CLB-08751; No. of pages: 2; 4C: Clinical Biochemistry xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Short Communication
Diagnosis of neonatal sepsis: What the clinician expects, what the laboratory tells Zeynep Ince Istanbul University School of Medicine, Department of Pediatrics, Division of Neonatology, Capa, 34093 Istanbul, Turkey
Introduction Neonatal sepsis is still one of the most frequent causes of mortality and morbidity in neonatal intensive care units (NICU), especially among very low birth weight (VLBW) infants. Despite advances in neonatal care and improvements in diagnostic tools, early and accurate diagnosis of sepsis remains a major challenge. A delay in the recognition of the non-specific and subtle signs and symptoms or misinterpretation of these findings as being due to non-infective causes may lead to a fulminant septic shock and death within a few hours. There is an urgent need to identify infected infants in order to institute appropriate treatment as quickly as possible and the neonatologists expect more clinical information to be provided by the laboratory. A positive blood culture is the gold standard for diagnosing neonatal sepsis; however it can take up to 48 h to detect a microorganism and false negative results are common because of low-density and intermittent bacteremia, small specimen volumes and prior antibiotic treatment. These drawbacks make blood culture less than an ideal marker leading the researchers to investigate a variety of serum biomarkers in the rapid diagnosis of infection. This review will provide information on novel biomarkers and physiomarkers which are being introduced and assessed in clinical settings in order to improve the diagnostic sensitivity of neonatal sepsis. A physiomarker of sepsis: heart rate characteristics Abnormal heart rate characteristics (HRC), like decreased variability and transient decelerations, may occur in response to systemic infection and inflammation, prior to the recognition of clinical signs. This observation led to the design of a novel monitor displaying HRC as an index score, which shows the fold-increase in the risk of sepsis during the next 24 h. Monitoring HRC has been shown to reduce sepsis associated in-hospital mortality in VLBW infants and is a promising method for the earlier detection of neonatal sepsis [1]. Biomarkers for diagnosis of neonatal infections From a clinical stand point, an ideal biomarker should have a high sensitivity and negative predictive value (N 99%) and a good specificity E-mail address: [email protected].
and positive predictive value (N85%). The biomarker should be elevated early in the course of infection, have an adequate window of opportunity for sampling and a well-defined cut-off value, and be able to reflect the disease progress and also the response to treatment. Various biomarkers have been assessed as potential indicators across all phases of neonatal sepsis. C reactive protein (CRP), which is widely used in neonatal intensive care units, is a very specific but not a very sensitive biomarker. The elevation in the serum concentration is delayed by 6–8 h after the onset of clinical symptoms, limiting its utility in early detection of infection. However CRP continues to be useful for monitoring the response to treatment and for ruling out an infection. The diagnostic accuracy of CRP may be improved by combining with another infection marker [2]. Procalcitonin (PCT) is a precursor of calcitonin and rises more rapidly in response to inflammation than CRP. Two separate meta-analysis including 22 and 29 studies showed that PCT was more accurate in the diagnosis of late onset sepsis with a pooled sensitivity of 81% and specificity of 79%. However the results should be interpreted with caution because of the heterogeneity of the studies [3]. Serum Amyloid A is also an acute phase reactant and the studies suggest that SAA may be a promising early diagnostic and prognostic biomarker in the course of neonatal sepsis [4]. Chemokines and cytokines, which are cell signaling proteins, are released in response to bacterial infection. The most extensively investigated mediators are interleukin-1β, IL-6, IL-8, IL-10, interferonγ (IFN-γ) and tumor necrosis factor-α (TNF-α). The levels of IL-6 and IL-8 increase very rapidly after infection with a high diagnostic sensitivity in early onset sepsis; however their short half-life limits the clinical usefulness. A variety of other chemokines and cytokines with favorable properties have been evaluated for early diagnosis of sepsis, but operational difficulties and lack of availability in many hospitals limit their integration in day-to-day practice in the NICU. Cell surface antigens are expressed on circulating inflammatory cells after activation by bacterial products and can be quantified by flow cytometry. Cluster of differentiation (CD)64 and CD11b are the most promising molecules in the diagnosis of sepsis [5,6]. Proteomic profiling technologies are used to identify protein signatures in various diseases. Serum amyloid A (SAA) and apolipoprotein C-II were identified as novel host-response biomarkers using proteomic analysis and a diagnostic equation was created (ApoSAA score) to
http://dx.doi.org/10.1016/j.clinbiochem.2014.05.045 0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: Ince Z, Diagnosis of neonatal sepsis: What the clinician expects, what the laboratory tells, Clin Biochem (2014), http:// dx.doi.org/10.1016/j.clinbiochem.2014.05.045
2
Z. Ince / Clinical Biochemistry xxx (2014) xxx–xxx
stratify VLBW infants by risk for sepsis. Although the high sensitivity and negative predictive value make it an appealing option, potential confounding variables and challenges in the generalization of this method must be considered [5,6]. Conclusion The diagnosis of neonatal sepsis continues to be a major clinical challenge for neonatologists due to the lack of an “ideal” biomarker or panel of markers with high diagnostic accuracy and reliability. Ongoing research on new molecular and biogenetic technologies may replace nonspecific biomarkers, hastening the diagnosis and providing information about the etiology of infection.
