As in other areas of medicine, the role of biomarkers in diagnosing sepsis can be crucial. The ideal sepsis bio marker should aid screening, facilitate early diagnosis, provide helpful information about prognosis, and, if possible, help select and monitor therapy. Three of these biomarkers have the best diagnostic performance: C-reactive protein (CRP), procalcitonin (PCT), and presepsin. In addition, another promising biomarker is adrenomedullin (ADM). On the other hand, concerning performance in guiding anti biotic therapy (especially in determining the optimal time to discontinue the same), the most solid evidence is in favor of PCT, albeit with some residual doubt. There is currently no solid evidence to suggest the use of other biomarkers, such as interleukin-6 (IL-6), lipopolysaccharide-binding protein (LBP), nCD64 (neutrophil CD64), sTREM-1 (soluble triggering receptor expressed on myeloid cells-1), and suPAR (soluble urokinase- type plasminogen activator receptor).

It is believed that PCT should be the biomarker of the first choice, possibly complemented by CRP to increase diagnostic sensitivity. Based on preliminary data, presepsin could replace PCT in the future, although data are currently insufficient. Whichever marker(s) is/are chosen, they should be measurable from the laboratory both routinely and on an emergency basis. Regarding the diagnostic threshold, it is preferable to use one that favors diagnostic sensitivity (e.g., 0.5 ng/mL for PCT) rather than a higher one that favors specificity. Regardless of its diagnostic performance, the bio marker value should always be interpreted according to the patient’s clinical data to optimize its diagnostic efficiency. The timing of the biomarker request should also follow a rational approach based on in vivo kinetics and half-life, as illustrated in Fig. 1. Therefore, for PCT (increases 2–4 hours after symptom onset, peaks at 6–8 hours, and has a half-life of 20–24 hours) and PCR (increases 12–24 hours after symptom onset, peaks at 48–72 hours, and has a half- life of 20 hours), the time interval between one determination and the next should not be less than 24 hours, which is reduced to 5 hours for presepsin (which shows an increase 2 hours after symptom onset, peaks at 3–4 hours, and has a half-life of 4–6 hours).

Fig1. Kinetics of presepsin, procalcitonin, and C reactive protein. (Copyright EDISES 2021. Reproduced with permission)

About antibiotic therapy, the use of PCT is helpful to identify early the possibility of suspending it, thus reducing both undesirable effects and the potential development of antibiotic resistance. Also, in this case, PCT monitoring should include an interval between two successive determinations of not less than 18–24 hours. A hypothetical PCT- based algorithm for the diagnosis of sepsis is described in Fig. 2.

Fig2. Algorithm for the diagnosis of sepsis based on procalcitonin levels (PCT). (Copyright EDISES 2021. Reproduced with permission)

C-Reactive Protein

CRP is commonly used in clinical practice to identify the presence of inflammatory and infectious processes. However, its specificity for diagnosing sepsis is relatively low. Indeed, CRP synthesis could be substantially enhanced by several stimuli other than sepsis (e.g., trauma). Moreover, CRP levels do not correlate sufficiently with the severity of the process; patients with severe sepsis might present only a moderate CRP increase. Finally, CRP is not considered an ideal sepsis biomarker because its values peak slowly and their decrease requires several days of treatment; therefore, CRP is not helpful for the early diagnosis of sepsis.

Procalcitonin

PCT is the precursor of the hormone calcitonin, which is involved in calcium homeostasis. Under physiological conditions, PCT has low blood concentration (usually (mainly by the liver, lungs, pancreas, kidney, intestine, and leukocytes), and its concentration increases from 100 to over 10,000 times. In subjects with sepsis, it is not uncommon to observe concentrations exceeding 10–100 ng/mL, with the extent of increase correlating to the severity of infection and prognosis. From a biological point of view, this production heterogeneity is justified by the restricted expression of the gene encoding for calcitonin (CALC-1) to thyroid C cells under physiological conditions. However, as a result of bacterial stimuli (either directly, due to endotoxin and other bacterial toxins, or indirectly, due to metabolic reactions of the body in response to infection), CALC-1 gene expression is considerably amplified in extra-thyroid tissues. In association with the increased extra-thyroidal synthesis, the degradation process of PCT into calcitonin, N-PCT, and catacalcin is considerably suppressed (Fig. 3).

Fig3. Biosynthesis and biochemistry of procalcitonin (PCT). N-PCT N-terminal PCT. (Copyright EDISES 2021. Reproduced with permission)

Sepsis and systemic inflammation can be ruled out if the plasma concentration of PCT is ≤0.5 ng/mL. PCT secretion begins within 2–4 hours of sepsis onset, and its levels peak at 6–8 hours. Although normal PCT levels have a high negative predictive value, this biomarker cannot replace clinical evaluation. Therefore, if PCT levels are low in a patient with suspected sepsis, the patient should still be treated for sepsis. The kinetics of PCT provide more helpful information than the absolute value. Increasing PCT values over time is associated with a worse outcome, while decreasing PCT levels over time is associated with lower mortality, even if absolute PCT values are high.

