Sepsis is deadly because it varies so greatly between different patients, and within individual patients over time, making it hard to diagnose and treat effectively. But scientists writing in Frontiers in Science explain how we can tackle the challenge by understanding sepsis as the result of multiple types of immune dysregulation. Using systems immunology to understand its mechanisms and target treatments, the researchers argue that we can lower deaths from some of the world’s most common illnesses, prevent deaths from future pandemic diseases, and treat survivors’ lingering symptoms.

Sepsis is an underestimated killer. Nearly a quarter of patients treated for sepsis in hospital will die, but because so many different illnesses can predispose patients to experiencing it, it’s overlooked as a direct cause of death. Yet approximately 20% of deaths worldwide are caused by sepsis, and currently we have no treatments that tackle it directly. Now researchers writing in Frontiers in Science explain how systems immunology can help us understand and treat sepsis — and how this could cut the death toll of future pandemics, no matter what disease causes them.

“We need to adopt a concerted approach to tackle sepsis,” said Prof Robert Hancock of the University of British Columbia, lead author of the article. “Only a very small amount of funding is currently invested in sepsis research and product development—and yet sepsis is as prominent a cause of death as heart disease and cancer, and the major cause of death in pandemics.”

Precision medicine for sepsis

One of the reasons it’s so hard to understand and treat sepsis is that it is multifaceted. Sepsis arises when the immune system fails to control an infection and malfunctions, causing multi-organ failure. Many different infections can cause sepsis, and its symptoms and progression vary between patients and over time in the same patient. Its early symptoms are similar to those of many other illnesses, which makes it difficult to diagnose quickly and initiate timely treatment, contributing to high mortality.

Systems immunology offers a potential solution to this diagnosis problem by using mathematical and computational modelling to study the immune system in the context of all the body’s other systems. It does this by using different types of clustering analysis to identify patterns in large volumes of omics data, ranging from transcriptomic data (what genes show altered expression) to proteomic and metabolomic data—data that tell us about the body’s reaction to its physical circumstances, in this case sepsis, in incredibly fine-grained detail.

These patterns help us work out the patterns and basis for the immune dysregulation that drives sepsis, come up with new hypotheses that we can research and use to develop new treatments, and identify diagnostic markers that we can use to catch sepsis early. For instance, using these clustering analyses, scientists have identified changes to gene expression that act as early warnings for sepsis. They’ve also been able to identify five different subtypes of sepsis which are caused by different kinds of immune dysregulation and have different prognoses. In the future, we could build on these advances to diagnose different subtypes of sepsis earlier and treat them with the right drugs when we do.

However, systems immunology analysis is not yet in widespread use, because it is expensive and demands significant volumes of data — so we don’t yet know how these diagnostics could translate into clinical results. The researchers call urgently for targeted funding and greater data availability.

“In sepsis we lack the depth of information required to enable more effective systems immunology and machine learning approaches,” urged Hancock. “We hope to encourage the development of large, in-depth omics-oriented patient studies that will trigger a new generation of insights.”

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The key to past and future pandemics

Successfully treating sepsis would be a multipurpose life-saver, preventing mortality regardless of the illness that triggered it. Viral sepsis is a major cause of deaths triggered by severe COVID-19, while many deaths in historical pandemics like the 1919 influenza pandemic and the bubonic plague are thought to have resulted from sepsis. If we can tackle sepsis, we might be able to protect ourselves against the worst consequences and the highest death tolls in future pandemics, no matter what kind of infection causes them. Since immune dysregulation linked to sepsis can linger, causing symptoms similar to post-viral syndromes like long COVID-19, learning to treat this could also benefit some chronic illness patients.

But to make this happen, the researchers caution, more funding and larger studies will be needed.

“The omics methods that underlie systems immunology are relatively expensive on a per patient basis,” said Hancock. “It will require a concerted drive from stakeholders to generate the data needed for further insights. We need to invest in larger omics studies of patients, develop new animal and organoid models that reflect sepsis heterogeneity, and invest in early diagnostics for sepsis and treatments that correct or supplement defective immunity in sepsis patients.”

This article is part of the Frontiers in Science multimedia article hub ’Solving sepsis using systems immunology’, which also features an editorial, viewpoint, and a policy outlook from other eminent experts: Prof Jean-Louis Vincent (Université libre de Bruxelles, Belgium), Dr Phillip Dellinger and Jason Bartock (Cooper Medical School of Rowan University, US), and Dr Mariam Jashi and Dr Niranjan Kissoon (Global Sepsis Alliance, Germany) —as well as an explainer with infographics.

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About Frontiers in Science

Frontiers in Science is Frontiers’ multidisciplinary, open-access journal focused on transformational science to accelerate solutions for healthy lives on a healthy planet.

The journal publishes a select number of exceptional peer-reviewed lead articles invited from internationally renowned researchers, whose work addresses key global challenges in human and planetary health. Each lead article is enriched by a diverse hub of content that extends its reach and impact across society – from researchers and policymakers to lay audiences and kids.

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