Serum Procalcitonin Assay for Investigations and Clinical Management of Neonatal Sepsis: A Review

Abstract

The diagnosis and management of sepsis are very challenging especially in pediatric cases where the clinical criteria for the diagnosis overlap with nonbacterial etiologies of systemic inflammation. Initiation of antibiotic therapy for sepsis is necessary although the diagnostic evaluation is ongoing because delayed antibiotic therapy is associated with increased mortality. A highly sensitive and specific biomarker, such as procalcitonin, that improves decisions about initiating, discontinuing, or changing antibiotic therapy could have substantial clinical benefits of managing neonatal sepsis. This is a review of relevant published articles using extensive literature search made through google, PubMed/Medline, NLM, Scopus, and HINARI on randomized controlled and observational studies of procalcitonin-based diagnosis and antimicrobial-guided therapy especially in neonatal sepsis. Our systematic review found that procalcitonin-guided diagnosis, need for antibiotics, treatment evaluation give better outcome and prognosis than any other biomarker that were hitherto utilized in neonatal sepsis. Now that sepsis especially in children has become a frequent medical emergency, there is a need to extensively evaluate and possibly consider serum procalcitonin as an adjunctive marker to be combined with other commonly used approaches such as blood culture, full blood count, and differentials in order to enhance prompt and rational clinical management before blood culture results are available.

Keywords

procalcitonin - sepsis - biomarker - diagnosis - neonates

• References

• 1 Chacko B, Sohi I. Early onset neonatal sepsis. Indian J Pediatr 2005; 72 (1) 23-26
• 2 Antia-Obong OE, Utsalo SJ, Udo JJ, Udo KT. Neonatal septicaemia in Calabar, Nigeria. Cent Afr J Med 1992; 38 (4) 161-165
• 3 Omene JA. Neonatal septicaemia in Benin City, Nigeria. A review of 74 cases. Trop Geogr Med 1979; 31 (1) 35-39
• 4 Klein JO, Marcy MS, Bacterial Sepsis and Meningitis. In Infectious Diseases of the Fetus and the Newborn. Edited by Remington JJ, Klein JO. Philadelphia: WB Sauders Co; 1995: 835-890
• 5 Sankar MJ, Agarwal R, Deorari AK, Paul VK. Sepsis in the newborn. Indian J Pediatr 2008; 75 (3) 261-266
• 6 Al-Zwaini EJ. Neonatal septicaemia in the neonatal care unit, Al-Anbar governorate, Iraq. East Mediterr Health J 2002; 8 (4-5) 509-514
• 7 Amiebenomo CS, Yakubu AM, Bello CSS, Ewa B. Neonatal Septicaemia in Zaria. Niger Med J 1988; 18: 349-351
• 8 Edwards MS. Postnatal Bacterial Infections. In Neonatal Perinatal Medicine: Diseasesm of the Fetus and Infants. 7th edition. Edited by Fanaroff AA, Martin RJ. St Louis, MO: CV Mosby; 2002: 706-726
• 9 Placzek MM, Whitelaw A. Early and late neonatal septicaemia. Arch Dis Child 1983; 58 (9) 728-731
• 10 Motara F, Ballot DE, Perovic O. Epidemiology of neonatal sepsis at Johannesburg Hospital. Southern Afr. J Epidemiol Infect 2005; 20 (3) 90-93
• 11 Whitney CG, Farley MM, Hadler J , et al; Active Bacterial Core Surveillance Program of the Emerging Infections Program Network. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med 2000; 343 (26) 1917-1924
• 12 Roberts RR, Hota B, Ahmad I , et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis 2009; 49 (8) 1175-1184
• 13 Ohl CA, Luther VP. Antimicrobial stewardship for inpatient facilities. J Hosp Med 2011; 6 (Suppl. 01) S4-S15
• 14 Gogos CA, Drosou E, Bassaris HP, Skoutelis A. Pro- versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis 2000; 181 (1) 176-180
• 15 Christ-Crain M, Müller B. Biomarkers in respiratory tract infections: diagnostic guides to antibiotic prescription, prognostic markers and mediators. Eur Respir J 2007; 30 (3) 556-573
