REVIEW

CURRENT
OPINION Paediatric sepsis
Luregn J. Schlapbach a,b,c

Purpose of review
Sepsis remains among the leading causes of childhood mortality worldwide. This review serves to highlight
key areas of knowledge gain and ongoing controversies pertinent to sepsis in children.
Recent findings
Several recent publications describe the epidemiology of paediatric sepsis, demonstrating the impact on
child health in terms of mortality and morbidity, and the shortcomings of current paediatric sepsis
definitions. Although emerging data support the importance of organ dysfunction as a hallmark of
paediatric sepsis, the understanding of host susceptibility to sepsis and to sepsis severity remains very
limited. Next-generation sequencing and host transcriptomics have the potential to provide new insights
into the pathogenesis of sepsis and may enable personalized medicine approaches. Despite good
observational data indicating benefit of sepsis recognition and treatment bundles, the evidence for the
individual bundle components remains scarce, implying an urgent need for large trials.
Summary
Recent studies have demonstrated distinct epidemiological patterns pertinent to age groups, healthcare
settings, and comorbidities in the era post meningococcal epidemics. Although sepsis quality improvement
initiatives have led to substantial outcome improvements, there is urgency for innovative trials to reduce
uncertainty around the optimal approach for the recognition and treatment of sepsis in children.
Keywords
antimicrobial stewardship, bacteraemia, child, host response, infant, mortality, quality improvement, sepsis,
septic shock, severe infection

INTRODUCTION review serves to highlight key areas of knowledge

Sepsis remains among the leading causes of child- gain and ongoing controversies pertinent to sepsis
hood mortality worldwide [1]. Analyses of large in children. It will not discuss neonatal sepsis in
databases in high-income countries indicate that detail as an entity of its own given recent excellent
only moderate achievements in outcome improve- reviews [5].
ment in children with sepsis have been achieved
over the past two decades. In Australia and New
NEW INSIGHTS INTO THE EPIDEMIOLOGY
Zealand, the reduction in sepsis mortality observed
OF PEDIATRIC SEPSIS
between 2002 and 2013 was almost identical to
that of children requiring critical care support for A meta-analysis on paediatric severe sepsis and sep-
noninfectious causes [2]. In the United States, the tic shock in children identified a pooled mortality of
case-fatality rate in neonates and children with 22.8% for 2011–2016, with the highest mortality
sepsis decreased from 10.3 to 8.9% between 1995
and 2005 [3], with annual costs estimated at $4.8
a
billion. In this context, the resolution on sepsis by Paediatric Critical Care Research Group, Child Health Research Cen-
the World Health Assembly on 26 May 2017 repre- tre, Faculty of Medicine, University of Queensland, bPaediatric Intensive
&& Care Unit, Queensland Children’s Hospital, Brisbane, Australia and
sents a landmark event [4 ]. The resolution urges c
Department of Pediatrics, Inselspital, Bern University Hospital, Univer-
member states to develop, implement, and sustain sity of Bern, Switzerland
activities leading to better prevention, diagnosis, Correspondence to Luregn J. Schlapbach, MD, FCICM, Paediatric
and management of sepsis. In order to achieve these Intensive Care Unit, Queensland Children’s Hospital, South Brisbane
goals, an improved understanding of the physiology QLD 4101, Australia. Tel: +61 7 3068 1111;
of paediatric sepsis, the inherent heterogeneity of e-mail: l.schlapbach@uq.edu.au
the disease, and challenges in current approaches to Curr Opin Infect Dis 2019, 32:497–504
identify and treat sepsis are required. The present DOI:10.1097/QCO.0000000000000583

