepsis, which resulted in

defining criteria for systemic inflam-

matory response syndrome (SIRS),

sepsis, severe sepsis, and septic

shock.4,5 These criteria were refined a

decade later (2001) by the participants

of the International Sepsis Definitions

conference 6 and were based exclu-

sively on adult criteria. The Interna-

tiona l Consensus Conf erence on Pe-

diatric Sepsis and Organ Dysfunctionwas convened in 2002 to develop

pediatric-specific definitions for

SIRS, sepsis, severe sepsis, septic

shock, and multiple-organ dysfunc-

tion syndrome.7

Through clinical observations, pedia-

tricians and neonatologists had recog-

nized that the systemic inflammatory

response of tachycardia, tachypnea,

hyperthermia, and leukocytosis (Table

1), most commonly triggered by infection, could also be present after

trauma, burn injury, pancreatitis, and

various other insults. As a result, this

physiologic response was defined as

SIRS with no reference to the presence

of infection. Sepsis was defined as an

SIRS response associated with infec-

tion on the basis of either microbio-

logic cultures or strong clinical evi-

dence of the presence of an infection.

Severe sepsis was defined as sepsis

plus evidence of organ dysfunction de-

fined around pediatric parameters

(Table 2), whereas septic shock was

defined as meeting sepsis criteria plus

the presence of “cardiovascular dys-

function” present after the administra-

tion of at least 40 mL/kg in 1 hour of

fluid. Cardiovascular dysfunction in-

cluded age-specific hypotension (Table

3 shows age-related normal values),

requirement of a vasoactive agent to

maintain normal blood pressure, or

evidence of poor end-organ perfusion(Table 2).

Although the International Consensus

Conference on Pediatric Sepsis and Or-

gan Dysfunction report listed criteria

for both “newborns” (aged 0–7 days)

and “neonates” (aged 1 week to

month), preterm newborns were spe-

cifically excluded from the definitions.7

This omission was related to a number

of factors including the charge of the

consensus conference, insufficient

representation by practitioners in neo-

natology, and a general agreement

that premature infants fell outside the

scope of clinical practice of the major-

ity of conference attendees. Further-

more, the diagnosis of sepsis can be

challenging in the very preterm infant

undergoing the physiologic transi-

tional period immediately after birth.

Other features that complicate the de-

lineation of this diagnosis include the

subtlety of nonspecific presenting

signs and the contribution of transitional physiology, which make it imper-

ative that clinicians maintain a high in-

dex of suspicion. This reliance on

clinical “gestalt” has been substanti-

ated by evidence showing that a physi-

cian’s clinical suspicion of culture-

positive sepsis has significant positive

predictive value (70%) in excess of

most laboratory studies.8,9 In some

neonatal cases, the clinical presenta-

TABLE 1 Definitions of SIRS, Infection, Sepsis, Severe Sepsis, and Septic Shock

SIRS

The presence of at least 2 of the following 4 criteria, 1 of which must be abnormal temperature or

leukocyte count:

Core temperature of 38.5°C or 36°C;

Tachycardia, defined as a mean heart rate at 2 SDs above normal for age in the absence of

external stimulus, chronic drugs, or painful stimuli or otherwise unexplained persistent elevation

over a 0.5- to 4-h time period;

For children younger than 1 year: bradycardia, defined as a mean heart rate at 10th percentile for

age in the absence of external vagal stimulus, -blocker drugs, or congenital heart disease; or

otherwise unexplained persistent depression over a 0.5-h time period;

Mean respiratory rate at 2 SDs above normal for age or mechanical ventilation for an acute

process not related to underlying neuromuscular disease or the receipt of general anesthesia; or

Leukocyte count elevated or depressed for age (not secondary to chemotherapy-induced

leukopenia) or 10% immature neutrophils

Infection

A suspected or proven (by positive culture, tissue stain, or polymerase-chain-reaction test) infection

caused by any pathogen; or

A clinical syndrome associated with a high probability of infection (evidence of infection includes

positive findings on clinical examination, imaging, or laboratory tests eg, white blood cells in a

normally sterile body fluid, perforated viscus, chest radiograph results consistent with

pneumonia, petechial or purpuric rash, or purpura fulminans)

