Intensive care case pattern study reported frequent prevalence of sepsis in India, with All types of microbes like bacteria, virus, fungi and parasites can cause sepsis, but bacteria cause the most common pathogenic invasion [ 8 — 10 ]. During sepsis, the microorganisms invade to the blood stream and directly proliferate locally and release various virulent factors into the bloodstream [ 11 ].
These products can stimulate the release of endogenous mediators of sepsis from endothelial cells, monocytes, macrophages neutrophils and plasma cell precursors [ 12 ]. Sepsis-related inflammatory response arise when the body attempts to neutralize pathogenic infection which in turn leads to the activation of various mechanism with the immune cells to secrete inflammatory protein which in turn damage tissues and organs of the host [ 13 , 14 ]. Clinical symptoms of sepsis include tachycardia, tachypnea, fever, leucocytosis, etc.
Usually severe sepsis is accompanied with hypoperfusion or dysfunction of at least one organ. Sepsis associated with multiple organ dysfunction syndrome MODS or hypotension is known as septic shock [ 15 ]. Early diagnosis and prompt antimicrobial therapy is crucial in the treatment of sepsis for saving lives. Sepsis is a systemic inflammatory response syndrome SIRS that affect all organs. Hence, host responses including cytokine, cell markers, receptor biomarkers, coagulations, vascular endothelial damage, vasodilation, organ failure and scientific advancement in the field of molecular biology can equip us to screen wide range of protein markers in acute phase of sepsis development that helps in identifying relevant biomarkers to diagnose sepsis [ 16 ].
Compared to CRP, PCT has better diagnostic and prognostic value and will clearly distinguish viral and bacterial meningitis [ 17 ]. Blood culture is considered as the gold standard for the confirmation of bacteraemia which can isolate and identify the causative agent and subsequently test the antimicrobial sensitivity, but the delayed process of bacterial culture emphasises the early diagnosis of sepsis [ 19 ].
Several studies mentioned the advantages of the precursor molecule of calcitonin, namely procalcitonin as a biomarker for sepsis. The serum PCT level rises rapidly than CRP levels and peaks within very short time; moreover, if the patient responds appropriately to the treatment, the level of PCT returns to normal range faster than CRP which makes it a better biomarker for sepsis [ 20 ].
In general, PCT alone or in combination with other biomarkers would serve as a promising tool for understanding the prediction, cause, diagnosis, progression, regression and outcome of the treatment regimes.
In , Moya F et al. The large biosynthetic molecule splits intracellularly to generate the hormone, and they named it as procalcitonin [ 21 ]. Later studies show that calcitonin is secreted after a sequential Co and post translational modification like glycosylation protiolytic cleavage, etc. The mRNA product is known as preprocalcitonin.
It is further modified to amino acid procalcitonin. Finally, it is cleaved into 3 distinct molecules; active calcitonin 32 amino acid , katacalcitonin 21 amino acid and N-terminal procalcitonin 57 amino acid. Calcitonin hormone is involved in the homeostasis of calcium and phosphorous [ 24 ]. Hence, the PCT level in healthy subjects is very low 0.
In bacterial septicaemia, PCT is produced by alternate pathways, either directly or indirectly. For better understanding of the pathophysiology of calcitonin precursor in sepsis, an experiment was conducted in animal hamsters analogue to human sepsis [ 25 ].
During sepsis, ubiquitous and uniform expressions of calcitonin CT mRNA in multiple tissues were observed in hamsters. In healthy hamsters, PCT mRNA was isolated primarily from the thyroid with minute amounts of synthesis associated with lung tissue. The next set of hamsters was infected with gram-negative bacteria, and the level of PCT mRNA in various tissues and cells were observed.
Many reports are available which shows that PCT levels are elevating rapidly between 2 and 6 h which peaks within 6—24 h during bacterial infection. An ideal biomarker should possess high diagnostic accuracy, for an early and rapid diagnosis. PCT is a recently re-discovered biomarker that fulfils many of these requirements especially in comparison to conventional and widely used other biomarkers that have demonstrated superior diagnostic accuracy for a variety of infections, including sepsis.
