American Journal of Therapeutics 0, 1–7 (2015)
Procalcitonin as Biomarker of Infection: Implications for Evaluation and Treatment Pedro Falcão Gonçalves, MD,1* Luiz Menezes Falcão, MD, PhD,1,2 and Isabel Duque Pinheiro, MD1
Procalcitonin (PCT) is a quickly measurable marker, assumed to have high sensitivity and specificity for sepsis and infection. A literature search was conducted to evaluate PCT ability as a diagnostic and prognostic tool in infectious processes and its ability to monitor the antibiotic therapy. PCT level is increased in bacterial and fungal infections, but not in viral infections, with a significantly higher level in patients with bacteremia compared with uninfected patients (2.5 vs. 0.3 ng/mL; P , 0.0001). A PCT value of #0.1 ng/mL discards bacteremia and microbiological tests (negative predictive value of 96.3%), .0.1 ng/mL needs microbiological tests, and .1.0 ng/mL is indicative of bacteremia. Antibiotic treatment algorithms guided by PCT decreased the need for antibiotic treatment in approximately 50%. PCT is a promising test in clinical practice to decide the introduction of antibiotic therapy in addition to the existing tools, without neglecting the clinical assessment, with a significant decrease in costs. Keywords: procalcitonin, sepsis, biomarker, antibiotic, pneumonia
INTRODUCTION A rapid recognition and action in infectious context is associated with a significant reduction in mortality and improved prognosis.1 A judicious use of antibiotics allows reduction in the emergence of multiresistant bacteria and unnecessary adverse effects, with economic benefits.2 Blood cultures are currently the gold standard in the diagnosis of bacteremia. The delay to have results does not give timely information for the choice of the right antibiotic in suspected sepsis, particularly in the emergency department (ED).1 Despite the ability to identify
1
University Hospital Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal and 2University of Lisbon, Faculty of Medicine, Lisbon, Portugal. The authors have no conflicts of interest to declare. *Address for correspondence: Centro Hospitalar Lisboa Norte (CHLN) - Hospital Santa Maria, Pneumology Department, Av. Professor Egas Moniz, 1649-035 Lisboa, Portugal. E-mail: [email protected]
a specific agent and implementation of antibiotic susceptibility tests, on initial investigation, a septic patient’s blood cultures do not overlap the clinical judgment, physical examination, or laboratory parameters of fast access.1,3 According to the data of the Centro Hospitalar Lisboa Norte during the year 2013, in 32,029 requests for blood cultures, the proved positivity rate was 8.3% and the contamination rate 4%. Within the positive blood cultures, Escherichia coli was isolated in 606 cases (22%) and Staphylococcus aureus in 465 cases (16.9%) (Data provided by Professor Melo Cristino, Head of the Microbiology Laboratory of the Department of Clinical Pathology of Centro Hospitalar Lisboa Norte). A more sensitive and specific biomarker of infection, in addition to allow a reduction in antibiotic prescription, limiting the emergence of multiresistant bacteria, the duration of treatment, and adverse side effects allows to select patients most likely to have a positive microbiological examination.1,4 The objective of this article was to search the literature on procalcitonin (PCT) as a biomarker of sepsis and its ability in monitoring antibiotic therapy in respiratory infections and other infectious diseases. PCT is easily measurable and reproducible, of rapid access,
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Falca˜o Gonc¸alves et al
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and one of the biomarkers with the highest sensitivity and specificity for sepsis and infection.5,6
MATERIAL AND METHODS A PubMed search was performed in 2014 with the terms “procalcitonin,” “sepsis,” “infection,” “bacterial,” “fungal,” “viral,” “blood culture,” “sputum culture,” “CRP,” “C-reactive protein,” “WBC,” “platelet,” “biomarker,” “inflammation,” “systemic inflammatory response syndrome,” “antibiotic,” “therapeutics,” “intensive care unit,” “ICU,” “community-acquired pneumonia,” and “CAP,” limited to 5 years, English and Portuguese. A total of 1157 articles were obtained, which were then selected by the title and abstract. Articles that fulfill at least 1 of the following exclusion criteria were excluded: studies in animals, “in vitro,” target of only pediatric population, only surgical pathology, only nonrespiratory pathology, PCT not being the main subject of the study, articles without abstract, review articles, meta-analysis, case reports, comments, and letters to the author. Articles in which the main theme was PCT were preferentially included correlating it with sepsis, systemic inflammatory response syndrome (SIRS), respiratory disease, antibiotics, pathogens, diagnostic utility, therapeutic, prognostic, and with cost–benefit analysis. Of all, 173 articles were selected, from which 38 articles were included and their results analyzed.
