Journal of Infection (2015) 71, S21eS26

www.elsevierhealth.com/journals/jinf

Pediatric sepsis in the developing world

b,c
Niranjan Kissoon a,*, Jonathan Carapetis

a
Global Child Health, Department of Pediatrics and Emergency Medicine, University of British
Columbia, Vancouver V6H 3V4, Canada
b
Telethon Kids Institute, University of Western Australia, West Perth, Western Australia 6872,
Australia

Accepted 21 April 2015

Available online 24 April 2015

KEYWORDS Summary Sepsis is the leading killer of children worldwide, but this is not reflected in esti-
Sepsis; mates of global mortality. While it is important to classify deaths according to specific causes
Children; such as pneumonia, malaria and diarrheal diseases, we contend that it is a mistake to ignore
Pneumonia; the unifying feature of all of these deaths e they are due to sepsis. The issue of highlighting
Malaria; sepsis as the end result of severe infections is not merely cosmetic but is important for a pro-
Diarrhea vision of care especially in resource limited environments where skilled healthcare workers are
in short supply and care is being delivered by teams with limited training and clinical skills.
Highlighting sepsis and the few simple emergency therapeutic interventions needed will focus
on the actual problems that confront clinicians in regions with limited resources.
ª 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Introduction sepsis. 1 While it is important to classify deaths according

to specific causes, we contend that it is a mistake to ignore
the unifying feature of all of these deaths e that they are
Sepsis is the leading killer of children worldwide, but this is
due to sepsis. The implications of recognising sepsis as an
not reflected in estimates of global mortality, such as in the
entity are dramatic, and are more likely to result in prac-
Global Burden of Disease study, a systematic analysis of
tical interventions to reduce these deaths than a focus on
global and regional mortality. 1In this report 17% of
specific infectious agents or the major organ system
neonatal deaths are classified as “sepsis and infectious dis-
involved.
orders of the newborn”; however another 15% of neonatal
The International Consensus Conference on Pediatric
deaths due to infections are not identified as death due
Sepsis 2 defines sepsis as the Systemic Inflammatory
to sepsis The term “sepsis” is also excluded in the under
5 childhood deaths although 61% of deaths are due to infec- Response Syndrome (SIRS) plus suspected or proven infec-
tion. From the clinician’s viewpoint, a diagnosis of sepsis
tions such as malaria (20.8%), diarrheal diseases (11.9%)
recognises that children who die from infections, regardless
and lower respiratory infections (12.4%) which all lead to

* Corresponding author. Tel.: þ1 604 875 2507.

E-mail addresses: nkissoon@cw.bc.ca (N. Kissoon), Jonathan.Carapetis@telethonkids.org.au (J. Carapetis).
c
Tel.: þ61 894897777.

