by Dr Elena Sukhacheva
Early diagnosis and fast treatment of sepsis is crucial for obtaining the best outcome possible for the patient. However, diagnosis is not easy clinically and the complexity of the condition means that there is not an obvious individual biomarker for it. However, research in recent years has shown that monocyte distribution width is an easily measured parameter that is able to discriminate sepsis from non-sepsis, particularly when combined with the patient’s white blood count.
Sepsis: what it is and why early diagnosis is crucial
Let’s start with defining sepsis. As you may know, for many years we had a definition for what was known as sepsis-2, which was introduced in 1992 . That definition of sepsis was based on the presence of at least two SIRS (systemic inflammatory response syndrome) criteria and either a clinically suspected or proven infection. In 2016, a new definition was established f or sepsis, and, today, sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection . Deaths from sepsis result not from the infection itself, but from dysregulated immunity and organ dysfunction, which makes it impossible to fight the infection efficiently.
Sepsis is one of the most deadly and costly medical conditions faced by physicians and hospitals. In fact, statistics show that sepsis is the third-leading cause of death in the USA . Mortality rates for sepsis are extremely high – approximately 25–30% – with more individuals dying of sepsis per year than of prostate cancer, breast cancer and HIV combined [4,5]. Hospitalizations due to sepsis cost the healthcare system more than any other condition in the USA , with a total annual cost greater than 24 billion US dollars .
Early detection of sepsis is critical, as a delay in antibiotic treatment has been documented as resulting in increased mortality, with a 7.6% increase in deaths among patients with severe sepsis and septic shock for every hour antibiotic administration is delayed . Therefore, the earlier sepsis is recognized and the earlier treatment is started, the better patient outcomes and the lower the cost that can be expected to be borne by the healthcare system.
How sepsis is usually diagnosed and the limitations of these methods
The main challenge of a timely diagnosis is that sepsis may manifest in dramatically different ways. Sepsis may affect anyone. For example, a young patient who may develop an infection from an appendectomy, for whom a dysregulated immune response leads to organ failure and death, or a patient undergoing aggressive cancer treatments, whose immune system is unable to fight infection due to immunosuppression. In both cases, the diagnosis would be ‘sepsis’, but symptoms in these two patients might look very different.
Practically speaking, clinicians may use SIRS criteria (if they are still using sepsis-2) or the SOFA score (sequential organ failure assessment, if they use the sepsis-3 definition) to diagnose sepsis. Additionally, laboratory tests are used to test for infection and help confirm a suspicion of sepsis [9–11]; examples of this include measuring the patient’s WBC (white blood cell) count, procalcitonin, C-reactive protein, interleukin-6 or presepsin levels, or culturing body fluids such as blood or urine for infectious organisms. Although positive cultures may be diagnostic of infection, none of these tests can definitively confirm a diagnosis of sepsis, so clinicians must rely on a combination of all the clinical and laboratory information available to diagnose sepsis.
Continuous research efforts are being made to identify new sepsis biomarkers, for example one review publication by Pierrakos and Vincent mentioned 178 biomarkers evaluated for use in sepsis diagnoses , but none of these performs perfectly, with the sensitivity and specificity required. Sepsis is so complex that an ideal single sepsis biomarker is very unlikely to exist, and the most efficient method used for early sepsis detection is the combination of several sepsis biomarkers .
Other biomarkers to aid the early diagnosis of sepsis
Monocyte distribution width (MDW) is a hematologic parameter that describes the changes in the size distribution (monocyte anisocytosis) of circulating monocytes that occurs during the transition of in infection to sepsis. MDW is, therefore, a reflection of changes in monocyte function and morphology in response to an infection and, in recent years, it has been found that this measurement can act as a new biomarker for sepsis. MDW is the only hematologic biomarker cleared by the U.S. Food and Drug Administration available to be automatically reported as part of a complete blood count (CBC), with a differential test made available for adults entering through A&E or emergency departments (DxH 900 hematology analyser, Beckman Coulter).
Three scientific papers have already demonstrated the analytical performance of MDW. The first results relating to early sepsis detection in the emergency department with MDW were published in the journal Chest in 2017 . This study, which was conducted by Ohio State University, demonstrated that an elevated MDW value was able to discriminate sepsis from non-sepsis (according to sepsis-2 criteria) with an area under the curve (AUC) of 0.79, 77% sensitivity and 73% specificity. The study also analysed the performance of the WBC count and the combination of WBC and MDW. When MDW and WBC values were combined, they produced an AUC of 0.89, which was significantly higher than the AUC for each individual parameter (WBC AUC was 0.74).
Another study published in Critical Care Medicine included more than 2 100 consecutive adult emergency-department patients and was conducted in three USA University Hospitals. This clinical trial confirmed the discriminatory capacity of MDW alone, and of MDW with WBC .
A very recent paper from the Journal of Intensive Care demonstrated that MDW is complementary to SIRS and qSOFA parameters, in essence, serving as a fifth SIRS criteria or a fourth qSOFA criteria to enhance the early detection of sepsis in the emergency department .
The involvement of monocytes in sepsis
Myeloid cells such as monocytes, macrophages and dendritic cells represent key components of the innate immune system, able to detect and signal the presence of pathogens and further instruct the adaptive immune system in order to efficiently control and eliminate pathogens.
There are at least three different monocyte subpopulations in peripheral blood: classical, intermediate and non-classical monocytes [16,17]. These three subpopulations differ in terms of their function and morphology [17,18], and subsets of non-classical monocytes are expanded dramatically in several pathological conditions including sepsis [19–21]. In sepsis, the proportions of different monocyte subsets are altered as monocytes are differentially lost from circulation . This can be one of the factors that contributes to increased monocyte variability in sepsis.
Another important factor is that monocytes are involved in two key events in sepsis pathogenesis: sepsis-induced inflammation and immunosuppression. Detailed analysis of gene expression in monocytes from patients with sepsis and post-recovery demonstrated the plasticity of monocytes in the course of the disease . Monocytes play a key role in disease progression with the possible polarization from a pro-inflammatory state to an immunosuppressive state, resulting in increased functional heterogeneity of monocytes in sepsis and then morphological variability, which can be detected using MDW.
Implementation of MDW and turnaround time
This new test, MDW, is available with CBC-Diff analysis on the Beckman Coulter hematology analyser DxH 900; it does not require additional blood to be drawn or a special order, and it is automatically reported for all adult patients. MDW results above cut-off should be used together with other laboratory findings and clinical information, as an aid in identifying patients with sepsis or at an increased risk of developing sepsis within the first 12 hours of hospital admission .
Future development of sepsis diagnosis
Sepsis is not a single disease; it is a very complex pathological phenomenon. As such, I believe that the most efficient way of diagnosing sepsis is to use all the information available for every patient, including laboratory results, clinical information and other findings.
Elena Sukhacheva PhD, Director of Medical and Scientific Affairs
Beckman Coulter, Eurocenter SA, 1260 Nyon, Switzerland
For further information visit Beckman Coulter DxH 900 hematology analyser (https://www.beckmancoulter.com/products/hematology/dxh-900)