Sepsis remains the major cause of acute illness and death in all age groups worldwide. Early diagnosis and treatment influence the morbidity and mortality. The definition of sepsis has evolved over the years. In 1914, Schottmuller defined sepsis as a state which is caused by microbial invasion from a local infectious source into the bloodstream which leads to signs of systemic illness in remote organs. Subsequently, sepsis was defined as an uncontrolled host response to injury in the presence of infection. This systemic inflammatory response syndrome (SIRS) was diagnosed clinically by the presence of at least two features: tachycardia, tachypnea, leukocytosis or leukopenia, and fever or hypothermia (Box 1). This definition was neither sensitive nor specific for sepsis. Several of these features are present in patients in the hospital, especially in postoperative patients. Many noninfective conditions such as burns, pancreatitis, trauma, and ischemia-reperfusion may also have features of SIRS. However, the presence or absence of infection is difficult to prove in these patients. The major dilemma was the diagnosis of infection. In addition, several patients with SIRS and suspected infection (postoperative patient with fever, or a patient with influenza) fitted the definition of sepsis, but had an excellent outcome. Thus, the SIRS plus infection criteria did not identify patients at a higher risk of death.
In 2016, sepsis was redefined as life-threatening organ dysfunction caused by dysregulated host response to infection. The focus shifted from inflammation to organ dysfunction in the presence of infection. Organ dysfunction was defined in terms of sequential organ failure assessment (SOFA) score increase in 2 points from baseline (Table 1). One of the main components of this definition is the presence of infection.
Present day methods for identification of pathogens such as blood culture take time and are not helpful for rapid recognition. Early and rapid recognition could lead to early institution of therapy, reduce morbidity and mortality and improve outcome. Hence, there is a role for biomarkers for early recognition of sepsis.1
The human body's response to sepsis is complex, comprising of inflammatory and anti-inflammatory processes, cellular and humoral responses. Biomarkers are naturally occurring molecules, genes, or other characteristics by which particular physiologic or pathologic processes can be identified. The characteristics of an ideal biomarker are: it should be an objective parameter, easy to measure, reproducible, inexpensive, have fast kinetics, high sensitivity and specificity, have a short turnaround time, show appropriate response to therapy (decline with response to therapy). However, no such ideal biomarker exists. Clinical biomarkers can be divided into two types: (1) diagnostic and (2) prognostic markers. Diagnostic biomarkers for sepsis are those which differentiate infectious from noninfectious causes as well as possible causative organisms or classes of organisms. Hence, diagnostic biomarkers can be used for prevention of unnecessary use of antibiotics. Prognostic biomarkers help in stratifying patients into risk groups and predict outcome. Biomarkers have also been used for differentiating local infection, disseminated infection and sepsis. They have been evaluated for the differentiation of viral and fungal from bacterial infection. Other potential uses of biomarkers include their role in prognostication, guidance of antibiotics, determine response to therapy, and prediction of organ dysfunction and complications.2
Initial biomarkers investigated in sepsis were white blood cell (WBC) counts, lactate, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The presence of leukocytosis or leukopenia was considered as response of infection and is a part of the SIRS criteria. However, noninfectious causes also lead to leukocytosis and hence it is not specific. Lactate, a byproduct of glycolysis has been investigated as a marker of sepsis. Several factors affect hyperlactatemia and lactate kinetics. Hypoperfusion leading to anaerobic glycolysis is an important mechanism. Currently, septic shock is defined as subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. It is clinically identified as sepsis with persisting hypotension requiring vasopressors to maintain mean arterial pressure >65 mm Hg and having a serum lactate level >2 mmol/L despite adequate volume resuscitation. Lactate levels are elevated in hypovolemia and hemorrhage during trauma and surgery. Lactate clearance is used as marker of adequate resuscitation. Thus, lactate levels are not useful biomarkers of sepsis, but are important indicators of the severity of shock and hypoperfusion, and the adequacy of resuscitation.
