LABORATORIO DE URGENCIAS

Novel Emergency Department Sepsis Diagnostic Test: INTELLISEP INDEX

                        Hollenbeak, Christopher S. PhD; Henning, Daniel MD, MPH; Geeting, Glenn MD; Ledeboer, Nathan A.PhD;                                  Faruqi, Imran MD; Pierce, Christi DSc, MSHA, MBA; Thomas, Christopher B. MD; O’Neal, Hollis R. Jr MD, MS

                                                                           Critical Care Explorations 5(7):p e0942, July 2023. (DOI: 10.1097/CCE.0000000000000942)

Sepsis remains a common and costly condition, both in terms of economic burden (¹) and lives lost (²) in the United States and globally (³). Despite multiple barriers, rapid recognition is an integral component in the successful treatment of sepsis, as successful intervention is time-dependent (⁴). Most cases of sepsis first present in the emergency department (ED), where rapid diagnosis remains challenging, often resulting in delayed diagnosis (⁵). Strategies to prompt early antibiotic therapy despite diagnostic uncertainty also lead to overuse of antibiotics and straining of progressively limited hospital resources (⁶).
Increasingly, circulating biomarker measurements have been integrated into clinical care to improve the diagnosis and treatment of sepsis, with mixed results. In particular, procalcitonin has been proposed as a clinical test to assist early identification of sepsis, despite modest sensitivity and specificity and data suggesting results do not influence clinical decision-making (^7–9). The IntelliSep Index (ISI) is a novel diagnostic test that analyzes deformability characteristics of WBCs and shows promise as an early signal for sepsis. A recent clinical trial showed promising diagnostic characteristics of the ISI (¹⁰), although the assay is not yet commercially available.
Before introducing new tests to clinical care, it is necessary to understand the ability of the test to improve clinical outcomes and the effect on resource utilization. Despite promising test characteristics, it remains unknown whether ISI might improve clinical outcomes and resource utilization compared with sepsis identification strategies based on procalcitonin. The objective of this study was to perform a cost-consequence analysis and estimate the costs and survival for ISI relative to procalcitonin for early sepsis diagnosis in the ED.

SETTING
Community hospital ED.
The population was calibrated to that of the population studied in a recent clinical trial of ISI in two academic medical centersC in Baton Rouge, LA (¹⁰). The target population had a mean age of 62 years, was 50.2% female, and 46.9% non-White (¹⁰). 

METHODS: 
A decision tree analysis was performed comparing ISI with procalcitonin. Model parameters included prevalence of sepsis, sensitivity and specificity of diagnostic tests (both ISI and procalcitonin), costs of hospitalization, and mortality rate stratified by diagnostic test result. Mortality and prevalence of sepsis were estimated from best available literature. Costs were estimated based on an analysis of a large, national discharge dataset, and adjusted to 2018 U.S. dollars. Outcomes included expected costs and survival.

