- Email: [email protected]
A Review of Biomarkers and Physiomarkers in Pediatric Sepsis
Abstract: Sepsis is a leading cause of morbidity and mortality in critically ill pediatric patients. The early diagnosis of sepsis is often difficult. Clinical signs and symptoms consistent with established criteria often occur late in the course of illness. In addition, early manifestations of sepsis are often nonspecific and can occur in many other disease processes, which confound the clinical picture. Therefore, identifying markers that are both sensitive and specific would be extremely helpful to the clinician for definitive diagnosis of sepsis before progression to severe disease. The purpose of this review is to describe the more common physiomarkers and biomarkers used that may aid in the diagnosis of sepsis as well as describe promising biomarkers that may be more widely available in the future.
Keywords: C-reactive protein; procalcitonin; lactate; CD-64; soluble triggering receptor expressed on myeloid cells 1; interleukin 6; interleukin 8; sepsis; biomarker; pediatrics Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL. Reprint requests and correspondence: Ranna A. Rozenfeld, MD, Associate Professor of Pediatrics, Feinberg School of Medicine, Northwestern University, Attending Physician, Pediatric Critical Care Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 E Chicago Ave, Box 73, Chicago, IL 60611. [email protected] (M.F. Alqahtani), [email protected] (L.E. Marsillio), [email protected] (R.A. Rozenfeld) 1522-8401 © 2014 Elsevier Inc. All rights reserved.
A Review of Biomarkers and Physiomarkers in Pediatric Sepsis Mashael F. Alqahtani, MBBS, Lauren E. Marsillio, MD, Ranna A. Rozenfeld, MD
S
epsis is a leading cause of morbidity and mortality in critically ill pediatric patients. More than 20 000 children are affected by severe sepsis annually in the United States, with mortality estimates ranging from 4.2% to 10.3%. 1,2 Multiple studies performed in the emergency department (ED) setting show that compliance rates with the American College of Critical Care Medicine/Pediatric Advanced Life Support septic shock guidelines are low. 3-6 Implementation of sepsis protocols in EDs has improved these numbers; however, there remains further room for improvement. This gap in compliance may be due, in part, to difficulties in discriminating patients with sepsis from the millions of children with benign infectious illnesses who present to the ED each day. Therefore, rapid and accurate identification is a crucial step in sepsis survival for children. The use of biomarkers and physiomarkers may potentially facilitate early diagnosis; however, it is important to have an understanding of the indication, appropriate utilization, and applicability of the multiple biomarkers and physiomarkers available to clinicians. In light of the increased focus on biomarkers, the National Institutes of Health Biomarkers Definitions Working Group created a definition of biomarkers as a “characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” 7 The term physiomarkers overlaps somewhat with biomarkers, but we describe a physiomarker as the physiologic parameters indicative of disease in hospitalized patients (Table 1).
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TABLE 1. Definitions of biomarker and physiomarker. Name
Definition
Examples Biomarker
An objectively measured indicator of normal or abnormal biological processes; CRP, PCT, CD64, IL-6, IL-8 Useful in diagnosis, monitoring, staging and prognosis of disease Lactate, ESR, sTREM-1 Physiomarker An objectively or subjectively measured physiologic indicator of a disease process; vital signs, ScvO2 Useful in diagnosis and monitoring of disease capillary refill time
To achieve a better understanding of the more widely known biomarkers and physiomarkers, we describe the advantages and disadvantages of the more common biomarkers, the evidence for use of
various physiomarkers, and several scoring systems that integrate the various markers.
BIOMARKERS C-Reactive Protein C-reactive protein (CRP) is an acute-phase reactant produced by hepatocytes and is measured in the blood (Figure 1). Levels are known to rise in the presence of infection or tissue injury approximately 4 to 6 hours after an inflammatory stimulus. C-reactive protein values usually peak around 36 to 50 hours with a half-life of approximately 20 hours. 8,9 Overall, CRP has relatively low sensitivity and specificity preventing it from being a good marker to differentiate between bacterial, viral, and noninfectious inflammatory processes such as trauma, surgery, or rheumatologic diseases. A systematic review evaluated the diagnostic accuracy of CRP in pediatric patients in an ED setting to evaluate if CRP could differentiate serious
Figure 1. A simplified depiction of biomarker production in inflammation. An inflammatory signal stimulates the production of PCT as well as IL-6 and IL-8 from various immune system cells, including macrophages as well as many other cell types. Triggering receptor expressed on myeloid cells 1 is expressed on neutrophils and macrophages as is CD64, which binds certain subclasses of immunoglobulin G. Downstream effects are numerous and further modulate the immune response. C-reactive protein, primarily produced by the liver in response to inflammation, participates in complement activation as well as other functions. Together, these biomarkers are just a few of the molecules that collectively function to further the inflammatory response. Lactate is a product of anaerobic metabolism in the presence of tissue hypoxia. TREM-1 indicates triggering receptor expressed on myeloid cells-1; IgG, immunoglobulin G.