Erythrocyte sedimentation rate is an indicator of inflammation and utility as a marker of sepsis is limited. It can be influenced by the presence of anemia, immunoglobulins, and changes in erythrocyte size, shape and number. It can be elevated in malignant neoplasms, tissue injury, and in trauma. Hence it has limited utility in sepsis.3
C-reactive protein (CRP) is an acute phase reactant protein which is synthesized in the liver in response to inflammation or tissue injury. Interleukin-6 (IL-6) upregulates the synthesis of CRP by hepatocytes. Normal CRP levels vary according to age, sex and race. CRP reference range varies from one laboratory to another. In general, levels less than 0.3–0.6 mg/L are considered normal. Its level can rise up to 1,000 times in response to an acute phase stimulus. CRP starts to rise after around 6 hours of the inciting stimulus, peaks at about 48 hours and has a plasma half-life of 19–20 hours. The role of CRP in acute inflammation is not clear. It has been found to bind to phospholipid components of microorganisms facilitating removal of necrotic and apoptotic cells by macrophages. CRP can also activate the complement system leading to binding to phagocytic cells and hence elimination. CRP levels can be elevated in both infectious and noninfectious inflammatory disorders. Modest elevations in CRP may be seen in noninflammatory or low-grade inflammatory conditions such as atherosclerosis, obesity, hypertension, diabetes and obstructive sleep apnea. Marked elevations in CRP are usually associated with infection, especially bacterial, however, modest elevations may be seen in viral infections. The primary drawback is its poor specificity although sensitivity is quite high. It appears to a better marker of inflammation rather than infection.4
Procalcitonin (PCT) is a 116 long amino acid peptide with a molecular weight of approximately 13 kDa. It is a precursor of calcitonin, produced by the C-cells of thyroid under the control of the calcitonin gene-related peptide 1 (CALC-1) gene. Under normal conditions C cells of thyroid secrete calcitonin after intracellular protoeolysis of the prohormone PCT. During microbial infections there is increase in CALC-1 gene expression in various extra-thyroid tissues and cells which is mediated by pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and IL-6. Parenchymal tissues such as lung, liver and kidney are the principal sources of circulating PCT in sepsis. Either microbial toxins directly or the host response by humoral or cell-mediated indirectly can lead to inflammatory release of PCT. Procalcitonin starts rising by 2 hours after a stimulus, peaks at around 6 hours, and maintains a plateau through 8 and 24 hours and decreases to baseline values after 2 days. The half-life of PCT is around 20–24 hours. Usually in normal healthy individuals, PCT is detectable in very low concentrations. Low or negligible rise in PCT levels may be seen in localized infections. However, it can increase 1000-fold during active infection and sepsis. Interferon-gamma released during viral infections suppresses PCT; hence high levels are not observed in viral sepsis. Gram-negative bacteremia causes higher elevation of PCT than that caused by gram- positive pathogens. The release of PCT is determined only in systemic infection. Therefore, local bacterial colonizations, encapsulated abscesses and localized and limited infections do not cause PCT release. In addition to bacterial infections, plasma PCT concentration has been shown to increase in acute forms of malaria and fungal infections.5
Procalcitonin may also be elevated in absence of bacterial infections in neonates <48 hours age, first days after major surgery, trauma, burns, pancreatitis, treatment with OKT3 antibodies, interleukins, TNF-α, invasive fungal infections, acute falciparum malaria, severe cardiogenic shock, malignancies, e.g., medullary C-cell carcinoma of thyroid, small cell Ca lung, bronchial carcinoid.
Procalcitonin levels may be falsely low in presence of bacterial infection in early course of infection, localized infections and subacute bacterial endocarditis. Table 2 summarizes the significance of PCT values in various conditions.
