Two case studies illustrate how a newly developed sepsis test improves turnaround times and diagnostic accuracy, buying clinicians critical time to administer life-saving treatments.      

By Roy F. Davis PhD, MD, MSc, MHA; Krupa A. Navalkar, PhD; and Prashant S. Wani, PhD    

Summary

Sepsis is a life-threatening condition caused by a dysregulated response to infection, posing significant global health challenges with high mortality and financial costs, while traditional diagnostic methods remain inadequate, highlighting the potential of modern molecular testing for better management.

Takeaways

  1. High Mortality and Costs: Sepsis causes over 11 million deaths annually worldwide and is extremely costly, with annual U.S. healthcare costs reaching $62 billion.
  2. Diagnostic Challenges: Traditional sepsis diagnosis methods like blood culture are slow and often inaccurate, leading to delayed or inappropriate treatments.
  3. Modern Molecular Testing: New diagnostic tools, such as the SeptiCyte RAPID test, use gene expression to quickly and accurately assess sepsis risk, improving timely and appropriate patient care.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and is a significant and expensive global health problem with high morbidity and mortality1. Annually, more than 11 million die worldwide from sepsis, and there are at least 1.7 million cases in the United States per year2. Sepsis is among the leading causes of death in the U.S., and it is ranked as the most expensive disease state to manage for admitted patients, with total annual costs estimated at $62 billion. Despite these significant expenditures, the incidence of sepsis continues to increase annually, and there has been no significant improvement in patient outcomes3.

Gold Standard Sepsis Test Doesn’t Measure Up

Early diagnosis and prompt implementation of treatment have been shown to improve outcomes for sepsis patients. However, diagnosing sepsis early is challenging for several reasons. Clinical signs presented by patients are common to many other non-infectious conditions4. The traditional diagnostic gold standard for sepsis, such as blood culture lacks timeliness with a longer turnaround time and efficiency with false negatives in 30-50% of retrospectively diagnosed cases5,6,7.

More importantly, unnecessary administration of broad-spectrum antibiotic therapy for presumed sepsis or sepsis mimics may adversely contribute to the growing problem of multidrug-resistant organisms and carries the risk of adverse drug reactions8.

Surviving Sepsis Campaign 2022    

The Surviving Sepsis Campaign (SSC) 2022 guidelines categorize potential sepsis patients into three groups9:

  • High-risk adults: Early antibiotics within one hour. If no infection is confirmed, re-evaluate and possibly discontinue antibiotics.
  • Possible sepsis without shock: Rapid assessment for infection, with antibiotics administered within three hours.
  • Low risk without shock: Withhold antibiotics while continuing evaluation and close monitoring.

Depending on the patient group, interventions involve lactate level measurement, blood culture acquisition, administration of broad-spectrum antibiotics, administration of 30 mL/kg of crystalloid fluids for hypotension or lactate levels ≥ 4.0 mM, use of vasopressors for persistent hypotension, re-evaluating lactate if elevated at initial assessment, and patient reassessment. However, several sensitive but non-specific biomarkers, such as lactate, WBC, bands, and C-reactive protein, are inefficient in ruling out patients not having sepsis. 

Molecular Testing Improves Diagnosis and Response

Diagnosis with modern molecular approaches measuring immune host response with highly specific biomarkers can help improve appropriate intervention, which will benefit managing sepsis patients more efficiently.

The cases described below are typical clinical encounters in which patients present with symptoms suggesting possible sepsis. However, when the SeptiCyte RAPID test, a host response assay measuring gene expression of specific biomarkers to enhance rapid sepsis evaluation (Fig. 1) is employed alongside routine clinical parameters, the test results helped in appropriate and timely intervention, prompting further patient monitoring for an alternative diagnosis.

