Sepsis and septic shock are identified clinically using the Sequential (Sepsis-Related) Organ Failure Assessment or SOFA. SOFA uses common clinical parameters to identify vital organs that are functioning incorrectly or failing in response to sepsis. SOFA can also be used for prognostic purposes, as an increase in SOFA score within the first two days implicates a 50% mortality rate. More recently, in 2016, quick SOFA or qSOFA was developed. qSOFA uses clinical data that can be obtained easily and quickly at the patient’s bedside. These measures include:
- Altered level of consciousness (determined by a score equal to or less than 13 on the Glasgow Coma Scale)
- Systolic blood pressure less than or equal to 100 mmHg
- Respiratory rate greater than or equal to 11 rpm
When the patient exhibits two or more of the qSOFA criteria, qSOFA is just as effective as SOFA at identifying patients with sepsis and predicting poor outcomes. However, further validation of this testing method is needed. Another drawback to qSOFA is that it may be difficult to implement in undeveloped and developing countries. In 2015, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) simplified the definition of sepsis to a life-threatening organ dysfunction or failure resulting from a dysregulated host response to an infection. Onset was defined as the beginning of organ dysfunction distant from the site of infection. In this case, infection was defined as an interaction between the host and a foreign pathogen that induces either a local or systemic host response. Septic shock used to be identified by the presence of hypotension (low blood pressure). However, because hypotension does not always appear or appears late into the onset of septic shock, the shock is now identified by the presence of tissue hypoperfusion (decreased blood flow). The 2015 Sepsis-3 recommended that septic shock is defined as needing vasopressor therapy to maintain blood pressure above 65 mmHg and an increase in a lactate level of more than 2 mmol per L (a sign of hypotension).
Laboratory testing is also done in conjunction with a clinical diagnosis for several reasons:
- Confirm sepsis diagnosis
- Rule out other potential causes of septic-like symptoms
- Evaluate and monitor organ function, blood oxygenation, and pH
Sepsis is confirmed through hematological, biochemical and microbiological testing. Because these tests can be slow, however, biomarkers may be used for early diagnosis. Biomarkers currently in use are C-reactive protein (CRP) and procalcitonin (PCT). These biomarkers and those in development need to be used in conjunction with other laboratory and clinical tests for adequate diagnosis. Researchers are still trying to identify biomarkers that can be used as reliable predictors of sepsis.
WHAT BIOMARKERS ARE THERE FOR SEPSIS?
Biomarkers, or characteristics that can be used to objectively indicate normal biological processes, pathogenic processes and pharmacological responses to treatment, can be used in a variety of ways including:
- Identifier of responders to specific therapies
- Predict efficacy
- Determine toxicity
Sepsis consists of two phases:
- An initial hyper-inflammatory phase (typically associated with SIRS)
- A later, immunosuppressive phase (typically associated with organ dysfunction and compensatory anti-inflammatory response syndrome (CARS))
Markers are available for both phases.
C-Reactive Protein (CRP)
CRP is a protein found in blood plasma. Following trauma, such as a microbial infection, CRP plasma levels rise within a few hours. This rise is mediated by interleukin-6 (IL-6), leukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α). Because of its rapid response and relatively short (approximately 19hr) short life, CRP is a great candidate for detecting infection and monitoring inflammatory response to infection and treatment. A moderate relationship between CRP levels and the number of organ failures has been observed, thus it may also be used to determine sepsis severity. However, there are drawbacks to using CRP as a biomarker for sepsis. Namely, CRP cannot differentiate from inflammation due to sepsis and that due to other diseases.
PCT is a precursor to the hormone calcitonin. It is also one of the best biomarkers for severe systemic inflammation. In healthy individuals, PCT levels are relatively low in the blood. However, inflammatory cytokines and bacterial endotoxins can significantly increase its expression, especially in response to systemic infections. There is evidence that it might be able to differentiate between viral and bacterial infections. PCT is primarily used as a positively correlated biomarker for inflammation. It is highly sensitive, making it one of the more sensitive biomarkers for sepsis. Compared to CRP, PCT response to inflammation is much more rapid. PCT also has a shorter half-life, suggesting that it may be a better biomarker for inflammation related to sepsis than CRP.
Biomarkers of the Immunosuppressive Phase
There are much fewer biomarkers for the second phase of sepsis, CARS.
Human Leukocyte Antigen-D Related (HLA-DR)
HLA molecules process and present antigens segments to CD4 T lymphocytes at the beginning of the immune response. Low expression of HLA-DR is associated with decreased activation of monocytes. Monocytes with low expression of HLA-DR also have a low ability to secrete cytokines and antigens. Monocyte levels are also lower in patients with sepsis. Thus, HLA-DR expression may be used as an indicator for severe immunosuppression. One drawback to this marker is that it is unspecific and may decrease in response to any weakening of the immune system.
Biomarkers of Organ Dysfunction
Lactate is the gold standard biomarker for hypoperfusion. High lactate levels are an indicator of organ dysfunction. Since dysfunctional organs may overproduce lactate, have difficulty clearing lactate or both. An increase in lactate is associated with a significant increase (up to 70%) in mortality. Hyperlactatemia is considered to be a severe marker of sepsis. Lactate levels can be used as a sepsis biomarker in multiple ways including to diagnose, determine the severity and to evaluate and adjust sepsis treatment.
Venous to Arterial Carbon Dioxide Pressure Difference (ΔpCO2)
ΔpCO2 and lactate are used to evaluate anaerobic metabolism in patients with sepsis. CO2 is highly susceptible to hypoperfusion and thus can be used as a marker for microcirculation and an indicator for septic shock. ΔpCO2 in the venous blood can predict the ability of the circulatory system to expel CO2 from a tissue. Specifically, levels above 6 mm Hg are associated with poor outcomes. Additional research is needed to determine the full potential of this biomarker.
Adrenomedullin or ADM is a peptide similar to PCT. Normally, ADM is cleared from the system to rapidly and travels bound to other proteins, making it difficult to measure as an indicator. However, the middle region of ADM called proadrenomedullin or MR-proADM can be detected in septic patients since it is at a significantly higher concentration. MR-proADM is associated with a poor prognosis and can discriminate between sepsis and the presence of SIRS. MR-pro AMD levels at the time of admission are typically used as indicators of the severity and outcome of severe sepsis or septic shock cases.
cell-free DNA (cf-DNA)
Cf-DNA is DNA fragments that were released into the plasma following cell apoptosis or necrosis. Cf-DNA levels are higher in patients with sepsis and non-survivors of sepsis compare to healthy individuals. However, because cf-DNA is not specific to sepsis, it is currently being considered as a prognostic factor.