SepsisSIRS in the presence of or as a result of suspected or proven infection

Severe sepsis

Sepsis plus 1 of the following:

Cardiovascular organ dysfunction as defined in Table 2; or

Acute respiratory distress syndrome

2 other organ dysfunctions as defined in Table 2

Septic shock

Sepsis and cardiovascular organ dysfunction as defined in Table 2

Modified from Goldstein B, Giroir B, Randolph A. Pediatr Crit Care Med . 2005;6(1):2– 8.

1032 WYNN et al at Indonesia:AAP Sponsored on November 15, 2013pediatrics.aappublications.orgDownloaded from









tion may be overtly obvious with signif-

icant apnea or respiratory distress,

cyanosis, hypotension, bradycardia,

poor perfusion, acidosis, and leth-

argy. Alternatively, the presence of 1

or more subtle and nonspecific signs

such as feeding intolerance, self-

resolving apnea or bradycardia, mild

tachypnea or tachycardia, abnormal

serum glucose level, or decreased

activity may be the only warning

before fulminant clinical deteriora-

tion.10,11 Although some useful ancil-

lary laboratory tests for the diagno-

sis of neonatal sepsis exist, the

diagnosis remains a significant clin-

ical challenge.12

EPIDEMIOLOGY OF PEDIATRIC

SEPSIS

Worldwide, sepsis is one of the most

common causes of death in children.

One of the first pediatric-specific stud-

ies to analyze data from 5 centers re-

ported that 21% to 25% of the 726

patients met criteria for “sepsis syn-

drome” (mortality rate of 11%).13

Proulx et al14 analyzed 1000 admis-

sions over a 1-year period and ob-

served that SIRS was present in 82% of

PICU patients, whereas sepsis was pre-sent in 23%, severe sepsis was present

in 4%, and septic shock was detected

in 2% of the patients. Although sepsis-

specific mortality rates were not re-

ported, the overall mortality rate of the

entire cohort (N 1058) was 6% and

differed among those patients with

multiple-organ dysfunction; the condi-

tion in many of these patients with

multiple-organ dysfunction was trig-

gered by sepsis.14

Watson et al15

exam-ined discharge data to show that se-

vere sepsis accounted for 9675 of the

1.6 million discharges of patients 19

years of age or younger, which results

in a national estimate of 42 371 cases

of pediatric sepsis per year (0.6 cases

per 1000 population). Not all centers

reported data for premature low birth

weight or very low birth weight (VLBW)

neonates who were, by convention, in-

cluded as “infants” in the analysis. The

grouping of infants (any child younger

than 1 year) comprised nearly half the

children with severe sepsis, and nearly

half of those in the sepsis cohorthad at

least 1 comorbid condition. The high-

est incidence of severe sepsis was

found in neonates (5.2 cases per 1000

population) compared with 5- to 14-

year-olds (0.2 cases per 1000 popula-

tion), and the mortality rate reported

for the entire cohort (including some

neonates within the infant category)

with severe sepsis was 10.3%, which

gives an estimate of 4364 deaths per

year nationally. These data positioned

sepsis as the third leading cause of

death in children nationwide. In a

follow-up study from 1995 and 1999,

Watson et al16 found that the rate of

severe sepsis had increased 11%,

mostly because of an increase in the

number of VLBW neonates succumbing

TABLE 2 Organ-Dysfunction Criteria

Cardiovascular dysfunction

Despite administration of isotonic intravenous fluid bolus of 40 mL/kg in 1 h:

Decrease in blood pressure (hypotension) to 5th percentile for age or systolic blood pressure at

2 SDs below normal for age (see Table 3); or

Need for vasoactive drug to maintain blood pressure in the normal range (dopamine 5 g/kg per

min or dobutamine, epinephrine, norepinephrine at any dose); or

2 of the following

Unexplained metabolic acidosis (base deficit 5.0 mEq/L);