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bacterial infection from benign infection (bacterial/ nonbacterial) and bacterial from nonbacterial infection. This study showed that CRP is of moderate value for ruling out serious bacterial infection in a child with a fever but is of limited value for ruling out all bacterial infections. 10 The neonatal population may be the group that benefits most from evaluation with CRP, especially in the first 48 hours of life. In one study of neonatal sepsis, CRP was found to be more reliable than procalcitonin (PCT), although additional studies have found conflicting results. 11 Because of its lack of specificity, CRP has often been used in conjunction with other biomarkers such as PCT, interleukin 6 (IL-6) or interleukin 8 (IL-8) as part of a diagnostic panel. Overall, outside the neonatal population, CRP has little value in diagnosis and prognosis of sepsis.
Procalcitonin Procalcitonin is a 116-amino acid peptide precursor of the hormone calcitonin, which has been described as a reliable diagnostic and prognostic biomarker of sepsis. In healthy subjects, it is secreted by the neuroendocrine C cells of the thyroid, but during an infection, PCT is secreted by many tissues and cells. 8,12 In the setting of inflammation, PCT rises faster than CRP and usually peaks around 24 hours. Procalcitonin is attenuated by interferon γ in viral infections, which supports the claim that it serves as a better indicator of bacterial infection than other biomarkers such as CRP. 13 Many studies have shown that PCT is better than CRP at differentiating systemic inflammatory response syndrome (SIRS) due to bacterial vs nonbacterial sources in critically ill children. 13,14 One study comparing the accuracy of PCT and CRP showed that PCT levels above the cut-off value of 2.5 ng/mL increased the probability of bacterial SIRS to 60%, whereas a CRP value more than 40 mg/L only increased the probability of bacterial SIRS to 50%. When clinical judgment suspecting infection was factored in along with a positive PCT, the probability increased to 92% for bacterial infection. 13 This data support PCT as a good marker to discriminate bacterial from viral infections. Several groups have demonstrated that PCT levels were significantly elevated in patients with sepsis, severe sepsis, or septic shock when compared with infected patients without signs of SIRS. 15,16 Furthermore, other studies comparing PCT and CRP in both the adult and pediatric populations show that PCT was better than CRP at discriminat-
ing SIRS from sepsis. 17,18 Limitations of the use of PCT include its variable levels in invasive fungal infections as well as limited utility in neonates within the first 48 hours of life. Overall, we recommend sending a PCT level in children with a suspicion for sepsis, noting that each institution’s testing capabilities and laboratory turnaround times may vary, potentially affecting the current utility of this test in the ED.
Lactate Lactate has been used extensively to distinguish sepsis from septic shock and has been recognized as a marker of tissue hypoxia. Lactate is the byproduct of anaerobic metabolism, although hyperlactatemia could develop independently of tissue hypoxia as in inborn errors of metabolism or toxin ingestion. A study in a pediatric ED showed that a venous lactate level of at least 4 mmol/L in patients with SIRS was associated with a 5.5 times increased risk for organ dysfunction within the first 24 hours after triage. 19 Another study showed that initial serum lactate was independently associated with mortality in adults who presented to the ED with severe sepsis. 20 Overall, lactate is a good marker of organ perfusion and, if elevated, may be consistent with sepsis. Therefore, we would recommend obtaining a freeflowing serum lactate level in the ED if clinical concern for SIRS or sepsis is present. In addition, lactate levels should be followed to help guide adequate resuscitation. However, lactate is neither sensitive enough nor specific enough to definitively diagnose patients as having sepsis.
Complete Blood Count A complete blood count with white blood cell (WBC) differential is a common laboratory test ordered when there is suspicion of infection. An elevated WBC count, or in the very young, a low WBC count, is associated with the presence of infection. In addition, the increased total number of immature granulocytes in the blood has been found to be a good marker in discriminating infected from noninfected adult patients very early during SIRS particularly within the first 48 hours after SIRS onset. 21 In pediatric patients, though, admission WBC has poor ability in predicting septic shock. 22 Overall, a complete blood count with WBC differential is important to obtain when evaluating for possible SIRS and sepsis; however, its low sensitivity and specificity limit its role as a predictor of infection.
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Cluster of Differentiation 64 Cluster of Differentiation 64 (CD64) is a highaffinity surface marker known as Fc γ receptor I that binds immunoglobulin G. It is constitutively found on monocytes but in the setting of inflammation will be significantly and rapidly (within 4-6 hours after stimulation) up-regulated on polymorphonuclear neutrophils. 23 The fact that few other disease states result in this up-regulation on neutrophils makes CD64 a good candidate for a sepsis biomarker in children and neonates. 24,25 One study in neonates and children found that CD64 had better diagnostic accuracy than PCT or CRP at the time of suspected sepsis and at 24 hours. 26 However, others have found conflicting results, showing CD64 to have difficulty discriminating bacterial from viral infections in pediatric patients. 27 Overall, CD64 expression on polymorphonuclear neutrophils could be a useful diagnostic cell-based parameter of bacterial infections, but currently, rapid testing is not widely available, and it remains unclear if CD64 offers a benefit over CRP or PCT.
