Sepsis explained (1/3): What is sepsis?
Sepsis is a complex and often misunderstood condition, and one of the leading causes of death worldwide. In the run-up to World Sepsis Day on 13 September, we are publishing a series of three articles on sepsis: what it is, how it is treated, and how innovative diagnostics could change the game. In this first article, PhD candidates Aryna Kolodyazhna, Floris de Vries and Susanne Doeleman, from the research group of Tom van der Poll and Joost Wiersinga, explain what sepsis is, why it can become life-threatening within hours, and how their research at Amsterdam UMC and the Amsterdam Institute for Immunology and Infectious Diseases (AI&I) helps us better understand the body's response to infection.
In simple terms, how would you explain what sepsis is to patients and families?
Sepsis, sometimes called blood poisoning, is what happens when the body's response to an infection turns against the body itself. The infection can start anywhere: in the lungs, the urinary tract, or an infected wound. But once sepsis develops, the pathogen is no longer the only thing doing damage: the immune response meant to contain it goes into overdrive and injures the patient's own tissue. Blood pressure drops, kidneys and lungs start to fail, patients can become confused, and someone who walked into the emergency department can need intensive care within hours. As sepsis progresses, the immune system can also swing the other way and become too weak to fight the infection.
Why can sepsis progress so quickly from mild symptoms to life-threatening illness?
Sepsis is a complex and dynamic cascade of events that can progress with remarkable speed. When an infection is detected, immune cells can respond within minutes. They release many types of molecules into the surrounding tissue and bloodstream, effectively signaling to other cells and tissues that a threat is present. Those activated cells can then generate additional signals of their own, amplifying the response in a rapidly expanding inflammatory cascade. What begins as a local response designed to contain an infection can, in some patients, escalate into damage to the lining of the blood vessels, altered blood flow, problems with blood clotting, and tissues that no longer receive enough oxygen.
‘This is one reason why early recognition and treatment of sepsis are so important: intervening early may help limit the progression of this cascade and reduce subsequent damage’. - Floris de Vries
How common is sepsis, and why is it still under-recognized worldwide?
Sepsis is one of the leading causes of death worldwide. According to the most recent Global Burden of Disease study (GBD 2021)1, there were 166 million sepsis cases and 21.4 million deaths in which sepsis played a role globally in 2021, representing 31.5% of all deaths (all deaths in which sepsis played a role, rather than only those directly attributed to it). This corresponds to about 59,000 deaths per day, 2,440 per hour, or 41 every minute, more than twice the number of deaths due to ischemic heart disease (~9 million per year). Importantly, the burden of sepsis is distributed highly unequally: approximately 88% of sepsis-related deaths occur outside high-income countries1, with the greatest burden concentrated in sub-Saharan Africa and Asia. Yet most research is conducted, and therefore most guidelines written, in high-income countries.
Despite its enormous global burden, sepsis remains under-recognized at both the policy and public-health level. In 2023, only 16 countries worldwide had explicitly prioritized sepsis in national health policies or strategies.2 Public awareness of the term "sepsis" varies enormously between countries, from 2% in Japan to 88.6% in Germany. In a survey conducted in the Netherlands, only 17% of respondents without a medical background were familiar with sepsis3, and only 19% of former sepsis patients were aware of it before they became ill.4
'This is why initiatives such as World Sepsis Day are important: they raise awareness at both the policy level and among patients and families, helping people recognize the signs of sepsis earlier and seek treatment sooner’. - Aryna Kolodyazhna
What aspect of sepsis do you focus on in your research at Amsterdam UMC?
Our group, led by Tom van der Poll and Joost Wiersinga, studies how the immune system behaves during sepsis. The treatment of sepsis has remained largely unchanged for decades and still relies on source control, antibiotics, and supportive care. Even though the immune system is central to what goes wrong in the body during sepsis, more than a hundred trials testing immunomodulatory treatment have failed.5 This is now widely accepted to be due to a heterogeneity problem: every patient and every immune system reacts differently to infection, so a one size fits all approach is not effective. In other words, grouping all patients under a single ‘sepsis’ umbrella has resulted in the enrolment of profoundly different groups into the same trials.
'This recognition has reframed the field, shifting attention towards personalized medicine: can we tailor treatment to a patient's individual immune system?' - Susanne Doeleman
To study the immune response across different types and stages of infection, our group has collected and collaborated on large patient cohorts. With the MARS cohort (NCT00131196) we gathered data from more than 8,000 patients admitted to the intensive care unit. The ELDER-Biome cohort (NCT02928367) provides in-depth multi-omic data, measuring thousands of genes, proteins and other molecules, from patients admitted to the hospital with community-acquired pneumonia. We are currently coordinating BIOSEP (Towards novel BIOmarkers to diagnose SEPsis) (NCT06178822), which recruits patients presenting to the emergency department with an infection; the first proteomics analyses for this study are already underway. Our colleagues have also led the MARS-India cohort, which has included more than 1,000 patients with sepsis in Manipal, South India, extending our sepsis research to a very different healthcare setting and patient population.
What do you hope to achieve in the future?
Each of us is tackling a different piece of the puzzle. Aryna Kolodyazhna mainly works on combining multiple omics layers, applying them to identify subgroups of patients whose immune systems respond in similar ways, so-called subphenotyping. Floris de Vries, focuses on recognizing sepsis earlier from data that is already being collected, such as electronic health records and routine blood tests (complete blood counts), in which far more is measured than ever reaches the clinician. Susanne Doeleman currently works with a novel machine-learning-based tool developed by our group, the Dysregulated Immune Profile (DIP) score6, that can quickly identify patients at risk of poor outcomes based on their degree of immune dysregulation.
Together, these projects aim to improve sepsis care at multiple stages: from earlier recognition and better patient stratification to laying the foundation for future precision immunotherapy.
This is the first article in a series of three. On Tuesday 8 September we look at how sepsis is treated, and on Thursday 10 September at innovative diagnostics, both in the run-up to World Sepsis Day on Sunday 13 September.
Reference list
1 GBD 2021 Global Sepsis Collaborators. Global, regional, and national sepsis incidence and mortality, 1990-2021: a systematic analysis. Lancet Glob. Health 13, e2013–e2026 (2025).
2 Combating sepsis: bottlenecks to breakthroughs. Lancet Reg. Health West. Pac. 38, 100923 (2023).
3 Fiest, K. M. et al. Patient, Public, and Healthcare Professionals’ Sepsis Awareness, Knowledge, and Information Seeking Behaviors: A Scoping Review*. Crit. Care Med. 50, 1187–1197 (2022).
4 A nationwide survey to explore sepsis awareness among the Dutch general public and former patients – De Intensivist. https://de-intensivist.nl/a-nationwide-survey-to-explore-sepsis-awareness-among-the-dutch-general-public-and-former-patients/.
5 Slim, M. A., van Mourik, N., Dionne, J. C., Oczkowski, S. J., Netea, M. G., Pickkers, P., ... & van Vught, L. A. (2022). Personalised immunotherapy in sepsis: a scoping review protocol. BMJ open, 12(5), e060411.
6 Michels, E. H. A. et al. Quantifying immune dysregulation in pneumonia and sepsis with a parsimonious machine-learning model: a multicohort analysis across care settings and reanalysis of a hydrocortisone randomised controlled trial. Lancet Respir. Med. 14, 327–340 (2026).