DISCUSSION Procalcitonin Characteristics PCT is constitutively produced in thyroid C cells independently of hormonal activity and increases in response to hypercalcemia and gastrin. PCT is normally cleaved into calcitonin and N-terminal residue before being released into the bloodstream.1,6–8 It is practically not dosable in healthy individuals (,0.1 ng/mL).6,8 In the inflammatory response, the production and release into the bloodstream are increased in response to proinflammatory cytokines (interleukin-1b and tumor necrosis factor-a) and to overexpression of the gene CALC-1, which is produced by parenchymal cells, lung and intestinal neuroendocrine cells, and blood mononuclear cells.1,6,8–10 PCT levels are increased in response to acute stimulation in approximately 2–6 hours and have a half-life of 20–24 hours.9 PCT has been considered one of the most useful biomarkers of bacterial sepsis and a tool American Journal of Therapeutics (2015) 0(0)
with diagnostic and prognostic value in various clinical conditions.5 There is a high agreement (88.88%) between increased PCT with DNA amplification studies.2 PCT levels are not increased in autoimmune diseases and during viral infections because of the inhibitory action of interferon-g produced.5 PCT increases in cases of severe trauma, pancreatitis, liver or kidney disease, circulatory shock, and multiorgan dysfunction, although in concentrations lower than those of bacteremia, due to the interaction of activated monocytes to injured tissues.1 PCT is useful for the quick diagnosis of sepsis but has no ability to differentiate bacterial from fungal etiology.2 Other biomarkers PCT and C-reactive protein (CRP) are the most commonly used biomarkers in infectious context, with PCT demonstrated in several studies to be more promising as a predictor of bacteremia. Unlike CRP, PCT is not elevated during viral infections. An increase in PCT is useful in deciding to initiate antibiotic therapy if it is not feasible to differentiate a bacterial or viral etiology.6,9,11 PCT demonstrates superiority over the CRP in SIRS patients with leukocytosis and fever as a predictor of bacteremia, with a mean level significantly higher in patients with bacteremia compared with uninfected patients (2.5 vs. 0.3 ng/mL; P , 0.0001).12 PCT alone is the only biomarker with usefulness in predicting bacteremia, and its predictive value is not higher with the addition of other clinical or laboratory parameters.12 Regardless of the number of clinical criteria for SIRS used, there is no statistically significant correlation with the results of microbiological tests (body temperature, $38°C or #36°C; leukocytes, $12,000/mL or #4000/mL; heart rate, $90 beats/min; and systolic arterial pressure, ,90 mm Hg).3 Arai et al reported that an elevation in PCT alone cannot be used as a predictor of a positive culture test, but it is of higher value when associated with a decrease in platelet count. PCT and decreased platelets are the best predictors of bacteremia or fungemia together, whereas elevated CRP and leukocytosis correlates better with SIRS.13 Microbiological tests Microbiological tests are the gold standard in the detection of bacteremia because they allow to identify the etiological agent and to perform antibiotic susceptibility tests. However, the results take at least 12–48 hours with a high false-negative rate and without the www.americantherapeutics.com
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Procalcitonin as Biomarker of Infection
ability to safely exclude infectious foci, with a rate contamination of 4%.1–3,9,11,12 Patients with positive cultures have higher statistically significant serum concentration levels of some biomarkers. Tromp et al12 proposed a PCT cutoff of 0.1475 ng/mL as the value from which there is a higher correlation with positivity of blood cultures tests. A high level of PCT is highly predictive of obtaining a positive culture test.14,15 A cutoff of 1.35 ng/mL had a sensitivity of 100% and specificity of 63%, allowing a reduction in the need to realize blood cultures of 47.5%.14 Riedel et al3 did not found consistent results between PCT level and results of blood cultures in 10% of patients with bacteremia proposing previous treatment with antibiotics (4% of the patients) as explanation. There is a statistically significant difference between the value of PCT in patients with positive and negative culture tests (P 5 0.00007) and between those who have positive results for pathogens and contaminants (P 5 0.01) with no significant difference between patients with negative and positive results for contaminants microbiological tests (P 5 0.39).3 PCT may be useful to differentiate bacteremia with pathogens such as S. aureus and skin commensal agents, coagulase-negative Staphylococcus, distinguishing infection from contamination.16 A cutoff of 0.99 ng/mL, with a specificity of 98.1%, was proved to be the ideal level to differentiate infection from contamination.1 Jeong et al showed an average concentration of PCT in case of bacteremia caused by gram-positive bacteria, gram-negative bacteria, and fungemia of approximately 2.0, 5.0, and 2.1 ng/mL, respectively. PCT levels are statistically higher in case of gram-negative bacteremia when compared with gram-positive bacteremia and fungemia (P 5 0.0007 and 0.0190, respectively).1,17 PCT concentration is higher in bacteremia by Escherichia, Klebsiella, and Pseudomonas species compared with a moderate increase in fungemia caused by Candida species or bacteremia by Streptococcus and Staphylococcus species.17 Clinical conditions Patients with chronic kidney disease submitted to renal replacement procedures are more susceptible to infectious processes as infection in the vascular access and peritonitis. The diagnosis could be complicated by subtlety and nonspecificity of the clinical signs and interaction between uremic syndrome and biomarkers concentrations.9 www.americantherapeutics.com