http://dx.doi.org/10.1016/j.jinf.2015.04.016
0163-4453/ª 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
S22
of their source, develop various combinations of septic
shock, cardiac failure, acute respiratory distress syndrome,
or other organ dysfunction. Indeed, the largest study of
children with severe febrile illness and impaired perfusion
in sub Saharan Africa support supports this contention.
All deaths were due to a combination of severe shock and
acidosis with or without respiratory and neurological
dysfunction, findings which satisfy all the criteria for severe
sepsis and septic shock. 2
Clinical pathophysiological rationale for sepsis
That severe infections leads to sepsis or severe sepsis and
septic shock is supported by clinical and robust pathophys-
iologic evidence. From the clinician’s standpoint, it is often
difficult to separate the three most common causes of
death (pneumonia, malaria and diarrheal diseases) in
children with certainty. These conditions often co-exist
and any or all, when severe, lead to sepsis and septic shock.
For instance, cerebral malaria is associated with pneu-
monia in 26e63% of cases as well as systemic activation of
the coagulation cascade. In4 addition, translocation of bac-
terial components from the gut has been postulated for the
endotoxemia, immune paralysis and increased risk of inva-
sive bacterial diseases with its increased morbidity and
mortality in malaria. 5,6Diarrheal illness beyond 14 days in-
creases the risk of pneumonia and 26% percent of pneu-
monia may be associated with recent diarrhea. Indeed,
7,8
pneumonia and diarrhea commonly coexist in children in
low income countries, and are frequently associated with
9e15
malnutrition with consequent high mortality. Diarrheal
disease is also commonly associated with severe sepsis
and septic shock with high mortality rates of 14% and 67%
respectively. 16Thus clinicians require an approach that
manages the complex syndrome (sepsis) rather than
focusing on a single disease entity which may result in
another equally dangerous, condition being missed. A child
presenting in shock may have any or all of pneumonia, ma-
laria, severe gastroenteritis, or other invasive bacterial
infection. Indeed, the best predictor of death of under 5
children with diarrhea following adequate vascular replen-
ishment is classical severe sepsis: fever or hyperthermia
associated with high leukocyte counts with immature leu-
kocytes in the blood and multi organ dysfunction. 17
That many children with diarrheal disease are septic is
not surprising because intestinal barrier dysfunction is
associated with diarrheal infection. This dysfunction may
result in translocation of infectious by products which can
incite systemic cytokine production leading to SIRS and
sepsis 18,19 and T and B cell activation 20in children after
natural cholera. Moreover, tumor necrosis factor alpha
(TNF Alpha) and interferon gamma (IFY) was increased in
children with acute diarrhea as compared to uninfected
controls which results in a systemic inflammatory response
8 swelling or redness
and sepsis.
Importance of highlighting sepsis
Highlighting sepsis as the end result of severe infections is
not merely cosmetic but important for the provision of care
especially in resource limited environments where skilled
N. Kissoon, J. Carapetis
healthcare workers are in short supply and care is being
delivered by teams with limited training and clinical skills.
While recognition of specific diseases is important for
epidemiology, research and preventative measures
3
including vaccine development, the failure to highlight
the syndrome of sepsis, regardless of the infecting organ-
ism(s), as a major killer and public health issue, is an
oversight with serious implications for the clinician because
the most important interventions to reduce sepsis
morbidity and mortality must be made generically and
before a definitive diagnosis is available. Thus, calling
attention to the need for time-sensitive treatment in
severe infections is unlikely to happen if severe infections
are compartmentalized in separate silos such as malaria,
pneumonia and diarrheal diseases. 21
While much separation may be necessary to explore
better diagnostic and therapeutic strategies, such separa-
tion is unnecessary for initial evaluation in which severe
infections will present with a limited number of danger
signs and symptoms (Table 1, Fig. 1). The initial treatment
options for most of the severe infections that can lead to
sepsis are also limited and are likely to include antimicro-
bial administration (based on local infectious agents pro-
file), fluid administration (based on ultra vascular volume
status), blood products (based on hemoglobin levels), oxy-
gen administration (based evaluation on oxygenation sta-
22
tus) and close monitoring. The WHO pocketbook
Integrated Management of Childhood Illness uses this
approach by highlighting danger signs and therapies rather
than individual diseases. Highlighting sepsis and the few
simple emergency therapeutic interventions needed will
focus on the actual problems that confront clinicians in re-
gions with limited resources.
The stark reality for children in the developing
world with severe infections
While sepsis accounts for a high proportion of under 5
deaths, most of these deaths occur in Sub Saharan Africa
and Asia, areas in which the resources are fairly limited
( 22,23 Fig. 2). However, financial resources, as reflected by
the gross national income per capita, are not the only fac-
tor that determines under 5 mortality in children worldwide
(24, Fig. 3). For instance, the gross national incomes of
Signs and symptoms leading to suspicion of
Table 1
infection.
e Feels feverish (hot) or cold e Not feeding
Any newborn Any child
e Peri-umbilical pus, e Feeling cold
e Convulsions
e Poor or no sucking e Disoriented, difficult
(not feeding) to engage
e Feeble or no cry e Repeated vomiting
e Drowsy, difficult to arose e Severe breathing
e Convulsions difficulties
e Repeated vomiting
e Severe breathing
difficulties
Pediatric sepsis in the developing world
Figure 1 Pathophysiology of severe infections leading to
sepsis.
South Africa and Malaysia are very similar, yet the under 5
mortality in South Africa is ten times that of Malaysia. Simi-
larly Cuba and the United States have similar under 5 mor-
tality of 7 per 1000 live births but the gross national income procedures are not followed.
of the United States is ten times that of Cuba. Childhood
deaths worldwide have decreased over the past decade
from about 9.5 million to approximately 7 million, largely