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Paediatric and neonatal infections

fatalities occurring within 48 h of admission

KEY POINTS && & &
[7 ,10 ,11 ]. Sepsis deaths prior to ICU admission
 Sepsis is a key contributor to paediatric morbidity and are often not accounted for in epidemiological
mortality worldwide, and population-based studies reports [12]. Several studies consistently demon-
indicate that outcome improvements in paediatric sepsis strated a pattern of rapid early mortality reflecting
over the past decade have been moderate at best. refractory shock, followed by late mortality predom-
inantly affecting patients with comorbidities and
 Although sepsis is defined as dysregulated host
response to infection leading to organ dysfunction, the characterized by persistence of multiorgan failure
mechanisms, immunological pathways, and host– and decisions to limit supporting therapies. These
pathogen interaction involved in dysregulated host findings have important implications for the design
response in children with sepsis remain of interventions to recognize and manage of sepsis,
poorly understood. which are unlikely to be effective if deployed too late.
 There is urgency to revise paediatric sepsis definitions A large population-based study on blood cul-
to address the gap created by Sepsis-3, and in view of ture-proven sepsis demonstrated that approxima-
the limitations of current paediatric sepsis definitions, tively a third of sepsis episodes below age 17 each
which are still based on systemic inflammatory occur in neonates, in children with underlying
response syndrome. health conditions, and in children that were previ-
&&

 Systematic screening for sepsis, followed by ously healthy [7 ]. These groups represent clearly
intravenous broad-spectrum antibiotics, and appropriate distinct phenotypes in terms of pathogens, age,
resuscitation including fluids and inotropes within 1 h of severity, and outcomes, with mortality ranging from
sepsis recognition represent the cornerstones of 3% in previously healthy children to 7% in children
paediatric sepsis treatment bundles. with comorbidities. In this study Escherichia coli,
 Although observational studies demonstrated mortality Stapylococcus aureus, coagulase-negative staphylo-
and morbidity benefit associated with bundle cocci (CoNS), and Streptococcus pneumoniae repre-
compliance, the evidence for individual bundle sented the leading pathogens, accounting for over
components is scarce, implying an urgent need for 50% of episodes. These findings are supported from
large trials on paediatric sepsis recognition, fluids and a number of recent studies indicating a shift from
inotropes in sepsis, and optimal antimicrobial the era when Neisseria meningitidis epitomized com-
stewardship in sepsis.
munity-acquired sepsis [13]. This trend, however, is
subject to regional variation, and will depend on the
uptake of antimeningococcal vaccine strategies
&&
observed in studies from developing countries [6 ].
&
[14 ]. Despite widespread pneumococcal immunisa-
Despite the burden sepsis imposes on child health, tion, S. pneumoniae continues to cause a substantial
robust figures on the population-based incidence of proportion of childhood sepsis, related to nonvac-
sepsis in children around the globe are scarce. cine strains and less effective protection from
Sepsis incidence remains strongly age-depen-
&
certain vaccine strains [15 ]. Recent studies demon-
dent, accounting for major discrepancies in inci- strate the impact of staphylococcal and streptococ-
dence estimates when studies including paediatric cal infections as leading pathogens for community-
ICU (PICU) [2] or neonatal ICU (NICU) patients only
&&
acquired and hospital-acquired sepsis [2,7 ,16]. The
&&
are compared with population-based studies [7 ]. A emergence of staphylococcal sepsis carries impor-
&&
recent systematic meta-analysis [8 ] identified 15 tant implications, as features such as multidrug-
studies describing sepsis incidence in 12 middle- resistance, abscess formation, and clot formation
income and high-income countries on four conti- often make source control and pathogen clearance
nents. The authors estimated the aggregate paediat- challenging.
ric sepsis incidence at 48 cases in children per It is important to note that only approxima-
100 000 person-years. However, heterogeneity tively half of children admitted to PICU with a
across studies was large and data from low-income clinical diagnosis of sepsis have a microbiologically
countries, where sepsis is known to impose the confirmed infection [2,17]. Even in the large
greatest burden, was lacking. Overall, these figures European Childhood Life-Threatening Infectious
may grossly underestimate the incidence and mor- Diseases Study (EUCLIDS), where extended micro-
tality related to sepsis at global scale, as sepsis very biological diagnostics were performed, no pathogen
probably accounts for the bulk of the three million
& &
was found in 41% of children with sepsis [18 ,19 ].
infection-related deaths annually in children under In addition, the relevance of viral pathogens identi-
5 years of age [9]. fied in children with sepsis remains often difficult to
Importantly, the majority of paediatric sepsis
&& &
ascertain [20 ,21 ]. For example, staphylococcal
mortality befall very early, with over 50% of sepsis is a well known complication of influenza