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Urinary levels of PCT are decreased in severe chronic kidney disease, but the rate of plasma clearance correlates weakly with renal failure, and so the cutoff of PCT should be considered the same as for the general population (0.5 ng/mL), with an optimal value of 0.597 ng/mL with a sensitivity of 89.66% and specificity 87.5%. Different values were obtained for dialyzed and transplanted patients (1.78 and 0.22 ng/mL, respectively).9 Patients with autoimmune diseases like Still disease, ankylosing spondylitis, Behcet disease, microscopic polyangiitis, polyarteritis nodosa, rheumatoid arthritis, Sjogren syndrome, systemic lupus erythematosus, systemic sclerosis, and Wegener granulomatosis have higher levels of PCT in the context of infection when compared with exacerbation of the underlying disease (2.44 6 6.55 vs. 0.09 6 0.09 ng/mL; P , 0.001).18 The diagnosis of bacterial pneumonia could be complicated in patients with preexisting lung parenchymal disease as chronic obstructive pulmonary disease (COPD) exacerbation and viral syndromes because of clinical similarities.4 Increased concentration of PCT associates with increased mortality rate by all causes within 90 days in patients with acute heart failure (P 5 0.0024). 20.8% of these patients are treated with antibiotics, but only 5.1% end up being diagnosed with pneumonia.19 ED and intensive care unit SIRS versus sepsis SIRS represents a host reaction to infectious and noninfectious stimuli and is defined based on easily applicable but nonspecific criteria, such as body temperature, heart rate, respiratory rate or oxygen saturation, leukocytosis, leukopenia, or increase in immature neutrophils.12 In clinical practice, a rapid identification of septic patients is crucial because a delay in the introduction of antibiotic therapy correlates inversely with the outcome.2 However, fever, chills, and systolic arterial pressure below 90 mm Hg are associated with bacteremia, and the positive predictive value of SIRS criteria in its prediction is only 7%.12 Clinical signs of sepsis do not add the predictive value of obtaining a positive microbiological test, however, they should not be discarded. Biomarkers should be used as additional information, not as a substitute to clinical evaluation.3,12 ED context Riedel et al considered PCT as a useful marker to discard bacteremia in the context of ED. A PCT value of #0.1 ng/mL discards bacteremia and turns American Journal of Therapeutics (2015) 0(0)
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Falca˜o Gonc¸alves et al
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unnecessary microbiological tests, with a negative predictive value of 96.3%. A value greater than 0.1 ng/mL needs microbiological tests to confirm or discard infection, and a value greater than 1.0 ng/mL is indicative of bacteremia.3 The value of PCT on admission correlates with the severity and prognosis in pneumonia with the same precision of the CURB-65 score.6 Intensive care unit context A PCT value of .10 mg/L, with a 72.4% sensitivity and 87.5%specificity, as a logarithmic ratio of CRP/ PCT , 0.5, with a sensitivity of 65.5% and specificity of 84.4%, at admission in ED are indicative of a higher probability of an admission to intensive care unit (ICU).20 Robriquet et al21 considered it beneficial to associate PCT with CRP and body temperature and proposed a score (0.068 3 PCTadmission + 0.005 3 CRPadmission + 0.7 3 temperature) as being more discriminative and specific than all parameters isolated. A score of 28 corresponds to a sensitivity of 97% and a specificity of 87% in the diagnosis of infection in IC.21 Antibiotic therapy guided by PCT is associated with a decrease of the treatment time in septic patients on the ICU without an increase in complications, rate, or costs.22 An increase in PCT on first and fifth day of hospitalization correlated with a significantly increase in mortality.20 Antibiotics monitoring Antibiotic algorithms guided by PCT reduce antibiotics usage in approximately 50% of hospitalized patients with symptoms of lower respiratory infection.4 The optimal cutoff of PCT to predict bacteremia is 0.253 mg/L, and the rate of adverse events did not vary in a statistically significant way between patients treated according to the values of PCT and control groups.12,23 Several studies concluded that with a level of PCT .0.25 ng/mL, bacterial infection is probable and antibiotic therapy is recommended (Figure 1).4,6,24,25 The length of exposure to antibiotics in respiratory diseases (pneumonia, COPD exacerbation, and acute bronchitis) decrease by 34.8% when PCT concentration is considered (8.7–5.7 days).23 Respiratory disease Infectious Patients with pneumonia have statistically significant higher levels of PCT and CRP levels than those with asthma or COPD.4 Bafadhel et al4 showed that a cutoff of PCT of 0.25 ng/mL may decrease antibiotic American Journal of Therapeutics (2015) 0(0)
FIGURE 1. Algorithm antibiotic therapy recommended by several studies: PCT.
therapy from 57% to 4% in exacerbations of asthma, 76% to 7% in COPD exacerbations, and 100% to 73% in pneumonia without an increase in adverse effects or treatment failure. Adding PCT to the management of septic patients demonstrates a significant decrease in the length of hospitalization time in patients with pneumonia (from 5.3 6 4.6 days to 3.7 6 2.8 days through the determination of PCT at first and third day; P , 0.00006).6 Streptococcus pneumoniae and Legionella pneumophila are etiological agents of pneumonia with contrasting susceptibility to antibiotics. Pneumonia caused by L. pneumophila is associated with significantly lower PCT values on admission (6.76 6 1.74 mg/L) compared with that caused by S. pneumoniae (20.94 6 3.99 mg/L) (P , 0.01).20 A logarithmic ratio of CRP/PCT below 0.5 is indicative of infection with S. pneumoniae and above 1.25 correlates with a higher probability of L. pneumophila involvement, allowing to discriminate infection between these 2 bacteria (P , 0.001).20 PCT is the marker of highest discriminative power of bacteremia caused by S. pneumoniae. A cutoff of 17 ng/mL demonstrates a sensitivity and specificity of 87% and 67%, respectively.26 PCT may have a role in the differential diagnosis when pulmonary tuberculosis is considered.27 PCT typically is not increased in tuberculosis context except in cases of disseminated tuberculosis, with a value above 0.5 ng/mL, and associated with an increased mortality and poor prognosis.28 PCT also may help to discriminate bacterial coinfection in viral infections. Throughout the time of the seasonal influenza virus, concomitant bacterial infection presents in approximately 40% of patients with the influenza infection who require hospitalization.29,30 Pleural effusion It is defined as fluid in the pleural space above 10–20 mL, wherein bacterial pneumonia is the leading cause, immediately after heart failure.8 PCT in serum and pleural fluid is significantly increased in patients with parapneumonic pleural effusion in comparison to other etiologies, such as pulmonary tuberculosis or oncologic diseases.7,8,31,32 www.americantherapeutics.com
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Procalcitonin as Biomarker of Infection
