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A pediatric perspective on World Sepsis Day in 2021: leveraging lessons from the pandemic to reduce the global pediatric sepsis burden?

2021; American Physical Society; Volume: 321; Issue: 3 Linguagem: Inglês

10.1152/ajplung.00331.2021

1522-1504

Luregn J. Schlapbach, Konrad Reinhart, Niranjan Kissoon,

Neonatal and Maternal Infections

EditorialA pediatric perspective on World Sepsis Day in 2021: leveraging lessons from the pandemic to reduce the global pediatric sepsis burden?Luregn J. Schlapbach, Konrad Reinhart, Niranjan Kissoon, and On behalf of the Pediatric Sepsis Data CoLaboratory (Sepsis CoLab) and the Global Sepsis Alliance (GSA)Luregn J. SchlapbachChild Health Research Centre, The University of Queensland and Queensland Children’s Hospital, Brisbane, Queensland, AustraliaDepartment of Intensive Care Medicine and Neonatology, and Children’s Research Center, University Children’s Hospital of Zurich, University of Zurich, Zurich, Switzerland, Konrad ReinhartIntensive Care Unit, Charité Universitätsmedizin, Berlin, Germany, Niranjan KissoonIntensive Care Unit, Charité Universitätsmedizin, Berlin, GermanyThe Centre for International Child Health, University of British Columbia and British Columbia Children’s Hospital, Vancouver, British Columbia, Canada, and On behalf of the Pediatric Sepsis Data CoLaboratory (Sepsis CoLab) and the Global Sepsis Alliance (GSA)1Child Health Research Centre, The University of Queensland and Queensland Children’s Hospital, Brisbane, Queensland, AustraliaPublished Online:07 Sep 2021https://doi.org/10.1152/ajplung.00331.2021This is the final version - click for previous versionMoreSectionsPDF (439 KB)Download PDFDownload PDFPlus ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmail INTRODUCTIONThe World Sepsis Day on September 13 serves to remind the public, researchers, healthcare workers, and politicians that the enormous burden due to sepsis continues to adversely affect the health of humans of all ages across the globe (1). World Sepsis Day in 2021 sees a global community completely engulfed in the second year of the coronavirus-19 (COVID-19) pandemic, with over 200 million infected and over 4 million dead due to the virus (https://coronavirus.jhu.edu/). Over the course of the past 20 months, the pandemic has amplified the detrimental effect beyond direct health-related mortality and morbidity, into widespread economic crisis, massive unemployment, and disruptions of the social fabric that have created many uncertainties among the peoples in many countries. At the same time, the pandemic has triggered an unprecedented response at the global, national, and institutional levels to contain, treat, and prevent further waves of COVID-19 infection. The coordinated, often mandated health measures in response to COVID-19 were novel to postwar healthcare; for the first time we witnessed the extent and rapidity of collaboration to share data in real time through large databases and networks. Institutions thereby were able to learn from the experience of others and share information on highly effective improvement measures. These efforts were further enhanced by highly productive research consortiums driving from the bench to the bedside—ranging from studies on the genomics of host-pathogen interaction to pragmatic trials which have dramatically improved survival rates for patients with COVID-19. And finally, the coordinated scientific efforts led to the largest rapid vaccination campaign in human history with over 4 billion humans having received a vaccine dose to date (https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html).SEPSIS AND COVID-19The pandemic has not only tragically demonstrated the vulnerability of humans to infectious disease but also provided a roadmap to improve health due to major infectious disease threats. It is time we consider the implications of these lessons learnt from patients with sepsis because there is no doubt that severe COVID-19 results in sepsis (2). Sepsis results when infection due to a bacterial, viral, fungal, or parasitic pathogen triggers a dysregulated host response leading to organ dysfunction. A systematic review found that almost 80% of patients with COVID-19 hospitalized in the ICU meet Sepsis-3 criteria and present with infection-associated organ dysfunction, as did one third of the patients with COVID-19 who were treated in the hospital ward (3). Thus, COVID-19 represents one of many etiologies leading to sepsis, and a large body of literature has shown how the mechanisms by which COVID-19 causes critical illness and death are part of the range of profound disturbances in host response seen in sepsis caused by other pathogens (4). The burden caused by COVID-19 further adds to the