Increased arterial lactate at 2 times the upper limit of normal;

Oliguria (urine output 0.5 mL/kg per h);

Prolonged capillary refill (5 s); or

Core-to-peripheral temperature gap 3°C

Respiratory

PaO2/FIO

2 300 in absence of cyanotic heart disease or preexisting lung disease; or

PaCO2 65 torr or 20 mm Hg over baseline PaCO

2; or

Proven need or 50% FIO2

to maintain saturation at92%; or

Need for nonelective invasive or noninvasive mechanical ventilation

Neurologic

Glasgow Coma Score 11; or

Acute change in mental status with a decrease in Glasgow Coma Score of 3 points from abnormal

baseline

HematologicPlatelet count 80 000/ L or a decline of 50% in platelet count from highest value recorded over the

past 3 d (for chronic hematology/oncology patients); or

International normalized ratio 2

Renal

Serum creatinine level2 times the upper limit of normal for age or twofold increase in baseline

creatinine level

Hepatic

Total bilirubin concentration 4 mg/dL (not applicable for newborns); or

ALT 2 times upper limit of normal for age

FIO2

indicates fraction of inspired oxygen; ALT, alanine aminotransferase.

Modified from Goldstein B, Giroir B, Randolph A. Pediatr Crit Care Med . 2005;6(1):2–8.

TABLE 3 Age-Specific Vital Signs and Laboratory Variables

Age Group Heart Rate, Beats per Min Respiratory Rate,

Breaths per Min

Leukocyte Count,

103/mm

Systolic Blood

Pressure, mm HgTachycardia Bradycardia

0 d to 1 wk 180 100 50 34.0 65

1 wk to 1 mo 180 100 40 19.5 or 5.0 75

1 mo to 1 y 180 90 34 17.5 or 6.0 100

2–5 y 140 NA 22 15.5 or 6.0 94

6–12 y 130 NA 18 13.5 or 4.5 105

13 to 18 y 110 NA 14 11.0 or 4.5 117

NA indicates not applicable.

Modified from Goldstein B, Giroir B, Randolph A. Pediatr Crit Care Med . 2005;6(1):2–8.












to sepsis. Despite this increase in

cases of severe sepsis, the mortality

rate caused by severe sepsis in previ-

ously healthy children was found to

be 9%.16

Odetola et al17 conducted a similar ret-

rospective study of hospitalized chil-

dren (aged 0–19 years) with severe

sepsis (sepsis with at least 1 organ

dysfunction as estimated from Inter-

national Classification of Diseases,

Ninth Revision coding) within the 2003

Kids’ Inpatient Database, which in-

cluded almost 3 million pediatric dis-

charges from 3438 hospitals in 36

states. The authors identified nearly

13 000 hospitalizations for severe sep-

sis in the database and provided a national estimate of 21 448 admissions

for severe sepsis and an overall mor-

tality rate of 4.2%. There was a similar

increase in the prevalence of and

mortality from severe sepsis in the

younger cohort (younger than 4

years), with a notable increase in ado-

lescents compared with 4- to 10-year-

olds. Perhaps most important is that

these investigators noted the signifi-

cant association of both comorbid con-ditions and existing organ dysfunction

to worsening outcomes and higher re-

source utilization.17

In the most recent epidemiology study

of pediatric sepsis, Czaja et al18 inves-

tigated readmission rates and late

mortality for children (1 month to 18

years of age) after severe sepsis.

There were 7183 children diagnosed

with severe sepsis from 1990 through

2004, 6.8% of whom died during what the authors termed the “sentinel ad-

mission” or within 28 days of dis-

charge. It is important to note that

death certificates confirmed that an

additional 434 (6.5%) of those who had

survived the initial 28 days after ad-

mission subsequently died during the

follow-up period, and the highest late

death rate occurred within 2 years of

the initial hospitalization.18 Although

most of the early, as well as the late,

deaths occurred in children with co-

morbidities (8% early death, 10.4% late

death), 8% of the children with no co-

morbidities died during their initial

hospitalization.