There is a statistically significant correlation between serum and pleural fluid PCT (r 5 0.846; P , 0.001).7,31 In the reviewed studies, only Porcel et al32 failed to find a strong relationship between PCT values in pleural fluid and the etiology of the effusion. Ko et al8 and Wang et al31 concluded that the cutoff of PCT in pleural fluid used for the diagnosis of bacterial parapneumonic effusion should be 0.17–0.18 ng/mL. Oncology Tulek et al33 did not demonstrate significant difference in PCT values between patients with small cell lung carcinoma and healthy individuals, regardless of the characteristics and tumor stage. Febrile neutropenia is a common condition in oncologic patients that associates with higher susceptibility to infections and higher mortality rate, with significant increase in costs. Masago et al34 concluded that increased PCT in these patients is most frequently associated with an infectious cause and with poor outcome. Lung transplantation Patients undergoing lung transplantation, major surgery, transfusion support, and immunosuppressive treatment tend to have a history of recurrent infections, complications, hospitalization in ICU, and long length of hospitalizations, therefore constituting a high-risk group.5 Early recognition and treatment of infectious complications minimizes severe postoperatively complications. Increased levels of PCT allow differentiate an infectious process, frequently fungal infection from acute rejection. A PCT value exceeding 1.1 ng/mL has a positive predictive value of 55.3% and negative of 73.1%.35 In infected patients, PCT values are significantly higher from the first postoperative day compared with uninfected or acute rejection.5 A cutoff of PCT 8.18 ng/mL at day 2 is highly predictive of infection, with a sensitivity and specificity of 80% and 100%, respectively.5 Cost/Benefit Antibiotic therapy guided by PCT reduces hospitalization length, microbiological tests, and antibiotics usage, conditioning a significant decrease in costs.6,36 Inappropriate use of antibiotics is associated with the emergence of multiresistant strains, adverse side effects, and prolonged hospital stay.4 Wilke et al37 found a reduction in costs of approximately 136.2€ in hospitalized patients and of 886.4€ in those treated at ICU with a PCT-guided antibiotic www.americantherapeutics.com
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therapy, corresponding to a reduction in costs by approximately 30%.38 The PCT assay has a price 80% lower than blood cultures, and a value of PCT exceeding 0.1 ng/mL has proven the ability to reduce the number of cultures in 12.6%, identifying 99% of positive cultures.39
CONCLUSIONS PCT levels are increased in bacterial and fungal infective processes, and a level above 1.35 ng/mL has 100% sensitivity in the prediction of positive blood cultures, the gold standard in bacteremia detection. Because PCT is quickly assessed, it may help in the decision to initiate antibiotic therapy and realize blood culture, optimizing their results by selecting patients who will benefit most. Serum PCT is also useful in making decision to initiate antibiotherapy when the clinical assessment does not allow discriminate bacterial or viral etiology. PCT-guided antibiotherapy demonstrates efficacy in reducing the days of hospitalization and in the reduction of antibiotics usage up to 50%. PCT seems promising, although there is a lack of the precise definition of the ideal value from which it is possible to rule out infection with confidence or the value from which it is imperative to introduce antibiotic. It can be a tool of high utility in medical daily practice in addition to other existing tools, without neglecting the clinical and medical assessments.
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6 6. Lindstrom S, Wong EK. Procalcitonin, a valuable biomarker assisting clinical decision making in the management of community-acquired pneumonia. Intern Med J. 2014;44:390–397. 7. Lee SH, Lee EJ, Min KH, et al. Procalcitonin as a diagnostic marker in differentiating parapneumonic effusion from tuberculous pleurisy or malignant effusion. Clin Biochem. 2013;46:1484–1488. 8. Ko YC, Wu WP, Hsu CS, et al. Serum and pleural fluid procalcitonin in predicting bacterial infection in patients with parapneumonic effusion. J Korean Med Sci. 2009;24: 398–402. 9. Dumea R, Siriopol D, Hogas S, et al. Procalcitonin: diagnostic value in systemic infections in chronic kidney disease or renal transplant patients. Int Urol Nephrol. 2014; 46:461–468. 10. Naffaa M, Makhoul BF, Tobia A, et al. Procalcitonin and interleukin 6 for predicting blood culture positivity in sepsis. Am J Emerg Med. 2014;32:448–451. 11. Ratzinger F, Schuardt M, Eichbichler K, et al. Utility of sepsis biomarkers and the infection probability score to discriminate sepsis and systemic inflammatory response syndrome in standard care patients. PLoS One. 2013;8: e82946. 12. Tromp M, Lansdorp B, Bleeker-Rovers CP, et al. Serial and panel analyses of biomarkers do not improve the prediction of bacteremia compared to one procalcitonin measurement. J Infect. 2012;65:292–301. 13. Arai T, Kumasaka K, Nagata K, et al. Prediction of blood culture results by measuring procalcitonin levels and other inflammatory biomarkers. Am J Emerg Med. 2014; 32:330–333. 14. Cortegiani A, Russotto V, Montalto F, et al. Procalcitonin as a marker of Candida species detection by blood culture and polymerase chain reaction in septic patients. BMC Anesthesiol. 2014;14:9. 15. Park JH, Wee JH, Choi SP, et al. The value of procalcitonin level in community-acquired pneumonia in the ED. Am J Emerg Med. 2012;30:1248–1254. 16. Shomali W, Hachem R, Chaftari AM, et al. Can procalcitonin differentiate Staphylococcus aureus from coagulase-negative staphylococci in clustered grampositive bacteremia? Diagn Microbiol Infect Dis. 2013;76: 158–161. 17. Brodska H, Malickova K, Adamkova V, et al. Significantly higher procalcitonin levels could differentiate Gram-negative sepsis from Gram-positive and fungal sepsis. Clin Exp Med. 2013;13:165–170. 18. Joo K, Park W, Lim MJ, et al. Serum procalcitonin for differentiating bacterial infection from disease flares in patients with autoimmune diseases. J Korean Med Sci. 2011;26:1147–1151. 19. Maisel A, Neath SX, Landsberg J, et al. Use of procalcitonin for the diagnosis of pneumonia in patients presenting with a chief complaint of dyspnoea: results from the BACH (Biomarkers in Acute Heart Failure) trial. Eur J Heart Fail. 2012;14:278–286. American Journal of Therapeutics (2015) 0(0)