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 Paediatric sepsis Schlapbach

& &&
virus infections, and human parechovirus fre- [28 ,29 ]. Finally, the revised sepsis criteria have
quently causes epidemics of sepsis-like presenta- been criticized in relation to their compatibility
tions in infants. On the other hand, positive viral with sepsis quality improvement initiatives [30].
testing for viruses in children with sepsis, such as The emphasis on highly specific criteria, which were
adenovirus, parainfluenza virus, and others may derived from models trained on mortality as primary
represent false positive results, ongoing viral shed- outcome risks falling short of the clinical need for
ding, viral coinfection, or a viral infection, which rapid early recognition, when changes in patient
facilitated the development of sepsis. management are more likely to lead to improved
outcomes. From a clinical perspective, criteria
that incorporate information on whether a patient
DEFINING PEDIATRIC SEPSIS ‘is likely to benefit from the sepsis bundle’ would be
The sepsis definition for adult patients characterizes highly desirable (Fig. 1). Let us assume three hypo-
sepsis as dysregulated host response to infection [22] thetical patients A (bronchiolitis), B (pneumonia
leading to life-threatening organ dysfunction, and with effusion) and C (septic shock without a source)
abandoned the concept of systemic inflammatory who present with tachycardia and tachypnea. All
response syndrome (SIRS), which had been consid- three may be sick, and all three may be on a trajec-
ered essential for the definition of sepsis for two tory towards organ dysfunction, or already have
decades. For the first time, criteria for sepsis were not organ dysfunction. Patients A, B and C may require
primarily consensus based, but derived from large respiratory support, and B and C will benefit from
databases including Electronic Health Records antibiotics. But only C may benefit from a sepsis
(EHR) [23]. Despite the undeniable benefits of bundle with fluids and inotropes. In the future,
this data-driven approach, which has certainly criteria may become available that identify pheno-
improved the robustness of sepsis incidence mea- types of children with sepsis or at risk for sepsis,
&
sures [24 ], a number of challenges result for the which are more likely to benefit from specific inter-
& &&
paediatric community [25 ]. ventions [31 ].
First, the Sepsis-3 definition excluded neonatal
and paediatric age groups, leaving a gap in the group
with the highest life-time sepsis incidence. A Paedi- THE HOST IN PEDIATRIC SEPSIS
atric Sepsis Definition Taskforce is currently in prog- Host susceptibility factors include maturational pro-
ress with the aim to develop and validate criteria for cesses, such as gestational and postnatal age [32],
sepsis in children. Second, although the concept of comorbidities, such as iatrogenic immunosuppres-
‘dysregulated host response’ has its appeal and in sion, and genetically determined susceptibility.
principle biologic rationale, it is neither well defined Up to 50% of paediatric sepsis episodes affect chil-
nor amenable to quantitative or qualitative mea- dren with chronic or complex health conditions,
& &&
surement [26 ,27]. Certainly, SIRS was a poorly spe- often related to indwelling medical devices [2,7 ].
cific construct, which was met in many febrile At least a fraction of these should be considered in
children with runny noses as much as children with principle preventable, highlighting the importance
overwhelming septic shock, and the performance of of robust implementation of bundles to prevent
SIRS to characterize children with infection at central line-associated bloodstream infections,
&
higher mortality risk is poor [28 ]. Translating the ventilator-associated pneumonia and catheter-
concept of dysregulated host response to a practical associated urinary tract infections [33]. The impact
meaning outside the simple operationalization of of healthcare-associated infections on costs, the
sepsis as infection with organ dysfunction may help health-care system and long-term outcome of
to differentiate patterns of excessive (for example, patients is considerable [17,34].
toxic shock) or insufficient (anergy) host response to Although sepsis is defined as dysregulated host
infection as a prerequisite to individualized treat- response to infection leading to organ dysfunction,
ment. Third, the strong focus in Sepsis-3 on organ the mechanisms, immunological pathways, and
dysfunction scores, which were developed in ICU host–pathogen interaction involved in dysregulated
settings poses problematic towards application in host response remain poorly understood [35], albeit
settings where laboratory resources are not avail- epidemiological data suggest a considerable genetic
able. In addition, the criteria are difficult to apply contribution [36]. This concept is supported by
in busy Emergency Departments where decision- genome-wide association studies, which have, for
making is often based on rapid clinical assessment example, identified common genetic variation in
before laboratory tests are available. The quick SOFA Complement Factor H and Complement Factor
(qSOFA) score was proposed in adults to address this H-related protein-3 as associated with meningococ-
gap; however, its performance is moderate at best cal infections [37]. It has been proposed that severe