Utility of Procalcitonin
Diagnosis of Bacterial Infection and Sepsis
Procalcitonin has been evaluated as a biomarker for infection and sepsis. Assicot et al. in 1993 first described that PCT values may be considerably increased in patients with sepsis and infections.6 Muller et al. studied whether biomarkers increased diagnostic and prognostic accuracy in community acquired pneumonia and found that procalcitonin indeed increased the accuracy and was useful in severity assessment.7 A prospective controlled trial concluded that procalcitonin is a reliable diagnostic and prognostic marker in patients with septic shock compared to nonseptic shock.8 In another study, PCT, CRP, IL-6 and lactate were evaluated for diagnosis of sepsis and PCT was found to be the most reliable marker for the diagnosis of sepsis, with 89% sensitivity and 94% specificity.9 However few studies found that PCT could not accurately differentiate infection from inflammation.10,11A systematic review and meta-analysis on PCT as a diagnostic marker of sepsis found sensitivity of 0.77 (95% CI 0.72–0.81) and specificity of 0.79 (95% CI 0.74–0.84) with area under receiver operating curve to be 0.85 (95% CI 0.81–0.88). The authors concluded that PCT is helpful for early diagnosis of sepsis in critically ill patients. However, they also warned that the results of the test must be interpreted carefully in the context of medical history, physical examination, and microbiological assessment.12
Differentiation of Bacterial and Viral Infections
Procalcitonin is produced in response to endotoxin or few inflammatory mediators released by human body through humoral or cell-mediated immune response such as ILs, TNF. This sort of a response is classically seen in bacterial infections. On the other hand, in viral infections there is release of interferon (IF), a cytokine which attenuates PCT production. Hence, PCT levels rarely increase in response to viral infections, indicating that PCT may be useful for discrimination between bacterial and viral infections.13,14
De-escalation of Antibiotics
Due to rampant usage of antibiotics in past few decades, there is emergence of antibiotic resistance and development of multidrug resistance in pathogens. The concept of antibiotic stewardship for optimal usage of antibiotics and early de-escalation of antibiotics is accepted and encouraged. This helps prevent unnecessary usage of antibiotics and development of drug resistance. Due to favorable kinetics of PCT (in the presence of systemic bacterial infections, levels start rising by 2 hours after stimulus, peak at around 6 hours, and maintain a plateau through 8 and 24 hours and decrease to their baseline values after 2 days), PCT has been evaluated for discontinuation of antibiotics. Several studies have studied PCT as an aid for de-escalation of antibiotics after clinical stabilization. Initial single center studies found significant reduction of usage of antibiotics by using PCT based algorithms where antibiotics were stopped when PCT decreased 90% from the initial value.15 Few studies considered cut-off value of PCT <1 µg/L or reduction by 25–35% of initial values over 3 days.16,17 A large multicenter RCT—the PROcalcitonin to Reduce Antibiotic Treatments in Acutely ill patients (PRORATA) trial randomized 621 adult patients with suspected bacterial infection and utilized an algorithm in which initial procalcitonin was used to assess whether to start antibiotics. Subsequent daily procalcitonin levels were used to help decide when to stop antibiotics. Antibiotics were discontinued when PCT levels were <0.5 µg/L or decreased from peak value by ≥80%. They found that the PCT group had significantly fewer days on antibiotics and mortality was noninferior to control group with no significant complications.18 ProGUARD, an RCT done in 11 Australian ICUs used an algorithm in which antibiotics were stopped if PCT levels were <0.1 µg/L or levels decreased by >90% from baseline. They enrolled 400 patients with suspected sepsis and did not find significant reduction in antibiotic use in PCT group. Probably the cut-off was too low and the study was under-powered which led to negative results.19 Subsequently, a multicenter randomized trial—Stop Antibiotics on Procalcitonin guidance Study (SAPS) was done in Netherlands. The algorithm used was similar to PRORATA where antibiotics was stopped when PCT decreased to ≥80% of peak value, or ≤0.5 µg/L and they found significant reduction in antibiotic requirement with no increased rates of complications or mortality. However, there was mild increase in reinfection rates in PCT arm. The study provides a strong evidence for use of PCT based algorithms in sepsis.20 Hence, the current evidence on PCT suggests utilization of PCT values as trends and de-escalation of antibiotics when there is significant reduction of PCT from baseline. Guidelines from the Infectious Diseases Society of America (IDSA) and the Surviving Sepsis Campaign (SSC) suggest utilization of PCT for cessation of antibiotics.