Neonatal sepsis is also a significant

global killer that is responsible for

1 million deaths annually and is

among the top 10 causes of neonatal

death in the United States.19 Stoll et

al20–23 reported that the incidence of

neonatal sepsis depends on gesta-

tional age and time of onset (early-

onset sepsis [EOS] [72 hours after

birth] versus late-onset sepsis [LOS]

[72 hours after birth]). Deficien-

cies in the immune system function

of neonates further delineated below

increase the risk of morbidity for

survivors (only 28% alive and consid-

ered normal at 18 months) and mor-

tality, the rate of which can exceed 70%

for the most immature neonates.24

Risk factors for developing sepsis in

the premature neonate have been

described and were reviewed in refs

10, 20, 21, and 25–30. Notable find-

ings from the 1996 National Instituteof Child Health and Human Develop-

ment Neonatal Research Network

report include the observation that

culture-proven EOS was uncommon

(only 1.9% of nearly 8000 VLBW

neonates). Group B streptococcus

(31%), Escherichia coli (16%), and

Haemophilus influenzae (12%) were

the most common pathogens associ-

ated with EOS in this era. The fact

that antibiotic therapy for suspectedsepsis was often started at birth in

VLBW neonates and continued for 5

or more days, despite a negative

blood culture result in 98% of cas-

es,27 underscores the challenge of

excluding sepsis in the symptomatic

VLBW neonate. In this report, 26% of

VLBW neonates with EOS died, but it

was not clear that all deaths were

attributable to infection because

only 4% of the 950 deaths that oc-

curred in the first 72 hours of life

were attributed to infection.27 Key

maternal factors such as group B

Streptococcus –positive vaginal cul-

ture, prolo nged rupture of mem-

branes, intrapartum fever, and cho-rioamnionitis are strongly associated

with EOS.28 Gender (male), birth

weight (1000 g), and gestational

age (30 weeks) as well as common

clinical interventions associated

with prematurity (eg, intubation, me-

chanical ventilation, and central ve-

nous access) are also associated

with an increased risk of sep-

sis.20,21,24 These data illustrate that

sepsis is a major health problem inpediatrics.

KEY DEVELOPMENTAL DIFFERENCES

THAT AFFECT NEONATAL AND

PEDIATRIC SEPSIS

Severe sepsis manifests with concur-

rent derangements in almost every

single organ system. The degree to

which any of these derangements are

manifest is variable and influenced by

multiple host and pathogen factors in-

cluding the patient’s age,15,31 gen-

der,32,33 race,34,35 and genetic back-

ground,36–39 as well as the presence of

comorbid conditions,15,17,40,41 the pa-

tient’s underlying immune status,15,40

and the specific pathogen involved42,43.

There are several key developmental

differences in the host response to in-

fection and therapy that clearly delin-

eate pediatric sepsis as a separate, al-

beit related, entity from adult sepsis. A

complete picture of pediatric sepsis,

therefore, requires a thorough under-

standing of those developmental differ-

ences and how they contribute to organ

dysfunction in the pediatric patient with

septic shock.

