The delay in sepsis diagnosis not only increases the risk of dying by as much as 8% every hour, but misdiagnosis leads to unnecessary use of strong antibiotic therapies causing health-related burdens on patients and economic burdens on healthcare systems.

By Silvia Cermelli, PhD, and Prashant Wani, PhD

The last three years of the COVID-19 pandemic have provided us lessons on the importance of maintaining our own personal health and in ensuring our healthcare systems are able to cope in a time of crisis. Although not classified as a pandemic, sepsis, a life-threatening organ dysfunction due to dysregulated immune response to an infection, affects ~49 million adults and causes ~11 million deaths each year globally1. The total number of global deaths from sepsis each year therefore exceeds that reported for the entire COVID-19 pandemic (WHO Dashboard). One in five deaths worldwide are caused by sepsis every year. Sepsis diagnosis remains a complex and challenging task. The delay in diagnosis not only increases the risk of dying from sepsis by as much as 8% every hour, but misdiagnosis leads to unnecessary use of strong antibiotic therapies causing health-related burdens on patients and economic burdens on healthcare systems.

Rapid sepsis diagnosis is important in reducing patient mortality and morbidity. Further, accurate identification of whether a patient has systemic inflammation related to an infection or not is important to determine an appropriate treatment strategy. Traditional methods like pathogen identification for initial sepsis diagnosis have several challenges and hence the focus of sepsis diagnosis has slowly been shifting to new modern approaches for rapid and better outcomes2,3. 

Current Challenges in Sepsis Diagnosis

Pathogen identification by blood cultures (BC) is well-integrated into the current routine clinical and diagnostic workflow and is considered the gold standard diagnostic for bacterial sepsis and bacteremia. However, BCs relies on the presence of a living bacterium in the patient’s bloodstream and there is an alarmingly high rate of false negative results (up to 50% of all patients diagnosed with sepsis have negative blood culture results) 4. Only 1.4% to 12.2% of all blood cultures taken are positive5.  Moreover, blood cultures are slow (24-72 Hrs.), insensitive, and often are inconclusive and do not provide any indication of the severity of sepsis. 

Considering that rapid action is essential to treat critically ill sepsis patients, blood culture seems to be an inappropriate test for the early initial sepsis diagnosis.

Newly developed pathogen identification techniques that do not rely on blood culture look for specific markers of common bacterial or fungal pathogens. Although faster and more accurate than BC, these methods often require large capital outlays with marginal return on investment. The success of these methods depends on the efficiency of specific probes that target known pathogens but leave novel or rare pathogens unidentified. In complex sepsis cases, where infections can also be viral or a combination of multiple pathogen types, laborious, expensive, and inconclusive, multiple test workflows can disappointingly provide false negatives results. Additionally, contamination of samples can add ambiguity and further delay in results.

A Different Approach to Sepsis Diagnosis

Given the limitations of blood culture and pathogen identification methods for diagnosing sepsis, and the fact that the new definition of sepsis includes a “dysregulated host immune response to infection,” many researchers have explored the utility of diagnostics based on measuring host immune response biomarkers.

More than 100 proteins, soluble receptors, cytokines, and chemokines have been proposed in the literature to serve as immune biomarkers to distinguish between infection and non-infectious inflammation, but either lack diagnostic power and utility or have not been appropriately validated6. A handful of well-established biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT) present desirable characteristic for biomarkers, i.e., immediate description of the current status of the host response of the patient, but discordances in their diagnostic and prognostic performance create the need toward a holistic approach to sepsis diagnostics, including a combination of clinical signs and symptoms, sepsis biomarkers, and microbiological tests7.

Currently, the Surviving Sepsis Campaign (SSC) and the recent American Association of Clinical Chemistry (AACC) guidelines advise against using PCT to aid the decision of when to start antimicrobials and suggest clinical evaluation alone. However, PCT use is suggested to help decide when to discontinue antimicrobials among adult patients with sepsis.