• 16 Christ-Crain M, Müller B. Procalcitonin in bacterial infections—hype, hope, more or less?. Swiss Med Wkly 2005; 135 (31-32) 451-460
• 17 Linscheid P, Seboek D, Zulewski H, Keller U, Müller B. Autocrine/paracrine role of inflammation-mediated calcitonin gene-related peptide and adrenomedullin expression in human adipose tissue. Endocrinology 2005; 146 (6) 2699-2708
• 18 Becker KL, Nylén ES, White JC, Müller B, Snider Jr RH. Clinical review 167: Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab 2004; 89 (4) 1512-1525
• 19 Schuetz P, Mueller B, Trampuz A. Serum procalcitonin for discrimination of blood contamination from bloodstream infection due to coagulase-negative staphylococci. Infection 2007; 35 (5) 352-355
• 20 Schuetz P, Suter-Widmer I, Chaudri A, Christ-Crain M, Zimmerli W, Mueller B ; Procalcitonin-Guided Antibiotic Therapy and Hospitalisation in Patients with Lower Respiratory Tract Infections (ProHOSP) Study Group. Prognostic value of procalcitonin in community-acquired pneumonia. Eur Respir J 2011; 37 (2) 384-392
• 21 Jensen JU, Heslet L, Jensen TH, Espersen K, Steffensen P, Tvede M. Procalcitonin increase in early identification of critically ill patients at high risk of mortality. Crit Care Med 2006; 34 (10) 2596-2602
• 22 Schuetz P, Albrich W, Christ-Crain M, Chastre J, Mueller B. Procalcitonin for guidance of antibiotic therapy. Expert Rev Anti Infect Ther 2010; 8 (5) 575-587
• 23 Meisner M. Pathobiochemistry and clinical use of procalcitonin. Clin Chim Acta 2002; 323 (1-2) 17-29
• 24 Ming J, Adil IK. Procalcitonin: uses in the clinical laboratory for the diagnosis of sepsis. LabMedcine 2010; 41: 173-177
• 25 The WHO Young Infants Study Group. Serious infections in young infants in developing countries: rationale for a multicenter study. Pediatr Infect Dis J 1999; 18 (10, Suppl): S4-S7
• 26 Dawodu A, Twum-Danso K, Al Umran K. A case control study of neonatal sepsis: experience from Saudi Arabia. J Trop paed 1997; 43: 84-88
• 27 World Health Organization. Perinatal mortality. Report No: WHO/FRH/MSM/967. Geneva: WHO; 1996
• 28 Jumah DS, Hassan MK. Predictors of mortality outcome in neonatal sepsis. Med J Basrah Univ 2007; 25: 11-18
• 29 Costello A, Francis V, Byrne A. The state of the world's newborns. Washington: Save the Children Fund; 2001. 411. 1929-1934
• 30 Vergnano S, Sharland M, Kazembe P, Mwansambo C, Heath PT. Neonatal sepsis: an international perspective. Arch Dis Child Fetal Neonatal Ed 2005; 90 (3) F220-F224
• 31 Ako-Nai AK, Adejuyigbe EA, Ajayi FM, Onipede AO. The bacteriology of neonatal septicaemia in Ile-Ife, Nigeria. J Trop Pediatr 1999; 45 (3) 146-151
• 32 Anah MU, Udo JJ, Ochigbo SO, Abia-Bassey LN. Neonatal septicaemia in Calabar, Nigeria. Trop Doct 2008; 38 (2) 126-128
• 33 Marshall JC, Reinhart K ; International Sepsis Forum. Biomarkers of sepsis. Crit Care Med 2009; 37 (7) 2290-2298
• 34 Tang H, Huang T, Jing J, Shen H, Cui W. Effect of procalcitonin-guided treatment in patients with infections: a systematic review and meta-analysis. Infection 2009; 37 (6) 497-507
• 35 Jones AE, Fiechtl JF, Brown MD, Ballew JJ, Kline JA. Procalcitonin test in the diagnosis of bacteremia: a meta-analysis. Ann Emerg Med 2007; 50 (1) 34-41
• 36 Dandona P, Nix D, Wilson MF , et al. Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab 1994; 79 (6) 1605-1608
• 37 Becker KL, Snider R, Nylen ES. Procalcitonin in sepsis and systemic inflammation: a harmful biomarker and a therapeutic target. Br J Pharmacol 2010; 159 (2) 253-264
• 38 Summary of B.R.A.H.M.S PCT sensitive KRYPTOR® Test System. Available at: www.accessdata.fda.gov/cdrh_docs/pdf7/K070310.pdf . Accessed September 18, 2014
