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Subspecialties Microbiology and immunology, Hematology, Clinical care, Technology and innovation

Spotting Sepsis Sooner

sponsored by Beckman Coulter

Despite advances in modern medicine and acute patient care, sepsis remains the leading cause of death from infection. It’s a life-threatening condition that represents a global health care problem; one in 23 hospital patients – over 27 million people worldwide – are affected (1). Sepsis claims more lives than any cancer and currently has a 25–30 percent mortality rate. But it’s not just an issue for patients; the health care cost of sepsis in the USA is estimated at US$24 billion each year (2).

That number is on the rise. The incidence of severe sepsis in the U.S. is increasing by 1.5 percent each year – faster than the projected population growth. The number of cases documented in 1995 was 750,000; in 2010, it rose to 934,000 and it is predicted to hit 1,110,000 in 2020 (3). This increase in incidence is due to:

  • increased awareness and tracking
  • a high incidence of severe sepsis in elderly patients
  • a disproportionate increase in the number of elderly Americans
  • growing numbers of antibiotic-resistant organisms
  • more people living with chronic or terminal diseases, such as diabetes or HIV
  • therapies that suppress the native immune system, such as chemotherapy or immunosuppression

Several studies have demonstrated that early intervention and diagnosis are key to reducing sepsis mortality; one well cited investigation found that there is a 7.6 percent increase in mortality for every hour’s delay in antibiotic treatment (4). For this reason, the key challenges for clinical laboratories in the management of sepsis involve striving for earlier diagnosis with reliable tests that accurately assess whether a patient’s immune system has started to become septic.

Defining sepsis

In 2016, sepsis was redefined by a panel of experts as “a life-threatening organ dysfunction caused by a dysregulated host response to infection,” an explanation that better reflects its clinical presentation. Previously, sepsis was defined solely using systemic inflammatory response syndrome-based criteria. Although initial inflammation is still used as the basis for suspicion of sepsis, we now recognize that many other pathological presentations can also cause inflammation. The new definition is accompanied by a set of criteria summarized in the quick Sepsis Related Organ Failure Assessment (qSOFA) score, which treats those with sepsis as a subset risk group of infected patients (see Table 1).

Table 1. qSOFA criteria for the probability of sepsis mortality.

Lab tests can be used at a variety of stages in the clinical management of sepsis – to indicate infection and inflammation, to detect the dysregulation of inflammation at the organ level following hypoperfusion and to mark coagulopathy and organ failure. Numerous biomarkers reflect these stages; however, only a few have sufficient sensitivity and specificity to identify sepsis. Among them, the most widely used are lactate, procalcitonin (PCT) and immune cells.

Laying down a biomarker

Although the role of lactate continues to be debated in the context of sepsis, high levels of lactate can be an early indicator of the condition. The challenge of this approach is knowing what cutoff to apply; a low cutoff to catch sepsis as early as possible might lead to overdiagnosis, which then results in unnecessary antibiotic administration. High cutoffs, on the other hand, risk missing cases and delaying treatment.

Another biomarker currently used is PCT – a peptide precursor of the hormone calcitonin, which helps to regulate calcium homeostasis. PCT concentrations in non-septic individuals are below 0.5 ng/mL, but they increase in multiple tissues throughout the body in response to sepsis. Because PCT levels rise rapidly within six to 12 hours of infection, this test can play an important role in spotting sepsis in the critical first 24 hours. Importantly, neither lactate nor PCT are specific for sepsis and elevated levels of either may be caused by other etiologies. Additionally, a lack of elevated lactate and/or PCT does not eliminate the possibility of sepsis.

Another class of sepsis biomarkers that is typically available more immediately are the body’s own white blood cells, including neutrophils and monocytes. These have been shown to exhibit morphological changes in response to infection; for example, when the human THP-1 monocytic cell line is infected with Chlamydia pneumoniae bacteria, infected cells are directly induced to differentiate to macrophages (5, 6). Unfortunately, increases in white blood count (WBC) are also nonspecific in patients who present in the emergency department (ED), so a biomarker that is routinely available during initial clinical evaluation could hold the key to alerting providers about the risk of sepsis earlier.