Developmental Differences in

Hemodynamics

Septic shock is caused by a combina-

tion of decreased intravascular vol-










ume (either absolute or relative hypo-

volemia), myocardial dysfunction, and

abnormalities in peripheral vasoregu-

lation. Absolute hypovolemia (ie, de-

creased intravascular volume second-

ary to poor oral intake, vomiting,

diarrhea, or increased insensiblelosses, etc) or relative hypovolemia (ie,

decreased intravascular volume sec-

ondary to capillary leak, increased ve-

nous capacitance, etc) is the most

common cause of shock in chil-

dren.44,45 However, abnormalities in pe-

ripheral vasoregulation and/or myo-

cardial dysfunction likely play a

greater role in the hemodynamic de-

rangements associated with pediatric

septic shock, especially in neonatesand young infants.46–50 Ceneviva et al51

placed 50 children with fluid-

refractory shock into 1 of 3 categories

on the basis of hemodynamic data ob-

tained with a pulmonary artery cathe-

ter: (1) a hyperdynamic state charac-

terized by high cardiac output (5.5

L/min/m2 body surface area) and low

systemic vascular resistance (800

dyne-seconds/cm5) (classically re-

ferred to as warm shock); (2) a hypo-

dynamic state characterized by low

cardiac output (3.3 L/min/m2 body

surface area) and normal-to-low sys-

temic vascular resistance (SVR); or (3)

a hypodynamic state characterized by

low cardiac output and high SVR

(1200 dyne-seconds/cm5) (classi-

cally referred to as cold shock). Thus,

in contrast to adults in whom septic

shock is characterized by high cardiac

output and low SVR, most children had

low cardiac output and high SVR (cold

shock) and required vasodilators to

decrease SVR, increase CI, and im-

prove peripheral perfusion.51 These

findings were confirmed in multiple

studies.52–57 For example, Feltes et al57

reported decreased left ventricular

systolic function and increased after-

load in 5 of 10 children with septic

shock. Thus, myocardial depression is

a common pathophysiological feature

in pediatric septic shock, which raises

the question as to differences unique

to myocardial functional response in

children as compared with adults.

Significant developmental differences

in both myocardial structure and func-

tion compromise the compensatory

response of children and neonates to

sepsis.48,58,59 For example, changes in

excitation-contraction coupling occur

as a result of the immaturity of the

calcium-regulation system (T tubules,

sarcoplasmic reticulum, L-type Ca2

channels). These developmental differ-

ences lead to alterations in the nor-

mal mechanisms that regulate the

Ca2-induced Ca2 releasethat triggers

excitation-contraction coupling such that the neonatal myocardium de-

pends more on extracellular versus in-

tracellular calcium for contractility

compared with the mature heart,60–63

which explains why neonates are more

sensitive to calcium-channel antago-

nists.61 Further differences in the neo-

natal myocardium include decreased

expression of adenosine triphosphate

(ATP)-sensitive K channels (KATP

)64

and alterations in -adrenergic receptor signal transduction.65 K

ATP chan-

nels are inhibited by intracellular ATP

and activated by intracellular nucleo-

side diphosphates (eg, adenosine

diphosphate). These channels are acti-

vated in response to ischemia or hyp-

oxia and, therefore, are important for

the adaptations that must occur dur-

ing sepsis.66–68

The infant’s myocardium also has a

relatively decreased left ventricularmass in comparison to that of the

adult myocardium,69,70 as well as an in-

creased ratio of type I (decreased elas-

ticity) to type III (increased elasticity)

collagen.71 In addition, the infantile

myocardium functions at a relatively

high contractile state, even at base-

line.48,72 Collectively, these develop-

mental changes result in a relatively

limited capacity to increase stroke vol-

ume during stress48,70,73; hence, neo-

nates and young infants are critically

dependent on an increase in heart rate

to generate increased cardiac output.

However, although adults can easily

double their heart rate to compensate

for decreased stroke volume, infantsare unable to compensate in this man-

ner because of their relatively higher

baseline heart rate.74 In addition, myo-

cardial perfusion occurs to the great-

est degree during diastole and de-

pends directly on the difference

between diastolic blood pressure and

left atrial pressure and inversely with

heart rate. Thus, as the heart rate in-

creases, diastolic filling will eventually

reach a point at which further in-creases in cardiac output are limited.

Cardiac output, however, is main-

tained for a time via peripheral vaso-

constriction (increased SVR in-

creased afterload) in an attempt to

maintain adequate preload.53–55,75 Fi-

nally, systolic performance in neo-

nates and young infants is critically de-

pendent on afterload.72,76 An increase

in systemic afterload in the setting of

septic shock, therefore, results in

markedly reduced left ventricular sys-

tolic performance and myocardial dys-

function. Collectively, these hemody-

namic changes, which are clinically

manifested as cold shock (decreased

CI, increased SVR), are more com-

monly observed in critically ill children

with septic shock.

