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ADC-FNN Online First, published on January 2, 2015 as 10.1136/archdischild-2014-307656 Review
The use of laboratory biomarkers for surveillance, diagnosis and prediction of clinical outcomes in neonatal sepsis and necrotising enterocolitis Pak Cheung Ng, Terence Ping Yuen Ma, Hugh Simon Lam Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Correspondence to Professor Pak Cheung Ng, Department of Paediatrics, Prince of Wales Hospital, 6th Floor, Lui Che Woo Clinical Sciences Building, Shatin, N.T., Hong Kong; [email protected] Received 5 November 2014 Revised 16 December 2014 Accepted 18 December 2014
ABSTRACT Biomarkers have been used to differentiate systemic neonatal infection and necrotising enterocolitis (NEC) from other non-infective neonatal conditions that share similar clinical features. With increasing understanding in biochemical characteristics of different categories of biomarkers, a specific mediator or a panel of mediators have been used in different aspects of clinical management in neonatal sepsis/NEC. This review focuses on how these biomarkers can be used in real-life clinical settings for daily surveillance, bedside point-of-care testing, early diagnosis and predicting the severity and prognosis of neonatal sepsis/NEC. In addition, with recent development of ‘multi-omic’ approaches and rapid advancement in knowledge of bioinformatics, more novel biomarkers and unique signatures of mediators would be discovered for diagnosis of specific diseases and organ injuries.
INTRODUCTION Systemic neonatal infection and necrotising enterocolitis (NEC) are devastating complications of prematurity. NEC causes intense inflammation of the bowel and often coexists with sepsis. In both conditions, the initial signs are vague and non-specific, and clinically, there is much difficulty in differentiating genuine infection/NEC from other noninfective causes, for example, exacerbation of bronchopulmonary dysplasia or gastrointestinal (GI) dysmotility of prematurity.1 2 Laboratory biomarkers that can assist in accurate diagnosis or predicting the severity and prognosis of sepsis/NEC will definitely be useful for clinical management.1 2 In addition, novel biomarkers should be discovered: for daily screening of these conditions so that neonatologists may be able to identify them ‘before’ clinical presentation; as a rapid, bedside point-of-care test so as to avoid unnecessary use of antibiotics; and for diagnosing a specific disease or for assessing the extent of organ injury (ie, as a disease-specific or organ-specific biomarker). This review focuses on principles governing the use of laboratory diagnostic biomarkers and how different biomarkers could be used in real-life clinical settings.
To cite: Ng PC, Ma TPY, Lam HS. Arch Dis Child Fetal Neonatal Ed Published Online First: [ please include Day Month Year] doi:10.1136/archdischild2014-307656
The ‘ideal biomarker’ of neonatal infection/NEC We have in our previous article summarised the critical clinical and laboratory properties of the ‘ideal biomarker’ of neonatal infection.1 Although the basic principles defining an ‘ideal biomarker’ remain unchanged, new practical criteria have been added to the updated table. First, it is of prime
importance that infants with systemic neonatal infection/NEC are identified early and accurately differentiated from non-sepsis/non-NEC cases.1 Daily surveillance offers the best hope for detecting these devastating conditions early and before clinical manifestations (box 1, point A2).3–5 For this purpose, the volume of blood required should be minute (0.85. Notes: In contrast, a biomarker with high specificity and positive predictive value is good for ‘ruling in’ infection/NEC 2. The ideal biomarker (or a panel of biomarkers) should provide an algorithm or a probability score (±taking into account clinical signs and symptoms) for guiding neonatologists whether to initiate antibiotic treatment (eg, ApoSAA score). 3. Detect infection at a very early stage ▸ daily surveillance and identify the condition before clinical manifestations (eg, neutrophil CD64) OR ▸ diagnostic at clinical presentation (‘early-warning’ biomarkers, eg, interleukin (IL)-6, interferon-gamma inducible protein 10 (IP-10), neutrophil CD64, etc). 4. Predict the severity of infection at the onset of clinical presentation, (eg, using IL-10, IL-6 and regulated upon activation normal T cell expressed and secreted (RANTES) sequentially). 5. Differentiate different categories of pathogens: (i) virus versus bacteria versus fungus, or (ii) Gram-positive organisms versus Gram-negative organisms (eg, Gram-specific qPCR test), within the first few hours of clinical presentation. 6. Diagnose a specific disease entity or identify specific organ injury, such as NEC and bowel injury (eg, ‘enhanced non-specific’ biomarkers, eg, faecal calprotectin and S100A12, and gut-associated biomarkers, eg, L-FABP, I-FABP, TFF-3 and LIT score). 7. Monitor disease progress, guide antimicrobial treatment and detect development of complications, such as formation of intra-abdominal abscesses or an inflammatory mass of matted necrotic bowel (eg, serial C-reactive protein (CRP) measurements). 8. Predict prognosis and mortality (eg, combined use of IL-6 and IL-10). B. Laboratory properties 1. A sustained increase or decrease in level of a stable biomarker allows an adequate time window (12–24 h) for specimen collection, storage and laboratory processing before decomposition of the active mediator (eg, neutrophil CD64, CRP). Notes: Unstable biomarkers with very short half-life are not clinically useful as neonatologists may not catch the peak or trough level during specimen collection 2. Very small volume of specimen (eg, 0.05 mL whole blood for neutrophil CD64 or 0.05 mL plasma for a panel of >10 chemokines/ cytokines measurement). 3. Excellent agreement of biomarker levels between capillary and venous samples, especially for daily surveillance (eg, neutrophil CD64). 4. Automatic laboratory measurement. 5. Quantitative measurement of biomarker level. 6. Quick turnaround time from specimen collection to reporting of results (eg,
ADC-FNN Online First, published on January 2, 2015 as 10.1136/archdischild-2014-307656 Review
The use of laboratory biomarkers for surveillance, diagnosis and prediction of clinical outcomes in neonatal sepsis and necrotising enterocolitis Pak Cheung Ng, Terence Ping Yuen Ma, Hugh Simon Lam Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Correspondence to Professor Pak Cheung Ng, Department of Paediatrics, Prince of Wales Hospital, 6th Floor, Lui Che Woo Clinical Sciences Building, Shatin, N.T., Hong Kong; [email protected] Received 5 November 2014 Revised 16 December 2014 Accepted 18 December 2014
ABSTRACT Biomarkers have been used to differentiate systemic neonatal infection and necrotising enterocolitis (NEC) from other non-infective neonatal conditions that share similar clinical features. With increasing understanding in biochemical characteristics of different categories of biomarkers, a specific mediator or a panel of mediators have been used in different aspects of clinical management in neonatal sepsis/NEC. This review focuses on how these biomarkers can be used in real-life clinical settings for daily surveillance, bedside point-of-care testing, early diagnosis and predicting the severity and prognosis of neonatal sepsis/NEC. In addition, with recent development of ‘multi-omic’ approaches and rapid advancement in knowledge of bioinformatics, more novel biomarkers and unique signatures of mediators would be discovered for diagnosis of specific diseases and organ injuries.
