When it comes to sepsis, time is of the essence. Research has shown that for each hour that antibiotic administration to sepsis patients is delayed, there is a linear increase in the risk of mortality.
Approximately 1.7 million individuals in the US develop sepsis each year, yet no gold standard exists for the diagnosis of sepsis in a clinical setting. Identification and treatment are determined based on a combination of tests and the clinician’s judgment. Although the field is rife with disagreements on the diagnostic criteria of sepsis, experts agree that early diagnosis is critical.
What is sepsis?
The Greek physician Hippocrates used the word “sepidon” circa 400 BC to describe the repugnant process of biological decay. It was not until the 19th century that infectious microorganisms were identified as the cause of that biological decay. Although the term “sepsis” has been used in the medical literature since the late 1800s, physicians still struggle to define it.
The definition of sepsis has been revised several times in recent years. In 1991, Sepsis-1 was defined as an infection leading to the onset of systemic inflammatory response syndrome (SIRS). By this definition, patients were diagnosed with sepsis if they met two of the four SIRS criteria: high heart rate, elevated rate of respiration, hyperthermia, and abnormal white blood cell counts. Sepsis-2, which came into use in 2002, retained the original Sepsis-1 definition but expanded the diagnostic criteria to include altered mental status, elevated plasma levels of C-reactive protein (CRP) and procalcitonin (PCT) as markers of inflammation, hemodynamic parameters including hypotension and oxygen saturation, lactate levels as a marker of tissue perfusion, and organ dysfunction.
The Sepsis-3 definition, coined in 2016, classifies sepsis as “life-threatening organ dysfunction due to a dysregulated host response to infection.” In addition, septic shock is defined as a subset of sepsis with circulatory and metabolic dysfunction associated with a greater risk of mortality than sepsis alone. Concerns have been raised about the clinical value of this new definition.
The considerable lack of consensus over the definition of sepsis is one of many reasons its diagnosis is fraught with challenges.
Challenges in sepsis diagnosis
Diagnosing sepsis is challenging primarily because it is a heterogeneous condition with different etiologies ranging from pneumonia and urinary tract infection to wound infections.
In a clinical setting, sepsis is usually diagnosed on the basis of an infection and the host’s response to it. Symptoms include fever and chills, tachycardia, rapid breathing, rash, and mental confusion or disorientation. Because these symptoms commonly occur in several other conditions, it is difficult to differentiate septic patients from those with a non-sepsis infection. To further complicate matters, elderly sepsis patients often have hypothermia and may not always present with a fever, whereas critically ill patients commonly have hyperthermia, tachycardia, and tachypnea that may not be indicative of sepsis.
The Surviving Sepsis Campaign guidelines were updated in 2018to include the hour-1 bundle. The revised guidelines require clinicians to initiate the following measures within an hour of patient presentation to the emergency department with sepsis:
Blood and diagnostic imaging tests, such as CT scans, are used to identify the source and location of infection in symptomatic patients. Aberrant white blood cell counts and the presence of inflammatory markers like cytokines, CRP, and PCT in blood are indicative of a host response to infection. However, these indicators may also be altered during non-infectious systemic inflammation in critically ill patients due to acute mesenteric ischemia or adrenal insufficiency. Blood or urine cultures help identify the causative microorganism and distinguish infectious SIRS from non-infectious SIRS. One issue with cultures is that time to results can be slow compared with the speed at which sepsis progresses. In addition, some patients may have negative bacterial cultures due to either prior antibiotic use or unusual viral or fungal infections.
Variable symptoms, inability to distinguish infectious versus non-infectious inflammatory responses, and delays in obtaining pathogen information are the major limitations of commonly used sepsis diagnostics.
How can point-of-care (POC) testing help?
POC testing is performed at or near the site of patient care to provide rapid diagnostic information that can inform clinical decisions and improve outcomes. Given the need for early detection and rapid intervention in sepsis management, POC testing may confer significant benefits.
To be a useful tool for sepsis diagnosis, POC testing must satisfy several requirements. Accurate sepsis diagnosis calls for the ability to distinguish an immune response to infection from an inflammatory or hemodynamic response to non-infectious disease states. The ability to monitor the host response can help stratify patients based on severity, which enables clinicians to predict which patients are more likely to deteriorate and require escalated care. Finally, the ability to obtain information about the causative pathogen allows clinicians to initiate targeted therapies early in the course of infection. Administration of broad-spectrum antibiotics in the face of rising antibiotic resistance is not a sustainable approach.
Accordingly, POC testing for sepsis aims to 1) monitor the host response for accurate diagnosis and patient stratification, and 2) acquire pathogen information for appropriate therapeutic support.