estimated 11 million sepsis-related deaths from other causes that occur globally every year (5). Yet, a recent joint statement by the European Society of Intensive Care Medicine (ESICM), the Global Sepsis Alliance (GSA), and The Society of Critical Care Medicine (SCCM) emphasized that “progress in response to COVID-19 stands in stark contrast to that of intensive care practitioners’ signature condition, namely, sepsis” (4).COVID-19 PANDEMIC AND SEPSIS BURDEN IN CHILDRENThe direct mortality and morbidity of young age groups from the COVID-19 pandemic are considerably less than sepsis from other causes. Severe COVID-19-related disease disproportionally affects the elderly, whereas neonates and children rarely suffer from life-threatening primary COVID-19 infection (6). Ages below 18 yr represent less than 1% of the global COVID-19 mortality burden. In contrast, more than 40% of all global sepsis cases due to other pathogens affect neonates and children under age 5, leading to approximately 3 million annual deaths in pediatric age groups (7). The steep increase of COVID-19 caused morbidity and mortality in older age groups with relative sparing of children led to health measures during the pandemic being—understandably, and necessarily—heavily focused on adult groups. This occurred with the notable exceptions of considerations for children as a potential disease reservoir, or of children manifesting multisystem inflammatory syndrome related to COVID-19 (MIS-C) (8). However, there is now a surge of cases of COVID-19 in children in the United States—an increase of 84% in 1 wk and 45% of infected children had no underlying conditions (https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/children-and-covid-19-state-level-data-report/). These are worrisome trends and can add to an increase in mortality and morbidity for sepsis for children worldwide, which is further aggravated by the cessation of immunization programs and food insecurity in many parts of the world. We would, therefore, like to address in this Editorial key aspects relevant to implementing the World Health Organization resolution of sepsis that relate to children on this World Sepsis Day in 2021 (9): First, we will provide an update on the burden of sepsis in children and encourage robust data collection, especially in resource-poor areas of the world, which should guide future sepsis improvement programs. We will highlight the effects of the pandemic on pediatric healthcare relevant to children with sepsis including the downstream effects of decreased access to healthcare and pause of vaccination programs, and we will also explore avenues for improved effectiveness and agility of research addressing priorities pertinent to pediatric age groups. Finally, we will propose that pediatric sepsis quality improvement initiatives should be informed from lessons learnt during the pandemic with the vision to develop globally connected learning platforms.WE NEED TO ACT ON AVAILABLE DATA AND IMPROVE DATA COLLECTIONIn recent years, a number of large contemporary population-based observational cohorts reporting on ongoing high incidence of pediatric sepsis have been published in several high-income countries such as Australia and New Zealand (10), the United States (11), Switzerland (12), and Germany (13). Although sepsis mortality in these settings overall is slowly decreasing, the mortality of children requiring ICU admission due to septic shock remains high and varies widely depending on resources (14–16). Of note, mandated quality improvement efforts in sepsis recognition and management have resulted in impressive outcome improvement not only in adults but also in the age groups of 0–17 yr (17). Despite the clear benefits which stem from systematic sepsis quality improvement initiatives (18–24), enormous variation persists in relation to which healthcare services, regions, or countries have implemented, or are implementing such measures—again contrasting dramatically with the concerted actions put in place to address the COVID-19 pandemic. Even across some of the richest countries in the world, wide discrepancies exist in this regard: New York State implemented in 2013 through Rory’s regulations a statewide mandate for sepsis protocols and rigorous data collection (25), and many large children’s hospitals in the United States participate in the Improving Pediatric Sepsis Outcomes (IPSO) Collaborative (26, 27). In Australia, the National Commission on Safety and Quality in Healthcare launched a sepsis program aiming to improve early recognition, treatment, outcomes, and postdischarge support for patients with sepsis (https://www.safetyandquality.gov.au/our-work/national-sepsis-program). Similar initiatives are lacking in many other wealthy countries such as Germany or