Soluble Triggering Receptor Expressed on Myeloid Cells 1 The soluble triggering receptor expressed on myeloid cells 1(sTREM-1) is a member of the immunoglobulin superfamily and is expressed on phagocytes with exposure to various pathogens. 28 Soluble triggering receptor expressed on myeloid cells 1 mediates the acute inflammatory response to microbes. In a meta-analysis, which evaluated the ability of sTREM-1 to differentiate sepsis from SIRS, a pooled sensitivity of 79% and specificity of 80% was found indicating some promise in its ability to be a valuable biomarker in diagnosing sepsis. 29 A small study evaluating adults with severe sepsis receiving appropriate early goal-directed therapy found that sTREM-1 was significantly higher in the nonsurvivors compared with survivors. 30 These findings, along with the fact that sTREM-1 is not elevated in noninfectious processes, indicate that this biomarker may prove to be useful for both early diagnosis of sepsis as well as prognostication for disease severity. However, like the other biomarkers above, it is best used in conjunction with other tests. In addition, rapid testing for sTREM-1 is not available in many centers, limiting its current utility.
Interleukin 6 Clinical studies have shown that IL-6, an important inflammatory cytokine released by macrophages as well as many other cell types, is elevated
in adult and pediatric sepsis patients. 15,31 It has been shown to be reliable in differentiating between sepsis and SIRS adult patients. 15 In pediatric meningococcal septic shock, serum levels were found to correlate with the degree of myocardial depression. 32 High serum levels of IL-6 (N 1000 pg/mL) have also been shown to predict sepsis-related death in adult patients. 16 However, IL-6 is also elevated in many noninfectious conditions such as trauma, surgery, and stroke, making it questionable as a diagnostic marker for sepsis.
Interleukin 8 Interleukin 8 is another proinflammatory cytokine that is elevated in pediatric septic patients. It is produced and released by phagocytes as well as many other cell types, peaks several hours after an inflammatory stimulus, and has been found to increase with illness severity. 16,31 Unlike several other biomarkers, IL-8 is not affected by gestational age or postnatal age. 25 Its utility in the oncology population has been evaluated. In one study of pediatric oncology patients with fever and neutropenia, elevated levels of IL-8 were strongly correlated with bacteremia, whereas low levels of IL-8 were associated with low risk of bacteremia. 33 In addition, serum IL-8 levels less than 220 pg/mL measured within 24 hours of admission had a high prediction for survival in pediatric patients with septic shock. 34 Interleukin 8 seems to hold promise as a useful biomarker for sepsis; however, limited availability of rapid testing limits its current usefulness.
Erythrocyte Sedimentation Rate Erythrocyte sedimentation rate (ESR) is a frequently ordered test for evaluating inflammation that has been in use in some manner since the 1920s. Initially designed to indirectly measure fibrinogen levels, it has become used as a measure of the rate at which red blood cells precipitate out of plasma in 1 hour. It is a nonspecific marker that rises in the setting of inflammation and has limited utility because it is elevated in multiple disease processes involving significant inflammatory response. It has been used to follow treatment response especially with rheumatologic disease. 35 In one study of burn patients, ESR was found to be elevated in this population but could not differentiate between those who were septic from those who were not. 36 Overall, ESR has largely fallen out of favor as a marker of sepsis in place of other biomarkers discussed above.
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In summary, the various biomarkers discussed above have distinct advantages and disadvantages for use in the ED (Table 2).
PHYSIOMARKERS Body Temperature One of the earliest clinical signs of infection is change in body temperature. In immunocompetent children, fever may be the initial marker of serious infection, whereas hypothermia may be the presenting sign in infants. Ultimately, although fever is part of the diagnostic criteria for SIRS and sepsis, it is too insensitive and nonspecific to be used alone in identifying patients with sepsis.
Heart Rate Heart rate is usually elevated in patients with sepsis and, like fever, it is an insensitive and nonspecific finding. However, loss of heart rate variability (HRV) or loss of the normal beat to beat oscillations present in healthy people has been associated with sepsis in both pediatric and adult patients. Development of autonomic dysfunction occurs early in sepsis and has been studied
extensively in critically ill adult patients. 37 -40 It is thought to be secondary to an “uncoupling” of the neurally mediated interorgan communication system, and one of the ways in which this is manifested is with loss of HRV. 37 Studies of adult patients with sepsis consistently show a loss of HRV before diagnosis of sepsis, and in one case, up to 24 hours before clinically evident sepsis. 41 The loss of HRV has also been shown to occur in neonates and pediatric patients with sepsis. 42,43 This loss of HRV is felt to reflect a loss of adaptive mechanisms and/or autonomic imbalance or dysfunction either as a consequence of critical illness or as a harbinger of clinical deterioration. In one study of adult ED patients, HRV analysis was able to predict development of sepsis. 44 However, the technology to evaluate these changes, although available, is difficult to implement in real time. As our monitoring methods improve, it is likely that we will be able to use this technique in the future.