Developmental Differences in the

Coagulation Cascade

Sepsis is one of the most common

causes of disseminated intravascular

coagulation (DIC), which results from

uncontrolled thrombin generation and,

subsequently, leads to both microvas-

cular thrombosis that contributes to

end-organ dysfunction and, paradoxi-

cally, bleeding diathesis caused by

the consumption of coagulation fac-

tors.77–79 One of the seminal findings

that has contributed to an improved












molecular understanding of sepsis-

induced organ dysfunction is this ob-

served “switch” from a homeostatic

balance of anticoagulant versus pro-

coagulant factors to a skewing toward

procoagulation with impaired anti-

coagulation favoring microvascular thromboses. A number of factors con-

tribute to dysregulation of the coagu-

lation cascade in sepsis: activation of

procoagulant pathways; consumption

of clotting factors; alterations in fibri-

nolysis; and reduced anticoagulant ac-

tivity, which results in what is com-

monly described as DIC (reviewed in

refs 78 and 80–82). Simultaneous to

enhanced fibrin production, attenu-

ated fibrinolysis caused by increasedplasminogen activator inhibitor type 1,

as well as dysfunction and/or deple-

tion of natural anticoagulants (anti-

thrombin III, protein C, protein S, and

tissue factor pathway inhibitor) oc-

curs. A correlation between a low anti-

thrombin III level and mortality in sep-

sis provided the impetus for studying

antithrombin III replacement; how-

ever, no consistent benefit has been

observed in adults,83–86 children,87,88 orneonates.89

Patients with sepsis also have sub-

stantial depletion of protein C (re-

viewed in refs 90 –92). Given encourag-

ing preclinical studies with the use of

activated protein C (APC) in sepsis,

clinical trials in adults were com-

menced, for example, in the Protein C

Worldwide Evaluation in Severe Sepsis

(PROWESS) trial.93 In this study, APC

was associated with a statistically sig-nificant reduction in the 28-day mortal-

ity rate for sepsis in adults. In further

analysis, APC seemed to confer benefit

only on those with the highest severity

of illness (Acute Physiology and

Chronic Health Evaluation [APACHE]

score 25); subsequent studies have

been executed in an attempt to identify

the adult patient population who

would most benefit from this thera-

py.93–95 The pediatric phase III study

that used APC for severe sepsis was

stopped after an interim analysis re-

vealed that APC was unlikely to im-

prove the resolution of organ dysfunc-

tion and that its use was associated

with an increased risk of serious ad-verse events in children younger than

60 days.96,97 To date, only case reports

have discussed the use of APC in neo-

natal sepsis.98–100 Taken together, the

current state of the use of APC in sep-

sis remains controversial in adults

and seems to be of no benefit in either

children or neonates.

There are important developmental

differences in the coagulation and fi-

brinolytic system that affect the patho-physiology and management of DIC in

children versus adults.101 For example,

neonates and infants are at an in-

creased risk for bleeding complica-

tions, primarily because of lower cir-

culating levels of vitamin K–dependent

procoagulant factors (factors II, VII, IX,

and X), a decreased capacity to gener-

ate thrombin, and decreased circulat-

ing levels of coagulation inhibitors. The

neonatal coagulation system containsall of the essential factors necessary

for an intact coagulation system, al-

though the amounts of factors are de-

creased relative to adult levels.101 Sim-

ilarly, although there are no distinct

differences in platelet quantity be-

tween children and adults, platelets are

relatively hyporesponsive to physiologic

agonists.102 These unique differences

mayexplaintheincreasedrisk of mortal-

ity in younger children with DIC, com-pared with older children103 and adults,

and why the therapeutic response to

modulators of coagulation differ.