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Paediatric and neonatal infections

Child with an infecon

(viral, bacterial, parasic, mycobacterial)

Likelihood of responding to specific treatment

Signs +/- laboratory markers of altered physiology
indicang likely trajectory of deterioraon

Dysregulated host response

leading to organ dysfuncon
Prevalence

Severity

Compromised organ
perfusion - shock

Refractory shock

MOF

death

FIGURE 1. Schematic representation of the step-wise diagnostic challenges relevant for defining criteria for paediatric sepsis.
MOF, multiorgan failure.

infections during childhood are more likely to repre- have been proposed, for example, to differentiate
sent the manifestation of rare, single-gene disorders SIRS from sepsis [45]. In addition, host transcriptom-
[38,39]. A study of 163 children with invasive pneu- ics may help to gain novel insights into the patho-
mococcal disease found that 10% harboured an genesis of sepsis: a study combining gene expression
underlying primary immunodeficiency [40]. These data from several adult and paediatric ICU cohorts
findings are supported by a proof-of-concept reported on 58 gene transcripts associated with sepsis
&&
study using whole exome sequencing in children mortality [46 ]. Nonsurvivors were found to have
with community-acquired Pseudomonas aeruginosa overexpression of inflammation-related pathways.
sepsis, which identified underlying primary immu- This approach holds promise to identify patient sub-
nodeficiencies in 25% of fatal cases [41]. With the groups more likely to benefit from targeted therapies,
rapidly increasing availability of next-generation such as immunomodulation [47]. Indeed, first obser-
sequencing to diagnose monogenic conditions in vational studies in critically ill children with sepsis
critically ill children [42], such approaches may indicate that the duration of organ dysfunction is
potentially become cost efficient in comparison to related to the degree of suppression of both innate
conventional genetic diagnostics. However, to date, and adaptive immunity during the early stage of
&&
it remains unclear, which children with sepsis benefit sepsis [48 ]. In the near future, we will witness trials
from more thorough immunologic or genetic inves- on personalized medicine using drug candidates for
tigations. host immunomodulation in children with sepsis,
More recently, host gene expression studies several of which are already undergoing investigation
have demonstrated that signatures of selected host in adults [49,50].
transcripts can provide discrimination between
infected and noninfected patients at high accuracy.
Herberg et al. identified a two-gene signature to QUALITY IMPROVEMENT INITIATIVES TO
differentiate bacterial from viral infection which IMPROVE RECOGNITION AND TREATMENT
performed well [43,44]. Translation of host tran- OF SEPSIS
script-based sepsis markers to commercialization is Timely intravenous broad-spectrum antibiotics, and
underway and a number of promising candidates appropriate resuscitation including fluids and

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 Paediatric sepsis Schlapbach

inotropes represent the cornerstones of paediatric deaths of children with sepsis [54]. Although ran-
sepsis treatment bundles as recommended by the domized controlled studies on sepsis quality
Surviving Sepsis Campaign [51] and the American improvement initiatives are lacking, a number of
&
College of Critical Care Medicine [52]. Most institu- observational studies [55 ,56,57] have reported sig-
tional audits on time to treatment of septic nificant mortality and morbidity reductions after
children have revealed large intrainstitutional and the implementation of sepsis bundles in paediatric
interinstitutional variability of care [53], confirming hospitals associated with increased reliability of
root-cause analyses into potentially preventable bundle delivery. The largest study in the field

Table 1. Gaps in knowledge and priorities for future research in paediatric sepsis
Theme Pragmatic research questions relevant for current practice Potentially promising human study designs

