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What is procalcitonin (PCT)?

       Procalcitonin (PCT) is a pro-calcin of procalcitonin. The production of procalcitonin is independent of calcitonin levels during infection and sepsis, and is closely related to the release of endotoxin and inflammatory mediators from bacterial infection Related. Traditional biological markers, clinical symptoms, and signs lack sufficient sensitivity and specificity to guide treatment decisions for infectious diseases. As a recently applied biomarker, procalcitonin has been increasingly supported by the detection of serum procalcitonin concentrations to diagnose the types of infectious pathogens early, evaluate the severity of infection, guide medication and determine prognosis. Procalcitonin has become the most useful biomarker in the management of infection and sepsis in most parts of the world.
 
       The diagnosis of infection has always been a major problem for clinicians. Although there are many monitoring methods, it still lacks sensitive and specific dynamic monitoring indicators. Since the first significant increase in procalcitonin concentration in the blood of patients with sepsis was first discovered in 1993, procalcitonin has become an important marker for the diagnosis of bacterial infections. Compared with traditional biological markers, procalcitonin has higher accuracy and specificity. At the same time, PCT concentration is related to the severity of the disease and can be used to guide antibacterial treatment.
 
 
1. Production and release of procalcitonin
 
       Procalcitonin is a pro-peptide substance of calcitonin, consisting of 116 amino acids. Normally, procalcitonin is encoded by the Calc-1 gene located on the short arm of thyroid chromosome C chromosome 11. In thyroid C cells, the Calc-1 gene is translated into a PCT precursor peptide containing 141 amino acids, and then enters the endoplasmic reticulum to form PCT under the action of glycosylase and specific enzymes. Then, PCT is passed through a specific peptide endonuclease Cleavage into N-PCT, calcitonin and calcitonin.
 
 
 
        Under normal circumstances, PCT is hardly secreted from the cells, and the blood content is <0.1ng / ml. Once the bacteria invade the body, the PCT concentration in the blood can rapidly increase to 5000 times. The reason is that some studies have suggested that bacterial infection stimulates specific transcription factors in tissues to activate Cala-1 regulatory genes and thereby activate PCT transcription, and some studies have suggested that PCT transcription is normally inhibited by specific transcription factors under normal circumstances. Is cleaved, causing PCT transcription.
 
       Unlike C-reactive protein, almost all peripheral tissues are involved in PCT production during bacterial infection. Studies on patients with thyroidectomy found that blood PCT concentrations were still high during bacterial infection. Morgenthaler and others injected endotoxin into the baboon and found that almost all tissues have PCT-mRNA expression. The liver and kidney are the main tissues that produce PCT 6 hours after the injection of endotoxin. The lung, stomach, The heart produces PCT at its peak. The half-life of PCT in the circulation is approximately 22-26 hours and does not depend on renal excretion.
 
       In addition to parenchymal cells during bacterial infection, whether peripheral blood cells are involved in the production of PCT is controversial. Oberhoffer and other peripheral blood studies of 17 patients with moderate to severe infection found that PCT was detectable in monocytes and lymphocytes. By intracellular antibody staining, Balog confirmed the expression of PCT in monocytes and neutrophils. However, Monneret et al. Postulated that peripheral blood mononuclear cells could not produce PCT even when stimulated by endotoxin and cytokines. Linscheid et al. Found that no PCT-mRNA was detected in endotoxin-stimulated macrophages and live isolated peripheral blood mononuclear cells. Therefore, whether peripheral blood cells are involved in PCT release during bacterial infection needs further study.
 
       Current research suggests that there are two pathways for bacterially induced PCT release, namely direct and indirect pathways. The bacterial tissue structure (DNA, pili, peptidoglycan, etc.) in the direct pathway directly induces intracellular signaling to release PCT, and the pathogen in the indirect pathway stimulates the body to produce mediators (such as pro-inflammatory cytokines) and then acts on target cells to produce PCT. Domenech believes that pathogens directly act on specific microbial-associated receptors at the 5th start site of the Calc-1 gene during bacterial infection and cause a large amount of PCT release. In contrast, Picariello et al. Found that during bacterial infection, bacterial endotoxin stimulates the body to produce a series of pro-inflammatory cytokines (such as TNFa, IL-1β, IL-8, and IL-6) to stimulate tissues other than the thyroid (intestine, lung, and immune cells). ) Release PCT into the blood. Clinical and animal studies have confirmed that direct injection of endotoxin results in the release of PCT in the blood. Some researchers have found that adding endotoxin to cells cultured in vitro can cause PCT to be produced in cells. Assicot found that intravenous injections of TNFa and IL-2 into cancer patients caused rapid and massive release of PCT. Balog et al. Reported that the injection of anti-TNFa monoclonal antibodies into human leukocytes inhibited the bacterial stimulation of PCT release. Other studies have found that IFN-r inhibits PCT release.
 