Inflammatory Response to Sepsis

To contextualize the developmental dif-

ferences in the host response to sep-

sis, specific contributions of some me-

diators and mechanisms must be

summarized briefly. Key mediators of

the inflammatory response to host in-

vasion include numerous gene prod-

ucts (eg, cytokines and chemokines,

coagulation-related factors, and im-

mune active proteins), all of which are

critical to ensuring recruitment andactivation of immune cells that are

necessary for pathogen eradication.

Literally hundreds of gene products

play some role in the complex host re-

sponse to sepsis, and a comprehen-

sive review of them is beyond the

scope of any single report on this sub-

ject. The reader is directed to recent

reviews of the mediators of this patho-

physiologic response in sepsis104–107

and gene-expression profiling. Here,we briefly highlight some key develop-

mental differences in the host innate

and adaptive immune responses (re-

viewed in ref 108 and summarized in

Table 4).

Although a number of mediators re-

sponsible for the initiation and propa-

gation of sepsis were identified early,

few researchers have attempted to

identify those responsible for the even-

tual resolution of inflammation. Thisconcept seems to be important, be-

cause failure to reduce proinflamma-

tory mediators over the course of

sepsis was associated with higher

mortality rates.109–111 Also, patients

who died from adult respiratory dis-

tress syndrome produced lower levels

of interleukin 10 (IL-10) compared with

survivors.112 More recently, the hypoth-

esis that an overexuberant counter-

regulatory process can lead to gene de-activation in sepsis and, thus, increase

mortality rates in both children113 and

adults114 has identified a need to better

understand this mechanism.

We now understand that immune activa-

tion triggered by pathogens also drives

expression of endogenous counterregu-

latorsof inflammation, which resultsin a

state termed the “compensatory anti-

inflammatory response syndrome.”










Such mediators include both cytokine

antagonists (eg, soluble tumor necrosis

factor [TNF] receptor, IL-1Ra) and “anti-

inflammatory” cytokines (eg, IL-10 and

transforming growth factor [TGF-])

(reviewed in refs 115–117). It is clear

that other regulatory cytokines (eg,

TGF-, IL-13) possess anti-inflammatory

properties and contribute to the endog-

enous regulation of the acute inflamma-

tory response to sepsis. On the basis of

additional observations, there is grow-

ing recognition that this compensatoryanti-inflammatory response may play a

greater role in the pathobiology of septic

shock and multiple organ failure in chil-

dren compared with adults.118

For example, Wynn et al119 compared

the host inflammatory response and

subsequent mortality rate in a fecal

slurry model of generalized peritonitis

between neonatal (aged 5–7 days) and

young adult (aged 7–10 weeks) mice.

Compared with young adult mice, sep-sis in the neonatal mice was associated

with a markedly attenuated systemic in-

flammatory response, decreased bacte-

rial clearance, and increased mortality

rate. Similar studies in a hemorrhagic

shock model revealed decreased lungin-

flammation and injury in immature mice

versus adult mice.120

Consistent with these results, Bars-

ness et al121 collected peritoneal

macrophages during laparoscopic

surgery in children (mean age: 3.6

years) and adults (mean age: 46.9

years) and treated them ex vivo with

IL-1 and lipopolysaccharide. Both

IL-1- and lipopolysaccharide-induced

proinflammatory cytokine (TNF- and

IL-6) production were markedly in-

creased in the peritoneal macrophage

cultures obtained from children ver-

sus adults. It is important to note that

the anti-inflammatory response, as de-

termined by IL-10 production, wasmuch greater in the cultures obtained

from children such that the ratio of

IL-10 to TNF- was significantly higher

in macrophage cultures from children

compared with those from adults,

which suggests a predominant anti-

inflammatory phenotype.121 These data

have provided the impetus to further

understand the immune-function dif-

ferences that exist across the entire

spectrum of ages, all of which are sub- ject to sepsis.


