YJINF3515_proof ■ 30 April 2015 ■ 1/6 Journal of Infection (2015) xx, 1e6

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Pediatric sepsis in the developing world

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Niranjan Kissoon a,*, Jonathan Carapetis b,c a

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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 - - -

KEYWORDS Sepsis; Children; Pneumonia; Malaria; Diarrhea

Summary Sepsis is the leading killer of children worldwide, but this is not reflected in estimates of global mortality. While it is important to classify deaths according to specific causes such as pneumonia, malaria and diarrheal diseases, we contend that it is a mistake to ignore the unifying feature of all of these deaths e they are due to sepsis. The issue of highlighting sepsis as the end result of severe infections is not merely cosmetic but is important for a provision 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 Published by Elsevier Ltd on behalf of The British Infection Association.

Introduction Sepsis is the leading killer of children worldwide, but this is not reflected in estimates of global mortality, such as in the Global Burden of Disease study, a systematic analysis of global and regional mortality.1 In this report 17% of neonatal deaths are classified as “sepsis and infectious disorders of the newborn”; however another 15% of neonatal deaths due to infections are not identified as death due to sepsis The term “sepsis” is also excluded in the under 5 childhood deaths although 61% of deaths are due to infections such as malaria (20.8%), diarrheal diseases (11.9%) and lower respiratory infections (12.4%) which all lead to

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 due to sepsis. The implications of recognising sepsis as an entity are dramatic, and are more likely to result in practical interventions to reduce these deaths than a focus on specific infectious agents or the major organ system involved. The International Consensus Conference on Pediatric Sepsis2 defines sepsis as the Systemic Inflammatory Response Syndrome (SIRS) plus suspected or proven infection. From the clinician’s viewpoint, a diagnosis of sepsis recognises that children who die from infections, regardless

* Corresponding author. Tel.: þ1 604 875 2507. E-mail addresses: [email protected] (N. Kissoon), [email protected] (J. Carapetis). c Tel.: þ61 894897777. http://dx.doi.org/10.1016/j.jinf.2015.04.016 0163-4453/ª 2015 Published by Elsevier Ltd on behalf of The British Infection Association. Please cite this article in press as: Kissoon N, Carapetis J, Pediatric sepsis in the developing world, J Infect (2015), http://dx.doi.org/ 10.1016/j.jinf.2015.04.016

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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.3 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 pathophysiologic 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 pneumonia in 26e63% of cases as well as systemic activation of the coagulation cascade.4 In addition, translocation of bacterial components from the gut has been postulated for the endotoxemia, immune paralysis and increased risk of invasive bacterial diseases with its increased morbidity and mortality in malaria.5,6 Diarrheal illness beyond 14 days increases the risk of pneumonia and 26% percent of pneumonia may be associated with recent diarrhea.7,8 Indeed, pneumonia and diarrhea commonly coexist in children in low income countries, and are frequently associated with malnutrition with consequent high mortality.9e15 Diarrheal disease is also commonly associated with severe sepsis and septic shock with high mortality rates of 14% and 67% respectively.16 Thus 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, malaria, severe gastroenteritis, or other invasive bacterial infection. Indeed, the best predictor of death of under 5 children with diarrhea following adequate vascular replenishment is classical severe sepsis: fever or hyperthermia associated with high leukocyte counts with immature leukocytes 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 sepsis18,19 and T and B cell activation20 in 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 and sepsis.8

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 including vaccine development, the failure to highlight the syndrome of sepsis, regardless of the infecting organism(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 separation 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 antimicrobial administration (based on local infectious agents profile), fluid administration (based on ultra vascular volume status), blood products (based on hemoglobin levels), oxygen administration (based evaluation on oxygenation status) and close monitoring.22 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 regions 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 factor that determines under 5 mortality in children worldwide (24, Fig. 3). For instance, the gross national incomes of

Table 1 Signs and symptoms leading to suspicion of infection.  Any newborn e Feels feverish (hot) or cold e Peri-umbilical pus, swelling or redness e Poor or no sucking (not feeding) e Feeble or no cry e Drowsy, difficult to arose e Convulsions e Repeated vomiting e Severe breathing difficulties

 Any child e Not feeding e Feeling cold e Convulsions e Disoriented, difficult to engage e Repeated vomiting e Severe breathing difficulties

Please cite this article in press as: Kissoon N, Carapetis J, Pediatric sepsis in the developing world, J Infect (2015), http://dx.doi.org/ 10.1016/j.jinf.2015.04.016

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3 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 hospitals for children with serious infections leading to sepsis.

Figure 1 sepsis.

Pathophysiology of severe infections leading to

The need for a broader conceptual framework

South Africa and Malaysia are very similar, yet the under 5 mortality in South Africa is ten times that of Malaysia. Similarly Cuba and the United States have similar under 5 mortality of 7 per 1000 live births but the gross national income 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 income 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.27

Figure 2

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 procedures are not followed.29,30 Beyond the issues related to recognition and treatment are social and economic barriers 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 remedies. Other barriers include long distances and nonavailability 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.31 In many parts of the developing world there is also a low emphasis on

Comparison of distribution of wealth and under 5 deaths. Source: Worldmapper.org.

Please cite this article in press as: Kissoon N, Carapetis J, Pediatric sepsis in the developing world, J Infect (2015), http://dx.doi.org/ 10.1016/j.jinf.2015.04.016

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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 rehydration 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.33 The adoption of a broader concept to highlight the burden and far reaching implications 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

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 solutions in building capacity to prevent and treat sepsis in resource poor areas are needed.34 Building capacity entails several factors including increasing community engagement, 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 reduced neonatal mortality,36 and reduced drug overuse and increased early treatment for pneumonia and malaria.37 The provision of low cost antibiotics, child health workers, day clinics and home treatments have revolutionized 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

Please cite this article in press as: Kissoon N, Carapetis J, Pediatric sepsis in the developing world, J Infect (2015), http://dx.doi.org/ 10.1016/j.jinf.2015.04.016

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Figure 4

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Sepsis treatment tailored to available resources.

and guidelines, should take into consideration the resources 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 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 guidelines are hindered by lack of resources40e42 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 recommendations could be implemented in those areas as compared to high income countries in which 100% could be implemented.40

Conclusion Addressing pediatric sepsis in the developing world and resource limited areas is of paramount importance. By 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 treatment of children with sepsis in resource limited environments.

Conflict of interest The authors have no conflict of interests to declare.

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Pediatric sepsis in the developing world.

Sepsis is the leading killer of children worldwide, but this is not reflected in estimates of global mortality. While it is important to classify deat...
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