Monitoring PCT levels in septic patients may also provide insights into the appropriateness of reducing antimicrobial therapy. In the literature, various algorithms based on PCT levels have been proposed to reduce the duration of antibiotic therapy in septic patients. Almost all algorithms support the discontinuation of therapy if PCT concentration is <0.5 ng/mL. As demonstrated by several randomized trials, the application of PCT protocols could reduce the length of antimicrobial treatment, thus leading to several benefits for patients (reduced antibiotic exposure) and the healthcare system (reduced resource consumption). However, conflicting evidence comes from a large retrospective cohort study that found no association between PCT-based strategies and improved antibiotic therapy use or reduced mortality. Therefore, further studies are needed to support the effectiveness of PCT-level-based algorithms.

Apart from its emerging role in the therapeutic monitoring of sepsis, an emerging aspect of PCT concerns its useful ness in the setting of severe localized infections, such as bacterial pneumonia. In this context, it has been suggested that the use of diversified cutoffs, always in combination with the clinic, can help in the diagnosis and initiation of antibiotic therapy (in the case of pneumonia, the cutoff should be set at 0.25 ng/mL, thus lower than the value of 0.5 ng/mL used in the diagnosis of sepsis).

Presepsin

The sCD14-ST (soluble cluster of differentiation 14-sub- type), also known as presepsin, is a soluble fragment of CD14 (cluster of differentiation 14). CD14 is a receptor for complexes consisting of lipopolysaccharide (LPS) and lipopolysaccharide- binding protein on the membrane of phagocytes, whose primary function is the activation of the inflammatory cascade, as occurs in patients with sepsis. Presepsin levels in healthy subjects are <6 μg/L. However, during sepsis, they increase significantly, and this increase is related to the severity of the pathology.

Clinical studies have shown that presepsin has better sensitivity and specificity than other sepsis biomarkers. For example, compared to PCT, presepsin levels increase more rapidly, within 2 hours, peak at 3 hours, and decline at 4–8 hours. Thus, presepsin represents an early sepsis bio marker. However, it has a relatively low specificity because its levels increase significantly in sepsis and other pathological conditions, such as coronary artery disease, heart failure, liver cirrhosis, liver disease, and decompensated diabetes mellitus. Therefore, this biomarker should always be used in conjunction with clinical data.

Presepsin levels also correlate with sepsis severity and mortality risk.

Overall, presepsin represents a helpful biomarker for the management of septic patients allowing both early diagnosis and severity assessment. However, further studies are needed to validate its use in clinical practice.

Adrenomedullin

Adrenomedullin is a peptide hormone with a potent vasodilator effect, which was isolated and characterized in 1993 from pheochromocytoma tissue. Subsequent studies revealed the presence of ADM in other tissues, such as adrenal glands, heart, kidney, gastrointestinal system, and arterial vessels.

In addition to its vasodilator property, ADM exerts various physiological effects (autocrine and paracrine) on the cardiovascular, respiratory, renal, immune, and neuroendocrine systems; these are protective and supportive of the proper function of these organs. Therefore, the increased expression and activity of ADM could represent a defense response to organ damage and dysfunction.

High levels of ADM have been identified in patients with sepsis. However, its levels are often underestimated because they are not easily assayed due to various factors, such as rapid circulating binding to physiological receptors and proteins, a short half-life (approximately 22 minutes) due to rapid degradation by proteases, and the complexity of the analytical procedure.

Alternatively, a 48 amino acid fragment, MR-proADM (mid-regional pro-adrenomedullin), has been identified, produced from the same precursor and released in equimolar amounts to ADM. Specifically, ADM is synthesized as a 185 amino acid pre-pro-hormone, known as pre- proadrenomedullin, which is converted to a 164 amino acid peptide upon removal of the signal peptide known as proadrenomedullin. Proadrenomedullin consists of three vasoactive peptides: ADM, proadrenomedullin aminoterminal peptide (PAMP), and adrenotensin. In addition, there is a region whose biological activity is not known, called MR-proADM (Fig. 4). The MR-proADM reflects the levels and activity of ADM but has a longer half-life (several hours) than ADM, and its levels can be easily determined in clinical practice.

Fig4. Biosynthesis of adrenomedullin (ADM). PAMP aminoterminal peptide of proadrenomedullin, MR-proADM mid regional pro-ADrenomeMedullin. (Copyright EDISES 2021. Reproduced with permission)

Compared to other biomarkers of sepsis, such as CRP and PCT, MR-proADM levels increase significantly in response to infections, indipendently of pathogen. In addition, several studies have shown that MR-proADM levels correlate significantly with sepsis severity and show high prognostic power in predicting mortality risk, superior to other biomarkers, including CRP and PCT.

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مواضيع ذات صلة

Role of the Laboratory in Sepsis

potassium, urine (K)

porphyrins and porphobilinogens

platelet function assay (Platelet closure time, PCT, Aspirin resistance tests, Bleeding time [BT], 11-Dehydro-thromboxane B2)

Laboratory Diagnosis of Rabies Virus

Procalcitonin

Erythrocyte Sedimentation Rate

C-Reactive Protein

plasminogen (Fibrinolysin)

placental growth factor (PGF)

PI-linked antigen (Phosphatidylinositol antigen)

Pre-implantation Diagnosis