Falca˜o Gonc¸alves et al 20. Bellmann-Weiler R, Ausserwinkler M, Kurz K, et al. Clinical potential of c-reactive protein and procalcitonin serum concentrations to guide differential diagnosis and clinical management of pneumococcal and Legionella pneumonia. J Clin Microbiol. 2010;48:1915–1917. 21. Robriquet L, Sejourne C, Kipnis E, et al. A composite score combining procalcitonin, C-reactive protein and temperature has a high positive predictive value for the diagnosis of intensive care-acquired infections. BMC Infect Dis. 2013;13:159. 22. Hohn A, Schroeder S, Gehrt A, et al. Procalcitoninguided algorithm to reduce length of antibiotic therapy in patients with severe sepsis and septic shock. BMC Infect Dis. 2013;13:158. 23. Schuetz P, Christ-Crain M, Thomann R, 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: 1059–1066. 24. Dusemund F, Bucher B, Meyer S, et al. Influence of procalcitonin on decision to start antibiotic treatment in patients with a lower respiratory tract infection: insight from the observational multicentric ProREAL surveillance. Eur J Clin Microbiol Infect Dis. 2013;32:51–60. 25. Albrich WC, Dusemund F, Bucher B, et al. Effectiveness and safety of procalcitonin-guided antibiotic therapy in lower respiratory tract infections in “real life”: an international, multicenter poststudy survey (ProREAL). Arch Intern Med. 2012;172:715–722. 26. Pereira JM, Teixeira-Pinto A, Basilio C, et al. Can we predict pneumococcal bacteremia in patients with severe community-acquired pneumonia? J Crit Care. 2013;28: 970–974. 27. Kang YA, Kwon SY, Yoon HI, et al. Role of C-reactive protein and procalcitonin in differentiation of tuberculosis from bacterial community acquired pneumonia. Korean J Intern Med. 2009;24:337–342. 28. Ugajin M, Miwa S, Shirai M, et al. Usefulness of serum procalcitonin levels in pulmonary tuberculosis. Eur Respir J. 2011;37:371–375. 29. Falsey AR, Becker KL, Swinburne AJ, et al. Bacterial complications of respiratory tract viral illness: a comprehensive evaluation. J Infect Dis. 2013;208:432–441. 30. Cuquemelle E, Soulis F, Villers D, et al. Can procalcitonin help identify associated bacterial infection in patients with severe influenza pneumonia? A multicentre study. Intensive Care Med. 2011;37:796–800. 31. Wang CY, Hsiao YC, Jerng JS, et al. Diagnostic value of procalcitonin in pleural effusions. Eur J Clin Microbiol Infect Dis. 2011;30:313–318. 32. Porcel JM, Vives M, Cao G, et al. Biomarkers of infection for the differential diagnosis of pleural effusions. Eur Respir J. 2009;34:1383–1389. 33. Tulek B, Koylu H, Kanat F, et al. Serum C-reactive protein and procalcitonin levels in non-small cell lung cancer patients. Contemp Oncol (Pozn). 2013;17:68–72. www.americantherapeutics.com
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Procalcitonin as Biomarker of Infection 34. Masago K, Fukuhara A, Ito Y, et al. Infectious background of febrile advanced lung cancer patients who received chemotherapy. Oncol Lett. 2010;1:849–853. 35. Zeglen S, Siola M, Wozniak-Grygiel E, et al. Procalcitonin serum concentration in lung transplant recipients during mold colonization or infection. Transplant Proc. 2011;43:3089–3091. 36. Saeed K, Dryden M, Bourne S, et al. Reduction in antibiotic use through procalcitonin testing in patients in the medical admission unit or intensive care unit with suspicion of infection. J Hosp Infect. 2011;78: 289–292.
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7 37. Wilke MH, Grube RF, Bodmann KF. The use of a standardized PCT-algorithm reduces costs in intensive care in septic patients—a DRG-based simulation model. Eur J Med Res. 2011;16:543–548. 38. Deliberato RO, Marra AR, Sanches PR, et al. Clinical and economic impact of procalcitonin to shorten antimicrobial therapy in septic patients with proven bacterial infection in an intensive care setting. Diagn Microbiol Infect Dis. 2013;76:266–271. 39. Muller F, Christ-Crain M, Bregenzer T, et al. Procalcitonin levels predict bacteremia in patients with community-acquired pneumonia: a prospective cohort trial. Chest. 2010;138:121–129.
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Procalcitonin as Biomarker of Infection: Implications for Evaluation and Treatment Pedro Falcão Gonçalves, MD,1* Luiz Menezes Falcão, MD, PhD,1,2 and Isabel Duque Pinheiro, MD1
Procalcitonin (PCT) is a quickly measurable marker, assumed to have high sensitivity and specificity for sepsis and infection. A literature search was conducted to evaluate PCT ability as a diagnostic and prognostic tool in infectious processes and its ability to monitor the antibiotic therapy. PCT level is increased in bacterial and fungal infections, but not in viral infections, with a significantly higher level in patients with bacteremia compared with uninfected patients (2.5 vs. 0.3 ng/mL; P , 0.0001). A PCT value of #0.1 ng/mL discards bacteremia and microbiological tests (negative predictive value of 96.3%), .0.1 ng/mL needs microbiological tests, and .1.0 ng/mL is indicative of bacteremia. Antibiotic treatment algorithms guided by PCT decreased the need for antibiotic treatment in approximately 50%. PCT is a promising test in clinical practice to decide the introduction of antibiotic therapy in addition to the existing tools, without neglecting the clinical assessment, with a significant decrease in costs. Keywords: procalcitonin, sepsis, biomarker, antibiotic, pneumonia
INTRODUCTION A rapid recognition and action in infectious context is associated with a significant reduction in mortality and improved prognosis.1 A judicious use of antibiotics allows reduction in the emergence of multiresistant bacteria and unnecessary adverse effects, with economic benefits.2 Blood cultures are currently the gold standard in the diagnosis of bacteremia. The delay to have results does not give timely information for the choice of the right antibiotic in suspected sepsis, particularly in the emergency department (ED).1 Despite the ability to identify
1
University Hospital Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal and 2University of Lisbon, Faculty of Medicine, Lisbon, Portugal. The authors have no conflicts of interest to declare. *Address for correspondence: Centro Hospitalar Lisboa Norte (CHLN) - Hospital Santa Maria, Pneumology Department, Av. Professor Egas Moniz, 1649-035 Lisboa, Portugal. E-mail: [email protected]