PCT is helpful for early detection of sepsis as well as to monitor the antimicrobial treatment regimen. In fact, PCT can be a useful tool for antimicrobial stewardship and its utilization may safely lead to significant reduction of unnecessary administration of antimicrobial therapy.
Laboratories and clinicians must comprehend the precincts of the present microbiological methods and the need for highly sensitive biomarker assays to facilitate accurate diagnosis and goal directed therapy in patients suspected of sepsis.
During sepsis conditions, microbes and their antigens stimulate numerous anti-inflammatory mediators, which will trigger the host immune response. Precursors, mature forms and degradation products of these mediators penetrate from the site of action into the circulation, where which can be measured theoretically.
These substances can be measured as surrogate markers for the diagnosis and the severity of infection. Exalted production of PCT during bacterial and its association with sepsis was first demonstrated by Asscot et al. The actual mechanism of production of PCT during infection is not known, but it assumes that bacterial lipopolysaccharides and sepsis released cytokines modulate the liver and peripheral blood mononuclear cells to produce PCT.
Microbial infection induces the elevated expression of CALC 1 gene followed by the release of PCT product which is correlated with severity of disease and mortality. The PCT as a biomarker proved successfully its clinical usefulness in determining the presence of sepsis. Moreover, it has been shown to correlate the extent and the severity of microbial invasion. It clearly showed the significance of early diagnosis of bacterial infected sepsis.
PCT can be used for early detection of sepsis and prediction of outcome after major trauma. Muller et al.
Out of patients with pneumonia symptoms consulting at the emergency department ED , were suspected with true bacterial pneumonia, with an area under the receiver operating characteristics AUROC curve for the PCT to predict bacterial pneumonia of 0. Several meta-analysis data suggest of heterogeneity for the PCT testing; however, elevated PCT concentrations strongly associated with all-cause mortality in sepsis patients [ 28 ].
Muller and colleagues conducted a study in consecutive critically ill patients to compare the usefulness of serum concentration of calcitonin precursor, CRP, IL-6 and lactate for the diagnosis of sepsis. Blood samples were collected at variable intervals during the course of disease systemic inflammatory response syndrome SIRS , sepsis and severe sepsis and septic shock.
Serum concentration of calcitonin precursor, CRP, IL-6 and lactate were elevated according to the severity of illness.
Ibrahim et al. Study of Young et al. They considered 49 patients and divided them into 2 groups: with and without septic shock. Platelet count, PCT, CRP, creatinine, erythrocyte sedimentation rate ESR , albumin and white blood cells WBC were measured at the time of admission to the emergency department before administrating antibiotic treatment. The multivariate model reveals that lower platelet count and higher PCT level are independent risk factors of septic shock.
At the cut-off of 0. The study demonstrated that elevated PCT is an early independent predictor of development of septic shock in patients with sepsis induced by acute pyelonephritis associate with ureteral calculi.
In , presepsin was identified as a diagnosis marker and evaluated for sepsis. It became an alternative biomarker to aid the diagnosis of sepsis [ 32 ]. Recent studies shows that soluble cluster of differentiation 14 sCD14 plays a significant role as biomarker with respect to diagnosis of sepsis.
CD14 is a surface marker constituent of glycoprotein on monocytes and macrophages mCD14 and serves as a high-affinity receptor towards lipopolysaccharides LPSs , which is an essential building block of outer cell wall of gram-negative bacteria, and LPS-binding proteins LPBs. CD14 binding to toll-like receptor 4 TLR4 lead to activation of pro-inflammatory signalling cascade in bacterial infection [ 33 , 34 ].
However, the clinical value of these biomarkers independently or in combination is still at investigative stages [ 35 ]. PCT level above 2. This diagnostic approach is also recommended in various guidelines [ 41 ]. The introduction of antibiotics was in midth century. Misuse and overuse of antibiotics launch the next misery known as antibiotic resistance by pathogens. Judicious use of antibiotics is of vital importance in clinical therapy [ 42 ].