References [1] Fairchild K, O'Shea TM. Heart rate characteristics: physiomarkers for detection of lateonset neonatal sepsis. Clin Perinatol 2010;37:581–98. [2] Hofer N, Zacharias E, Müller W, Resch B. An update on the use of C-reactive protein in early-onset neonatal sepsis: current insights and new tasks. Neonatology 2012;102:25–36. [3] Bhatti M, Chu A, Hageman JR, Schreiber M, Alexander K. Future directions in the evaluation and management of neonatal sepsis. NeoReviews 2012;13:e103–10. [4] Ng PC, Ang LI, Chiu RWK, et al. Host response biomarkers for late onset septicemia and necrotizing enterocolitis in preterm infants. J Clin Invest 2010;120:2989–3000. [5] Srinivasan L, Harris MC. New technologies for the rapid diagnosis of neonatal sepsis. Curr Opin Pediatr 2012;24:165–71. [6] Ng PC, Lam HS. Biomarkers for late-onset neonatal sepsis: cytokines and beyond. Clin Perinatol 2010;37:599–610.
Please cite this article as: Ince Z, Diagnosis of neonatal sepsis: What the clinician expects, what the laboratory tells, Clin Biochem (2014), http:// dx.doi.org/10.1016/j.clinbiochem.2014.05.045
Contents lists available at ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Short Communication
Diagnosis of neonatal sepsis: What the clinician expects, what the laboratory tells Zeynep Ince Istanbul University School of Medicine, Department of Pediatrics, Division of Neonatology, Capa, 34093 Istanbul, Turkey
Introduction Neonatal sepsis is still one of the most frequent causes of mortality and morbidity in neonatal intensive care units (NICU), especially among very low birth weight (VLBW) infants. Despite advances in neonatal care and improvements in diagnostic tools, early and accurate diagnosis of sepsis remains a major challenge. A delay in the recognition of the non-specific and subtle signs and symptoms or misinterpretation of these findings as being due to non-infective causes may lead to a fulminant septic shock and death within a few hours. There is an urgent need to identify infected infants in order to institute appropriate treatment as quickly as possible and the neonatologists expect more clinical information to be provided by the laboratory. A positive blood culture is the gold standard for diagnosing neonatal sepsis; however it can take up to 48 h to detect a microorganism and false negative results are common because of low-density and intermittent bacteremia, small specimen volumes and prior antibiotic treatment. These drawbacks make blood culture less than an ideal marker leading the researchers to investigate a variety of serum biomarkers in the rapid diagnosis of infection. This review will provide information on novel biomarkers and physiomarkers which are being introduced and assessed in clinical settings in order to improve the diagnostic sensitivity of neonatal sepsis. A physiomarker of sepsis: heart rate characteristics Abnormal heart rate characteristics (HRC), like decreased variability and transient decelerations, may occur in response to systemic infection and inflammation, prior to the recognition of clinical signs. This observation led to the design of a novel monitor displaying HRC as an index score, which shows the fold-increase in the risk of sepsis during the next 24 h. Monitoring HRC has been shown to reduce sepsis associated in-hospital mortality in VLBW infants and is a promising method for the earlier detection of neonatal sepsis [1]. Biomarkers for diagnosis of neonatal infections From a clinical stand point, an ideal biomarker should have a high sensitivity and negative predictive value (N 99%) and a good specificity E-mail address: [email protected].