Procalcitonin in the Postoperative Period
The body's response to surgery consists of a complex inflammatory response to promote healing. Following cell disruption, hemorrhage or ischemia-reperfusion injury there occurs activation of the innate proinflammatory response as well as adaptive anti-inflammatory response. The proinflammatory response helps in destruction of harmful molecules whereas the anti-inflammatory response promotes healing by restricting inflammatory process. Apart from usual mediators which are released following tissue injury such as oxygen reactive species, cytokines and nitric oxide, molecules such as high-mobility group B1 (HMGB1), mitochondrial DNA, glycosaminoglycans, heat shock protein (HSP), adenosine triphosphate (ATP), protein S100 and uric acid collectively called damage associated molecular patterns (DAMPs) are also released. The activation of innate immunity leads to release of cytokines such as IL-6, IL-1b, IL-8, TNF, etc. IL-6 stimulates production of PCT. Depending on the degree of tissue injury during surgery, levels of PCT rise in the postoperative period based on inflammatory response. Normally levels rise up to 9 ng/mL in the postoperative period.21 Usually in postoperative period PCT levels start rising few hours after surgery, peak around 24 hours and start declining to normal levels. However, persistently high levels should raise suspicion of postoperative infection.22 Any PCT more than 10 ng/mL in the postoperative non-transplant patient is considered to be abnormal. Site of surgery influences levels of PCT. Typically, PCT elevations are greatest with abdominal and retroperitoneal surgery. Other sites such as thoracotomies lead to minor elevations in PCT.23 PCT has been used for detection of postoperative complications and has been found to be more useful than CRP, white cell count, and IL6 in detecting infections.24 Some studies have utilized PCT kinetics for detection of postoperative infection and sepsis. Trásy et al. used delta-PCT (PCT level from preceding day subtracted from PCT level on day of suspected infection) and found that patients with an infection exhibited a significantly higher delta PCT than those without an infection.25 Tsangaris et al. in their study concluded that a twofold increase in PCT within a 24-hour period together with fever was useful to detect infections in an intensive care unit (ICU) population.26 Few studies have looked at PCT kinetics for appropriateness of initial antibiotic therapy as well as adequacy of source control after abdominal surgery; however more studies and RCTs are required to reach conclusions.27
Guide Antibiotic Therapy in Respiratory Infections
Several studies have been done looking at PCT as a guide for initiation and discontinuation of antibiotics in respiratory infections. An initial study PROCAP trial done in a single hospital in Switzerland first demonstrated that in patients who presented to the emergency department with suspected lower respiratory tract infections, use of procalcitonin to determine whether not to initiate antibiotics, a cut-off threshold of 0.25 µg/L had a 47% reduced rate of antibiotic exposure in the procalcitonin group with no difference in laboratory or clinical outcomes.28 Subsequent RCTs on respiratory tract infections have explored PCT levels for initiation and discontinuation of antibiotics. Prominent among them is the PROHOSP study which was a multicenter RCT which explored whether PCT based algorithm could reduce antibiotic exposure in patients with lower respiratory tract infections. Patients were randomized into either PCT based algorithm group—antibiotics were strongly discouraged if procalcitonin was <0.1, discouraged if 0.1–0.25, encouraged if 0.25–0.5, strongly encouraged if >0.5. They found that antibiotic exposure and antibiotic associated adverse events were significantly decreased in the PCT group while adverse outcomes were similar in both groups.29 Hence in patients with suspected respiratory tract infections, procalcitonin can help differentiating between infectious and noninfectious causes as well as differentiating bacterial from viral causes. However, if patients present with features of lower respiratory tract infections, clinical picture and radiology is suggestive of bacterial infections, antibiotics are initiated without procalcitonin levels, as delay in initiation has been found to increase mortality. In these cases, procalcitonin is used primarily after initiation and trends of procalcitonin are used for discontinuation of antibiotics.