Scott Fridin et al. According to their study, reduction of incorrect antibiotic prescription can improve the use and patient safety [ 43 ]. Implementation of antibiotic stewardship helps to control unnecessary antibiotic prescribing as well as ensure the efficiency of treatment [ 44 ]. Inappropriate usage of medicines may lead to the development of antibiotic resistance in patients [ 45 ].
An ideal marker should assist early diagnosis and capabilities to track the disease and facilitate the therapeutic interventions and decisions. The PCT is a better choice, compared to other markers which satisfy these features. An algorithm based on serial measurement of PCT can reduce the antibiotic exposure in septic patients [ 46 ]. According to the level of serum PCT, therapeutic decisions in patients were taken Fig. Based on reports, in transplant recipients, to minimize delays in the diagnosis of sepsis, it is paramount to recognize the specific risk factors for infection associated with each allograft type.
Hence, PCT can be a better biomarker in detecting bacterial sepsis at initial stages. But the major limitations are to identify the causative bacteria. In addition, the particular surgical techniques involved in each type of transplantation may be closely related to the clinical manifestations of the infection process.
Hence, further culturing and gram staining is required to identify the type of bacteria for further accurate treatments. A study conducted in acutely febrile patients reveals that measurement of PCT is helpful in differentiating bacteria and non-bacterimic infectious episodes in patients.
Based on the above observations, serum PCT level measurement is recommended for the guidance of antibiotic therapy [ 47 ]. Stolz D et al. Schroeder et al. For all patients, drug administration was based on microbiological spectrum.
In control group, treatment was based on empirical rules. They observed that PCT-based algorithm reduces the use of antibiotic as well as the expense of treatment [ 49 ]. Lavrentieva et al. They enrolled 46 burn ICU patients for the study, wherein 24 patients received the therapy based on PCT guidance, which resulted in a smaller antibiotic exposure Kip and colleagues assessed the cost effectiveness of PCT-based algorithm.
It was found to reduce the length of hospital stay, number of blood cultures and the duration of antibiotic therapy [ 51 ]. Antibiotic treatment based on PCT monitoring is a sensitive way of antibiotic usage in ICU patient with severe sepsis and septic shock [ 52 ].
Anna Prkno and co-workers reviewed various studies regarding the clinical trials and compared PCT-guided antibiotic stewardship with standard care and hospital mortality, duration of antimicrobial therapy and length of stay in the ICU.
It was noticed that PCT guidance could not make better change in the mortality rate, but there was definitely a noteworthy effect on the duration of antimicrobial treatment [ 53 , 54 ]. Various studies are published revealing the wide application of PCT in medical field.
Before selecting PCT as a biomarker, its limitations have to be studied. Further studies should be conducted to disclose even more application of PCT. The assay used for the detection must distinguish PCT levels between healthy individuals, non-bacteremia patients and progressing SIRS. More sensitive assays should be developed to take forward the studies to the clinical level [ 55 , 56 ]. The PCT is a unique biomarker having wide range of application in the medical field, compared to other conventional markers for sepsis.
However, to diagnose invasive bacterial infection and their severity assessment of PCT levels alone may not be enough. Because of the possible complication in diagnosis of sepsis and the challenge in differentiating between microbial and non-microbial infection cases, it is unlikely that a single biomarker serve as an effective diagnosis tool. A combination of biomarkers may be more functional in the case of clinical application, but this may require further investigation in various aspects as a reliable diagnostic tool [ 57 , 58 ].
Measurement of combinational biomarkers may require reliable and cost effective technology development. Selection of biomarkers plays a crucial role in technology development; consequently, assessment of combination of biomarkers like procalcitonin, sCDST and other new biomarkers can be made use in evaluation of sepsis in all age groups. Combination of emerging new biomarkers with PCT could be used in terms of good clinical judgement based on which antimicrobial therapy may suggested, thus reducing the prescription and duration of antibiotic treatment.
