The challenge of sepsis: new approaches to old scourge
Sepsis is a potentially fatal condition after the immune system over-reacts to an infection, leading to shock and organ failure. It is most frequently provoked by commonplace bacteria. Globally, over 30 million people develop sepsis each year. Some 6 million die as a result. Although there has been progress in controlling deaths from sepsis in recent decades, the challenge is still a major one. Indeed, in industrialized countries, the incidence of sepsis is higher than that of new cases of cancer.
Unpredictable and terrifying
Sepsis is frequently encountered in a hospital setting. It is also a leading cause for hospital readmission. In the US, studies estimate that one of 3 people who die in hospital have sepsis.
One of the biggest challenges for clinicians is that sepsis occurs unpredictably and progresses at terrifying speed. This makes timely diagnosis a tough call.
Definitions of sepsis have also tended to vary. In 2018, a working group of 19 specialists, convened by the Society of Critical Care Medicine in the US and the European Society of Intensive Care Medicine (ESICM), updated the clinical definitions and criteria for sepsis and septic shock. The taskforce recommended defining sepsis as “life- threatening organ dysfunction caused by an inappropriate host response to infection.” It also concluded that the term ‘ severe sepsis ‘ was redundant.
Nevertheless, there has been some progress in recent years in understanding sepsis and standardizing approaches to diagnose, manage and treat the condition.
In 2012, Rory Staunton, a healthy 12-year-old from New York, died due to the fact that his sepsis was not diagnosed. In the wake of this, the government of New York State mandated all hospitals to comply with protocols to improve the early diagnosis and treatment of sepsis and septic shock, and made it compulsory for reporting all sepsis cases to the Department of Health.
The New York Sepsis Initiative, which the media called Rory’s Regulations after the young victim, essentially consist of two treatment bundles.
The first is a 3-hour bundle, and is indicated for patients with severe sepsis and needs to be activated within three hours of a patient’s arrival at hospital. It includes blood culturing to determine choice of antibiotics, starting antibiotic treatment and assessing blood lactate levels – an important marker for sepsis.
The second, 6-hour bundle, is earmarked for patients with septic shock and needs to be carried out within six hours of their arrival at hospital. It includes administration of intravenous fluid, vasopressors to contract blood vessels and a follow-up check on lactate levels.
Assessing the New York Sepsis Initiative
The New York Sepsis Initiative was assessed earlier this year by a team from Warren Alpert Medical School at Brown University. They studied data from 91,357 patients, treated over a period of 27 months at 183 hospitals.
The findings were encouraging. The two sepsis bundles were used in 81.3 percent of patients. After implementation of the protocols, compliance steadily increased across hospitals in the State. The study’s most important finding, however, was that patients administered the bundles saw a reduction in mortality risk over 4 percentage points, at 24.4 percent. The mortality risk in those who did not receive the bundles was 28.8 percent. In addition, hospitals complying with the protocols saw a significant reduction in average length of stay.
Limits to fighting sepsis
While the New York State initiative provides strong evidence of the potential for standardizing sepsis-fighting measures, another study this year shows there may be limits to its scope. The study, by researchers from Brigham and Women’s Hospital in Massachusetts, was published in March by ‘JAMA Network Open’. It sought to investigate the precise role of sepsis in hospital deaths and estimate how many were preventable.
The researchers studied records of 568 people from six acute care hospitals for the years 2014 and 2015, who had died in the hospital or after discharge to hospice care. Using a 6-point Likert scale, ranging from “definitely preventable” to “definitely not preventable,” they concluded that some 90 percent of deaths were not preventable in a hospital setting. On the other side, 1 in 8 sepsis-related deaths were deemed “potentially preventable with better hospital-based care.”
The key reason for such a prognosis was that most sepsis fatalities occur in medically complex, older patients with severe co-morbidities, including chronic conditions such as cancer, heart and lung disease. In the few cases of death due to sub-optimal care, the most common causes included late antibiotic administration.
The lead author of the study, Dr. Chanu Rhee, called for more “innovation in the prevention of underlying conditions” to reduce sepsis mortality by a significant margin.
Long term decline in sepsis death rates
Although the challenge of sepsis remains serious, there has been significant progress over recent decades. In October 2018, the annual meeting of ESICM (the European Society of Intensive Care Medicine) was presented with an analysis of 30-year trends in sepsis deaths. Using World Health Organization figures, researchers from Harvard Medical School and Imperial College London (ICL) found that the average death rate from sepsis in Europe, North America and Australasia fell from 36.2 per 100,000 men in 1985 to 27.1 in 2015, and for women, from 23.2 per 100,000 women to 19.6.
Countries which managed to reduce death rates most significantly were Finland, Iceland and Ireland, while increased rates were noted in both Denmark and Lithuania.
