How testing and teamwork are helping diagnose sepsis faster

The challenges arising from the sepsis crisis remain a primary concern throughout the global healthcare community. The economic and human tolls amassed by this frequently deadly, often-enigmatic condition are high and affect everyone—patients and their loved ones, clinicians, laboratorians, medical administrators, and organizational leaders. The multifaceted and complex nature of sepsis requires a wide-reaching, multi-level, comprehensive solution. It also requires collaboration. And, while no single tool can alone solve the problems presented by sepsis, there is a singular focus emerging among those seeking a solution: To identify sepsis as quickly and accurately as possible to enable timely intervention for more positive patient outcomes.

Understanding the global impact of sepsis

Sepsis, a dysregulated response by the body to an infection, is a life-threatening medical emergency.¹ It is a condition that, as stated by Machiavelli, “at its inception is difficult to recognize but easy to treat; left unattended it becomes easy to recognize and difficult to treat.”

Currently, sepsis affects 30 million people worldwide² and claims 258,000 U.S. lives, annually.³ Each year, an estimated 1.6 million people are diagnosed with sepsis in the U.S. and it is the leading cause of hospitalizations. To that end, sepsis places an overwhelming strain on U.S. hospital resources, costing more than $24 billion annually,⁴ a figure that is rising 19 percent per year.⁵

Because two-thirds of patients with sepsis enter the healthcare system through the emergency department (ED),6 it is critical that those making first contact with the patient—clinicians and nurses—are equipped with tools to identify sepsis earlier so that treatment can be more effective, and thus economic burden reduced. 

Driving action at the first interaction

Although new innovations and initiatives addressing sepsis are introduced into the healthcare landscape on an ongoing basis, the most critical efforts center around early diagnosis and treatment. Early identification of sepsis leads to faster treatments, including antibiotic administration, which has been proven to reduce the likelihood of death by 7.6 percent for every hour saved.⁷

Testing—a novel biomarker for early sepsis detection

There has never been a single diagnostic test for sepsis.⁸ Traditional testing, such as white blood cell count (WBC), blood cultures, and biomarkers are often nonspecific and have limitations. For example, blood cultures require up to three days to obtain results and are positive in only 20 to 30 percent of sepsis patients.⁸ Recent evidence of a novel hematology-based biomarker, however, has shown promise in helping ED clinicians detect sepsis sooner, when used with the current standard of care. The biomarker measures morphological changes in monocytes—cells of the innate immune system that serve as first responders in the fight against infection. In a single-center feasibility study, Crouser et al. demonstrated that measuring the monocyte distribution width (MDW)—the increase in distribution of sizes of these cells—improved detection of sepsis over neutrophil morphological measurements and over WBC count alone.⁹ Moreover, using both MDW and WBC count was more effective than using either parameter individually.

In a subsequent multicenter study, Crouser et al. again examined the diagnostic accuracy of MDW alone, and in combination with WBC count, in identifying sepsis in the ED.¹⁰ With an established cutoff of >20.0, MDW distinguished sepsis from all other conditions based on either Sepsis-2 or Sepsis-3 criteria. The negative predictive values for MDW <20 were 93 percent for Sepsis-2 and 94 percent for Sepsis-3. Combining MDW with WBC count was predicted to inform clinical decision making for clinicians managing septic or potentially septic patients in the ED.

To determine the predicted economic impact of MDW clinical utilization on hospital resources, Paoli et al. conducted a counterfactual analysis.¹¹ Sixty-seven percent of 349 sepsis patients were predicted to benefit from the MDW results, potentially decreasing the time to antibiotic administration from an average of 3.98 hours based on the standard of care alone, to 2.07 hours when MDW was added, assuming a 30-minute turnaround time for the CBC. Potentially, this could reduce mortality by 14.2 percent, hospital length of stay by a mean of 1.48 days, and cost per hospitalization by $3,460. Considering a national mean of 206 sepsis hospitalizations each year per hospital, the modeled predicted annual savings for each hospital totaled $712,783. Note that additional study is required to validate this model.