Combinational biomarker with PCT-guided antibiotic stewardship could be properly fabricated to develop a safer and affordable strategy for diagnosis of sepsis and its prognosis. The authors would like to thank the management team of HLL for the extended support and guidance. The authors are thankful to Dr. Rajmohan G Scientist E3 for the valuable comments during scripting of this article. We are also thankful to Ms. Jeslin Varghese Senior Project Fellow for the technical support in completing the study.
All authors have read and approved the final manuscript. Ashitha Vijayan, M. Vani Maya, M. Shilpa Ravindran, M. Saikant R, M. Lakshmi S, Ph. Kartik Ramaswami, Ph. Manoj G, Ph. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. National Center for Biotechnology Information , U.
Journal List J Intensive Care v. J Intensive Care. Published online Aug 3. Ashitha L. Vijayan , Vanimaya , Shilpa Ravindran , R. Saikant , S. Lakshmi , R. Kartik , and Manoj. Author information Article notes Copyright and License information Disclaimer.
G, Email: moc. Corresponding author. Received May 5; Accepted Jul This article has been cited by other articles in PMC. Abstract Background Sepsis is a global healthcare problem, characterized by whole body inflammation in response to microbial infection, which leads to organ dysfunction. Conclusion Further studies are needed to better understand the application of PCT in the diagnosis of sepsis, differentiating between microbial and non-microbial infection cases and determining the therapeutic approaches for sepsis.
Keywords: Procalcitonin, Sepsis, Antibiotic therapy, Diagnostic marker. PCT synthesis is triggered by bacterial toxins, such as endotoxin and cytokines [e. Due to cytokines released during viral infections that inhibit the production of TNF-alpha, PCT synthesis is not induced in the most viral infections 27 - Moreover, PCT has a wide biological range, a short time to induction after bacterial stimulation and a long half-life Thus, PCT has good discriminatory properties for the differentiation between bacterial and viral inflammations with rapidly available results.
PCT per se cannot isolate or detect specific pathogens, but the level of PCT may be useful to estimate the probability of a severe bacterial infection 26 , The diagnostic accuracy of PCT for sepsis has already been investigated in several observational studies, which however yielded divergent results. These conflicting results are most likely explainable by differences in the analyzed study population and different reference standard for infection used in the studies.
A meta-analysis conducted by Tang et al. Further, the calculated area under the summary receiver operating characteristic curve SROC was 0. In contrast, a more recent conducted meta-analysis including 30 high quality studies and 3, patients demonstrated with an ROC-curve of 0. However, the PCT levels should always be interpreted in a context with clinical presentation, medical history, physical examination and if available microbiological assessment of the patients A more recently published international expert consensus, recommended PCT cut-off levels for critically ill patients in order to estimate the probability of bacterial infections and therefore, improve initial clinical assessment Figure 2 The presented guidelines recommend the use of cut-off ranges with higher and lower positive and negative predictive values for sepsis, instead of one general cut-off.
Procalcitonin use in patients with severe illness in the ICU. Please note: caution in patients with immunosuppression including HIV , cystic fibrosis, pancreatitis. Risk stratification and prognostication are important prerequisites, in order to appropriately apply health-care resources and available therapeutic options. This may help to find those patients who are most likely to benefit from targeted and extensive therapy without causing unnecessary harm. The Sequential Organ Failure Assessment SOFA , which is based on the recently updated definition of sepsis, represents a complex tool mainly appropriate for patients in the intensive care unit.
This in turn, reflects the need for newly available biomarkers that are measurable with high precision and reproducibility, respond to clinical recovery and provide real-time information Numerous biomarkers, which reflect the complex pathophysiology of sepsis, have been identified and evaluated in regard to their prognostic value.
In this context, PCT and especially its kinetics is one of the most studied biomarkers. In fact, PCT kinetics over time has shown to improve the monitoring of critically ill patients with sepsis 38 - Since decreasing PCT values correlate with good outcomes and increasing values are associated with adverse outcomes which also include mortality, PCT kinetics have demonstrated prognostic implications 45 - PCT kinetics also showed a correlation with severity of illness A Finnish observational study identified PCT concentrations being higher in more severe cases of already advanced sepsis.