POC devices to evaluate host response
Recent guidelines endorse sustained elevation of lactate as an identifier of sepsis in the emergency department. Several devices have been approved by the US Food and Drug Administration (FDA) for POC lactate measurement. These include near-patient analyzers such as Siemens’s RAPIDPoint 500, Roche’s Cobas b 221, and IL’s GEM Premier 5000 or portable devices such as Nova Biomedical’s StatStrip Lactate and Abbott’s i-STAT. In one study, in-hospital bedside lactate POC testing significantly reduced test turnaround time and mortality in the emergency department; however, another study found no improvement in pre-hospital diagnostic accuracy when POC analyzers were used by paramedics.
Serum levels of PCT and CRP are significantly elevated in systemic inflammation and are associated with the severity of organ dysfunction. Since PCT concentrations more closely reflect patient recovery than do CRP concentrations, PCT results are also used to guide antibacterial therapy in critically ill patients. POC devices that measure the levels of these biomarkers offer the ability to rapidly determine the host response to infection, accelerating diagnosis and potentially improving patient outcomes. Several healthcare companies have received FDA approval for their PCT assays to be used on automated testing devices such as BioMérieux’s VIDAS 3, Roche’s Elecsys BRAHMS, Siemens’s Atellica IM, DiaSorin’s LIAISON, and Fujirebio’s Lumipulse. In 2018, Thermo Fisher Scientific’s BRAHMS PCT direct was approved in Europe for use in POC settings. In the US, PCT testing was initially cleared by the FDA to assess the risk of critically ill patients progressing to severe sepsis, but it has now been expanded to determine whether antibiotics can be safely discontinued in hospitalized sepsis patients.
A Race Against Time
A retrospective analysis of over 28,000 sepsis patients from 165 ICUs in the US, South America, and Europe found a linear increase in the risk of mortality for each hour that antibiotic administration was delayed.
Ultimately, given the diversity of immune responses to infection, one biomarker alone may be inadequate in accurately diagnosing sepsis. Consequently, Nanomix is currently performing clinical trials on a POC device that will concomitantly quantify levels of lactate, PCT, and CRP. SeptiCyte LAB is an FDA-approved diagnostic test that detects and combines the gene expression results of four host mRNA transcripts (CEACAM4, LAMP1, PLA2G7, and PLAC8) to reliably differentiate the host response to infection from inflammation. In addition, the predictive power of a microfluidics-based biochip improved when combined with lactate levels or with data from patients’ electronic medical records. Therefore, a POC device that is able to quantify several immune biomarkers from a small quantity of blood within a short time will vastly improve diagnosis and patient stratification.
POC devices for microbial identification and antibiotic susceptibility
Blood cultures are currently the gold standard for pathogen identification in sepsis. However, cultures require up to five days of incubation, which often results in initiation of inappropriate treatment or prolonged use of broad-spectrum antibiotics while waiting for pathogen information. Nucleic acid amplification technologies (NAATs) that can detect pathogens from positive blood cultures or directly from whole blood can reduce pathogen identification time to 2–12 hours.
Several NAAT-based tests are able to distinguish between numerous strains of Gram-negative and Gram-positive bacteria as well as some fungi. Most of these—Roche’s SeptiFast, Molzym’s SepsiTest, and GenMark’s ePlex—have received regulatory approval only in Europe. In the US, T2Biosystems’ T2Bacteria and T2Candida are the only tests for detection of bacterial and fungal species from whole blood to receive FDA market clearance. All these assays are also capable of detecting antibiotic resistance genes, which provides added value in informing antimicrobial therapy. However, they all require bulky benchtop equipment for analysis, limiting their use in emergency departments or at the patient’s bedside. Miniaturizing detection sensors and simplifying sample processing would improve their use in POC settings.
Currently, most sepsis diagnostic devices require access to specialized laboratory equipment, such as thermocyclers for nucleic acid amplification, when used in hospitals and emergency departments. This limits their use in low- to middle-income countries and resource-limited settings where microbial infections may be more prevalent. Several innovative systems have been developed to transform mobile phones into POC diagnostics for human cells and pathogens. Recently, a smartphone-based system reported robust bacterial identification in urine samples from sepsis patients that matched hospital diagnostics but took only a fraction of the time and costs less than $100. These technologies will eventually be harnessed and streamlined for sepsis diagnosis on a wider scale.
The inherent complexity of sepsis warrants adoption of machine learning approaches that can parse several measurements of validated biomarkers, patient data, and pathogen information to accurately diagnose, stratify, and manage sepsis. Recently, an electronic triage system based on machine learning and real-time interactions with patients’ electronic health records reliably identified sepsis patients in need of critical care. Similarly, AI Clinician, a computational model using reinforcement learning, is able to suggest individualized treatment strategies that improve outcomes in sepsis patients. Although these technologies require further validation, preliminary findings suggest that integrating POC testing and predictive analytics into clinical workflows may further improve sepsis diagnosis and outcomes.
In the US…