Definition of Can Sepsis-3 be translated to paediatric age groups? Prospective international development and
paediatric sepsis What is the diagnostic performance of SIRS and 2005 definitions of validation cohorts
severe sepsis in comparison with other organ dysfunction measures? Study collaborations include global settings
Can criteria be developed that are applicable to high-income, middle- Big data, including Electronic Health Records
income and low-income settings? Machine learning/Artificial intelligence
Can we identify distinct sepsis phenotypes more likely to respond to
certain interventions? What is fluid refractory shock, what is refractory
shock?
Burden and What is the global burden of paediatric sepsis burden in terms of mortality Large-scale linkage studies of mandatory health
outcome of and morbidity? data, including ICD-10, hospital coding,
sepsis What are direct and indirect costs of paediatric sepsis at patient and hospital costing data.
population level in different settings? Qualitative and quantitative longitudinal
What is the postdischarge mortality after sepsis in different settings? surveys/questionnaires to survivors and families
What are long-term outcomes after sepsis, including neurocognitive, embedded in prospective cohorts
quality of life, and psychological outcomes? Smartphone app facilitated data capture
Which sepsis outcomes do children and families care most about?
Sepsis What is the age-specific maturational impact on the paediatric immune Functional longitudinal sepsis studies
pathogenesis system? Targeted testing of children with sepsis for
What characterizes dysregulated host response to infection, and which primary immunodeficiencies ‘OMICs’ –
dynamic markers identify and quantify dysregulated host response in proteomics, metabolomics, GWAS, WGS, and
children? What leads to multiorgan dysfunction? RNA sequencing
What is the role of common and rare genetic variation in paediatric
sepsis susceptibility? How should children with sepsis be investigated in
terms of immunological and genetic studies?
Screening and Do systematic screening tools improve the accuracy of sepsis recognition? Cluster randomized-controlled trials including
recognition of How can sensitivity be maintained without a too high false positive rate? stepped wedge trials
sepsis Clinician-driven versus paper-based versus electronic health-record based Artificial intelligence-driven algorithms for sepsis
approaches? recognition
Do routine lactate measurements improve the diagnostic accuracy of
sepsis recognition?
Cost effectivity of novel biomarkers to support sepsis screening?
Initial resuscitation What type, volume, and rate of fluid should be administered during initial Trial platforms
of sepsis sepsis resuscitation? How should treatment response be assessed Adaptive trials
(physiological markers, lactate, pulse contour analysis, etc.)?
How early should inotropes be started and which inotrope should be
initially used?
Immuno-modulation Should hydrocortisone be routinely administered in septic shock? Trials using predictive and prognostic enrichment
in sepsis Is there benefit of metabolic resuscitation (hydrocortisone, ascorbic acid, strategies (for example, using biomarkers)
thiamine) in paediatric sepsis? Precision medicine
Can we identify patients/disease stages more likely to benefit from
targeted immunomodulative agents, such as monoclonal antibodies?
Extracorporeal Optimal indications for extracorporeal membrane oxygenation in refractory Propensity-matched studies
therapies in septic shock? Feasibility of RCTs
sepsis Impact of extracorporeal blood purification methods on host response,
duration of organ dysfunction and survival?
Sepsis quality Adaptation of quality improvement initiatives to different healthcare settings? Big/linked data
improvement Balancing measures of sepsis quality improvement studies – what is the Cluster randomized-controlled trials including
impact, morbidity, and costs related to treatment delivered to children stepped wedge trials
who post hoc do not have sepsis?
Antimicrobial Can the use of blood cultures be optimized to increase diagnostic yield? Diagnostic accuracy and comparative health
stewardship Can novel molecular technologies replace blood cultures in a cost economic studies on molecular diagnostics
effective way? Effective strategies to deal with increasing multidrug- including rapid pathogen sequencing
resistant bacteria. RCT allocating patients to specific algorithms for
Do broad sepsis quality improvement initiatives lead to excessive diagnostic procedures
antimicrobial usage, and how could such be addressed? Novel antibiotic drug candidate trials
Impact of early antibiotic exposure on microbiome.
Can novel sepsis markers (including transcriptomic markers) improve
antimicrobial usage, and increase safe stopping of antibiotics?
What is the optimal duration and choice of antimicrobial therapy in
pediatric sepsis? Does individualized antimicrobial dosing (dosing
software, enhanced therapeutic drug monitoring, pharmacogenomics)
result in improved outcomes?