       Studies have suggested that PCT can be used as an immunoregulatory molecule, and pointed out that increasing the synthesis of PCT is harmful to the body. In vivo and in vitro studies have found that PCT can amplify the inflammatory response and lead to a vicious cycle during disease progression after bacterial infection. Studies have reported that injecting anti-PCT antibodies into septic pigs can significantly improve blood pressure, increase cardiac index and stroke volume, and significantly improve survival rates. However, whether PCT can be used as a target for the treatment of sepsis needs further research.
 
 
 
 
2. Application of PCT in infectious diseases
 
2.1 Identification of bacterial infections and non-bacterial infectious diseases
 
       The American Society of Infectious Diseases and the American Academy of Critical Diseases jointly recommend PCT as an auxiliary diagnostic marker to distinguish sepsis from non-infectious systemic inflammatory responses. When bacterial infection causes a systemic inflammatory response, the PCT concentration will increase significantly. However, during inflammatory reactions such as viral infection, cancerous fever, and graft host rejection, the blood PCT concentration does not increase or only slightly increases.
 
       PCT in blood will increase rapidly 4 ~ 12 hours after bacterial infection, and PCT can decrease by 50% within one day with infection control. In community-acquired pneumonia and urinary tract infections, taking PCT at a cut-off value of 0.1 μg / L is highly sensitive to the exclusion of bacterial infections. Kim et al. Found that when the critical value of PCT was 0.4ng / ml, the accuracy rate of bacterial infection was 95% in patients with acute fever. William et al. Found that blood PCT concentrations in patients with bloodstream infection were significantly higher than those with local infection (median PCT ratio: 1.06ng / ml: 0.30ng / ml) and non-infected patients (median PCT ratio: 1.06ng / ml: 0.31). ng / ml). At the same time, research also found that PCT is also important in distinguishing bacterial infection and tumor-related fever. After treatment with antibacterial drugs, the blood PCT concentration of patients with bacterial infection decreased by ≥50%, while the PCT concentration of tumor-related fever was not Significantly decreased. Studies of patients with autoimmune diseases such as Weger's granulomatosis, Behcet's disease, rheumatoid arthritis, reactive arthritis, etc. show that PCT concentrations in the fever group with bacterial infection are significantly higher than those in the fever group with nonbacterial infection and the disease itself. Fever group.
 
       Studies have found that fungal infections, and even patients with severe fungal sepsis or septic shock, do not increase blood PCT concentrations. PCT cannot be used to distinguish fungal infections and colonization, but PCT has a higher ability to identify fungal infections and bacterial infections. Accuracy, its sensitivity height and specificity are 88% and 81%, respectively.
 
        PCT also has certain significance in identifying the type of bacteria. Lipopolysaccharide is the main marker of the cell wall of Gram-negative bacteria. Peptidoglycan is the main component of Gram-positive bacteria, but Gram-positive bacteria lack lipopolysaccharide. LPS and inflammatory factors stimulate PCT production. When Gram-negative bacteria invade the body, lipopolysaccharide can rapidly induce PCT mRNA translation to produce PCT. Some researchers have studied 62 blood culture-positive patients and divided them into Gram-positive bacteria (G +) group and Gram-negative bacteria group (G-). The PCT values ​​of the two groups were measured. The PCT value was ≥2.0ng / ml, and the G- group was ≥10.0ng / ml. When the PCT was ≥10.0ng / ml, the PCT value of the G- bacteria group was significantly greater than the PCT value of G +.
 
 
  2.2 Evaluation of the degree of infection and prognosis
 
       Blood PCT concentration is not only a specific indicator of infectious diseases, but also the severity of host infection and the prognosis can be monitored through continuous monitoring of PCT levels. The concentration of PCT is related to the severity of bacterial infection and bacterial load.
 
       Studies have shown that plasma PCT production in patients with multiple organ dysfunction syndrome (MODS) secondary to systemic inflammatory response syndrome (SISR) is earlier than CPR. Plasma PCT begins to increase 4 hours after the inflammatory response, and then increases sharply and then Maintaining high levels within 8-12 hours, the PCT content gradually decreases with the recovery of the disease, and the time required to return to normal levels is shorter than CPR. Boussekey et al. Studied 110 patients with severe community-acquired pneumonia in ICU. 27.3% of the patients died of critical illness. The median PCT in the death group was 5.6ng / ml (2.4 ~ 61), and the median PCT in the surviving group was 1.5ng. /ml(0.6~5.4), (P <0.0001). At the same time, it was found that the mortality rate increased with the increase of the initial PCT level. The initial PCT> 2ng / ml, the mortality rate was 41.8 (23/55), and the initial PCT <2ng / ml, the mortality rate was 12.7%. Patients with septic shock have found that PCT decline within 30 hours is greater than 30% or its absolute value is less than 0.25ng / ml, indicating that the patient has a good prognosis; conversely, if the PCT level continues to rise or its decline is less than 30%, it indicates empirical antibacterial drugs. Incorrect treatment and poor prognosis.
 