Switzerland, despite studies showing a substantial burden (12, 13).However, there remains a scarcity of recent epidemiological data and only very limited population-based data on pediatric sepsis incidence from South America, Asia, and Africa, where the burden due to sepsis remains highest (28–32). The challenges related to accurate coding of sepsis are further accentuated in neonates, where adjudication of organ dysfunction presents additional difficulties (33–35). Of note, the development and validation of new pediatric sepsis criteria are currently being undertaken by the International Pediatric Sepsis Definition Taskforce sponsored by the Society of Critical Care Medicine (7, 36–38).Importantly, indirect effects of the pandemic on pediatric sepsis have not been broadly assessed. Although contact precautions and social distancing have been shown to reduce circulating viruses and alter the prevalence of other infectious diseases in children (39), systematic epidemiological assessment of sepsis in children during the pandemic has not been reported so far. Of great concern, for preventive efforts against sepsis are the widespread disruptions in childhood vaccination program delivery observed since the start of the pandemic (40). As a result, more children globally are likely to develop sepsis from vaccine-preventable diseases such as H. influenza, S. pneumoniae, or N. meningitidis. Furthermore, data indicate worsening of inequities in access to health care, and a potential for delayed presentations to hospital during lockdowns (41, 42). Deprivation from education as a direct and indirect sequelae of the pandemic is likely to have an impact ultimately on childhood sepsis mortality (43). Hence, socioeconomic and educational initiatives need to be a part of the overall strategy to improve the prevention, recognition, and treatment for children with sepsis—aligned with the sustainable development goals and the UN resolution (44).WE NEED EFFECTIVE AND AGILE RESEARCH IN PEDIATRIC SEPSISThe 2020 Pediatric Surviving Sepsis Campaign systematically reviewed the available evidence of each component of pediatric sepsis management (45). In contrast to adult age groups, where a multitude of large randomized trials ranging from common interventions [such as early goal-directed therapy or hydrocortisone (46–48)], or novel potential interventions [such as ascorbic acid (49)], to highly personalized therapies [such as monoclonal antibodies (50–52)] have been published in the past decade, the evidence base for currently recommended pediatric sepsis management remains weak and randomized controlled trials of sufficient sample size have been sparse (53, 54). We need to understand the physiological differences between adults and children because children usually suffer severe morbidity and mortality from viral infections but less from COVID-19. In this context, it is encouraging that very recently, several pilot studies have been conducted in the field (55–58), and that new large trials have been commenced (NCT03401398, NCT04102371). These conventionally designed trials, however, follow classic standards of trial preparation and operate in relative isolation, primarily in high-income settings. As evidenced by trials on COVID-19, much greater generalizability of trial results can be achieved by including high-risk and disadvantaged populations in diverse settings (59). Contrary to the global scope of the Surviving Sepsis Campaign, modern trial design in pediatrics has not been sufficiently optimized to be applicable to a broad range of healthcare settings, implying a need for new trials recruiting across high-income, low-income, and middle-income countries. The deployment of novel study designs such as trial platforms, and the use of additional methodologies such as enrichment strategies and response-adaptive randomization, could greatly enhance the effectiveness and impact of future pediatric research collaborations on sepsis. The success of trial platforms like RECOVERY, REMAP-CAP, or PRINCIPLE, and the fact that over 1 million adults participated in COVID-19 trials in the United Kingdom alone since the beginning of the pandemic, is unprecedented and demonstrates the huge potential of agile, data-driven, and patient-centered research (https://www.nihr.ac.uk/covid-19/). Importantly, future pediatric sepsis research may gain power incorporating evidence generated in adult populations through Bayesian statistical modeling (60). Finally, pediatric sepsis research should endeavor to apply novel trial methodology to assess the effectiveness of quality improvement initiatives, such as cluster randomized or stepped-wedge trials (61).WE NEED TO DEVELOP LEARNING HEALTHCARE SYSTEMS TO IMPROVE THE CARE OF CHILDREN WITH SEPSISIn conclusion, to implement the World