Figure 1: FDA-cleared automated SeptiCyte RAPID assay and interpretation: Workflow for analyzing mRNA expression from two white blood cell genes that are either up or downregulated in the presence of systemic inflammation with infection (Sepsis) or non-infectious systemic inflammation (Systemic Inflammatory Response Syndrome or SIRS). The differential in the Cq values of these genes generates the score (called SeptiScore onwards), which helps ascertain the concomitant risk of sepsis. Image: Immunexpress

Further Reading: Why Better Sepsis Diagnosis Results in Better Outcomes

Case 1: Sepsis Test Result – High Probability

The patient was a 63-year-old African American male who was admitted to the ED with 3 SIRS criteria including fever (39.5°C), heart rate of 103 beats per minute, a respiratory rate elevated to 34 breaths per minute. Their WBC count was normal, and lactate was only mildly elevated to 1.1 mmol/L. The patient’s systolic blood pressure (SBP) elevated at 177. His initial qSOFA – quick sequential organ failure assessment score was normal (<2) at 1, but SOFA was (>=2) at 4, indicating a mortality risk of 10%1.

The patient had a history of UTIs, so an ultrasound of the kidney and bladder, along with a chest X-ray, was ordered. The chest X-ray indicated evidence of pneumonia, but the ultrasound did not conclusively rule in cystitis. PCRs for Influenza A, B, RSV, parainfluenza, metapneumovirus, adenovirus, rhinovirus, and COVID-19 were negative.

The SeptiScore from SeptiCyte RAPID test was in Band 4 indicating an elevated probability of sepsis, blood and urine cultures were collected and sent out for microbiology, and the patient was started on antibiotics. The patient was treated for 1.5 days in the ICU and then transferred to the ward for continued treatment before discharge from the hospital. Three days into their hospital stay, their blood and urine culture identified Enterobacter, and the patient was discharged from the hospital on the third day with an antibiotic Levofloxacin. 

Case 2: Sepsis Test Negative

A 56-year-old Caucasian man was transferred from another hospital due to a deteriorating health condition, with signs of tachypnea, tachycardia, and a fever of 38.1°C. Fever is a symptom of multiple conditions, including sepsis or SIRS. Physical exam was unremarkable except for labored breathing which worsened, and the patient was intubated and put on mechanical ventilation.

His admission qSOFA score was 2, and his laboratory tests showed a WBC count of 14,800 cells/µL, a platelet count of over 150,000/µL, and a lactate level of 0.6 mmol/L. His creatinine and bilirubin levels were within normal ranges. The SeptiCyte RAPID test was performed to rapidly evaluate the probability of sepsis, and the SeptiScore obtained was 3.4 in Band 1, indicating a low likelihood of sepsis.

Blood and urine samples were collected for culture, and he was started on antibiotics as a precautionary measure against potential sepsis. However, he developed hypotension and an irregular heartbeat, which led to a consultation with cardiology. A cardiology consult was obtained, EKG showed acute ST elevation, suggesting a myocardial infarction and the patient was taken to the cath lab.

Three days after his admission to the ICU, his blood culture was negative, and his urine culture tested positive for E. coli after 72 hours. They also identified gram-positive cocci in sputum culture ~72 hours after admission. The patient was treated with Piperacillin/Tazobactam antibiotic from admission for up to ~1.5 days.

While a blood culture was taken and later reported to be negative, a low SeptiScore in Band 1 indicated a lower probability of sepsis in this case. In the clinical validation of this gene expression test, only 11.5% of patients had a positive blood culture, and none have Band 1 SeptiScore. Antibiotics were started for this patient but were discontinued within two days of his ICU admission. After four days in the ICU, during which he was extubated, he was transferred out of the ICU. He was discharged home two days later, making his total hospital stay six days.