Blood Pressure Hypotension is often a late finding in sepsis and septic shock, especially in the pediatric population. Using blood pressure at the time of presentation as a predictor of sepsis has been evaluated. In a small
TABLE 2. Biomarker usefulness for sepsis diagnosis. Biomarker CRP
Performance
Turnaround time
Somewhat sensitive somewhat specific Sensitive Specific Insensitive Not specific Insensitive Not specific Somewhat sensitive Moderately specific Somewhat sensitive
1-6 h
IL-6
Moderately specific Moderately sensitive Not specific
If not send out 1-3 hours if If not send out
IL-8
Variable sensitivity reported
Days
Moderately specific
Likely a send out lab
PCT Lactate WBC CD64 sTREM-1
0.5-3 h Immediate 0.5-1.5 h 1-2 h If not send out Approx. 5 hours
Lab indicates laboratory; approx, approximately.
Special considerations Does not differentiate viral from bacterial process; Elevated in noninfectious processes Useful in predicting serious bacterial infection early May be useful in immunosuppressed patients Widely available; higher levels associated with morbidity Elevated with certain inborn errors of metabolism Poor at predicting sepsis or septic shock Not widely available; useful for predicting bacterial infection Not widely available; moderate ability to discriminate sepsis from SIRS in adults Limited pediatric data Good at predicting sepsis and myocardial dysfunction May also be elevated in other conditions including trauma and stroke High levels associated with bacteremia in patients with febrile neutropenia Good marker of illness severity and predictor of survival
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study of adult patients with sepsis, there was no significant difference in mean arterial blood pressure on admission in survivors compared with nonsurvivors. However, aggressive treatment of hypotension did improve short-term survival. 45 Recent focus has shifted to evaluating pulse pressure or systolic pressure variability, but although it is commonly accepted that a widened pulse pressure is consistent with warm shock, it is not specific to septic shock.
Shock Index The Shock Index (SI) is defined as the ratio of heart rate to systolic blood pressure and was first described in 1967 as a way to assess for hypovolemia in various shock states. Over time, SI has been found to correlate with hypovolemia in both animal and human models as well as persistent left ventricular failure. 46,47 In one study of adult ED patients, an elevated SI that was greater than 0.7 was associated with a lactate level at least 4 mmol/L, a marker for disease severity, and SI performed just as well SIRS criteria. 48 In the pediatric population, there are few studies, but one group found that, among patients whose SI was above the 50th percentile at intensive care unit admission, improvement of SI was associated with lower intensive care unit mortality in children ages 1 to 3 and over 12 years. 49 Although blood pressure is not a good physiomarker for sepsis, SI may provide a useful tool to gauge effectiveness of resuscitation in the ED.
Capillary Refill Time Capillary refill time has long been considered an important component of the physical examination in patients with suspected sepsis for both assessment of disease severity as well as evaluation of adequate resuscitation. Normal capillary refill time is considered to be less than or equal to 2 seconds. Despite our reliance on this physiologic sign, there is wide variability in clinician assessment of capillary refill time, and overall, it alone is a poor indicator of sepsis. In addition, its ability to predict outcomes is limited. One study in the PICU showed that capillary refill time at least 2 seconds was a poor predictor of hemodynamic status and should thus be interpreted with caution. 50
Central Venous Oxygen Saturation Central venous oxygen saturation (ScvO2) is obtained by measuring the oxygen saturation in venous blood returning to the heart at the level of the superior vena cava/right atrium junction. It is
important to note that this serves as a substitute for true mixed venous oxygen saturation that is obtained from the pulmonary artery. Central venous oxygen saturation is an indirect index of global tissue oxygenation. It represents the balance between oxygen delivery and oxygen consumption. Although central venous access is often not obtained in many pediatric EDs, ScvO2 is a useful physiomarker to follow in the early phases of resuscitation in pediatric sepsis. Optimization of ScvO2 is considered one of the main resuscitation targets of the early goal-directed therapy along with normalization of central venous pressure, mean arterial pressure, and urine output as recommended by the Surviving Sepsis Campaign 2012 guidelines and American College of Critical Care Medicine/Pediatric Advanced Life Support guidelines. 3,51 A multicenter adult study found that, for patients in whom a normal ScvO2 goal was targeted during early goal-directed therapy, they were twice as likely to survive compared with patients who did not reach this end point. 52 Similar findings have been shown in children. 53 The limitation of using ScvO2 as a physiomarker in pediatric patients has proven to be the lack of central venous lines in septic pediatric patients in the ED. However, patients who already have a central venous line (such as patients requiring chemotherapy for oncologic disease or who require total parenteral nutrition) should have a central venous saturation checked.
SCORING SYSTEMS Mortality in Emergency Department Sepsis Score The Mortality in Emergency Department Sepsis (MEDS) score is a validated tool used to risk-stratify patients to predict 28-day mortality in adults with presumed sepsis. The MEDS score assigns patients to 1 of 5 mortality risk groups based on multiple clinical variables. The MEDS serves as a good predictor of mortality in septic adult patients. 54,55 Unfortunately, there is no equivalent score in the pediatric population, which makes this a potential area for future research.