Indication at the earliest stage

Beckman Coulter has addressed this need with the Early Sepsis Indicator (ESId)—which analyzes morphological changes in monocytes. Recent studies have indicated that volumetric increases in immune cells might be useful for detecting sepsis, and taken together with current standard of care, ESId can augment the suspicion of sepsis or risk of developing sepsis within 12 hours. ESId measures the change in the size distribution of circulating monocytes, known as monocyte distribution width (MDW).

In a prospective cohort study of 1,320 adult ED patients that included 98 with sepsis, the addition of MDW to WBC significantly improved the probability of having sepsis in comparison to WBC alone (7). An advantage of this method over other biomarkers, such as PCT, is its availability to health care providers at an earlier stage of clinical evaluation, when sepsis diagnosis might not ordinarily be considered. It can be offered as part of a routine complete blood count, making it a hematology-based test that can alert ED clinicians in identifying adult patients with sepsis or at increased risk of developing sepsis in the emergency department.

ED clinicians play a crucial role on the front lines of care for acutely ill patients, and early sepsis detection using MDW and WBC in combination fits neatly into the typical care pathway (see Figure 1). After a patient presents to the ED and the initial triage indicates possible infection, a CBC with differential is ordered. This is where the results of the early detection test might come back indicating possible sepsis, leading to further tests and the application of qSOFA criteria at the inpatient stage. The marker was recently cleared by the FDA and is marketed under the name Early Sepsis Indicator.

Figure 1. The sepsis patient care pathway.

The bottom line

Spotting sepsis early is challenging and must be balanced against overdiagnosis to prevent over administration of antibiotics. No single set of criteria or biomarkers is perfect, so clinicians are best served using a combination of tests and observations to complete the puzzle after reviewing the entire clinical picture. When it comes to sepsis, time equals life – and, given that 80 percent of cases begin outside the hospital (8), it is crucial to recognize and treat sepsis as quickly as possible once patients enter the ED. Early Sepsis Indicator offers a unique approach and will complement other tests that use alternative biomarkers—giving sepsis patients the best chance of survival through earlier initiation of antimicrobial therapy.

The Application of Knowledge

The free Escavo Sepsis Clinical Guide is an intuitive, informative smartphone application that contains comprehensive information on the symptoms, diagnosis and treatment of sepsis. As the top-ranked app on sepsis care, it is regularly used by thousands of acute and critical care clinicians across the world as a reference tool. Not only does its use benefit health care professionals who treat patients in acute settings, but medical students and residents looking to learn more about sepsis will also find it invaluable. The app, which is available for iOS and Android devices, includes:

  • A simple, easy-to-use interface
  • Pocket risk-scoring calculators
  • High quality, well-referenced and cutting-edge clinical information

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  1. Sepsis Alliance (2019). Available at: bit.ly/2Tz3SvG.
  2. CM Torio et al (2016). Available at: bit.ly/2VyQFQU.
  3. DC Angus et al., Crit Care Med, 29, 1303 (2001).
  4. A Kumar et al., Crit Care Med, 34, 1589 (2006).
  5. H Yamaguchi et al., Infect Immun, 70, 2392 (2002).
  6. M Prucha, et al., Clinica Chimica Acta, 440, 97 (2015).
  7. ED Crouser et al., Chest, 152, 518 (2017).
  8. K Rheinhart et al., N Engl J Med, 377, 414 (2017).

About the Author

Rachel Burnside

Rachel Burnside, Ph.D., MBA leads global marketing for Beckman Coulter’s Hematology Business Unit, and has extensive clinical diagnostic laboratory experience, serving as a lab director for over a decade. She completed a Ph.D. in microbiology, immunology and molecular genetics at the University of Kentucky, and an MBA from Duke's Fuqua School of Business with a concentration in Health Sector Management.

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