and positive predictive value (N85%). The biomarker should be elevated early in the course of infection, have an adequate window of opportunity for sampling and a well-defined cut-off value, and be able to reflect the disease progress and also the response to treatment. Various biomarkers have been assessed as potential indicators across all phases of neonatal sepsis. C reactive protein (CRP), which is widely used in neonatal intensive care units, is a very specific but not a very sensitive biomarker. The elevation in the serum concentration is delayed by 6–8 h after the onset of clinical symptoms, limiting its utility in early detection of infection. However CRP continues to be useful for monitoring the response to treatment and for ruling out an infection. The diagnostic accuracy of CRP may be improved by combining with another infection marker [2]. Procalcitonin (PCT) is a precursor of calcitonin and rises more rapidly in response to inflammation than CRP. Two separate meta-analysis including 22 and 29 studies showed that PCT was more accurate in the diagnosis of late onset sepsis with a pooled sensitivity of 81% and specificity of 79%. However the results should be interpreted with caution because of the heterogeneity of the studies [3]. Serum Amyloid A is also an acute phase reactant and the studies suggest that SAA may be a promising early diagnostic and prognostic biomarker in the course of neonatal sepsis [4]. Chemokines and cytokines, which are cell signaling proteins, are released in response to bacterial infection. The most extensively investigated mediators are interleukin-1β, IL-6, IL-8, IL-10, interferonγ (IFN-γ) and tumor necrosis factor-α (TNF-α). The levels of IL-6 and IL-8 increase very rapidly after infection with a high diagnostic sensitivity in early onset sepsis; however their short half-life limits the clinical usefulness. A variety of other chemokines and cytokines with favorable properties have been evaluated for early diagnosis of sepsis, but operational difficulties and lack of availability in many hospitals limit their integration in day-to-day practice in the NICU. Cell surface antigens are expressed on circulating inflammatory cells after activation by bacterial products and can be quantified by flow cytometry. Cluster of differentiation (CD)64 and CD11b are the most promising molecules in the diagnosis of sepsis [5,6]. Proteomic profiling technologies are used to identify protein signatures in various diseases. Serum amyloid A (SAA) and apolipoprotein C-II were identified as novel host-response biomarkers using proteomic analysis and a diagnostic equation was created (ApoSAA score) to
http://dx.doi.org/10.1016/j.clinbiochem.2014.05.045 0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Please cite this article as: Ince Z, Diagnosis of neonatal sepsis: What the clinician expects, what the laboratory tells, Clin Biochem (2014), http:// dx.doi.org/10.1016/j.clinbiochem.2014.05.045
2
Z. Ince / Clinical Biochemistry xxx (2014) xxx–xxx
stratify VLBW infants by risk for sepsis. Although the high sensitivity and negative predictive value make it an appealing option, potential confounding variables and challenges in the generalization of this method must be considered [5,6]. Conclusion The diagnosis of neonatal sepsis continues to be a major clinical challenge for neonatologists due to the lack of an “ideal” biomarker or panel of markers with high diagnostic accuracy and reliability. Ongoing research on new molecular and biogenetic technologies may replace nonspecific biomarkers, hastening the diagnosis and providing information about the etiology of infection.
References [1] Fairchild K, O'Shea TM. Heart rate characteristics: physiomarkers for detection of lateonset neonatal sepsis. Clin Perinatol 2010;37:581–98. [2] Hofer N, Zacharias E, Müller W, Resch B. An update on the use of C-reactive protein in early-onset neonatal sepsis: current insights and new tasks. Neonatology 2012;102:25–36. [3] Bhatti M, Chu A, Hageman JR, Schreiber M, Alexander K. Future directions in the evaluation and management of neonatal sepsis. NeoReviews 2012;13:e103–10. [4] Ng PC, Ang LI, Chiu RWK, et al. Host response biomarkers for late onset septicemia and necrotizing enterocolitis in preterm infants. J Clin Invest 2010;120:2989–3000. [5] Srinivasan L, Harris MC. New technologies for the rapid diagnosis of neonatal sepsis. Curr Opin Pediatr 2012;24:165–71. [6] Ng PC, Lam HS. Biomarkers for late-onset neonatal sepsis: cytokines and beyond. Clin Perinatol 2010;37:599–610.
Please cite this article as: Ince Z, Diagnosis of neonatal sepsis: What the clinician expects, what the laboratory tells, Clin Biochem (2014), http:// dx.doi.org/10.1016/j.clinbiochem.2014.05.045