Immune System

There are other significant differences

in the host immune response between

the different ages. Clearly, compared

with immunologically mature popula-

tions, neonates have an increased risk

for the development and progression

of a systemic infection. Broad deficits

across both innate and adaptive im-

mune function have been identified

and have been reviewed in detail (sum-

marized in Table 4).122–124 In particular,

the preterm neonate exhibits signifi-

cant vulnerability because of exacer-bated immunologic immaturity as well

as the need for life-sustaining clinical

interventions that increase the likeli-

hood of infection. Adaptive immune

function is hindered by deficiencies in

(1) T-cell function (T-helper 2 skewed

cytokine responses, increased re-

quirement for CD4 T-cell stimulation,

decreased CD8 T-cell cytolytic activity,

abundant and potent T-regulatory pop-

ulation), (2) B-cell function (weak immu-noglobulin [Ig] production [predomi-

nantly IgM], poor Ig class switching,

decreased maternal-derived serum IgG

level caused by premature delivery, poor

antibody response to polysaccharide

antigens, poor T-cell–dependent B-cell

stimulation, and limited antecedent

antigen exposure before birth), and (3)

underdeveloped secondary lymphoid

tissues.

Although the contribution of the distinct adaptive immune-system func-

tion in neonates in the setting of sepsis

has not been fully defined in humans,

the results of experimental work in

mice have suggested that substantial

differences exist. In contrast to find-

ings from adult mice, transgenic

neonatal mice that lacked an adap-

tive immune system showed no dif-

ference in sepsis survival when com-

pared with wild-type neonatal mice.124

Altered adaptive immune-system func-

tion leaves the neonate largely depen-

dent on the innate immune system for

defense against pathogenic challenge.

The neonatal innate immune system is

also limited in function compared with

that of adults and children. Deficits

exist in barrier integrity, circulating

complement components, expression

of antimicrobial proteins and peptides

TABLE 4 Timing of Acquisition of Mature Immune Function

Gray shading indicates the estimated age range at which near–adult-level function is attained.












(intercellular and circulating), produc-

tion of type I interferons, and T-helper

1 polarizing cytokines. Furthermore,

there are quantitative and qualitative

impairments in neutrophil, monocyte,

macrophage, and dendritic cell func-

tion and decreased response to mostToll-like receptor agonists. The net ef-

fect of these deficits is a functional im-

munocompromised state that leaves

the premature neonate extremely sus-

ceptible to microbial invasion. Future

studies aimed at characterizing the

unique neonatal pathophysiologic re-

sponse, including defining critically

important elements and the capacity

for positive immunomodulation, are

necessary.125

CONCLUSIONS

Sepsis, a syndrome characterized by

variable, systemic physiologic changes

triggered by infection, continues to

provide an extraordinary challenge to

clinicians who manage critically ill ne-

onates, children, and adolescents. The

incidence of sepsis continues to in-

crease with a mortality rate (both

early and late) that positions it among

the leading causes of death for chil-

dren. Developmental differences that

affect the hemodynamic, inflamma-

tory, coagulation, and immune re-

sponses make it difficult to extrapolate

data from adult studies to these vul-

nerable pediatric populations. In light

of emerging data that suggest develop-

mental influences on epigenetic regu-

lation of gene expression in sepsis, it is

imperative that neonatal and pediatric

clinician-investigators drive and exe-

cute sepsis studies in their respective

populations. Only through mechanistic

studiescomplementedwithwell-crafted,network-based interventional trials will

we make an impact on this most chal-

lenging pathologic syndrome.

ACKNOWLEDGMENTS

This work was supported by National

Institutes of Health grants K12HD047349

(to Dr Cornell), R01GM064619 and

1RC1HL100474-01 (to Dr Wong),

and RO1HL097361, RO1GM066839, and

UL1RR024986 (to Dr Shanley).

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DOI: 10.1542/peds.2009-3301

; originally published online April 26, 2010;2010;125;1031Pediatrics

WheelerJames Wynn, Timothy T. Cornell, Hector R. Wong, Thomas P. Shanley and Derek S.

The Host Response to Sepsis and Developmental Impact

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