The Challenge of Sepsis: Solving This Global Health Problem Requires Cross-Disciplinary Innovation

Sepsis is one of the largest health crises of our time, and an ideal group to fight it are the innovators who comprise IEEE. That is the assessment of Timothy G. Buchman (Figure 1), Ph.D., M.D., an expert on the infection-triggered condition that each year claims the lives of more than 11 million people worldwide, including more than 350,000 [1] in the United States. “IEEE is a wonderful catalytic environment for biomedical specialists, engineers, computational scientists, epidemiologists—lots of people in different disciplines—to say, ‘What can we do today?’ The next breakthrough technology is already on somebody’s lab bench. It just hasn’t been connected to the problem,” he remarked.

Buchman’s breadth of experience includes: professor of surgery, anesthesiology, and biomedical informatics within the Emory University School of Medicine, founding director emeritus of the Emory Center for Critical Care, head of the Emory Electronic ICU, past president of the Society of Critical Care Medicine (SCCM), editor-in-chief of two SCCM journals, including its flagship publication Critical Care Medicine; and a medical adviser to the U.S. Biomedical Advanced Research and Development Authority (BARDA), Division of Research, Innovation, and Ventures (DRIVe), which are part of the Department of Health and Human Services’ (HHS) Administration for Strategic Preparedness and Response. He has written extensively on sepsis, including analyses of sepsis among Medicare beneficiaries [2], [3], [4], [5].

In a wide-ranging discussion with IEEE Pulse, Buchman described the gaps in current medical care that could be filled by innovators who put their minds and skills to the task. (Note: For this interview, Buchman spoke as an individual and not as a representative of Emory, the SCCM or its journals, or the HHS. His responses are his own.)

IEEE Pulse: To begin, what exactly is sepsis?

Buchman: One way for the non-clinician to think about sepsis is to recognize that we live in a dirty world. There are microorganisms on the surfaces we touch, on the food we eat, and on our skin and mucus membranes, and yet we live in some kind of balance with that world. Periodically, though, microorganisms achieve a toehold and gain access to our entire bodies, which can cause the body to respond in a dysregulated way that can lead to life-threatening organ dysfunction [6]. That dysregulation is sepsis, and it can have myriad presentations.

IEEE Pulse: What makes sepsis such a challenge in terms of medical care?

Buchman: Sepsis moves fast. In fact, your readers likely know someone who was fine Tuesday, and was hospitalized on Thursday with multiple organ failure as the clinical team tried to fight sepsis. Fortunately, we’re getting better with the recognition of sepsis, but controlling the infectious source is more of a challenge. We need to determine that there is an infection, identify the pathogenic organism, and choose the right approaches, which might be surgical intervention or use of antibiotics—or both—in the context of the patient in front of us. Why “in the context of the patient in front of us”? Because everyone is different. We are not genetically identical mice in a cage. We are outbred humans with different genetic backgrounds, different life experiences, and a different acute illness, for instance, an infection with Staphylococcus versus Streptococcus versus Escherichia coli. All those things are going to change the approach clinicians need to take.

IEEE Pulse: What are some of the issues that need solving?

Buchman: For these purposes, I’ll skip all of the critical public health measures aimed at prevention of infection, for example, sanitation and immunization. Let’s begin instead with patients who are already infected and becoming sick. Half of all episodes of sepsis proceed with the pathogen undetected, much less identified. And therein lies the first big opportunity: improve detection and identification.

This might take several forms. It might take the form of invasive studies, or at least a blood draw and better lab tests; or population sensing, where there’s a quick identification of a pathogen when a group of people simultaneously and suddenly get sick as happened initially in Wuhan, China, with COVID. An early task is finding the organism and figuring out what it is, and that remains a formidable challenge.

The next issue is determining the resistance profile of the pathogen, which may be different from one patient to the next. That knowledge makes a difference when choosing the best antibiotic, so this is another area ripe for a new approach.

In addition, there are opportunities when it comes to localizing the infection site so the site can be drained rapidly to reduce the bacterial count. At present, imaging relies on ultrasound, computed tomography (CT) scans, and magnetic resonance imaging (MRI), each of which requires specialized equipment. There are opportunities for improvement there as well.

IEEE Pulse: You described sepsis as a dysregulated response to an infection. What impact does that have, and does it also present windows for innovation?