a specific agent and implementation of antibiotic susceptibility tests, on initial investigation, a septic patient’s blood cultures do not overlap the clinical judgment, physical examination, or laboratory parameters of fast access.1,3 According to the data of the Centro Hospitalar Lisboa Norte during the year 2013, in 32,029 requests for blood cultures, the proved positivity rate was 8.3% and the contamination rate 4%. Within the positive blood cultures, Escherichia coli was isolated in 606 cases (22%) and Staphylococcus aureus in 465 cases (16.9%) (Data provided by Professor Melo Cristino, Head of the Microbiology Laboratory of the Department of Clinical Pathology of Centro Hospitalar Lisboa Norte). A more sensitive and specific biomarker of infection, in addition to allow a reduction in antibiotic prescription, limiting the emergence of multiresistant bacteria, the duration of treatment, and adverse side effects allows to select patients most likely to have a positive microbiological examination.1,4 The objective of this article was to search the literature on procalcitonin (PCT) as a biomarker of sepsis and its ability in monitoring antibiotic therapy in respiratory infections and other infectious diseases. PCT is easily measurable and reproducible, of rapid access,
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www.americantherapeutics.com
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Falca˜o Gonc¸alves et al
2
and one of the biomarkers with the highest sensitivity and specificity for sepsis and infection.5,6
MATERIAL AND METHODS A PubMed search was performed in 2014 with the terms “procalcitonin,” “sepsis,” “infection,” “bacterial,” “fungal,” “viral,” “blood culture,” “sputum culture,” “CRP,” “C-reactive protein,” “WBC,” “platelet,” “biomarker,” “inflammation,” “systemic inflammatory response syndrome,” “antibiotic,” “therapeutics,” “intensive care unit,” “ICU,” “community-acquired pneumonia,” and “CAP,” limited to 5 years, English and Portuguese. A total of 1157 articles were obtained, which were then selected by the title and abstract. Articles that fulfill at least 1 of the following exclusion criteria were excluded: studies in animals, “in vitro,” target of only pediatric population, only surgical pathology, only nonrespiratory pathology, PCT not being the main subject of the study, articles without abstract, review articles, meta-analysis, case reports, comments, and letters to the author. Articles in which the main theme was PCT were preferentially included correlating it with sepsis, systemic inflammatory response syndrome (SIRS), respiratory disease, antibiotics, pathogens, diagnostic utility, therapeutic, prognostic, and with cost–benefit analysis. Of all, 173 articles were selected, from which 38 articles were included and their results analyzed.
DISCUSSION Procalcitonin Characteristics PCT is constitutively produced in thyroid C cells independently of hormonal activity and increases in response to hypercalcemia and gastrin. PCT is normally cleaved into calcitonin and N-terminal residue before being released into the bloodstream.1,6–8 It is practically not dosable in healthy individuals (,0.1 ng/mL).6,8 In the inflammatory response, the production and release into the bloodstream are increased in response to proinflammatory cytokines (interleukin-1b and tumor necrosis factor-a) and to overexpression of the gene CALC-1, which is produced by parenchymal cells, lung and intestinal neuroendocrine cells, and blood mononuclear cells.1,6,8–10 PCT levels are increased in response to acute stimulation in approximately 2–6 hours and have a half-life of 20–24 hours.9 PCT has been considered one of the most useful biomarkers of bacterial sepsis and a tool American Journal of Therapeutics (2015) 0(0)
with diagnostic and prognostic value in various clinical conditions.5 There is a high agreement (88.88%) between increased PCT with DNA amplification studies.2 PCT levels are not increased in autoimmune diseases and during viral infections because of the inhibitory action of interferon-g produced.5 PCT increases in cases of severe trauma, pancreatitis, liver or kidney disease, circulatory shock, and multiorgan dysfunction, although in concentrations lower than those of bacteremia, due to the interaction of activated monocytes to injured tissues.1 PCT is useful for the quick diagnosis of sepsis but has no ability to differentiate bacterial from fungal etiology.2 Other biomarkers PCT and C-reactive protein (CRP) are the most commonly used biomarkers in infectious context, with PCT demonstrated in several studies to be more promising as a predictor of bacteremia. Unlike CRP, PCT is not elevated during viral infections. An increase in PCT is useful in deciding to initiate antibiotic therapy if it is not feasible to differentiate a bacterial or viral etiology.6,9,11 PCT demonstrates superiority over the CRP in SIRS patients with leukocytosis and fever as a predictor of bacteremia, with a mean level significantly higher in patients with bacteremia compared with uninfected patients (2.5 vs. 0.3 ng/mL; P , 0.0001).12 PCT alone is the only biomarker with usefulness in predicting bacteremia, and its predictive value is not higher with the addition of other clinical or laboratory parameters.12 Regardless of the number of clinical criteria for SIRS used, there is no statistically significant correlation with the results of microbiological tests (body temperature, $38°C or #36°C; leukocytes, $12,000/mL or #4000/mL; heart rate, $90 beats/min; and systolic arterial pressure, ,90 mm Hg).3 Arai et al reported that an elevation in PCT alone cannot be used as a predictor of a positive culture test, but it is of higher value when associated with a decrease in platelet count. PCT and decreased platelets are the best predictors of bacteremia or fungemia together, whereas elevated CRP and leukocytosis correlates better with SIRS.13 Microbiological tests Microbiological tests are the gold standard in the detection of bacteremia because they allow to identify the etiological agent and to perform antibiotic susceptibility tests. However, the results take at least 12–48 hours with a high false-negative rate and without the www.americantherapeutics.com
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Procalcitonin as Biomarker of Infection
