Addressing sepsis requires speedy solutions: enter rapid diagnostics

A patient arriving in A&E or another clinical setting, with suspected or known infection and the risk of sepsis, requires immediate action. Antibiotic admission more than one hour after suspected sepsis is associated with a 20% increase in mortality risk. Timely intervention is therefore paramount.

However, sepsis is not one disease, this syndrome presents with variable symptoms and different pathogens underlie and contribute to severity. Patient advocates and sepsis charities have made significant contributions that have meaningfully changed clinical practice. Campaigns from the Sepsis Trust encourage clinicians to ask, “Could it be sepsis?” and the Sepsis-6 – a time-critical bundle of six interventions to improve patients with severe sepsis – have improved awareness and recognition of this disease.

Diagnosis of sepsis depends on clinical judgement and the often non-specific and variable symptoms contribute to this difficulty. In spite of extensive research, advocacy, and global collaboration, mortality remains unacceptably high. In the United Kingdom alone, sepsis is estimated to cause nearly 50,000 deaths each year.

Better sepsis care starts with better diagnosis. If time is the critical factor, then a rapid solution is needed. But speed is not the only factor. The ‘ideal’ test must address a long list of questions. Where perfection is often the enemy of progress, we need to address the complex, interdependent factors influencing sepsis, while recognising that this represents only one component of the broader systemic challenge.

No time: act first, ask questions later

Sepsis is most often bacterial in origin, although viral and fungal sources contribute significantly to the pathophysiology and mortality. Conventional testing, based on blood culture and antimicrobial susceptibility testing (to identify antimicrobial resistance or AMR) is too slow. Clinicians more often than not must act before they have results from these tests. Added to this, in 30% of cases, the cause of infection is unknown and clinicians must balance any caution against any indications of urgency or uncertainty.

Broad spectrum antibiotics are a backstop solution to sepsis with adverse consequences for the patient, particularly from the disrupted microbiome. Additionally, failed treatment as a result of AMR is driving sepsis. If administering antibiotics is critical to reducing patient mortality, the same logic requires that clinicians should know that a patient will respond and benefit from the treatment. New antibiotics create more options, but the development and market models for antibiotics are flawed. The pipeline for new antibiotics is almost completely dry; meaning there is an urgent need for better tools to guide clinical decision making.

The right test, at the right time 

For clinicians to make better decisions, they would want to know:

• What is the infection? 
• Is there antimicrobial resistance?
• What is the patient’s prognosis?

Significant advances have been made, and yet no single test will provide all the answers clinicians seek in the time frame required. 

Progress is being made and current technologies are narrowing the gap. This rapidly advancing field presents many areas of opportunity. There are now rapid tests to identify the pathogen, the presence of AMR and signs of sepsis, which are often faster than the current standard of care. However, barriers remain, particularly considering that pathogen identification often requires a culture from a blood sample. This takes time and requires some assumptions of the most likely pathogenic cause.

Getting ahead of the question 

While research and industry are making rapid progress circumventing current dependence on blood cultures, no tools are specific to sepsis. An ideal test would be pathogen-agnostic and not require prior knowledge of what may be causing the infection. Advances in next generation sequencing are demonstrating promise to rapidly detect common, rare and hard-to-culture pathogens. Additionally, identification of polymicrobial infection (i.e. opportunistic pathogens such as C. difficile following initial infection) and antimicrobial resistance genes can reduce the need for separate resistance testing. The potential of metagenomic sequencing, where all DNA in a sample is sequenced rather than prioritising specific or known infections, is gaining traction in clinical practice.

Rapid metagenomics is being evaluated in the UK. This test has been successfully demonstrated to change clinical decision making for the majority of patients, but is yet to be demonstrated at scale. The UK Health and Security Agency (UKHSA) and a consortium of healthcare and academic partners are leading the way in implementation of this technology and metagenomics will increasingly shape clinical practice. This data has the potential to open doors, leading to new opportunities and added benefits for patients. Critical insights into the pathogens that drive sepsis, and could inform wider public health strategies, clinical guidelines, and innovation in rapid diagnostics. 

Driving innovation: the UK’s role in combating sepsis

Following successful pilot testing, the metagenomics Surveillance Collaboration and Analysis Programme (mSCAPE) initiative, which is being used for both diagnostics and surveillance,  stands out as a leading example of metagenomic implementation at scale. This initiative will start with severe respiratory infections and encephalitis, generating data to inform clinical decision making. 

To tackle sepsis, however, it would be advantageous to address the steps that lead to severe illness in the first place. Researchers have proposed that early diagnosis or ‘pre-sepsis’ could reframe discussions. Identification of pre-sepsis could offer timely, actionable insights as well as informing diagnostics that enable treatment when patients are more likely to respond. 

Rapid sequencing has been enabled by the uptake of Oxford Nanopore Technologies’ sequencers. Real-time metagenomics can provide results in hours, informing treatment before the test is complete and enabling clinical decision making. 

mSCAPE has begun to lay the groundwork for implementation of rapid metagenomics, as well as building the data infrastructure that could unlock better diagnosis. The emphasis remains on high-resource and acute settings. Widespread and routine use remains an ambition, and in building this system, how do we build a system that delivers better diagnosis of sepsis for all patients.

Realising the vision

Sepsis will never be a single, simple disease to diagnose, but the tools available to clinicians are changing rapidly. The promise of rapid diagnostics, and particularly metagenomic sequencing, lies not only in reducing the critical delays that cost lives, but also in offering a deeper understanding of infection and resistance patterns that can transform patient care and public health. The challenge ahead is to move from promise to practice: validating technologies in real-world settings, integrating them into clinical workflows, and ensuring that speed, accuracy, and accessibility are balanced.

The UK’s leadership in this area demonstrates what is possible when innovation, healthcare, and research align with urgency. The path forward is clear: investing in rapid, reliable diagnostics that empower clinicians to make informed decisions at the right moment. Doing so will not only save lives but will also reshape the fight against sepsis for the next decade.