• 39 Schneider HG, Lam QT. Procalcitonin for the clinical laboratory: a review. Pathology 2007; 39 (4) 383-390
• 40 Bone RC, Balk RA, Cerra FB , et al; The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101 (6) 1644-1655
• 41 Summary of VIDAS B.R.A.H.M.S PCT Assay. Available at: www.accessdata.fda.gov/cdrh_docs/pdf7/K071146.pdf . Accessed September 18, 2014
• 42 Müller B, Becker KL. Procalcitonin: how a hormone became a marker and mediator of sepsis. Swiss Med Wkly 2001; 131 (41-42) 595-602
• 43 Monneret G, Pachot A, Laroche B, Picollet J, Bienvenu J. Procalcitonin and calcitonin gene-related peptide decrease LPS-induced tnf production by human circulating blood cells. Cytokine 2000; 12 (6) 762-764
• 44 Stocker M, Fontana M, El Helou S, Wegscheider K, Berger TM. Use of procalcitonin-guided decision-making to shorten antibiotic therapy in suspected neonatal early-onset sepsis: prospective randomized intervention trial. Neonatology 2010; 97 (2) 165-174
• 45 Raimondi F, Ferrara T, Maffucci R , et al. Neonatal sepsis: a difficult diagnostic challenge. Clin Biochem 2011; 44 (7) 463-464
• 46 Joram N, Boscher C, Denizot S , et al. Umbilical cord blood procalcitonin and C reactive protein concentrations as markers for early diagnosis of very early onset neonatal infection. Arch Dis Child Fetal Neonatal Ed 2006; 91 (1) F65-F66
• 47 Savagner C, Leboucher B, Gascoin-Lachambre G, Gras-Leguen C. Relevance of procalcitonin for the diagnosis of early and late-onset sepsis in newborns. In: Luciano Azevedo ed. Sepsis - An Ongoing and Significant Challenge. InTech; 2012: 250-258
• 48 Altunhan H, Annagür A, Örs R, Mehmetoğlu I. Procalcitonin measurement at 24 hours of age may be helpful in the prompt diagnosis of early-onset neonatal sepsis. Int J Infect Dis 2011; 15 (12) e854-e858
• 49 Stocker M, Hop WC, van Rossum AM. Neonatal Procalcitonin Intervention Study (NeoPInS): Effect of Procalcitonin-guided decision making on duration of antibiotic therapy in suspected neonatal early-onset sepsis: A multi-centre randomized superiority and non-inferiority Intervention Study. BMC Pediatr 2010; 10: 89
• 50 Whang KT, Vath SD, Becker KL , et al. Procalcitonin and proinflammatory cytokine interactions in sepsis. Shock 2000; 14 (1) 73-78
• 51 Summary of Safety and Effectiveness. B.R.A.H.M.S PCT LIA. Available at: www.accessdata.fda.gov/cdrh_docs/pdf4/K040887.pdf . Accessed September 18, 2014
• 52 Christ-Crain M, Stolz D, Bingisser R , et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med 2006; 174 (1) 84-93
• 53 Schuetz P, Christ-Crain M, Müller B. Procalcitonin and other biomarkers to improve assessment and antibiotic stewardship in infections—hope for hype?. Swiss Med Wkly 2009; 139 (23-24) 318-326
• 54 Krüger S, Ewig S, Papassotiriou J , et al; CAPNETZ Study Group. Inflammatory parameters predict etiologic patterns but do not allow for individual prediction of etiology in patients with CAP: results from the German competence network CAPNETZ. Respir Res 2009; 10: 65
• 55 Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med 2006; 34 (7) 1996-2003
• 56 Sponholz C, Sakr Y, Reinhart K, Brunkhorst F. Diagnostic value and prognostic implications of serum procalcitonin after cardiac surgery: a systematic review of the literature. Crit Care 2006; 10 (5) R145
• 57 Schuetz P, Affolter B, Hunziker S , et al. Serum procalcitonin, C-reactive protein and white blood cell levels following hypothermia after cardiac arrest: a retrospective cohort study. Eur J Clin Invest 2010; 40 (4) 376-381
• 58 Jensen JU, Hein L, Lundgren B , et al; Procalcitonin and Survival Study (PASS) Group. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med 2011; 39 (9) 2048-2058
• 59 Schumm J, Pfeifer R, Ferrari M, Kuethe F, Figulla HR. An unusual case of progressive shock and highly elevated procalcitonin level. Am J Crit Care 2010; 19 (1) 96-3