ability to safely exclude infectious foci, with a rate contamination of 4%.1–3,9,11,12 Patients with positive cultures have higher statistically significant serum concentration levels of some biomarkers. Tromp et al12 proposed a PCT cutoff of 0.1475 ng/mL as the value from which there is a higher correlation with positivity of blood cultures tests. A high level of PCT is highly predictive of obtaining a positive culture test.14,15 A cutoff of 1.35 ng/mL had a sensitivity of 100% and specificity of 63%, allowing a reduction in the need to realize blood cultures of 47.5%.14 Riedel et al3 did not found consistent results between PCT level and results of blood cultures in 10% of patients with bacteremia proposing previous treatment with antibiotics (4% of the patients) as explanation. There is a statistically significant difference between the value of PCT in patients with positive and negative culture tests (P 5 0.00007) and between those who have positive results for pathogens and contaminants (P 5 0.01) with no significant difference between patients with negative and positive results for contaminants microbiological tests (P 5 0.39).3 PCT may be useful to differentiate bacteremia with pathogens such as S. aureus and skin commensal agents, coagulase-negative Staphylococcus, distinguishing infection from contamination.16 A cutoff of 0.99 ng/mL, with a specificity of 98.1%, was proved to be the ideal level to differentiate infection from contamination.1 Jeong et al showed an average concentration of PCT in case of bacteremia caused by gram-positive bacteria, gram-negative bacteria, and fungemia of approximately 2.0, 5.0, and 2.1 ng/mL, respectively. PCT levels are statistically higher in case of gram-negative bacteremia when compared with gram-positive bacteremia and fungemia (P 5 0.0007 and 0.0190, respectively).1,17 PCT concentration is higher in bacteremia by Escherichia, Klebsiella, and Pseudomonas species compared with a moderate increase in fungemia caused by Candida species or bacteremia by Streptococcus and Staphylococcus species.17 Clinical conditions Patients with chronic kidney disease submitted to renal replacement procedures are more susceptible to infectious processes as infection in the vascular access and peritonitis. The diagnosis could be complicated by subtlety and nonspecificity of the clinical signs and interaction between uremic syndrome and biomarkers concentrations.9 www.americantherapeutics.com
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Urinary levels of PCT are decreased in severe chronic kidney disease, but the rate of plasma clearance correlates weakly with renal failure, and so the cutoff of PCT should be considered the same as for the general population (0.5 ng/mL), with an optimal value of 0.597 ng/mL with a sensitivity of 89.66% and specificity 87.5%. Different values were obtained for dialyzed and transplanted patients (1.78 and 0.22 ng/mL, respectively).9 Patients with autoimmune diseases like Still disease, ankylosing spondylitis, Behcet disease, microscopic polyangiitis, polyarteritis nodosa, rheumatoid arthritis, Sjogren syndrome, systemic lupus erythematosus, systemic sclerosis, and Wegener granulomatosis have higher levels of PCT in the context of infection when compared with exacerbation of the underlying disease (2.44 6 6.55 vs. 0.09 6 0.09 ng/mL; P , 0.001).18 The diagnosis of bacterial pneumonia could be complicated in patients with preexisting lung parenchymal disease as chronic obstructive pulmonary disease (COPD) exacerbation and viral syndromes because of clinical similarities.4 Increased concentration of PCT associates with increased mortality rate by all causes within 90 days in patients with acute heart failure (P 5 0.0024). 20.8% of these patients are treated with antibiotics, but only 5.1% end up being diagnosed with pneumonia.19 ED and intensive care unit SIRS versus sepsis SIRS represents a host reaction to infectious and noninfectious stimuli and is defined based on easily applicable but nonspecific criteria, such as body temperature, heart rate, respiratory rate or oxygen saturation, leukocytosis, leukopenia, or increase in immature neutrophils.12 In clinical practice, a rapid identification of septic patients is crucial because a delay in the introduction of antibiotic therapy correlates inversely with the outcome.2 However, fever, chills, and systolic arterial pressure below 90 mm Hg are associated with bacteremia, and the positive predictive value of SIRS criteria in its prediction is only 7%.12 Clinical signs of sepsis do not add the predictive value of obtaining a positive microbiological test, however, they should not be discarded. Biomarkers should be used as additional information, not as a substitute to clinical evaluation.3,12 ED context Riedel et al considered PCT as a useful marker to discard bacteremia in the context of ED. A PCT value of #0.1 ng/mL discards bacteremia and turns American Journal of Therapeutics (2015) 0(0)
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Falca˜o Gonc¸alves et al
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unnecessary microbiological tests, with a negative predictive value of 96.3%. A value greater than 0.1 ng/mL needs microbiological tests to confirm or discard infection, and a value greater than 1.0 ng/mL is indicative of bacteremia.3 The value of PCT on admission correlates with the severity and prognosis in pneumonia with the same precision of the CURB-65 score.6 Intensive care unit context A PCT value of .10 mg/L, with a 72.4% sensitivity and 87.5%specificity, as a logarithmic ratio of CRP/ PCT , 0.5, with a sensitivity of 65.5% and specificity of 84.4%, at admission in ED are indicative of a higher probability of an admission to intensive care unit (ICU).20 Robriquet et al21 considered it beneficial to associate PCT with CRP and body temperature and proposed a score (0.068 3 PCTadmission + 0.005 3 CRPadmission + 0.7 3 temperature) as being more discriminative and specific than all parameters isolated. A score of 28 corresponds to a sensitivity of 97% and a specificity of 87% in the diagnosis of infection in IC.21 Antibiotic therapy guided by PCT is associated with a decrease of the treatment time in septic patients on the ICU without an increase in complications, rate, or costs.22 An increase in PCT on first and fifth day of hospitalization correlated with a significantly increase in mortality.20 Antibiotics monitoring Antibiotic algorithms guided by PCT reduce antibiotics usage in approximately 50% of hospitalized patients with symptoms of lower respiratory infection.4 The optimal cutoff of PCT to predict bacteremia is 0.253 mg/L, and the rate of adverse events did not vary in a statistically significant way between patients treated according to the values of PCT and control groups.12,23 Several studies concluded that with a level of PCT .0.25 ng/mL, bacterial infection is probable and antibiotic therapy is recommended (Figure 1).4,6,24,25 The length of exposure to antibiotics in respiratory diseases (pneumonia, COPD exacerbation, and acute bronchitis) decrease by 34.8% when PCT concentration is considered (8.7–5.7 days).23 Respiratory disease Infectious Patients with pneumonia have statistically significant higher levels of PCT and CRP levels than those with asthma or COPD.4 Bafadhel et al4 showed that a cutoff of PCT of 0.25 ng/mL may decrease antibiotic American Journal of Therapeutics (2015) 0(0)
FIGURE 1. Algorithm antibiotic therapy recommended by several studies: PCT.