Confirmatory testing—leveraging sepsis biomarkers

While nonspecific for sepsis, several currently used biomarkers play a supportive but significant role in sepsis care.

Procalcitonin (PCT) is a prohormone that is normally produced in the thyroid, but with bacterial infections is produced by monocyte-lineage cells in the liver. In healthy individuals, PCT levels in the blood are below 0.5 ng/mL. In response to infection, PCT levels rise quickly, becoming elevated between two and six hours after exposure and peaking within six to 24 hours.¹² However, PCT may also be elevated for other reasons, such as after surgery, or from autoimmune conditions. And, while PCT is primarily used to examine a patient’s response to antibiotics, some hospitals in the U.S. may use it to differentiate between bacterial and non-bacterial sepsis.

Lactate is used as an indication of sepsis progression and severity. Lactate values >2 mmol/L (>18 mg/dL) are included in the Sepsis-3 definition for septic shock.¹³ Monitoring lactate levels is recommended as part of the Surviving Sepsis Campaign 1- and 3-hour bundles, as persistence of elevated lactate has been associated with increased mortality.¹⁴  

Two additional biomarkers, Interleukin-6 (IL-6) and C-reactive protein (CRP), are related to inflammation, and, thus, are also widely used to confirm infection in patients presenting to the ED, although they are less commonly used in the U.S. than in other countries. 

Teamwork—a multi-level, collaborative approach

It is clear that lab testing is critical in both diagnosing and managing sepsis. Clinical insight offered by laboratory testing can now be augmented using new evidence-based resources for ED clinicians, highlighting the importance of collaboration between clinicians and laboratorians in the acute-care setting.

Managing sepsis requires an expanded approach beyond the ED. Multidisciplinary sepsis committees are leading the charge at the hospital level, developing processes and introducing new technologies to help elevate sepsis care within their organizations.

Additionally, in the U.S., the Sepsis Alliance is “working in all 50 states to save lives and reduce suffering from sepsis.”¹⁵ Sepsis protocols are often state led but sharing information across state lines could prove beneficial.

On a global level, much has been done to drive commonality in language and protocols and to advance conversations surrounding sepsis care. The general nature of the language surrounding sepsis is often vague and can be challenging for hospitals. Initiatives put forth by the Global Sepsis Alliance—World Sepsis Day held on September 13th and the World Sepsis Congress—have drawn attention to the sepsis crises for clinicians and patients. World Sepsis Day has created awareness in the general population of the dangers of sepsis, and the World Sepsis Congress has created opportunities for the exchange of information among industry thought leaders to advance awareness.¹⁶

In conclusion

Through both technological advancements in testing and continued collaboration among people on all sides of the sepsis crisis, great strides have been made in understanding and managing sepsis in recent years. As this work continues, there is hope that one day we will all realize what the Sepsis Alliance envisions: “A world in which no one is harmed by sepsis.”¹⁸

REFERENCES

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2. Sepsis Alliance. Fact Sheet 2018. Sepsis.org. Accessed 6 Mar 2019.
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11. Paoli CJ, Reynolds MA, Coles C, et al. Predicted Economic Benefits of a Novel Biomarker for Earlier Sepsis Identification and Treatment: A Counterfactual Analysis. Scientific poster presented at the 71st AACC Annual Scientific Meeting & Clinical Lab Expo.
12. Vijayan AL, Vanimaya, Ravindran S, et al. Procalcitonin: A Promising Diagnostic Marker for Sepsis and Antibiotic Therapy. Journal of Intensive Care. 2017; 5:51. 
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14. Surviving Sepsis Campaign. 3-Hour Bundle. http://www.survivingsepsis.org/SiteCollectionDocuments/Bundle-Three-Hour-SSC.pdf. Accessed 21 Jul. 2019.
15. Sepsis Alliance. About Sepsis Alliance. https://www.sepsis.org/about/our-story/. Accessed 21 Jul. 2019. 
16. Global Sepsis Alliance. World Sepsis Day. https://www.worldsepsisday.org. Accessed 21 Jul. 2019.