Sepsis is what we call the situation where an infection becomes severe and the body’s vital organ systems start to fail. The damage to the organ systems arises not so much from the microbes that are causing the infection as from the body’s own immune response, with inflammation which is not confined to the site of infection and becomes ‘systemic’. The next decade of sepsis research will need to address a wide range of challenges, ranging from understanding the complex immune biology that drives organ damage to more applied work improving our ability to recognise and rapidly diagnose infections and subsequent sepsis. Alongside looking for treatments that can help patients survive this critical illness, we also need to understand why it can cast such a long shadow, with prolonged recovery and persistent disability. It is in rehabilitation and recovery, and the long-term impact borne by patients and families, that we find the most neglected area of an already neglected condition.
Sepsis is a major global challenge, with an estimated 50 million cases a year and sadly 11 million deaths. This means that it ranks alongside cancer and heart disease as one of the world’s major killers. Despite its prevalence, research into and understanding of sepsis lag behind these other major disease groups. The greatest burden of sepsis is found in the areas of the world with the highest rates of infection, in sub-Saharan Africa, South and Southeast Asia and South America, these are also the areas with the least resources to deal with this challenge. Sepsis also intersects with another growing problem, that of antimicrobial resistance. Resistant bacteria are hard to treat, and at least 10% of all sepsis deaths arise directly from these resistant organisms. We should not think sepsis is only a problem in other parts of the world, however. In the UK there are an estimated 250,000 cases of sepsis a year and at least 40,000 deaths, with this figure likely to be an underestimate, as it is not always well-recorded on hospital admissions or death certificates.
Sepsis can arise from any infection, and the mechanisms by which the organs are damaged are multiple. Direct damage may occur – say in the lungs where an infection resulting in pneumonia blocks the air sacs and leads to dangerously low levels of oxygen. Indirect damage can occur when inflammatory proteins cause blood vessels to dilate, producing low blood pressure and therefore insufficient nutrients getting to the tissues. More challenging to understand is when the inflammatory response starts to deactivate mitochondria – the small bodies inside cells that generate the energy needed for vital cellular functions. Another aspect that remains hard to explain is how the immune cells which drive organ damage also fail to clear the infecting microbes. As perhaps can be gathered, sepsis is not a single disease but rather a broad syndrome covering a multitude of different infections and damaging responses. As such, it has been very difficult to find treatments that work, and target these at the correct patients.
If we consider the patient’s journey from onset of disease to recovery, we can see where innovations are likely to come from and how these could be transformative.
A patient starts to feel unwell, perhaps with cough, fever and chest pain. Fearing they may be developing a chest infection they attend their GP. A rapid blood test at the GP identifies that this patient is already showing early signs of serious infection and organ damage, sometime before this would be apparent by standard examination. Given this profile, the GP gives immediate antibiotics and arranges for emergency transport to the hospital. Despite the antibiotics, the severe inflammatory reaction to the infection has already started. In the hospital the emergency department team, and then the intensive care team, run tests that pinpoint where the infection is coming from (it’s a pneumonia) and rapidly identify both the bug that is causing it and the bug’s antibiotic susceptibility, ensuring this can be targeted appropriately. Simultaneously a rapid immune profile identifies the key parts of the immune system that are working, and which parts are struggling. Based on this, and data from thousands of previous patients with sepsis, a series of immune-modifying drugs are given, with the aim of limiting the damage. Over the next couple of days, the patient’s immune response goes through a number of phases, and the profiling of immune and other body organ systems helps the medical team adjust the treatments. Despite this optimal therapy, a combination of the patient’s pre-existing medical conditions, prior life experience and genetics mean that their organs suffer considerable damage and need support from a ventilator and kidney machine. Thankfully, with time and careful treatment, they start to improve. A week after first falling ill they are ready to leave intensive care. The immune profile and clinical impression indicate that they are likely to experience a prolonged period of reduced functioning and they enter a tailored rehabilitation process that is able to get them home three weeks later. A combination of preventative and active medications is combined with ongoing physical and mental health rehabilitation, and within six months our patient is back to how they were before the illness struck.
This story above is not far from reality already. But right now, a patient like this might have their severe infection detected later, or suffer repeated set-backs whilst in hospital due to hospital-acquired infections, each of which could lead to their sudden demise or protracted stay in hospital. Sepsis researchers and healthcare professionals are working hard to make this story a reality, developing the tools and strategies needed to realise this. They are also working on ensuring that we use current treatments and organ support approaches as safely and effectively as possible, as we await the developments that future research will bring.
From its first identification in the second half of the 20th century till now, we’ve seen significant improvements in our understanding and management of sepsis. This has been made possible by research, building across biological, clinical and social sciences to improve outcomes for patients and reduce the impact of this devastating condition. The next ten years promise to be very exciting, as some of the knottier challenges come under sustained scientific and research pressure. Sepsis Research FEAT is here to advocate for this research to be done and support the teams doing it. Together with public awareness and community support, we will beat sepsis.