The Pediatric Sepsis Biomarker Risk Model The pediatric sepsis biomarker risk model is a model that was created and validated as a riskstratification tool for outcomes prediction in pediatric septic shock. It includes 12 biomarkers derived from genome-wide expression profiling. The model was derived and tested using 355 subjects less than
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the age of 11years admitted with a diagnosis of septic shock. Testing of this model found a sensitivity of 93% and a specificity of 74% for 28day all-cause mortality. 56 A similar model was also recently tested and validated in adults, which found good sensitivity, although slightly less specificity for mortality in septic shock. 57 Once risk models like these are widely available with a rapid turnaround time, they could potentially become useful tools in the ED to assist clinicians in identifying who is at highest risk for dying of sepsis.
Summary The timely diagnosis of pediatric sepsis in the ED poses a significant challenge for clinicians for a variety of reasons. These include lack of rapid and accurate diagnostic tools, absence of simple and specific diagnostic criteria, and vague symptoms during the early phase of illness. The wide range of biomarkers currently available for testing offers an attractive option to assist with diagnosis, triage, and prognosis; however, none to date has been identified as the single best marker. Furthermore, many are not widely available in EDs nor is the testing turnaround time uniform from one institution to another. In addition, the physiomarkers described above also have limited utility in current practice, due to their lack of specificity for any one disease process. However, recent advances have been made in creating tools and algorithms that are able to combine the available biomarkers and physiomarkers. The best predictive tool in the future will likely be a combination of multiple biomarkers and physiomarkers that also account for patient-specific factors.
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26. Groselj-Grenc M, Ihan A, Pavcnik-Arnol M, et al. Neutrophil and monocyte CD64 indexes, lipopolysaccharide-binding protein, procalcitonin and C-reactive protein in sepsis of critically ill neonates and children. Intensive Care Med 2009;35:1950–8. 27. Rudensky B, Sirota G, Erlichman M, et al. Neutrophil CD64 expression as a diagnostic marker of bacterial infection in febrile children presenting to a hospital emergency department. Pediatr Emerg Care 2008;24:745–8. 28. Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol 2000;164:4991–5. 29. Wu Y, Wang F, Fan X, et al. Accuracy of plasma sTREM-1 for sepsis diagnosis in systemic inflammatory patients: a systematic review and meta-analysis. Crit Care 2012;16:R229. 30. Jeong SJ, Song YG, Kim CO, et al. Measurement of plasma sTREM-1 in patients with severe sepsis receiving early goaldirected therapy and evaluation of its usefulness. Shock 2012;37:574–8. 31. Sikora JP, Chlebna-Sokol D, Krzyzanska-Oberbek A. Proinflammatory cytokines (IL-6, IL-8), cytokine inhibitors (IL-6sR, sTNFRII) and anti-inflammatory cytokines (IL-10, IL-13) in the pathogenesis of sepsis in newborns and infants. Arch Immunol Ther Exp (Warsz) 2001;49:399–404. 32. Pathan N, Hemingway CA, Alizadeh AA, et al. Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock. Lancet 2004;363:203–9. 33. Cost CR, Stegner MM, Leonard D, et al. IL-8 predicts pediatric oncology patients with febrile neutropenia at low risk for bacteremia. J Pediatr Hematol Oncol 2013;35:206–11. 34. Wong HR, Cvijanovich N, Wheeler DS, et al. Interlukin-8 as a stratification tool for interventional trials involving pediatric septic shock. Am J Respir Crit Care Med 2008;178:276–82. 35. Saadeh C. The erythrocyte sedimentation rate: old and new clinical applications. South Med J 1998;91:220–5. 36. Barati M, Alinejad F, Bahar MA, et al. Comparison of WBC, ESR, CRP, and PCT serum levels in septic and non-septic burn cases. Burns 2008;34:770–4. 37. Schmidt H, Hoyer D, Wilhelm J, et al. The alteration of autonomic function in multiple organ dysfunction syndrome. Crit Care Clin 2008;24:149–63. 38. Pontet J, Contreras P, Curbelo A, et al. Heart rate variability as early marker of multiple organ dysfunction syndrome in septic patients. J Crit Care 2003;18:156–63. 39. Schmidt H, Muller-Werdan U, Hoffmann T, et al. Autonomic dysfunction predicts mortality in patients with multiple organ dysfunction syndrome of different age groups. Crit Care Med 2005;33:1994–2002. 40. Werdan K, Schmidt H, Ebelt H, et al. Impaired regulation of cardiac function in sepsis, SIRS, and MODS. Can J Physiol Pharmacol 2009;87:266–74. 41. Yokota Y, Kawamura Y, Matsumaru N, et al. Septic shock prediction by real time monitoring of heart rate variability. In: Jobbágy Á, editor. 5th European IFMBE Conference, IFMBE Proceedings, 37. 2011. p. 195–8.