Several studies have looked at levels of PCT as well as PCT clearance as prognostic markers and found varying results. A systematic review and meta-analysis which evaluated prognostic value of procalcitonin in adult patients with sepsis found that an elevated PCT was associated with higher risk of death, initial PCT value had limited prognostic value and PCT nonclearance was significant prognostic factor for mortality. However, the optimal cut-offs and definition of procalcitonin clearance is not yet defined.30
Procalcitonin in Renal Failure
In patients with renal dysfunction and on renal replacement therapy, basal PCT may be raised as half-life increases, however kinetics is not altered and hence PCT decline rates may be unaltered.31,32
Several other biomarkers are investigated for sepsis. Some of them are triggering receptor expressed on myeloid cells-1 (TREM-1), interleukin 27 (IL-27), presepsin, cell free DNA, miRNA. Biomarkers related to the symptoms of sepsis rather than the mechanisms of inflammation have also been tested, such as CT-pro-AVP (C-terminal segment of pro-arginine vasopressin), which aids in regulation of blood pressure; however, these biomarkers have not proven effective in diagnostic testing.33 TREM 1, an immunoglobulin induces inflammatory process by activation of production of chemokines, cytokines and reactive oxygen species. Levels of its soluble form sTREM-1 can be detected by enzyme linked immunosorbent assay (ELISA). A recent review and meta-analysis by Jiyong et al. showed that elevated sTREM-1, sampled and measured from the location of infection, is highly predictive of bacterial infection. However further studies are required for validation and to be used clinically.34
Interleukin 27 is a cytokine produced upon exposure to microbial products and inflammatory stimuli which has found to have both pro- and anti-inflammatory effects. Initial studies done in pediatric population was found to have good specificity and positive predictive value however similar results through subsequent studies in adults could not be reproduced. Combination of IL-27 along with PCT is being explored but yet not validated.35 CD64 is an immunoglobulin which when activated by proinflammatory cytokines leads to phagocytosis of bacteria. Studies have found that CD64 is specific to bacterial infection hence used as a biomarker in sepsis. A systematic review and meta-analysis by Cid et al., found sensitivity and specificity of CD64 to be 79% and 91% respectively, however authors concluded that methodological quality of studies to be poor.36 Hence, further studies are required to confirm its validity.
Presepsin is a soluble form of CD14 which is expressed on monocytes and macrophages leading to activation of toll-like receptors and TNF alpha. A multicenter study was done to evaluate utilization of presepsin in SIRS without infection, sepsis, severe sepsis and septic shock. It was noted that presepsin was consistently elevated with higher degrees of sepsis and was significantly lower in noninfected patients and concluded to be a good diagnostic biomarker.37 A recent systematic review and meta-analysis which compared diagnostic accuracy of presepsin and procalcitonin for sepsis in critically ill adults concluded that both were useful for early detection of sepsis and lead to reduction of mortality in critically ill patients.38 Cell-free plasma DNA (cfDNA) are fragments of DNA that are released because of cell necrosis or apoptosis. This is being explored as a prognostic biomarker of sepsis and is usually associated with cell death. Observational studies found that nonsurvivors of sepsis and septic shock had higher levels of cfDNA compared to survivors. Hence, it is being explored as a prognostic biomarker35 miRNAs are a newly identified class of biomarkers that may serve as diagnostic or prognostic role in various human pathologic conditions, including sepsis. miRNAs are short sequences of endogenous RNAs that are involved in translational gene regulation.
The combination of three sentinel biomarkers, IL-6, PCT, and sTREM-1, is uncommon, but pairs within the three have been attempted before to predict and/or prognosticate sepsis: sTREM-1 and PCT or sTREM-1 and IL-6.39 Finally, it is being increasingly recognized that while sepsis is often thought of as an exaggerated proinflammatory state, there may be a significant anti-inflammatory and immunosuppressive component, especially in late sepsis or sepsis occurring in elderly patients. New biomarkers to estimate the degree of immunosuppression include circulating blood monocyte expression of HLA-DR, monocyte expression of programmed cell-death ligand-1 (PD-L1), and low absolute lymphocyte counts. These could help identify patients who might require immunostimulating or immunomodulating therapy rather than anti-inflammatory therapies in the immunosuppressed stages.40 However, this is still experimental.
