Rethinking sepsis: why research should pivot to early diagnosis

The sepsis definition describes three elements: infection, the host response and life-threatening organ dysfunction. Diagnosis is made based on myriad signs and symptoms, and although infection underlies sepsis, in 30% of cases, the underlying pathogen is not known. Diagnosis for many comes too late and, although significant progress has been made, sepsis remains a leading cause of mortality globally.

Despite significant investment from industry to identify novel diagnostics and treatments, clinical trials for sepsis have failed to change patient outcomes. No treatment has been identified from 200 randomised controlled trials that consistently saves lives in sepsis patients. Research is at a tipping point. The current approach is not working – so, what needs to change?

Immunology of sepsis

Better outcomes for patients requires a better understanding of the role of the immune system in sepsis. More specifically, if the loss of balance of the immune system is known to drive sepsis, how does this relate to the differences seen in patients for diagnosis, treatment and prognosis? This loss of homeostasis includes both the immunological and non-immunological dysregulation, for example, organ dysfunction, that drives critical illness underlying sepsis. The dysregulation is dynamic and changes over time, which further complicates both recognition of sepsis and clinical judgment around prognosis.

Infection is the trigger that puts patients on the path to sepsis. Yet, the pathogen is often missing from diagnosis, patients often require near immediate clinical action, and clinical guidelines necessitate empirical use of broad-spectrum antibiotics. Rapid diagnostics to identify antimicrobial resistance remain an ambition to improve patient outcomes.

The emphasis of organ dysfunction in clinical practice, assessed using the Sequential Organ Failure Assessment (SOFA) score, is important for determining how ill a patient is and clinical management. Best practice for sepsis care promptly initiates treatment, including antimicrobial therapy and appropriate hemodynamic support to prevent septic shock, caused by a rapid drop in blood pressure. However, this approach places the burden of attention on the outcomes of sepsis, the result of the dysregulated host response and not the response itself.

Addressing this gap requires a new framing to interventions prior to sepsis onset.

Pre-sepsis and the opportunity of early diagnosis

Pre-sepsis, broadly, describes the changes that lead to the onset of sepsis. In practice, researchers are proposing that pre-sepsis could represent the exhaustion of the host’s response and the overwhelm of the immune response. Sepsis may be prevented either through the self-limiting nature of the infection or with antimicrobial treatment. 

The consequence of sepsis is not solely defined by the intensity of the response infection, but also by the host’s ability to maintain ‘normal’ function, or homeostasis. From this view, “pre-sepsis” reflects a progressive exhaustion of the host’s functional reserves and sepsis occurs when this ‘adaptive capacity’ is overwhelmed.

Perhaps the most compelling evidence for this is the fact that sepsis is mostly affecting the very young and elderly. Older or comorbid patients may be less resilient when faced with infection. Similarly, the naïve immunity of newborns results in unique vulnerability when exposed to infection. Differences in the source of infection, dependent on the age of onset, suggests some differences underlie this shared risk.

Sepsis is a syndrome

Sepsis likely represents not one, but many diseases. Researchers are already seeking to identify more specific patient populations – known as endotypes – to better understand the differences. These approaches ultimately want to facilitate clinical decision making,  both in terms of treatment and prognosis, leading to more targeted interventions. 

More time would improve  options for patients, and this is what makes pre-sepsis an attractive proposition. However, achieving ‘early diagnosis’ of sepsis will be a challenge. Current research shows that sepsis ‘endotypes’ are dynamic and a single patient will have multiple endotypes, at least according to current biomarkers in research. This changeable state does offer some hope that, with the right intervention administered at the right time, better outcomes for sepsis is possible.

Realising the vision

Researchers are proposing there needs to be more research into pre-sepsis with the aim to detect, characterise and define this syndrome. This is necessary for two reasons: 1) to identify the therapeutic window and 2) to shift attention to the stage before onset of sepsis. This means focusing on the dynamics following infection, during the pathogen-host encounter and the ensuing dysregulation, before overt organ damage starts to occur.

Early diagnosis could lead to better and more personalised treatment decisions, such as administering the right antibiotic as first line treatment. Better understanding of the changes that lead to sepsis could lead to targeted interventions, particularly where we understand the relationship between the host and immune response. During sepsis a patient’s immune state changes over time, therefore biomarkers for sepsis should reflect these transient states and support clinical decision-making.

Context is likely to be important and while specialised testing is plausible in hospital or high-risk settings, consideration must also be given to referral settings. Identification of pre-sepsis in primary or community care settings could significantly reduce the time from diagnosis to receipt of appropriate treatment.

Why does this matter?

Sepsis accounts for 50 million cases and 11 million deaths globally, disproportionately affecting global majority populations. Unequal access to antimicrobial therapies and high-quality healthcare are significant contributors to these inequities.  Treatment of sepsis represents a significant cost to health systems, and despite significant effort, the field of sepsis risks being seen as impenetrable. Ageing populations and increasing AMR will only make sepsis more probable, leaving policy makers in a difficult position. Pre-sepsis represents a new lens through which research and innovation in sepsis may be achieved.