 
 
  2.3 Application of PCT in special population infections
 
       Neonatal bacterial infection is one of the most important health problems. Due to the non-specific and high mortality of symptoms and signs after neonatal bacterial infection, early diagnosis and treatment are very important. Monsef and other studies found that blood PCT concentrations in newborns with sepsis, urinary tract infections, and meningitis significantly increased. Current research has confirmed the value of PCT in neonatal infections. Based on the results of these studies, the sensitivity and specificity of PCT They were 76.9% and 100%, respectively, and the positive and negative prediction rates were 100% and 78%, respectively. Kopyra and other 48 pregnant women with premature rupture of membranes found that using 5ng / ml as the near value of serum PCT levels in pregnant women (ROC: 0.647) has important value in judging whether there is a serious infection in the newborn. The higher the PCT level in pregnant women, the greater the likelihood of severe infections in the newborn.
 
       Chronic obstructive pulmonary disease is a common disease in the elderly. Studies have found that blood PCT concentration increases during the acute exacerbation of chronic obstructive pulmonary disease in the elderly, which can guide the use of antibacterial drugs and can reduce the number of antibacterial drug prescriptions and time.
 
 
3. Application of PCT in antimicrobial management
 
       Although the timely use of antibacterial drugs is the most effective measure to prevent the morbidity and mortality of bacterial infections, because it is difficult to distinguish virus and bacterial infections from the symptoms and signs, clinicians often use antibacterial drugs empirically and cause abuse. Prolonged exposure to antibacterial drugs will increase the emergence of drug-resistant strains and lead to drug toxic reactions. Short treatment periods or insufficient drug doses will increase infection recurrence. Therefore, it is essential to safely reduce the use of antimicrobials.
 
       In respiratory tract infections, antibiotics are strongly recommended for PCT> 0.5 μg / L, antimicrobials can be used for PCT> 0.25 μg / L, and antimicrobials should be discontinued for PCT <0.1 μg / L. It is recommended to review PCT within 2 to 3 days after using antibiotics Concentration, 6 to 24 hours after discontinuation of the antibacterial drug, if the patient's condition does not improve on its own, it is recommended to measure the PCT level again. Some studies recommend that patients with severe respiratory infections in the ICU have an initial PCT that is very high. In the course of antibacterial treatment, if the PCT decreases by 80 ~ 90%, consider discontinuing antibacterials.
 
       Thirteen randomized controlled studies of 4,395 patients evaluated the role of PCT in antimicrobial management. PCT-guided antimicrobials were reduced by 11% to 74% a, and the number of days in which antimicrobials were used decreased by 13% to 55%. Schuetz et al. Conducted a clinical study on 1002 patients with lower respiratory tract infections and divided the patients into PCT-guided and conventional treatment groups. Both groups were followed up for 18 months. No significant difference was found in clinical prognosis and readmission rates between the two groups, but The PCT treatment group had lower antibacterial use, hospital stay, and cost than the conventional treatment. A French multicenter study of 630 patients in ICU also supported the role of PCT in antimicrobial therapy. There was no significant difference in mortality, recurrent infections, and multiple organ failure in the PCT-guided treatment group compared with the conventional treatment group, but the PCT guidance The treatment time in the treatment group was significantly lower than that in the conventional treatment group.
 
 
4. Limitations of PCT
 
       PCT has certain limitations as a biological marker for the diagnosis of infection and sepsis. Some studies have shown that when the body is subjected to huge trauma (such as trauma, cardiogenic shock), there is a non-specific increase in blood PCT concentration even without bacterial infection, which is why clinically PCT identifies bacterial infections for medical systems. Some non-bacterial infectious systemic inflammation (heat shock, acute graft-versus-host response, and different types of immunotherapy), autoimmune diseases (such as Kawasaki disease or different types of vasculitis), and para-cancer syndromes are also accompanied by blood PCT Nonspecific increase in concentration. These will lead to false positives in the diagnosis of PCT. Therefore, for patients with different underlying diseases and sepsis, the reference range of PCT needs to be further clarified.
 
       Among biomarkers currently used for the diagnosis of sepsis and infection, PCT is by far the most widely used and clinically validated. Although PCT and other biomarkers have false positives and false negatives, the use of PCT for the differential diagnosis of infectious and non-infectious diseases can provide clinicians with effective and simple addition to clinical manifestations and imaging studies. The adjuvant method can avoid delaying treatment, and can also play an important role in reducing the amount of antibacterial drugs and shortening the course of anti-infectives. PCT, as an important indicator of systemic inflammatory response to bacterial infection, has strong specificity and long-lasting sensitivity. It is suitable for clinical use as the bacteria gradually decrease. However, affected by measurement methods, patient conditions, and treatment-related factors, PCT cannot replace medical history and physical examination. The diagnosis of bacterial infection still requires comprehensive judgment by combining clinical observation, patient history, physical examination and imaging examinations.



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