The Challenges of Sepsis Diagnosis

The first case presented with symptoms of pneumonia and possible UTI with 3 SIRS criteria including fever, tachypnea, and tachycardia. This patient’s WBC count was normal and the patient’s tests from the sepsis bundle, except for a mildly elevated lactate, were unremarkable. A key aspect to note for both cases is that microbiology culture results often arrived three days after initial admission. For the first case, a SeptiScore elevated in Band 4 (highest probability of sepsis) indicated the need for appropriate treatment much in advance of culture positivity. In the clinical validation of this gene expression test, 70% of blood culture-positive patients had a Band 4 score, indicating a higher probability of sepsis due to bacteremia.

The second case demonstrates the inherent challenges in distinguishing sepsis from alternative diagnoses. The patient, presenting with a qSOFA score of 2, 3 SIRS criteria, and an elevated white blood cell count, developed respiratory failure and hypotension, leading to sepsis treatment. However, the results from the SeptiCyte test that measures the expression of sepsis-specific biomarkers suggested a low probability of sepsis. This, coupled with the absence of an infectious source, warranted further patient evaluation for alternative etiologies. The negative blood cultures further supported the discontinuation of antibiotics when an alternative diagnosis was identified.

The patient’s symptoms and routine sepsis bundle laboratory tests often hint to sepsis but are not definitive. As shown in Figure 2, test results from rapid and modern molecular approaches such as SeptiCyte outperform routine clinical variables frequently used in sepsis diagnosis, either alone or in combination with each other, in differentiating sepsis from non-infectious systemic inflammation14.

Figure 2: Performance of frequently used clinical variables (Lactate and PCT) in sepsis diagnosis SeptiScore ROC AUC significantly outperforms PCT and Lactate alone and combined with commonly measured clinical variables in prospectively collected and tested samples. Image: Immunexpress

Such FDA-cleared rapid diagnostic sepsis tests can be used with minimal intervention by drawing a blood sample in PAXgene or EDTA blood collection tube. If the score is elevated (Band 4) and the patient meets at least 2 SIRS criteria, the patient has a high probability of sepsis.

However, despite the SeptiScore having a high AUC (0.85), clinical intervention should also consider the status of other clinical parameters. Measuring immune host response with gene expression of sepsis-specific biomarkers can drive timely initiation of therapy and source detection with its one-hour turnaround time versus assessing a change in SOFA score which may take hours to compute. If the test results fall in Band 1 or 2, indicating a lower probability of sepsis, it supports antibiotic stewardship and prompts an appropriate early diagnostic evaluation to ascertain an alternative etiology of the patient’s presentation. If the SeptiScore is elevated in Band 3 or 4, it should prompt early initiation of antibiotics and source detection.

This approach can significantly improve the management and treatment of sepsis which in turn fulfills SSC management guidelines.

Featured Image: Sepsis is difficult to diagnose, which delays treatment. A new sepsis test may improve diagnostic turnaround time, and better treatment outcomes for patients. Photo: Immunexpress

About the Authors    

Roy F. Davis PhD, MD, MSc, MHA, is chief medical officer at Immunexpress. Roy has 30 years’ experience in clinical medicine (Neonatal, Pediatric Critical Care) and hospital administration. He is a clinical asst. Prof. in the Dept. of Pediatrics at the University of Washington. Roy is also a consultant in health care standards and quality of care delivered. As CMO of Providence Alaska, he assisted in the implementation of MEWS and sepsis surveillance algorithms across their network.  

Krupa A. Navalkar, PhD, is director of Bioinformatics at Immunexpress. Krupa has 20 years’ experience in developing, testing & validating infectious disease diagnostics in hospital systems. Her prior training is in microbiology, pathology, and bioinformatics. She developed diagnostics to detect exposure to priority pathogens using peptide microarrays through the Immunosignature technology at Arizona State University.

Prashant S. Wani, PhD, is molecular diagnostic manager at Immunexpress. Prashant has more than 12 years of experience in biochemistry and molecular biology research and assay development and commercialization. At Immunexpress, his focus is to provide scientific expertise and application support to products related to sepsis diagnosis.

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