Buchman: Thankfully some patients are able to bring sepsis under control once source control of the infection is obtained. Sepsis that is not self-limiting, however, often manifests in two phases. The first is a hyperinflammatory state and the second is a period of immune suppression. We saw some similar attributes with COVID, and that mental model of a biphasic response helps explain why certain medications were helpful at tempering the insult of COVID, but only if given at the appropriate time, at a given severity. In other words, you don’t want to shut down the “good” inflammation and leave the patient in an immunosuppressed state; you just want to temper the excess inflammation.

The questions then become: How do we detect that transition from hyperinflammation to immunosuppression, and how do we personalize the treatment to support the patient’s immune system toward effective function? There is opportunity to not only personalize our care for the individual, but also to adjust it to follow the trajectory of each individual’s response, bearing in mind that the treatment that is administered to help temper inflammation today may actually make matters worse two days from now. This is yet another opportunity—to more quickly and precisely characterize the pathophysiology in order to select and to time therapy—that IEEE Pulse readers have to make a difference in the war on sepsis.

IEEE Pulse: What are some of the tools that are available or in development that might help fill some of these gaps, even in quickly determining whether a patient definitely has sepsis or definitely does not?

Buchman: I’m going to mention some recent advances simply as examples. None of the mentions constitute a personal endorsement.

One advance is a measure called monocyte distribution width [7], which looks at mononuclear cells. Monocytes are the single-nucleated cells in the blood. It turns out this measure of those cells’ size distribution, in combination with other clinical findings, may help identify patients with evolving sepsis. This advance came from Beckman Coulter and was cleared by the U.S. Food and Drug Administration (FDA) in 2019 [8], [9]. (Beckman Coulter is headquartered in Brea, CA, USA.)

Another approach comes from Cytovale, which recognized that changes in the mechanical deformability of white blood cells are associated with sepsis initiation. Their technology, called IntelliSep, allows them to “bin” the patients according to their evolving severity based on cell deformability. This technology recently cleared FDA approval [10], [11]. (Cytovale is headquartered in San Francisco, CA, USA.)

We need faster sensing: Is there an infection? We need earlier precision: Is the pathogen a virus, a bacterium, or a fungus? Many companies are working on technologies to help answer those questions quickly. Again, here are some examples.

For molecular sensing, Immunexpress’ SeptiCyte RAPID received 510(k) clearance from the FDA as an aid in differentiating sepsis from infection-negative systemic inflammation in hospitalized patients suspected of sepsis [12], [13]. (Immunexpress is headquartered in Seattle, WA, USA.)

For discriminating among pathogen types, Inflammatix [14] has been gathering data on its suite of molecular tests aimed at reporting presence, type, and severity of infection. If one test could illuminate all of those questions, it could help clinicians take better, faster, more precise care of patients. (Inflammatix is headquartered in Sunnyvale, CA, USA.)
These and other new technologies hold great promise. Still, we would like to move detection of infection and recognition of sepsis earlier, into the home. Could that be done with a salivary test? How about a breath test or a urine test? Could it be packaged as a lateral flow device, like the swab-the-nostril home test for COVID, or a home pregnancy test?

IEEE Pulse: Are there any other areas ripe for exploration?

Buchman: Absolutely! No two patients are alike. Where alternatives exist, how do I decide what to offer as the best treatment for the patient in front of me right now? What differentiates among the host responses not just to the infection, but as a doctor, to my specific treatments? We’re just at the beginning of really understanding what’s going on and choosing the right therapy for the patient.

Know that even sepsis survivors have long-term health challenges. Their overall health is worse, and among survivors they are much more likely to die over the next three years. We don’t really understand, much less know how to mitigate, and even much less how to prevent this excess mortality.

That leads to the need for prevention, and speaking with the passion of a clinician, I would rather prevent an illness than try to treat it. For that reason, we need better insights into how immunizations work to potentially find ways to prevent the dysregulation behind sepsis.

IEEE Pulse: Where do you see the most need for innovation in battling sepsis?

Buchman: Early detection is key to effective treatment, but current approaches to detection are complicated and costly. Many investigators have worked on mass screening using, for example, thermography, exhaled breath analysis, and so forth to figure out who might be evolving sepsis, but we haven’t made a lot of progress in this area. We are still waiting for someone to invent the “sepsis dipstick,” some simple device that would help a mom with a sick child answer the question, “Could this be sepsis?” Perhaps there are opportunities to make use of these marvelous computers we carry with us—our smartphones—by adding software, sensors, widgets, and dongles that can sense various aspects of our physiology.