• 60 Sabat R, Höflich C, Döcke WD , et al. Massive elevation of procalcitonin plasma levels in the absence of infection in kidney transplant patients treated with pan-T-cell antibodies. Intensive Care Med 2001; 27 (6) 987-991
• 61 Brodska H, Drabek T, Malickova K , et al. Marked increase of procalcitonin after the administration of anti-thymocyte globulin in patients before hematopoietic stem cell transplantation does not indicate sepsis: a prospective study. Crit Care 2009; 13 (2) R37
• 62 Caruhel P, Mazier C, Kunde J, Morgenthaler NG, Darbouret B. Homogeneous time-resolved fluoroimmunoassay for the measurement of midregional proadrenomedullin in plasma on the fully automated system B.R.A.H.M.S KRYPTOR. Clin Biochem 2009; 42 (7-8) 725-728
• 63 Baylan O, Balkan A, Inal A , et al. The predictive value of serum procalcitonin levels in adult patients with active pulmonary tuberculosis. Jpn J Infect Dis 2006; 59 (3) 164-167
• 64 Rau B, Steinbach G, Gansauge F, Mayer JM, Grünert A, Beger HG. The potential role of procalcitonin and interleukin 8 in the prediction of infected necrosis in acute pancreatitis. Gut 1997; 41 (6) 832-840
• 65 Heyland DK, Johnson AP, Reynolds SC, Muscedere J. Procalcitonin for reduced antibiotic exposure in the critical care setting: a systematic review and an economic evaluation. Crit Care Med 2011; 39 (7) 1792-1799
• 66 Schuetz P, Christ-Crain M, Albrich W, Zimmerli W, Mueller B ; ProHOSP Study Group. Guidance of antibiotic therapy with procalcitonin in lower respiratory tract infections: insights into the ProHOSP study. Virulence 2010; 1 (2) 88-92
• 67 Steinbach G, Rau B, Debard AL , et al. Multicenter evaluation of a new immunoassay for procalcitonin measurement on the Kryptor System. Clin Chem Lab Med 2004; 42 (4) 440-449
• 68 Hubl W, Krassler J, Zingler C , et al. Evaluation of a fully automated procalcitonin chemiluminescence immunoassay. Clin Lab 2003; 49 (7-8) 319-327
• 69 de Wolf HK, Gunnewiek JK, Berk Y, van den Ouweland J, de Metz M. Comparison of a new procalcitonin assay from roche with the established method on the brahms kryptor. Clin Chem 2009; 55 (5) 1043-1044
• 70 Schuetz P, Christ-Crain M, Huber AR, Müller B. Long-term stability of procalcitonin in frozen samples and comparison of Kryptor and VIDAS automated immunoassays. Clin Biochem 2010; 43 (3) 341-344
• 71 Stolz D, Smyrnios N, Eggimann P , et al. Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study. Eur Respir J 2009; 34 (6) 1364-1375
• 72 Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med 2008; 177 (5) 498-505
• 73 Hochreiter M, Köhler T, Schweiger AM , et al. Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial. Crit Care 2009; 13 (3) R83
• 74 Schroeder S, Hochreiter M, Koehler T , et al. Procalcitonin (PCT)-guided algorithm reduces length of antibiotic treatment in surgical intensive care patients with severe sepsis: results of a prospective randomized study. Langenbecks Arch Surg 2009; 394 (2) 221-226
• 75 Nnanna II, Ehis OJ, Sidiquo II, Nnanna IG, Adekunle O. Serum procalcitonin: Early detection of neonatal bacteremia and septicemia in a tertiary healthcare facility. N Am J Med Sci 2011; 3 (3) 157-160
• 76 Adib M, Bakhshiani Z, Navaei F, Saheb Fosoul F, Fouladi S, Kazemzadeh H. Procalcitonin: a reliable marker for the diagnosis of neonatal sepsis. Iran J Basic Med Sci 2012; 15 (2) 777-782
• 77 Khoshdel A, Mahmoudzadeh M, Kheiri S , et al. Sensitivity and specificity of procalcitonin in diagnosis of neonatal sepsis. Iranian J Pathol 2008; 3: 203-207
• 78 Zahedpasha Y, Ahmadpour KM, Hajiahmadi M, Haghshenas M. Procalcitonin as a marker of neonatal sepsis. Iran J Pediatr 2009; 19: 117-122