Biomarkers are naturally occurring molecules, genes, or other characteristics by particular physiologic or pathologic processes can be identified. Several biomarkers such as WBC count, ESR, lactate, CRP and procalcitonin have been investigated. CRP has been found to have high sensitivity but poor specificity for infection. It has been found to be a better indicator of inflammation than infection. Procalcitonin (PCT), a precursor of calcitonin which is usually undetectable has been found to be increased several fold in sepsis. PCT is used in diagnosis of sepsis, de-escalation of antibiotics, and differentiation of bacterial and viral infections. In postsurgical patients, PCT levels raise on first postoperative day depending on degree of injury. PCT levels start rising few hours after surgery, peak around 24 hours and start declining to normal levels by 48 hours. Persistent elevations of PCT especially >10 ng/L in nontransplant postsurgery patients should raise suspicion of postoperative infection. PCT is recommended for de-escalation of antibiotics when PCT reduces significantly from baseline. Newer biomarkers such as triggering receptor expressed on myeloid cells-1 (sTREM-1), interleukin 27 (IL-27), presepsin, cell free DNA, miRNA are being evaluated for sepsis but are not yet validated.
- Gül F, Arslantaş MK, Cinel İ, Kumar A. Changing definitions of sepsis. Turkish J Anesthesiol. 2017;45:129–38.
- van Engelen TSR, Wiersinga WJ, Scicluna BP, Poll TVD. Biomarkers in sepsis. Crit Care Clin. 2018;34:139–52.
- Barati M, Alinejad F, Bahar MA, Tabrisi MS, Shamshiri AR, Bodouhi NO, et al. Comparison of WBC, ESR, CRP and PCT serum levels in septic and non-septic burn cases. Burns. 2008;34:770–4.
- Faix JD. Biomarkers of sepsis. Crit Rev Clin Lab Sci. 2013;50:23-36.
- Iskandar A, Susianti H, Anshory M, Di Somma S. Biomarkers utility for sepsis patients management. London: Intechopen; 2018.
- Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet. 1993;341:515–8.
- Clec'h C, Ferriere F, Karoubi P, Fosse JP, Cupa M, Hoang P, et al. Diagnostic and prognostic value of procalcitonin in patients with septic shock. Crit Care Med. 2004;32:1166–9.
- Müller B, Becker KL, Schächinger H, Rickenbacher PR, Huber PR, Zimmerli W, et al. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med. 2000;28:977–83.
- Ugarte H, Silva E, Mercan D, De Mendonça A, Vincent JL. Procalcitonin used as a marker of infection in the intensive care unit. Crit Care Med. 1999;27:498–504.
- Ruokonen E, Ilkka L, Niskanen M, Takala J. Procalcitonin and neopterin as indicators of infection in critically ill patients. Acta Anaesthesiol Scand. 2002;46:398–404.
- Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis. 2013;13:426–35.
- Delèvaux I, André M, Colombier M, Albuisson E, Meylheuc F, Bègue RJ, et al. Can procalcitonin measurement help in differentiating between bacterial infection and other kinds of inflammatory processes? Ann Rheum Dis. 2003;62:337–40.
- Lee H. Procalcitonin as a biomarker of infectious diseases. Korean J Intern Med. 2013;28:285–91.
- Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med. 2008;177:498–505.
- Hochreiter M, Köhler T, Schweiger AM, Keck FS, Bein B, von Spiegel T, et al. Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial. Crit Care. 2009;13:R83.
- Schroeder S, Hochreiter M, Koehler T, Schweiger AM, Bein B, Keck FS, et al. Procalcitonin (PCT)-guided algorithm reduces length of antibiotic treatment in surgical intensive care patients with severe sepsis: results of a prospective randomized study. Arch Surg. 2009;394:221–6.
- Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, et al. Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet. 2010;375:463–74.
- Shehabi Y, Sterba M, Garrett PM, Rachakonda KS, Stephens D, Harrigan P, et al. Procalcitonin algorithm in critically ill adults with undifferentiated infection or suspected sepsis. A randomized controlled trial. Am J Respir Crit Care Med. 2014;190:1102–10.
