The Difficulties of Diagnosing Sepsis

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Sepsis takes a heavy toll on society, causing millions of fatalities worldwide per year and costing upwards of US$50 billion yearly in the US alone. Sepsis can develop from viral, bacterial, and even fungal infections, but bacterial infections are by far the most common cause – accounting for more than 80 percent of sepsis cases. The term is a manufactured one, and medical definitions have evolved over time; however, fundamentally, what is referred to as “sepsis” is a severe, dysregulated host immune response to infection. This severe response can be life-threatening, and the lack of tissue and organ oxygenation typically seen in sepsis can lead to organ failure and acute kidney injury.

When a sepsis patient arrives at the emergency room – a common path to medical care for these patients – they often present with a vague set of clinical signs, including altered mental capacity, pain, rapid heart rate, and rapid breathing. Because the symptoms may resemble other conditions, such as heart failure and stroke, clinicians face an immediate diagnostic challenge, but they must identify sepsis under significant time pressure; after all, outcomes depend on how quickly treatment can be administered.

Richard Brandon

One traditional method of identifying sepsis is to pinpoint the infectious agent causing the response which, as mentioned, is typically bacterial. This requires culturing and identifying the microbe – a process that can take hours, days, or in some cases, weeks. During this time, the patient is often treated with antibiotics. However, taking such a proactive approach can have deleterious consequences because antibiotics can cause adverse side effects, while their overuse or misuse contributes to the ever-growing problem of antibiotic resistance.

On the other hand, operational approaches monitor a set of clinical parameters to assess the probability and severity of sepsis; for example, the quickSOFA (qSOFA) score identifies high-risk patients for in-hospital mortality using measures of respiratory rate, blood pressure, and mental state. However, it is not used to diagnose sepsis, but rather to predict patient mortality. There are other parameters that could have application in diagnosing sepsis, such as blood cell width and elasticity or levels of procalcitonin or C-reactive protein, but these may actually be indicative of inflammatory processes related to non-sepsis causes.

Given that sepsis is fundamentally a dysregulated immune response, it may be fruitful to directly measure the underlying process: dysregulated immune gene expression. In addition to accuracy and the ability to discriminate sepsis from other conditions, this approach could form the basis for a rapid, accessible, and widely applicable test. Having access to such a test could address the variation in sepsis incidence and outcomes among countries, with regions such as sub-Saharan Africa currently shouldering the highest burden.

Critical to this accessibility is ease of sampling. Early studies in a horse model of sepsis (endotoxemia) provided proof of concept that gene expression analysis of white blood cells in a peripheral blood sample could be used to identify the early stages of sepsis. This provided the foundation for further clinical studies and investment to identify specific biomarkers of human sepsis. Peripheral blood biomarkers and their measurement using gene expression analyses are now widely used in the diagnosis of infectious disease and cancer. The clinical utility of this approach is its ability to provide rapid, accurate, and early identification so that clinicians can respond quickly to sepsis.

Infectious diseases are a significant human health issue in their own right, but one cannot overlook the downstream consequences of the host’s own dysregulated immune response in causing negative health outcomes. Rapid and accurate sepsis diagnosis can improve patient outcomes while helping to avoid adding to the growing problem of antibiotic resistance. With several new technologies entering the market, earlier diagnosis of sepsis is becoming a more achievable goal every day.