Equity in prevention, detection, and treatment of sepsis is a major challenge. There are huge swaths of humanity that are especially vulnerable to sepsis and do not have access to technology that we enjoy in developed nations. It becomes very important to find not just effective but also cost-efficient technologies. Just keep in mind that it’s not just the 350,000 Americans who die every year of sepsis. Sepsis is a global threat for which we need global solutions.

The answers are out there. Let’s work together to find them, to engineer them, to produce them, and to deploy them.

References

1. R. B. Dantes et al., “Sepsis program activities in acute care hospitals—National healthcare safety network, United States, 2022,” Morbidity Mortality Weekly Rep., vol. 72, no. 34, pp. 907–911, Aug. 2023, doi: 10.15585/mmwr.mm7234a2.
2. T. G. Buchman et al., “Sepsis among Medicare beneficiaries: 1. The burdens of sepsis, 2012–2018,” Crit. Care Med., vol. 48, no. 3, pp. 276–288, Mar. 2020, doi: 10.1097/CCM.0000000000004224.
3. T. G. Buchman et al., “Sepsis among Medicare beneficiaries: 2. The trajectories of sepsis, 2012–2018,” Crit. Care Med., vol. 48, no. 3, pp. 289–301, Mar. 2020, doi: 10.1097/CCM.0000000000004226.
4. T. G. Buchman et al., “Sepsis among Medicare beneficiaries: 3. The methods, models, and forecasts of sepsis,” Crit. Care Med., vol. 48, no. 3, pp. 302–318, Mar. 2020, doi: 10.1097/CCM.0000000000004225.
5. C. Frank et al. “Sepsis among Medicare beneficiaries: 4. Precoronavirus disease 2019 update January 2012-February 2020,” Crit Care Med., vol. 49, no. 12, pp. 2058–2069, Dec. 2021, doi: 10.1097/CCM.0000000000005332.
6. M. Singer et al. “The third international consensus definitions for sepsis and septic shock (Sepsis-3),” J. Amer. Med. Assoc., vol. 315, no. 8, pp. 801-810, Feb. 23, 2016, doi: 10.1001/jama.2016.0287.
7. E. Crouser et al. “Monocyte distribution width: A novel indicator of Sepsis-2 and Sepsis-3 in high-risk emergency department patients,” Crit. Care Med., vol. 47, no. 8, pp. 1018–1025, Aug. 2019, doi: 10.1097/CCM.0000000000003799.
8. U.S. Food and Drug Administration. (Mar. 18, 2019). 510(k) Premarket Notification. Accessed: Oct. 4, 2023. https://www.accessdata.fda.gov/scrIpts/cdrh/cfdocs/cfpmn/pmn.cfm?id=K181599
9. Beckman Coulter. Hematological Biomarker in the Emergency Department. Accessed: Oct. 4, 2023. [Online]. Available: https://www.beckmancoulter.com/en/solutions/detect-sepsis-earlier?gclid=Cj0KCQjwmvSoBhDOARIsAK6aV7i8uyGUoj0TSn9FJk811Jcxzvem-I6UzIw7lISm1OrmL85iQXXdoRcaAmoZEALw\_wcB
10. U.S. Food and Drug Administration. (Dec. 20, 2022). (510[k] Notification). Accessed: Oct. 4, 2023. [Online]. Available: https://www.accessdata.fda.gov/cdrh_docs/pdf22/K220991.pdf
11. Cytovale. IntelliSep. Accessed: Oct. 4, 2023. [Online]. Available: https://cytovale.com/intellisep
12. U.S. Food and Drug Administration. (Nov. 29, 2021). (510[k] Notification). Accessed: Oct. 4, 2023. [Online]. Available: https://www.accessdata.fda.gov/cdrh_docs/pdf20/K203748.pdf
13. Immunexpress. About SeptiCyte. Accessed: Oct. 4, 2023. [Online]. Available: https://immunexpress.com/products/?cn-reloaded=1
14. Inflammatix. Inflammatix Pipeline. Accessed: Oct. 4, 2023. [Online]. Available: https://inflammatix.com/inflammatix-tests/#triverity