Prospects for managing and treating sepsis in future years is likely to improve due to several new weapons, ranging from targeted drug development to artificial intelligence. Growing interest in this field is indicated by more than 200 sepsis biomarkers approved by the US Food and Drug Administration (FDA), among them interleukins, C-reactive protein and procalcitonin.
MIT’s IL-6 sensor system
It is known that interleukin-6 (IL-6), a protein produced in response to inflammation, begins to increase a few hours prior to other sepsis symptoms. IL-6 levels have not been strong enough to be detected by traditional tests. However, new sensor technologies appear to offer promise.
Researchers at the Massachussets Institute of Technology (MIT) have developed a small microfluidic sensor which can reportedly detect sepsis in a small blood sample (such as that obtained from a finger prick) within 25 minutes. The system uses antibody-laced magnetic microbeads in one fluid channel, which mixes with the blood sample and identifies the IL-6 biomarker. Meanwhile, another channel attaches the biomarked beads to an electrode. When a current is run through the electrode, a signal is produced each time an IL-6 bead passes through.
The magnetic detection system is far less expensive than the high-end optics required by conventional assays, and requires far less blood. The MIT researchers state that they will eventually be able to detect minute increases in IL-6 during the test itself. They are now continuing work on researching other proteins which act as early markers for sepsis detection and would reinforce diagnostic accuracy.
Early warning sepsis indicator
A new hematological biomarker, introduced in 2018 by Beckman Coulter as the Early Sepsis Indicator, is reported as part of a routine complete blood count (CBC) and measures morphological changes in monocytes, cells which play a role in the dysregulated immune response to sepsis. A positive result alerts clinicians to a higher probability of sepsis at an early stage
Another novel diagnostic technique is based on the fact that abnormal body temperature patterns accompany the earliest stages of sepsis. University of Missouri researchers have proposed using infrared thermography to measure the difference between body extremities and a patient’s core temperature. The team have developed an automatic real-time system which calculates this, based on a frontal and lateral infrared thermogram of the face. Writing in a recent edition of the ‘International Journal of Data Mining and Bioinformatics’, they state the system works successfully, irrespective of the angle of the head relative to the imager and differences in backgrounds.
Other efforts involve new drugs. One priority consists of signalling pathways which control immune cell behaviour during sepsis. So far, most research on inflammation has focused on kinases, the enzymes which transfer phosphate groups to specific substrates.
In August 2019, researchers from the University of California San Diego (UCSD) School of Medicine discovered a wholly new target area – the enzymes which remove them. In particular, they focused on PHLPP1, an enzyme which impacts upon inflammation by removing phosphates from the transcription factor known as STAT1, which controls inflammatory genes.
Using a mouse model, the researchers administered live E. coli bacteria and lipopolysaccharide (LPS), to both PHLPP1-deficient and normal mice. They found that the former fared far better, with half surviving infection-induced sepsis after 5 days – compared to zero for normal mice. The UCSD researchers believe that inhibiting PHLPP1 might form the basis for new sepsis treatments in humans, offering the means to control the dangerous inflammation of sepsis while maintaining the critical bactericidal properties of white blood cells.
Non-antibiotic drugs against sepsis
Researchers at the Royal College of Surgeons in Ireland (RCSI) have tested a compound called cilengitide (brandname InnovoSep) in a preclinical trial. A key feature of InnovoSep is that it is not an antibiotic, and does not face the limitations associated with the latter – namely, the need for rapid identification of causative bacteria and growing resistance to antibiotics.
Cilengitide is an antagonist of alpha-v beta-3, the key endothelial cell integrin which mediates the adhesion of cells to the extracellular matrix. In everyday terms, the drug prevents bacteria “from getting into the bloodstream from the site of infection by stabilizing the blood vessels so that they cannot leak bacteria and infect the major organs,” according to Steven Kerrigan of the RCSI.
To some, however, artificial intelligence (AI) is seen as potentially the most exciting frontier in the fight against sepsis. In 2018, the journal ‘Nature Medicine’ featured an AI system developed by scientists at Imperial College London, which proved to be more reliable predicting the best treatment for sepsis, as compared to human doctors. This was after it had ‘learned’ from an analysis of 100,000 patient records and clinical decisions in intensive care units about sepsis over a 15-year period.
Another promising AI system against sepsis has been developed by Sentara Healthcare in the US. Sentara’s sepsis prediction tool is based on identifying at-risk patients by using an algorithm to spot patterns from some 4,500 pieces of data in an electronic record. These focus on metrics such as body temperature, heart rate, blood tests, gender, medical history, etc.. Sentara had previously developed a ‘sepsis sniffer’ which detected when a patient had just begun to have sepsis. The current system goes further, and does not wait until a patient has already developed the disease.