42. Ellenby MS, McNames J, Lai S, et al. Uncoupling and recoupling of autonomic regulation of the heart beat in pediatric septic shock. Shock 2001;16:274–7. 43. Griffin MP, O’Shea TM, Bissonette EA, et al. Abnormal heart rate characteristics preceding neonatal sepsis and sepsis-like illness. Pediatr Res 2003;53:920–6. 44. Chen W-L, Kuo C-D. Characteristics of heart rate variability can predict impending septic shock in emergency department patients with sepsis. Acad Emerg Med 2007;14:392–7. 45. Bernardin G, Pradier C, Tiger F, et al. Blood pressure and arterial lactate level are early indicators of short-term survival in human septic shock. Intensive Care Med 1996;22:17–25. 46. Rady MY, Rivers EP, Martin GB, et al. Continuous central venous oximetry and shock index in the emergency department: use in the evaluation of clinical shock. Am J Emerg Med 1992;10:538–41. 47. Rady MY, Nightingale P, Little RA, et al. Shock index: a reevaluation in acute circulatory failure. Resuscitation 1992;23:227–34. 48. Berger T, Green J, Horeczko T, et al. Shock index and early recognition of sepsis in the emergency department: pilot study. West J Emerg Med 2013;14:168–74. 49. Yasaka Y, Khemani RG, Markovitz BP. Is shock index associated with outcome in children with sepsis/septic shock? Pediatr Crit Care Med 2013;14:e372–9. 50. Tibby SM, Hatherill M, Murdoch IA. Capillary refill and coreperipheral temperature gap as indicators of haemodynamic status in paediatric intensive care patients. Arch Dis Child 1999;80:163–6. 51. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe s e p s i s a n d s e pt i c s h oc k : 2 0 12 . C r i t C a r e M e d 2013;41:580–637. 52. Pope JV, Jones AE, Gaieski DF, et al. Multi-center study of central venous oxygen saturation (ScvO2) as a predictor of mortality in patients with sepsis. Ann Emerg Med 2010;55:40–46.e1. 53. de Oliveira CF, de Oliveira DSF, Gottschald AFC, et al. ACCM/PALS haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation. Intensive Care Med 2008;34:1065–75. 54. Shapiro NI, Wolfe RE, Moore RB, et al. Mortality in emergency department sepsis (MEDS) score: a prospectively derived and validated clinical prediction rule. Crit Care Med 2003;31:670–5. 55. Sankoff JD, Goyal M, Gaieski DF, et al. Validation of the mortality in emergency department sepsis (MEDS) score in patients with the systemic inflammatory response syndrome (SIRS). Crit Care Med 2008;36:421–6. 56. Wong HR, Salisbury S, Xiao Q, et al. The pediatric sepsis biomarker risk model. Crit Care 2012;16:R174. 57. Wong HR, Lindsell CJ, Pettila V, et al. A multibiomarkerbased outcome risk stratification model for adult septic shock. Crit Care Med 2014;42:781–9.
Keywords: C-reactive protein; procalcitonin; lactate; CD-64; soluble triggering receptor expressed on myeloid cells 1; interleukin 6; interleukin 8; sepsis; biomarker; pediatrics Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL. Reprint requests and correspondence: Ranna A. Rozenfeld, MD, Associate Professor of Pediatrics, Feinberg School of Medicine, Northwestern University, Attending Physician, Pediatric Critical Care Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 E Chicago Ave, Box 73, Chicago, IL 60611. [email protected] (M.F. Alqahtani), [email protected] (L.E. Marsillio), [email protected] (R.A. Rozenfeld) 1522-8401 © 2014 Elsevier Inc. All rights reserved.
A Review of Biomarkers and Physiomarkers in Pediatric Sepsis Mashael F. Alqahtani, MBBS, Lauren E. Marsillio, MD, Ranna A. Rozenfeld, MD
S
epsis is a leading cause of morbidity and mortality in critically ill pediatric patients. More than 20 000 children are affected by severe sepsis annually in the United States, with mortality estimates ranging from 4.2% to 10.3%. 1,2 Multiple studies performed in the emergency department (ED) setting show that compliance rates with the American College of Critical Care Medicine/Pediatric Advanced Life Support septic shock guidelines are low. 3-6 Implementation of sepsis protocols in EDs has improved these numbers; however, there remains further room for improvement. This gap in compliance may be due, in part, to difficulties in discriminating patients with sepsis from the millions of children with benign infectious illnesses who present to the ED each day. Therefore, rapid and accurate identification is a crucial step in sepsis survival for children. The use of biomarkers and physiomarkers may potentially facilitate early diagnosis; however, it is important to have an understanding of the indication, appropriate utilization, and applicability of the multiple biomarkers and physiomarkers available to clinicians. In light of the increased focus on biomarkers, the National Institutes of Health Biomarkers Definitions Working Group created a definition of biomarkers as a “characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” 7 The term physiomarkers overlaps somewhat with biomarkers, but we describe a physiomarker as the physiologic parameters indicative of disease in hospitalized patients (Table 1).