therapy from 57% to 4% in exacerbations of asthma, 76% to 7% in COPD exacerbations, and 100% to 73% in pneumonia without an increase in adverse effects or treatment failure. Adding PCT to the management of septic patients demonstrates a significant decrease in the length of hospitalization time in patients with pneumonia (from 5.3 6 4.6 days to 3.7 6 2.8 days through the determination of PCT at first and third day; P , 0.00006).6 Streptococcus pneumoniae and Legionella pneumophila are etiological agents of pneumonia with contrasting susceptibility to antibiotics. Pneumonia caused by L. pneumophila is associated with significantly lower PCT values on admission (6.76 6 1.74 mg/L) compared with that caused by S. pneumoniae (20.94 6 3.99 mg/L) (P , 0.01).20 A logarithmic ratio of CRP/PCT below 0.5 is indicative of infection with S. pneumoniae and above 1.25 correlates with a higher probability of L. pneumophila involvement, allowing to discriminate infection between these 2 bacteria (P , 0.001).20 PCT is the marker of highest discriminative power of bacteremia caused by S. pneumoniae. A cutoff of 17 ng/mL demonstrates a sensitivity and specificity of 87% and 67%, respectively.26 PCT may have a role in the differential diagnosis when pulmonary tuberculosis is considered.27 PCT typically is not increased in tuberculosis context except in cases of disseminated tuberculosis, with a value above 0.5 ng/mL, and associated with an increased mortality and poor prognosis.28 PCT also may help to discriminate bacterial coinfection in viral infections. Throughout the time of the seasonal influenza virus, concomitant bacterial infection presents in approximately 40% of patients with the influenza infection who require hospitalization.29,30 Pleural effusion It is defined as fluid in the pleural space above 10–20 mL, wherein bacterial pneumonia is the leading cause, immediately after heart failure.8 PCT in serum and pleural fluid is significantly increased in patients with parapneumonic pleural effusion in comparison to other etiologies, such as pulmonary tuberculosis or oncologic diseases.7,8,31,32 www.americantherapeutics.com
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Procalcitonin as Biomarker of Infection
There is a statistically significant correlation between serum and pleural fluid PCT (r 5 0.846; P , 0.001).7,31 In the reviewed studies, only Porcel et al32 failed to find a strong relationship between PCT values in pleural fluid and the etiology of the effusion. Ko et al8 and Wang et al31 concluded that the cutoff of PCT in pleural fluid used for the diagnosis of bacterial parapneumonic effusion should be 0.17–0.18 ng/mL. Oncology Tulek et al33 did not demonstrate significant difference in PCT values between patients with small cell lung carcinoma and healthy individuals, regardless of the characteristics and tumor stage. Febrile neutropenia is a common condition in oncologic patients that associates with higher susceptibility to infections and higher mortality rate, with significant increase in costs. Masago et al34 concluded that increased PCT in these patients is most frequently associated with an infectious cause and with poor outcome. Lung transplantation Patients undergoing lung transplantation, major surgery, transfusion support, and immunosuppressive treatment tend to have a history of recurrent infections, complications, hospitalization in ICU, and long length of hospitalizations, therefore constituting a high-risk group.5 Early recognition and treatment of infectious complications minimizes severe postoperatively complications. Increased levels of PCT allow differentiate an infectious process, frequently fungal infection from acute rejection. A PCT value exceeding 1.1 ng/mL has a positive predictive value of 55.3% and negative of 73.1%.35 In infected patients, PCT values are significantly higher from the first postoperative day compared with uninfected or acute rejection.5 A cutoff of PCT 8.18 ng/mL at day 2 is highly predictive of infection, with a sensitivity and specificity of 80% and 100%, respectively.5 Cost/Benefit Antibiotic therapy guided by PCT reduces hospitalization length, microbiological tests, and antibiotics usage, conditioning a significant decrease in costs.6,36 Inappropriate use of antibiotics is associated with the emergence of multiresistant strains, adverse side effects, and prolonged hospital stay.4 Wilke et al37 found a reduction in costs of approximately 136.2€ in hospitalized patients and of 886.4€ in those treated at ICU with a PCT-guided antibiotic www.americantherapeutics.com
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therapy, corresponding to a reduction in costs by approximately 30%.38 The PCT assay has a price 80% lower than blood cultures, and a value of PCT exceeding 0.1 ng/mL has proven the ability to reduce the number of cultures in 12.6%, identifying 99% of positive cultures.39
CONCLUSIONS PCT levels are increased in bacterial and fungal infective processes, and a level above 1.35 ng/mL has 100% sensitivity in the prediction of positive blood cultures, the gold standard in bacteremia detection. Because PCT is quickly assessed, it may help in the decision to initiate antibiotic therapy and realize blood culture, optimizing their results by selecting patients who will benefit most. Serum PCT is also useful in making decision to initiate antibiotherapy when the clinical assessment does not allow discriminate bacterial or viral etiology. PCT-guided antibiotherapy demonstrates efficacy in reducing the days of hospitalization and in the reduction of antibiotics usage up to 50%. PCT seems promising, although there is a lack of the precise definition of the ideal value from which it is possible to rule out infection with confidence or the value from which it is imperative to introduce antibiotic. It can be a tool of high utility in medical daily practice in addition to other existing tools, without neglecting the clinical and medical assessments.
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