Health Organization resolution which urges member states to improve the prevention, diagnosis, and management of sepsis (62), it is imperative to develop learning healthcare systems which apply principles of agile, data-driven, and effective interventions to reduce the burden of sepsis in children. The pediatric research and healthcare community should thus seek to leverage off collaborations and data systems established through the pandemic and adapt those to sepsis as one of the major ongoing healthcare challenges across the globe. The increase in rapid data exchange, shorter time to set up trials addressing key questions pertinent to clinicians, and faster translation of research into guidelines and practice witnessed in the context of MIS-C should serve as a model approach in this regard (8, 63–65). For this purpose, the Centre for International Child Health at University of British Columbia and the World Federation of Pediatric Intensive and Critical Care Societies promoted the recent creation of the Pediatric Sepsis Data CoLaboratory (Sepsis CoLab) collaboration (https://wfpiccs.org/pediatric-sepsis-colab/) with the aim to enable an “international data-sharing network of healthcare workers, policymakers, researchers, and advocacy partners collaborating to address the high burden of pediatric sepsis mortality and morbidity globally.” Such collaborations will yield the necessary power to generate the urgently needed evidence as well as to address the heterogeneity of sepsis (66) and will be optimally positioned to increase the cost-effectiveness of healthcare policy development and implementation by ensuring lessons learnt can be shared globally.DISCLOSURESAll authors work on the Global Sepsis Alliance Executive Board. No conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSL.J.S., K.R., and N.K. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.ACKNOWLEDGMENTSThe Global Sepsis Alliance (GSA) Executive Board: Niranjan Kissoon (President), Children’s and Women’s Global Health, University of British Columbia and British Columbia Children’s Hospital, Vancouver, Canada; Konrad Reinhart (Past President), Intensive Care Unit, Charité Universitätsmedizin, Berlin, Germany; Abdulelah Alhawsawi, Saudi Patient Safety Center – Director General, Riyadh, Saudi Arabia;Maha H. Aljuaid, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia; Ron Daniels, Department of Critical Care, University Hospitals Birmingham NHS Foundation Trust; Luis A. Gorordo-Delsol, Adult Intensive Care Unit - Hospital Juárez de México, Juarez, Mexico; Flavia Machado, Global Sepsis Alliance (GSA), Sao Paolo, Brazil; Imrana Malik, Department of Critical Care, The University of Texas, Anderson Cancer Center, Houston, TX, USA; Emmanuel Fru Nsutebu, Infectious Diseases Division, Sheikh Shakhbout Medical City, Abu Dhabi, UAE; Luregn J. Schlapbach, Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia, and Department of Intensive Care Medicine and Neonatology, and Children's Research Center, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland; Simon Finfer, The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, AustraliaThe Pediatric Sepsis Data CoLaboratory (Sepsis CoLab): Niranjan Kissoon, British Columbia Women and Children’s Hospital, Vancouver, Canada; John Mark Ansermino, Department of Anesthesiology, Pharmacology & Therapeutics, British Columbia Women and Children’s Hospital, Vancouver, Canada; Guoping (Robert) Lu, Pediatric Emergency and Critical Care Medicine, Fudan Children`s Hospital, Fudan, China; Luregn J Schlapbach, Department of Intensive Care and Neonatology, University Children`s Hospital Zurich, Switzerland, and Child Health Research Centre, The University of Queensland, Brisbane, Australia; Mark Peters, University College London Great Ormond Street Institute of Child Health, London, UK; Lauren R. Sorce, Ann & Robert H. Lurie Children’s Hospital and Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, USA; Roberto Jabornisky, Department of Maternal and Child Health, National University of North East, Corrientes, Argentina; Pierre Tissieres, Hospital de Bicetre, Paris, France; Suchitra Ranjit, Apollo Hospitals, Chennai, India; Samuel Akesh, Health Services Unit, KEMRI/Wellcome Trust Programme, Nairobi, Kenya; Satoshi Nakagawa, National Center for Child Health & Development, Tokyo, Japan; Andrew Argent, Department of Paediatrics and Child Adolescent Health, Red Cross War Memorial Children’s Hospital and University of Cape Town, Cape Town, South Africa; Daniela Carla Souza, University Hospital of The University of São Paulo, Sao Paulo, BrazilREFERENCES1. Schlapbach LJ, Kissoon N, Alhawsawi A, Aljuaid MH, Daniels R, Gorordo-Delsol LA, Machado F, Malik I, Nsutebu EF, Finfer S, Reinhart K. 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