due to decreases in mortality from infectious diseases
including diarrheal diseases, measles and pneumonia and
malaria. 25 However, the outcome for children in low in-
come countries is now worse: children from these countries
are now more than 18 times more likely to die before the
age of 5 years than in high income countries, whereas, in
1990, they were 14 times more likely to die. 26,27
Figure 2 Comparison of distribution of wealth and under 5 deaths. Source: Worldmapper.org.
S23
This is not surprising when one considers the major
barriers to care that face children with infections in
resource limited areas in developing countries. In many
cases a parent with a sick child has to walk several miles to
a district clinic in which there may be a medical assistant or
a nurse with two years training and with limited ability to
provide care beyond antibiotics or antimicrobials and
treatment of seizures with rectal medications. It is in the
district hospital that the general practitioner and a nurse
may be able to do simple tests such as malaria and parasite
screening tests and provide intravenous medications and
oxygen. 28 Thus, there is a need to address the barriers to
access as well as provision of care in district clinics and hos-
pitals for children with serious infections leading to sepsis.
The need for a broader conceptual framework
Sepsis has clinical, social, economic and political origins
and implications. Care for sepsis in the developing world is
plagued by delays in recognition and in many cases basic
29,30
Beyond the issues related
to recognition and treatment are social and economic bar-
riers to care in the developing world. These include poor
health seeking behavior because of lack of education and
money, and faith in supernatural causes and home rem-
edies. Other barriers include long distances and non-
availability of transport as well as many stops and long
waiting time In addition, lack of empowerment of women
in many parts of the world results in poor health seeking
care behavior for their children. In31 many parts of the
developing world there is also a low emphasis on
S24
Figure 3 Under 5 mortality versus gross national income. Source: www.gapminder.org.
preventative services, the management of staff shortages,
dealing with inequity in health care and poorly regulated
managed health care sectors. Another major issue is the
migration of many of the medical personnel from resource
poor countries to the developed world.
The impact of preventative factors is well illustrated in a
review of over 14 years of hospital admission for bacterial
sepsis in children in Brazil. During this period, the number of
admissions for bacterial sepsis decreased more than 50%,
largely due to immunization, sanitation, trash collection,
water treatment and a national nutrition and oral rehydra-
tion program. 32 That sepsis has implications beyond acute
therapy is also exemplified by the issue of late mortality
post discharge after an episode of sepsis. Studies in Kenya,
Tanzania, Malawi, and Guinea Bissau have all shown that
post discharge mortality, among those who have had sepsis,
in resource poor countries are extremely high and in many
cases higher than during admission. The 33 adoption of a
broader concept to highlight the burden and far reachingim-
plications of sepsis is paramount for advocacy for resources
to support innovative programs in resource poor areas.
Innovative ideas and solutions for treatment of
sepsis in resource limited areas
One of the major barriers to sepsis care in resource limited
areas is education of healthcare workers. In many cases
N. Kissoon, J. Carapetis
specialists are unavailable and much of healthcare is
delivered by village health workers, nurses and general
practitioners. Thus we need tailored training for teams with
limited medical skills and knowledge base. In addition we
need to determine the setting in which they will be trained
and what technologies can be leveraged to assist in
diagnosis and treatment. Beyond training, innovative solu-
tions in building capacity to prevent and treat sepsis in
resource poor areas are needed. Building 34 capacity entails
several factors including increasing community engage-
ment, strengthening competencies at all levels, adapting
guidelines based on available resources and best current
evidence, use of innovative technologies for diagnosis and
treatment as well as strengthening transport and referral
systems. 34,35 Just as importantly we need to evaluate the
impact of interventions and stimulate collaboration and
sharing of best practices such that care can be provided
for larger numbers.
There are other innovative solutions such as intervention
packages used by child health workers which has resulted in
36
reduced neonatal mortality, and reduced drug overuse
and increased early treatment for pneumonia and ma-
laria. 37 The provision of low cost antibiotics, child health
workers, day clinics and home treatments have revolution-
ized care and saved lives in many environments (Pakistan,
Bangladesh, Egypt, Ghana and Vietnam). 38,39 In addition,
global child sepsis initiatives, as well as clinical pathways
Pediatric sepsis in the developing world
Figure 4 Sepsis treatment tailored to available resources.
and guidelines, should take into consideration the re-
sources that are available to treat infections in many areas
(22 , Fig. 4). Indeed this is the approach taken by the World
Federation of Pediatric Intensive and Critical Care Societies 2.
in crafting guidelines that are relevant and based on the
local context and resources. Local context is important in
that studies have shown that the surviving sepsis campaign 3.
40e42
guidelines are hindered by lack of resources in many
African and Sub Saharan African countries to the extent
that only 1.5% (4 of 263) had resources to implement the
guidelines in its entirety. In addition, only 72% of recom- 4.
mendations could be implemented in those areas as
compared to high income countries in which 100% could
be implemented. 40 5.
Conclusion 6.
Addressing pediatric sepsis in the developing world and
resource limited areas is of paramount importance. By
7.
highlighting sepsis as the final common pathway to death
and disability from serious infections it is hoped that there
will be a new focus on pragmatic issues facing the clinician.
This approach is likely to facilitate the diagnosis and 8.
treatment of children with sepsis in resource limited
environments.
Conflict of interest 9.
The authors have no conflict of interests to declare.
10.
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