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Paediatric and neonatal infections

reported on 1179 children with sepsis at 54 hospitals excessive fluid therapy [69]. The FEAST trial demon-
in New York State and observed that the completion strated increased mortality associated with fluid
of the sepsis bundle (consisting of blood cultures, administration in children with life-threatening
intravenous antibiotics, and initiation of fluid resus- infections in a low-income setting [70]. Very recently,
citation) within 1 h was associated with a significantly a post hoc analysis of the FEAST study revealed clus-
lower risk-adjusted mortality (odds ratio 0.59, 95% ters of patients with respiratory, cardiovascular and
confidence interval 0.38–0.923, P ¼ 0.02) [58 ].
&&
neurologic dysfunction using a novel simple clinical
Due to the relative rarity of sepsis in comparison score to identify severity and progression of organ
&&
with large numbers of mostly mild febrile encoun- dysfunction [71 ]. This study underpins the contri-
ters in paediatric Emergency Departments, sepsis bution of hyperchloraemic acidosis and worsening
screening tools need to balance the risk of overtreat- respiratory and neurological dysfunction towards
ment carefully with the risk of missing children with increased mortality associated with fluid bolus. The
&
sepsis (Fig. 1) [59 ]. Sepsis recognition tools – such as findings support the need for large trials on type
& & &
the NICE guidelines [60] – range from paper-based [72 ,73 ] and volume of fluids [74 ] in paediatric
tools incorporating physiological markers, lactate sepsis resuscitation, and alternative fluid-sparing
&
[61 ], and other items, such as parental concern strategies. Interestingly, a recent study comparing
&
[62 ], to sophisticated EHR-assisted trigger tools Artificial Intelligence-based decision-making in a ret-
[63], the performance of which may be enhanced rospective cohort of critically ill adults with sepsis
&
using machine learning [64 ]. There is urgency to revealed better outcomes with increased use of ino-
&&
develop more specific approaches ruling out sepsis tropes and reduced use of intravenous fluids [75 ].
to reduce unnecessary antibiotic administration in
&
children where sepsis is not confirmed [65 ]. Such
CONCLUSION
approaches need to consider the local epidemiology
and pretest probability in combination with the Sepsis in children remains one of the leading causes
severity of presentation, and may benefit from of mortality and morbidity. Long-term sequelae
integrating markers indicating higher versus lower include disability related to amputations and brain
likelihood of sepsis. Importantly, the observational injury. Recent studies have demonstrated distinct
data suggesting survival benefit of rapid antibiotics epidemiological patterns pertinent to age groups,
within 1 h of sepsis identification are based on healthcare settings, and comorbidities in the era
cohorts of predominantly shocked patients post meningococcal epidemics. Although wide-
&&
[58 ,66], whereas emergency departments and spread sepsis quality improvement initiatives have
wards are commonly faced with children where led to substantial outcome improvements, there is
sepsis is but one of several diagnostic options. In urgency for innovative trials to reduce uncertainty
view of potential adverse effects, long-term risks to around the optimal approach for the recognition
the patient and the community, such as multidrug- and treatment of sepsis in children.
resistance and necrotizing enterocolitis, and costs to
&& Acknowledgements
the healthcare system [67 ], judicious antimicrobial
stewardship in children evaluated for sepsis repre- None.
sents an important balancing measure for sepsis
quality improvement initiatives [59 ].
&
Financial support and sponsorship
L.J.S. is supported by a Practitioner Fellowship of the
National Health and Medical Research Council of
IMPLICATIONS FOR RESEARCH AND Australia and New Zealand, and by the Children‘s
PRACTICE Hospital Foundation, Brisbane, Australia.
Table 1 provides an overview on selected pragmatic
research questions relevant for current and future Conflicts of interest
practice in paediatric sepsis. Importantly, the major- There are no conflicts of interest.
ity of components of currently recommended strate-
gies to recognize and treat sepsis in children remain
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& of special interest
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