INTRODUCTION Systemic neonatal infection and necrotising enterocolitis (NEC) are devastating complications of prematurity. NEC causes intense inflammation of the bowel and often coexists with sepsis. In both conditions, the initial signs are vague and non-specific, and clinically, there is much difficulty in differentiating genuine infection/NEC from other noninfective causes, for example, exacerbation of bronchopulmonary dysplasia or gastrointestinal (GI) dysmotility of prematurity.1 2 Laboratory biomarkers that can assist in accurate diagnosis or predicting the severity and prognosis of sepsis/NEC will definitely be useful for clinical management.1 2 In addition, novel biomarkers should be discovered: for daily screening of these conditions so that neonatologists may be able to identify them ‘before’ clinical presentation; as a rapid, bedside point-of-care test so as to avoid unnecessary use of antibiotics; and for diagnosing a specific disease or for assessing the extent of organ injury (ie, as a disease-specific or organ-specific biomarker). This review focuses on principles governing the use of laboratory diagnostic biomarkers and how different biomarkers could be used in real-life clinical settings.
To cite: Ng PC, Ma TPY, Lam HS. Arch Dis Child Fetal Neonatal Ed Published Online First: [ please include Day Month Year] doi:10.1136/archdischild2014-307656
The ‘ideal biomarker’ of neonatal infection/NEC We have in our previous article summarised the critical clinical and laboratory properties of the ‘ideal biomarker’ of neonatal infection.1 Although the basic principles defining an ‘ideal biomarker’ remain unchanged, new practical criteria have been added to the updated table. First, it is of prime
importance that infants with systemic neonatal infection/NEC are identified early and accurately differentiated from non-sepsis/non-NEC cases.1 Daily surveillance offers the best hope for detecting these devastating conditions early and before clinical manifestations (box 1, point A2).3–5 For this purpose, the volume of blood required should be minute (0.85. Notes: In contrast, a biomarker with high specificity and positive predictive value is good for ‘ruling in’ infection/NEC 2. The ideal biomarker (or a panel of biomarkers) should provide an algorithm or a probability score (±taking into account clinical signs and symptoms) for guiding neonatologists whether to initiate antibiotic treatment (eg, ApoSAA score). 3. Detect infection at a very early stage ▸ daily surveillance and identify the condition before clinical manifestations (eg, neutrophil CD64) OR ▸ diagnostic at clinical presentation (‘early-warning’ biomarkers, eg, interleukin (IL)-6, interferon-gamma inducible protein 10 (IP-10), neutrophil CD64, etc). 4. Predict the severity of infection at the onset of clinical presentation, (eg, using IL-10, IL-6 and regulated upon activation normal T cell expressed and secreted (RANTES) sequentially). 5. Differentiate different categories of pathogens: (i) virus versus bacteria versus fungus, or (ii) Gram-positive organisms versus Gram-negative organisms (eg, Gram-specific qPCR test), within the first few hours of clinical presentation. 6. Diagnose a specific disease entity or identify specific organ injury, such as NEC and bowel injury (eg, ‘enhanced non-specific’ biomarkers, eg, faecal calprotectin and S100A12, and gut-associated biomarkers, eg, L-FABP, I-FABP, TFF-3 and LIT score). 7. Monitor disease progress, guide antimicrobial treatment and detect development of complications, such as formation of intra-abdominal abscesses or an inflammatory mass of matted necrotic bowel (eg, serial C-reactive protein (CRP) measurements). 8. Predict prognosis and mortality (eg, combined use of IL-6 and IL-10). B. Laboratory properties 1. A sustained increase or decrease in level of a stable biomarker allows an adequate time window (12–24 h) for specimen collection, storage and laboratory processing before decomposition of the active mediator (eg, neutrophil CD64, CRP). Notes: Unstable biomarkers with very short half-life are not clinically useful as neonatologists may not catch the peak or trough level during specimen collection 2. Very small volume of specimen (eg, 0.05 mL whole blood for neutrophil CD64 or 0.05 mL plasma for a panel of >10 chemokines/ cytokines measurement). 3. Excellent agreement of biomarker levels between capillary and venous samples, especially for daily surveillance (eg, neutrophil CD64). 4. Automatic laboratory measurement. 5. Quantitative measurement of biomarker level. 6. Quick turnaround time from specimen collection to reporting of results (eg,