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TABLE 1. Definitions of biomarker and physiomarker. Name
Definition
Examples Biomarker
An objectively measured indicator of normal or abnormal biological processes; CRP, PCT, CD64, IL-6, IL-8 Useful in diagnosis, monitoring, staging and prognosis of disease Lactate, ESR, sTREM-1 Physiomarker An objectively or subjectively measured physiologic indicator of a disease process; vital signs, ScvO2 Useful in diagnosis and monitoring of disease capillary refill time
To achieve a better understanding of the more widely known biomarkers and physiomarkers, we describe the advantages and disadvantages of the more common biomarkers, the evidence for use of
various physiomarkers, and several scoring systems that integrate the various markers.
BIOMARKERS C-Reactive Protein C-reactive protein (CRP) is an acute-phase reactant produced by hepatocytes and is measured in the blood (Figure 1). Levels are known to rise in the presence of infection or tissue injury approximately 4 to 6 hours after an inflammatory stimulus. C-reactive protein values usually peak around 36 to 50 hours with a half-life of approximately 20 hours. 8,9 Overall, CRP has relatively low sensitivity and specificity preventing it from being a good marker to differentiate between bacterial, viral, and noninfectious inflammatory processes such as trauma, surgery, or rheumatologic diseases. A systematic review evaluated the diagnostic accuracy of CRP in pediatric patients in an ED setting to evaluate if CRP could differentiate serious
Figure 1. A simplified depiction of biomarker production in inflammation. An inflammatory signal stimulates the production of PCT as well as IL-6 and IL-8 from various immune system cells, including macrophages as well as many other cell types. Triggering receptor expressed on myeloid cells 1 is expressed on neutrophils and macrophages as is CD64, which binds certain subclasses of immunoglobulin G. Downstream effects are numerous and further modulate the immune response. C-reactive protein, primarily produced by the liver in response to inflammation, participates in complement activation as well as other functions. Together, these biomarkers are just a few of the molecules that collectively function to further the inflammatory response. Lactate is a product of anaerobic metabolism in the presence of tissue hypoxia. TREM-1 indicates triggering receptor expressed on myeloid cells-1; IgG, immunoglobulin G.
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bacterial infection from benign infection (bacterial/ nonbacterial) and bacterial from nonbacterial infection. This study showed that CRP is of moderate value for ruling out serious bacterial infection in a child with a fever but is of limited value for ruling out all bacterial infections. 10 The neonatal population may be the group that benefits most from evaluation with CRP, especially in the first 48 hours of life. In one study of neonatal sepsis, CRP was found to be more reliable than procalcitonin (PCT), although additional studies have found conflicting results. 11 Because of its lack of specificity, CRP has often been used in conjunction with other biomarkers such as PCT, interleukin 6 (IL-6) or interleukin 8 (IL-8) as part of a diagnostic panel. Overall, outside the neonatal population, CRP has little value in diagnosis and prognosis of sepsis.
Procalcitonin Procalcitonin is a 116-amino acid peptide precursor of the hormone calcitonin, which has been described as a reliable diagnostic and prognostic biomarker of sepsis. In healthy subjects, it is secreted by the neuroendocrine C cells of the thyroid, but during an infection, PCT is secreted by many tissues and cells. 8,12 In the setting of inflammation, PCT rises faster than CRP and usually peaks around 24 hours. Procalcitonin is attenuated by interferon γ in viral infections, which supports the claim that it serves as a better indicator of bacterial infection than other biomarkers such as CRP. 13 Many studies have shown that PCT is better than CRP at differentiating systemic inflammatory response syndrome (SIRS) due to bacterial vs nonbacterial sources in critically ill children. 13,14 One study comparing the accuracy of PCT and CRP showed that PCT levels above the cut-off value of 2.5 ng/mL increased the probability of bacterial SIRS to 60%, whereas a CRP value more than 40 mg/L only increased the probability of bacterial SIRS to 50%. When clinical judgment suspecting infection was factored in along with a positive PCT, the probability increased to 92% for bacterial infection. 13 This data support PCT as a good marker to discriminate bacterial from viral infections. Several groups have demonstrated that PCT levels were significantly elevated in patients with sepsis, severe sepsis, or septic shock when compared with infected patients without signs of SIRS. 15,16 Furthermore, other studies comparing PCT and CRP in both the adult and pediatric populations show that PCT was better than CRP at discriminat-
ing SIRS from sepsis. 17,18 Limitations of the use of PCT include its variable levels in invasive fungal infections as well as limited utility in neonates within the first 48 hours of life. Overall, we recommend sending a PCT level in children with a suspicion for sepsis, noting that each institution’s testing capabilities and laboratory turnaround times may vary, potentially affecting the current utility of this test in the ED.