Moreover, it was shown that a substantial decrease in PCT concentration was more relevant for survival prediction compared to absolute values The analysis of retrospective data from two independent US critical care institutions indicated a high prognostic power for the hour PCT kinetics for predicting sepsis mortality S based hospitals However, to demonstrate that prognostic information can also result in improved clinical outcomes of patients, has poses several challenges.
This was reflected in a large interventional study, which showed that survival was not improved by a PCT-guided diagnostic and therapeutic management escalation.
Moreover, the use of broad-spectrum antibiotics was prolonged which, in turn, had a negative impact on organ function and lengths of stay in the ICU A further important aspect to consider in patients with sepsis is the presence of renal impairment and the reduced glomerular filtration rate that may lower PCT clearance and levels thus may be higher than assumed 51 , Early empirical antibiotic therapy has demonstrated to be highly effective for the reduction of mortality and morbidity in sepsis 53 , However, a prolonged and unnecessary e.
Furthermore, antibiotic overuse, still represents an important risk factor for the development of antibiotic-resistant bacteria 55 , For many physicians, determining the duration of an antibiotic therapy is a challenging decision, due to the fact that clinical signs and symptoms lack sensitivity and specificity to ensure differentiation between self-limited and mild viral infections from more severe bacterial infections.
In recent years, there has been great interest in biomarkers that are able to indicate the risk for bacterial infection in a short time after admission and thus, can help to reduce antibiotic overuse and potentially diminish antibiotic associated side effects, mortality and treatment failure 12 , This decision was based on several randomized controlled trials which have analyzed infections of different severity in various clinical settings ranging from primary care to ICU and have investigated and demonstrated the efficacy and safety of PCT-guided decision-making with regard to antibiotics 42 , 57 , Table 1 shows a summary of previously published randomized controlled trials investigating PCT-guided antibiotic therapies in critically ill patients.
Nobre et al. Using a PCT-guided algorithm the exposure to antibiotics could be reduced without causing any harm or negative outcome In case of critically ill patients with a high probability for bacterial infection early empiric antibiotic therapy is crucial and PCT is mainly used for treatment cessation, based on its kinetics. PCT use in patients with sepsis treated in the ICU was investigated in a recent meta-analysis, including 11 studies and 4, patients.
The analysis demonstrated a significant reduction in mean treatment duration from Further, it was shown that the mortality rate was lower in the PCT-guided group compared to the control group Subgroup analyses based on sepsis 3 definition, sepsis severity, presence of renal failure as well as in different types of infection revealed similar effects.
The observed positive effects are probably due to the lower risk for antibiotics associated toxic effects in the PCT-guided group. Despite a not yet fully understood pathophysiological mechanism, several observational analyses have reported a reduced risk of treatment failure and mortality which was associated with early antibiotic de-escalation in patients with sepsis 62 , Despite the available evidence regarding PCT-guided therapy de-escalation, the use of PCT-guided antibiotic therapy escalation is not yet recommended.
A randomized trial analyzing 1, critically ill patients in nine multidisciplinary intensive care units in Denmark, demonstrated that therapy escalation did not improve outcome when PCT-algorithms were used A more widespread use of PCT in critically ill patients was limited by the fact, that a commonly accepted algorithm for the utilization of PCT in those patients was long lacking However, the applied PCT-protocols used in the different studies were all similar and based on the same concept: The initiation of an antibiotics therapy was recommended in all patients with a suspected sepsis based on the clinical grounds and PCT kinetics over time were used for recommendations concerning an early discontinuation of the antibiotic therapy According to the current body of evidence an international expert group recently published a consensus algorithm for the PCT use in patients with suspected bacterial infections.
The proposed algorithm was utilized in various interventional trials, which all resulted in significantly reduced antibiotic exposure, without increasing mortality or adverse event rates. Figure 2 Flowchart PCT provides a practical guide for the rational use of PCT in a high risk setting in conjunction with clinical assessment, including interpretation of PCT and recommendations for antibiotic use 21 , The interventional non-inferiority proACT trial revealed low adherence rates to the PCT protocol, indicating a shortcoming of experience in the use of PCT as well as in its interpretation in a clinical context.