A more recent innovative approach to sepsis diagnosis is measurement of gene expression using Polymerase Chain Reaction (PCR) using a patient’s blood sample.  This approach uses robust PCR platforms and provides results fast enough to have a clinical impact on patient management. Just a small number of critical transcriptional biomarkers can determine whether the patient’s dysregulated host immune response is due to a pathogen or is not infectious and thus non-life threatening8.

Making a Breakthrough in Rapid Sepsis Diagnosis

Immunexpress’s SeptiCyte RAPID measures host response to differentiate sepsis from non-infectious systemic inflammation (i.e., SIRS). It is an FDA cleared test for this purpose and has a one-hour turnaround time requiring minimal technician hands-on time. SeptiCyte RAPID measures gene expression of two host immune response biomarkers, PLAC8 and PLA2G7, from peripheral blood injected into the fully automated sample-to-answer Biocartis Idylla system. 

These biomarkers are regulated up and down respectively when a patient has systemic inflammation due to an infection. Gene expression is measured using quantitative PCR, and on the Idylla platform from Biocartis. Results are provided as a probability of sepsis (SeptiScore). A SeptiScore is derived by the ratio between PLAC8 and PLA2G7. SeptiScores fall into a range of 0-15, with higher scores indicating a higher likelihood of sepsis. Patient results can fall into one of four bands (1-4) with SeptiScores in higher bands indicating a higher likelihood of sepsis. 

SeptiCyte RAPID has been clinically validated using retrospectively and prospectively collected patient samples at multiple sites in the USA and Europe.

SeptiCyte RAPID provides high sensitivity (0.94) and high specificity (0.90) for cases with low and high SeptiScores, respectively. Such results can be provided in the same time frame as other laboratory parameters such as white cell count, C-reactive protein, and high sensitivity troponin. Current culture-based microbiology results take at least 24 hours.

Because of the short turnaround time and high accuracy, SeptiCyte RAPID has the potential to improve clinician’s diagnostic and therapeutic stewardship. Patients with high SeptiScores can be put on antibiotics until culture results are obtained while antibiotic administration for those patients with low SeptiScores might be deferred while non-infectious etiologies might be investigated further.  The 1-hour turnaround time from sample to results with clear interpretation on probability of sepsis vs SIRS fits with the 1-hour bundle response to guide antibiotic administration and meet the 3-hour CMS SEP-1 quality metric and Surviving Sepsis Campaign care management guidelines.

Improving Quality and Economics of Sepsis Management

Management of sepsis in hospitals is costly since it is complex to diagnose and treat. The median hospital cost for a sepsis patient is $18,000 and can go up to $51,000 if not identified early. The median length of stay for these patients is 11 to 13 days compared to 4.5 days for non-sepsis patients9. Claim denials and reimbursement challenges due to inaccurate diagnosis and documentation add further economic stress in sepsis management.

It is evident that traditional practices of sepsis identification have put an immense burden on the healthcare system with delayed diagnosis, poor outcomes, and overall increased cost for patient management in EDs and ICUs. To overcome these challenges, not only is it important to have rapid and accurate diagnosis of sepsis, but being able to stratify patients showing clinical signs of systemic inflammatory response without any infection is also equally crucial. The dual approach will help avoid delays in treatment for true sepsis patients, reducing hospital stay, and optimizing antibiotic therapy.

Despite poor public awareness of the impacts of sepsis, global action is required as recommended by the WHO. As we continue to make progress in deciphering the difficulty in accurately identifying patients with sepsis, we should also acknowledge the limitations of traditional diagnostic methods that rely on pathogen identification and embrace more recent approaches that can accurately and specifically measure the host response to infection. The adoption of innovative approaches, such as SeptiCyte RAPID, to aid in sepsis diagnosis is expected to provide benefits to patients, clinical utility to physicians and financial benefits to hospital and health systems.

ABOUT THE AUTHORS

Silvia Cermelli, PhD, is senior director of Clinical Operations at Immunexpress where she provides clinical operations leadership and scientific expertise in support of clinical studies, programs, and trial activities.

Prashant Wani, PhD, is a molecular diagnostic manager at Immunexpress where his focus is to provide scientific expertise and application support to products related to sepsis diagnosis.

 References

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