So, my disclosures, I have some research collaborations with the following companies listed here, but all the funding goes to my employer and not to myself. So, we've heard from the previous speakers about the variability in presentation. And when a child presents with suspected sepsis, they represent a continuum which goes from undifferentiated febrile illness through to infection, organ dysfunction, and death. And so, they present on this trajectory, and it's difficult to define. Added to that, sepsis is used synonymously with infection, which leads to difficulties in measuring disease burden, as we've heard, in optimizing management, recruitment trials, and compromises quality improvement initiatives. But the Phoenix sepsis score, which you've heard about today, allows us to define children with life-threatening organ dysfunction due to infection, and that can be operationalized across different geographical settings. And in this respect, as we've heard earlier, context is everything. And so, these criteria must be applicable across all the global settings in which these children present. So they need to be sensitive enough, and we've seen that in the data presented, but also specific enough. They need to be flexible enough, and we've seen the pragmatic approach that was taken with the development of the score, including the redundancy that's built into the score, as well as the parsimonious approach, which allows for that flexibility and adaptability across global settings. And then the score must correlate with biologically relevant phenotypes, so that we can identify those patients with organ dysfunction that would benefit from specific therapies. So this is an infographic from the manuscript, which we published last year, and goes through the different considerations that we developed in operationalization. So I'll go through those in turn, looking at the biology, the epidemiology, the timing, resources, and access. Firstly, the biology. In the different settings in which children present globally, represented in the huge data sets that we use to derive the score, we have different manifestations from pathogens that are different in adults and children. A good example of that is RSV and SARS-CoV-2, where the same virus manifests differently in adults and children. And the pathogens responsible are different in high-income versus low-income countries, for example, malaria, non-typhoidal salmonella. And of course, there are non-bacterial pathogens, which present like sepsis, like dengue, enterovirus. And we've heard about some co-infections and co-morbidities, which also influence the host response. Added to that, endemicity and seasonality increase suspicion of underlying etiology. So there are also some other underlying predisposing factors, immunodeficiencies, malnutrition, co-infection, as well as genetic polymorphisms. We saw in the data presented that there was an impressive spread of age from neonates right through to adolescents. And that's one of the complexities of pediatrics compared to adults, in that children don't come in one size. There's also underlying co-morbidities, like prematurity, low birth weight, and children and infants under a year, which present major risk factors for sepsis and poor outcome. And so the data development of the score had to take into account all of these considerations. We know that infants and young children have lesser reserves to compensate because of their ability to maintain blood pressure. Therefore, this leaves a much smaller opportunity, window of opportunity to intervene. Then, of course, there's existing therapies and vaccine-preventable infections, which have almost virtually disappeared from high-income countries, some of which may be present still. In some low- and middle-income settings. Antimicrobial-resistant infections are highly prevalent in some low- and middle-income settings due to poor regulation with drugs and antimicrobials, and also with quality control of antimicrobials. The antimicrobials themselves may be affected by other drugs, such as drugs for treating TB, rifampicin, dehydration due to gastrointestinal illness. And with advancing technologies, immune-modulating drugs, such as steroids and monoclonals, may also increase susceptibility to severe infection. Next, we looked at epidemiology, and again, as we've seen from the data, we were able to capture this from a wide range of geographies, globally and settings, north and south, and that seasonality also affects the presentations, winter presentations in the temperate climates, and rainy season in low- and middle-income countries, and of course, there's a meningitis belt across the middle of sub-Saharan Africa. And then some pathogens which are present in other low- and middle-income countries are rarely seen in high-income countries. Presentation is also affected by factors like climate change, floods and droughts, and also wars and other crises. And then we also looked at timing of presentation, and we've heard a lot about this from the previous speakers. When high-income settings, we have presentations to the primary care or to the ED, predominantly of worried well patients, and early presentations requiring observation. They're often very highly skilled staff, easy access to critical care and outreach. And on the contrary, in low-income settings, these are often in remote locations with late presentations because children first have to present at a local health center, and then are transported to a centralized facility, and there may be delays with transport, which means by the time they present a critical care facility, there's established organ dysfunction and a high mortality. So finally, I'll talk about resources and access. And one of the considerations we had was that it wasn't just about high-income and low-income, but about the resources available to a particular facility when a child presents. We heard earlier on in the open ceremony about marginalized populations in high-income countries which are remote and for whom there is often a delay in accessing critical care. The low-income settings tend to have high patient load, limited skilled expertise, and limited resources in terms of drugs and organ support, in contrast to the high-income setting with skilled expertise and high resources. And of course, the criteria can be incorporated into electronic patient algorithms, which makes them data-rich as compared to low-income settings. So finally, we ended up with some new considerations, which I won't go through but are listed in detail in the paper, but I'll just highlight a couple. And they are that developing the minimum variable data sets allows the sort of collaboration that we've heard about this morning for new criteria to be validated and to be used for further research and progress. Additionally, clinical decision support systems can be used, the criteria can be incorporated into electronic patient records in high-income settings or mobile devices in mobile phones in lower-income settings to allow these criteria to be operationalized. And finally, the development of affordable diagnostics could then help with the re-stratification of sepsis wherever children present. So in conclusion, hopefully this morning we've outlined some of the challenges and opportunities in operationalizing sepsis. The Phoenix sepsis score is operationalized with a score of two or more, and septic shock with sepsis with organ dysfunction. Some challenges remain in that the score is not designed to identify children at risk of developing sepsis or children who have early infection, but we hope that the score can help us to identify and manage those children with life-threatening organ dysfunction wherever they present. The score that we've presented this morning are unambiguous and flexible, and they're designed to be used in a wide variety of contexts so that they can be implemented locally. So I'd like to acknowledge all the co-authors on the manuscript as well as all the members of the Pediatric Sepsis Definition Task Force, and thank you for your attention.

sepsis assessment

Phoenix sepsis score

organ dysfunction

pediatric sepsis

global healthcare