DISCUSSION
This study supports the hypothesis that an ISI diagnostic strategy may provide effective reductions in the clinical and financial burden of treating sepsis when compared with a procalcitonin diagnostic strategy. When compared with using procalcitonin in our model, the ISI resulted in both decreased cost and increased survival, with both outcomes improved over a wide range of cost input assumptions and performance characteristics for each laboratory test.
The majority of sepsis admissions originate from the ED (¹³), and improving rapid recognition and risk stratification of potentially septic patients in this setting could improve both outcomes and costs (¹⁴). The ISI has been validated as a diagnostic marker of sepsis for patients presenting to the ED with possible sepsis. The result is standardized into three interpretation bands (band 1, band 2, and band 3 corresponding to low, intermediate, and high probability of sepsis) with reproducible results. In contrast, procalcitonin has been postulated as a biomarker for guiding the treatment of acute respiratory infection, and previous efforts have evaluated the utility of procalcitonin for the risk stratification of patients with possible sepsis in the ED. However, the widespread implementation of these protocols has been difficult because of variability in procalcitonin threshold values used for diagnosis and risk stratification (¹⁵). In addition, some of these protocols require serial procalcitonin measurements, limiting their utility in the ED (^8,9,16,17).
Finally, procalcitonin levels, even when very high, may not correlate well with severity of illness, raising concern for procalcitonin’s utility in guiding such treatment decisions as prioritization or level of care for admission (¹⁸). These attributes are in contrast to the ISI, which, in addition to being a validated and standardized sepsis diagnostic, also correlates well with severity of illness as measured by standardized severity of illness scoring systems (Sequential Organ Failure Assessment, Acute Physiology and Chronic Health Evaluation-II) and clinical outcomes, including hospital admission, ICU admission, and hospital length of stay (¹⁰).
With its high mortality and disproportionate impact on the healthcare workforce, the burden of sepsis is more than financial. Systematic improvements in sepsis care are essential components to reduce unnecessary clinical variability, limit the financial burden of sepsis on patients and healthcare systems, and create a reproducible and efficient care delivery model. Protocolized care for septic patients has already been shown to both improve outcomes and reduce overall costs (¹⁹), and consensus guidelines exist for guiding sepsis care (²⁰); however, there is concern that the indiscriminate application of these protocols and guidelines may result in the overuse of constrained resources and broad-spectrum antibiotics and IV fluids, further straining overtaxed EDs (²¹). An objective mechanism for the identification of high-risk patients is necessary for the optimal application of these limited resources without adversely impacting outcomes. This study suggests risk stratification with an ISI-based strategy could improve survival for patients with sepsis as compared with procalcitonin for all reasonable estimates of survival with relation to timeliness of care. This finding is important given that outcomes in sepsis have been proven to be dependent upon prompt recognition and action (²²).
Delayed appropriate care should result in worse survival outcomes than timely appropriate care. In our model, for procalcitonin to be associated with superior survival, delayed care would need to be superior to timely care.
The study has many strengths. The parameters of the model were based on data derived from a diverse group of patients enrolled through a high-volume ED into a prospective cohort for the validation of the ISI as a diagnostic for sepsis (¹⁰). Since no reference standard for the diagnosis of sepsis exists, all patients underwent a rigorous adjudication process for the determination of the disease state (septic or not septic) that involved retrospective review of laboratory tests, cultures, and imaging results by two independent physicians (¹⁰). Procalcitonin levels were obtained at the time of enrollment on the majority of patients as part of the research protocol, not only as standard of care. Finally, estimates of mortality and cost were derived from published sources. Despite these strengths, there are also weaknesses. Our model cannot account for all clinical factors that influence cost, length of stay, and mortality, and must simplify the decision-making process and certain clinical parameters, including length of stay and cost of care, both of which are difficult to assess on a large scale (²³). In some settings, pathology will guide decision-making in addition to blood tests; for the sake of parsimony, this has not been accounted for in the model. Also, the model requires several assumptions, for instance, that sepsis is the only consideration in the differential diagnosis, whereas in reality, many conditions may present similar to sepsis and result in admission. Although we have tried to use the best available data for these model parameters, the results can only be as strong as the best available evidence. Furthermore, we assume that the discharge of septic patients from the ED is associated with poor outcome. Because the decision to admit or discharge a patient is complex and dependent upon a number of factors (not only the diagnosis of sepsis), some patients who meet criteria for sepsis may be safely discharged to home, though we assume that doing so is more likely associated with adverse outcomes (²⁴). There are also limitations in the set of comparators. As mentioned earlier, procalcitonin is more likely to be used to assist in antimicrobial stewardship and to help distinguish between bacterial versus viral infection, as opposed to use as a diagnostic test for sepsis. EDs are more likely to rely on clinical expertise and suspicion for sepsis diagnosis. There are no published studies that we are aware of that report reliable data on diagnostic characteristics of clinical gestalt. If such data become available in the future it could be added as a comparator strategy. Finally, our study assumes that the only outcomes are survival and death, and does not account for such outcomes as discharge to nursing home or intermediate care facilities.

CONCLUSIONS
The search for solutions and improvements in sepsis care has become increasingly complicated, as the incidence of sepsis continues to rise due to increased awareness, changes in the risk profile of the population such as increasing age and comorbidities, and the impact of the COVID-19 pandemic on pre-existing workforce shortages (^25–29). Solutions that will safely reduce the cost of care without sacrificing outcomes will require addressing the many factors driving the soaring economic burden of the disease in this new, postpandemic era of medicine. Additionally, these solutions should facilitate treatment of the condition according to consensus guidelines (²⁰). The ISI could serve as an invaluable element of sepsis care by quickly and efficiently focusing care on those with the highest risk of the condition while expediting the care of those with lower risk.

NOTE: Full text, graphs, tables can be consulted in the above-mentioned publication.

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