- Jong EA, Lange DW, Van Oers JA, Nijsten MW, Twisk JW, Beishuizen A. Stop Antibiotics on guidance of procalcitonin Study (SAPS): A randomised prospective multicenter investigator-initiated trial to analyse whether daily measurements of procalcitonin versus a standard-of-care approach can safely shorten antibiotic duration in intensive care unit patients. BMC Infect Dis. 2013;13:178.
- Paruk F, Chausse JM. Monitoring the postsurgery inflammatory host response. J Emerg Crit Care Med. 2019;3:47.
- Lindberg M, Hole A, Johnsen H, Asberg A, Rydning A, Myrvold HE, et al. Reference intervals for procalcitonin and C-reactive protein after major abdominal surgery. Scand J Clin Lab Invest. 2002;62:189–94.
- Meisner M, Tschaikowsky K, Hutzler A, Schick C, Schüttler J. Postoperative plasma concentrations of procalcitonin after different types of surgery. Intensive Care Med. 1998;24:680–4.
- Domínguez-Comesaña E, Estevez-Fernández SM, López-Gómez V, Ballinas-Miranda J, Domínguez-Fernández R. Procalcitonin and C-reactive protein as early markers of postoperative intra-abdominal infection in patients operated on colorectal cancer. Int J Colorectal Dis. 2017;32:1771–4.
- Tsangaris I, Plachouras D, Kavatha D, Gourgoulis GM, Tsantes A, Kopterides P, et al. Diagnostic and prognostic value of procalcitonin among febrile critically ill patients with prolonged ICU stay. BMC Infect Dis. 2009;9:213.
- Novotny AR, Emmanuel K, Hueser N, Knebel C, Kriner M, Ulm K, et al. Procalcitonin ratio indicates successful surgical treatment of abdominal sepsis. Surgery. 2009;145:20–6.
- Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR, Tamm M, et al. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet. 2004;363:600–7.
- Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA. 2009;302:1059–66.
- Liu D, Su L, Han G, Yan P, Xie L. Prognostic value of procalcitonin in adult patients with sepsis: a systematic review and meta-analysis. PLoS One. 2015;10(6):e0129450.
- Meisner M, Lohs T, Huettemann E, Schmidt J, Hueller M, Reinhart K. The plasma elimination rate and urinary secretion of procalcitonin in patients with normal and impaired renal function. Eur J Anaesthesiol. 2001;18:79–87.
- Grace E, Turner RM. Use of procalcitonin in patients with various degrees of chronic kidney disease including renal replacement therapy. Clin Infect Dis. 2014;59:1761–7.
- Laribi S, Lienart D, Castanares-Zapatero D, Collienne C, Wittebole X, Laterre P. CT-proAVP is not a good predictor of vasopressor need in septic shock. Shock. 2015;44(4):330–5.
- Jiyong J, Tiancha H, Wei C, Huahao S. Diagnostic value of the soluble triggering receptor expressed on myeloid cells-1 in bacterial infection: a meta-analysis. Intensive Care Med. 2009;35:587–95.
- Sandquist M, Wong HR. Biomarkers of sepsis and their potential value in diagnosis, prognosis and treatment. Expert Rev Clin Immunol. 2014;10:1349–56.
- Cid J, Aguinaco R, Sanchez R, García-Pardo G, Llorente A. Neutrophil CD64 expression as marker of bacterial infection: a systematic review and meta-analysis. J Infect. 2010;60:313–9.
- Ulla M, Pizzolato E, Lucchiari M, Loiacono M, Soardo F, Forno D, et al. Diagnostic and prognostic value of presepsin in the management of sepsis in the emergency department: a multicenter prospective study. Crit Care. 2013;17(4):R168.
- Kondo Y, Umemura Y, Hayashida K, Hara Y, Aihara M, Yamakawa K. Diagnostic value of procalcitonin and presepsin for sepsis in critically ill adult patients: a systematic review and meta-analysis. J Intensive Care. 2019;7:22.
- Gibot S, Béné MC, Noel R, Massin F, Guy J, Cravoisy A, et al. Combination biomarkers to diagnose sepsis in the critically ill patient. Am J Resp and Crit Care Med. 2012;186(1):65–71.
- Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13:260–8.