In order to gain more confidence with PCT measurements, repeated education for antibiotic stewardship could be advantageous for physicians. This statement was also confirmed by a retrospective cohort study of Broyles et al.
Through education-based antibiotic stewardship, which includes also the use of PCT measurements, a reduction of antibiotic prescriptions and lower resistance rates could be achieved. Moreover, an association with improved outcomes like lower readmission rates, shorter length of stay and lower Clostridium difficile infections was observed PCT studies are limited to the use in patients with respiratory infections and sepsis. Data about the use of PCT in immunosuppressed patients including patients with HIV, cystic fibrosis, pancreatitis, trauma, pregnancy and high volume transfusion are very low.
Moreover, it should be noted that some non-infectious disorders, such as C-cell carcinoma or trauma, can lead to a systemic inflammation resulting in elevated PCT levels. Further, the use of PCT-guided stewardship is not recommended in patients suffering from a chronic infection such as osteomyelitis or endocarditis, since observational studies were unable to identify any benefit and interventional investigations in this context are still lacking An early diagnosis and the initiation of an appropriate antibiotic treatment are still the cornerstones of effective sepsis care.
In this respect, PCT has shown promising results for the treatment of patients with sepsis. However, it should be noted that PCT values are not intended to replace good clinical practice, but should be used as a complementary tool combined with available clinical and diagnostic parameters.
In order to estimate the probability of bacterial infections, it is recommended to use cut-off ranges with higher and lower positive and negative predictive values for the identification of sepsis, instead of one general cut-off.
A further important consideration is the quality of the used PCT assays The use of high-sensitive PCT assays should be preferred in clinical practice since the use of semi-quantitative assays is not able to detect an increased PCT in lower ranges.
The prognostic information derived from PCT kinetics can influence further procedure with regard to diagnostic testing, but also therapeutic decisions and timing of patients discharge 40 , To date, integration of the host-response marker PCT into a comprehensive clinical assessment seems to be a promising approach to reduce diagnostic uncertainties and antibiotic overuse. Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Conflict of Interest: Prof. Schuetz reports receiving grants form bioMerieux Thermo Fischer and Roche Diagnostics paid to the institution. National Center for Biotechnology Information , U. Journal List J Thorac Dis v. J Thorac Dis. Author information Article notes Copyright and License information Disclaimer.
Corresponding author. Correspondence to: Prof. Email: moc. Received Nov 20; Accepted Nov Copyright Journal of Thoracic Disease. All rights reserved.
This article has been cited by other articles in PMC. Abstract Important aspects of sepsis management include early diagnosis as well as timely and specific treatment in the first few hours of triage.
Keywords: Antibiotic stewardship, biomarker, high risk setting, procalcitonin, sepsis. Introduction Sepsis, defined as a life-threatening organ dysfunction caused by a dysregulated host-response to infection, is a worldwide highly prevalent syndrome, associated with significant morbidity and mortality 1. Open in a separate window. Figure 1. Procalcitonin as a diagnostic biomarker for bacterial infection and sepsis Despite decades of research efforts, there is still no sepsis-specific treatment option available.
Figure 2. Procalcitonin as a therapeutic biomarker for antibiotic stewardship in patient with severe infection and sepsis Early empirical antibiotic therapy has demonstrated to be highly effective for the reduction of mortality and morbidity in sepsis 53 , Table 1 Summary of Procalcitonin randomized trials for infections in critically ill patients.
Practical consideration for the use of procalcitonin testing Figure 2 Flowchart PCT provides a practical guide for the rational use of PCT in a high risk setting in conjunction with clinical assessment, including interpretation of PCT and recommendations for antibiotic use 21 , Limitation of procalcitonin PCT studies are limited to the use in patients with respiratory infections and sepsis.
Conclusion and outlook An early diagnosis and the initiation of an appropriate antibiotic treatment are still the cornerstones of effective sepsis care. Acknowledgments None. Notes Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Footnotes Conflict of Interest: Prof.
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