Fighting sepsis to improve outcomes and reduce cost

Despite its modest public profile, sepsis ranks as the leading cause of death in hospitals today. Approximately 30 to 60 percent of patients diagnosed with the condition die,^1,2 and one in every three patients who die in a hospital in the U.S. has sepsis.³ Each year, the condition strikes more patients than HIV/AIDS, stroke, and breast and prostate cancer combined.⁴

In addition, 19 percent of hospital patients with sepsis are readmitted within 30 days, contributing to a significant financial burden that makes sepsis the single most expensive condition U.S. hospitals face—costing an estimated $24 billion dollars annually.⁵

Reducing mortality and alleviating the impact that sepsis has on hospital workflow and budgets remains a top healthcare priority, with many institutions establishing a multidisciplinary sepsis management team to design a formal process for identifying and managing the condition. The clinical laboratory provides critical value in this process, as new diagnostic tests can help physicians diagnose this life-threatening complication quickly, saving lives and reducing treatment costs.

The difficulty of accurate diagnosis

Sepsis is the body’s extreme immune response to persistent infection, essentially turning the immune system against the body itself. The immune response causes poor blood flow, and the decreased blood flow deprives cells of oxygen and other nutrients, potentially leading to tissue damage, organ failure and, eventually—in a condition known as septic shock—death.

While the most common cause of sepsis is bacterial infection, other types of pathogens can cause it as well. This broad pathogenesis for sepsis and the historical lack of specific diagnostic tests has perhaps led to the overuse of antibiotics and, paradoxically, contributed to its increasing prevalence. The number of patients hospitalized for sepsis in the U.S. doubled between 2000 and 2008,⁶ and now exceeds 1.7 million annually.⁷ Approximately 270,000 people die from sepsis each year in the U.S.⁸

With appropriate recognition, early diagnosis and optimal treatment, it is estimated that 80 percent of sepsis deaths could be prevented.⁹ The CMS SEP-1 core measure,¹⁰ which prescribes the tests and interventions required when sepsis is suspected in an adult, has led to changes in care. However, diagnosing sepsis can be very difficult, especially in light of the unspecific signs and symptoms of the condition. In addition, the progression of sepsis is rapid and the corresponding mortality rate for each stage increases dramatically.

Selecting the right test

Traditionally, clinicians have ordered several different tests to aid in the diagnosis and treatment of sepsis.

Blood cultures are used to identify the infecting pathogen when a systemic infection is suspected. Unfortunately, cultures normally take 24 to 48 hours to show growth, and this delay in obtaining results renders them ineffective as a diagnostic test for sepsis. In addition, they often lack the sensitivity to identify the specific infecting pathogen, and many critically ill patients are already receiving antibiotics, which further decreases culture sensitivity. Only about 30 to 40 percent of patients with a clinical diagnosis of sepsis have positive blood cultures.¹¹ The primary role of cultures in sepsis management is to provide information about the identity of the pathogen to help the clinician understand whether the therapy being administered is correct or needs to be modified.

Lactate at increased levels is an indicator of tissue hypoperfusion (oxygen deprivation) and thus, the test can be used to help measure the extent of organ or tissue damage. Many conditions can cause elevated lactate levels--such as strenuous exercise, heart failure or a damaged or diseased liver--and thus, lactate is not a specific biomarker for sepsis. However, lactate helps in sepsis management by improving the identification of patients in need of early and aggressive fluid resuscitation.¹²

C-reactive protein (CRP), an acute phase reactant produced by the liver, is elevated when there is inflammation in the body. However, elevated levels of CRP may be due to a variety of conditions that can cause inflammation, and as such, this biomarker is not specific to sepsis. Rather, it is a general test to check for inflammation rather than to pinpoint the exact location or cause.

Procalcitonin (PCT) has emerged as one of the most clinically important biomarkers for sepsis today. A PCT test does not replace blood cultures, lactate or CRP, as each of these tests gives the clinician different patient risk information. The advantage of PCT is that it is both an early and a specific biomarker for a systemic reaction to a bacterial infection. The early recognition and confirmation of bacterial sepsis is a crucial factor to improve patient outcomes.

PCT in the race against time

When exposed to bacterial toxins, cells release PCT along with inflammatory cytokines,¹³ so the biomarker can be used to gauge levels of inflammation and assess the degree of bacterial infection within the body.¹⁴ During viral infections, PCT production is lessened by Interferon gamma (IFN-γ) that is released during the host response to the virus.¹⁵ Thus, PCT concentration will not rise in viral infections as it does in the presence of a bacterial infection.

As a result, determining PCT concentrations can give physicians the confidence to determine whether antibiotic therapy is appropriate and to administer it quickly. This is critical especially for emergency department physicians, who can be the first point of contact with septic patients.

PCT concentrations are also associated with the progression of sepsis to more advanced stages - severe sepsis and septic shock. Measuring PCT concentrations on the first day of patient assessment can help clinicians identify the risk of progression in order to take appropriate anti-infection control measures. In addition, some PCT assays have a risk assessment claim in which changes in the level of PCT from day 1 to day 4 can be used to help assess the 28-day all-cause mortality risk. Thus, clinicians can assess PCT concentrations over time to monitor patient risk and gain confidence that the control measures and antibiotics they have selected are working. Conversely, if results indicate they are not working, appropriate adjustments can be made quickly.

The evolution of PCT assays

The first manual PCT assays¹⁶ were developed and used in Europe in the late 1990s and were approved for use in the U.S. a decade later. Designed for single-point evaluations, the systems could only handle a limited number of tests at one time. A number of manufacturers licensed the original patented assay technology and used it to develop their own platforms.

In 2014, a groundbreaking clinical trial,¹⁷ the MOSES PCT Monitoring Sepsis Study, showed that the odds of patients with sepsis surviving doubled if their measured PCT concentrations decreased by more than 80 percent between the first and fourth day of their treatment. According to Kumar et al., every hour that proper treatment for sepsis was delayed reduced survival chances by 7.6 percent.¹⁸ The significance of these findings was addressed in the indications of use for the first fully automated PCT assay cleared by the FDA in 2016, which enabled PCT tests to be processed in less than 20 minutes. Thus, the combination of automation and faster tests can help expedite diagnosis and contribute to improved outcomes, including decreased mortality.

Multiple studies indicate that healthcare institutions that implement automated PCT testing to evaluate patients who present with suspected infection are seeing significant and quantifiable results. In one retrospective study, investigators found that the use of PCT screening on the first day of ICU admission was linked to significantly shorter (1.2 days) hospital stays, as well as an overall decrease in the cost of care ($2,759 per patient).¹⁹ Another study comparing the effectiveness of antimicrobial treatment before and after PCT testing was introduced to guide antibiotic decision-making found that the length of hospitalization decreased by 47 percent, in-hospital mortality went down by 62 percent, and 30-day readmission levels were cut in half.²⁰

In light of the growing prevalence of sepsis and its troubling mortality statistics, the clinical lab can provide significant value to healthcare institutions as they formulate strategies to identify and manage the challenge effectively. By helping clinicians identify and accurately diagnose sepsis quickly, they can help improve hospital workflow, enhance antibiotic stewardship, reduce treatment costs and, ultimately, save lives.

References

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