Lactate Lactate has been used extensively to distinguish sepsis from septic shock and has been recognized as a marker of tissue hypoxia. Lactate is the byproduct of anaerobic metabolism, although hyperlactatemia could develop independently of tissue hypoxia as in inborn errors of metabolism or toxin ingestion. A study in a pediatric ED showed that a venous lactate level of at least 4 mmol/L in patients with SIRS was associated with a 5.5 times increased risk for organ dysfunction within the first 24 hours after triage. 19 Another study showed that initial serum lactate was independently associated with mortality in adults who presented to the ED with severe sepsis. 20 Overall, lactate is a good marker of organ perfusion and, if elevated, may be consistent with sepsis. Therefore, we would recommend obtaining a freeflowing serum lactate level in the ED if clinical concern for SIRS or sepsis is present. In addition, lactate levels should be followed to help guide adequate resuscitation. However, lactate is neither sensitive enough nor specific enough to definitively diagnose patients as having sepsis.
Complete Blood Count A complete blood count with white blood cell (WBC) differential is a common laboratory test ordered when there is suspicion of infection. An elevated WBC count, or in the very young, a low WBC count, is associated with the presence of infection. In addition, the increased total number of immature granulocytes in the blood has been found to be a good marker in discriminating infected from noninfected adult patients very early during SIRS particularly within the first 48 hours after SIRS onset. 21 In pediatric patients, though, admission WBC has poor ability in predicting septic shock. 22 Overall, a complete blood count with WBC differential is important to obtain when evaluating for possible SIRS and sepsis; however, its low sensitivity and specificity limit its role as a predictor of infection.
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Cluster of Differentiation 64 Cluster of Differentiation 64 (CD64) is a highaffinity surface marker known as Fc γ receptor I that binds immunoglobulin G. It is constitutively found on monocytes but in the setting of inflammation will be significantly and rapidly (within 4-6 hours after stimulation) up-regulated on polymorphonuclear neutrophils. 23 The fact that few other disease states result in this up-regulation on neutrophils makes CD64 a good candidate for a sepsis biomarker in children and neonates. 24,25 One study in neonates and children found that CD64 had better diagnostic accuracy than PCT or CRP at the time of suspected sepsis and at 24 hours. 26 However, others have found conflicting results, showing CD64 to have difficulty discriminating bacterial from viral infections in pediatric patients. 27 Overall, CD64 expression on polymorphonuclear neutrophils could be a useful diagnostic cell-based parameter of bacterial infections, but currently, rapid testing is not widely available, and it remains unclear if CD64 offers a benefit over CRP or PCT.
Soluble Triggering Receptor Expressed on Myeloid Cells 1 The soluble triggering receptor expressed on myeloid cells 1(sTREM-1) is a member of the immunoglobulin superfamily and is expressed on phagocytes with exposure to various pathogens. 28 Soluble triggering receptor expressed on myeloid cells 1 mediates the acute inflammatory response to microbes. In a meta-analysis, which evaluated the ability of sTREM-1 to differentiate sepsis from SIRS, a pooled sensitivity of 79% and specificity of 80% was found indicating some promise in its ability to be a valuable biomarker in diagnosing sepsis. 29 A small study evaluating adults with severe sepsis receiving appropriate early goal-directed therapy found that sTREM-1 was significantly higher in the nonsurvivors compared with survivors. 30 These findings, along with the fact that sTREM-1 is not elevated in noninfectious processes, indicate that this biomarker may prove to be useful for both early diagnosis of sepsis as well as prognostication for disease severity. However, like the other biomarkers above, it is best used in conjunction with other tests. In addition, rapid testing for sTREM-1 is not available in many centers, limiting its current utility.
Interleukin 6 Clinical studies have shown that IL-6, an important inflammatory cytokine released by macrophages as well as many other cell types, is elevated
in adult and pediatric sepsis patients. 15,31 It has been shown to be reliable in differentiating between sepsis and SIRS adult patients. 15 In pediatric meningococcal septic shock, serum levels were found to correlate with the degree of myocardial depression. 32 High serum levels of IL-6 (N 1000 pg/mL) have also been shown to predict sepsis-related death in adult patients. 16 However, IL-6 is also elevated in many noninfectious conditions such as trauma, surgery, and stroke, making it questionable as a diagnostic marker for sepsis.
Interleukin 8 Interleukin 8 is another proinflammatory cytokine that is elevated in pediatric septic patients. It is produced and released by phagocytes as well as many other cell types, peaks several hours after an inflammatory stimulus, and has been found to increase with illness severity. 16,31 Unlike several other biomarkers, IL-8 is not affected by gestational age or postnatal age. 25 Its utility in the oncology population has been evaluated. In one study of pediatric oncology patients with fever and neutropenia, elevated levels of IL-8 were strongly correlated with bacteremia, whereas low levels of IL-8 were associated with low risk of bacteremia. 33 In addition, serum IL-8 levels less than 220 pg/mL measured within 24 hours of admission had a high prediction for survival in pediatric patients with septic shock. 34 Interleukin 8 seems to hold promise as a useful biomarker for sepsis; however, limited availability of rapid testing limits its current usefulness.
Erythrocyte Sedimentation Rate Erythrocyte sedimentation rate (ESR) is a frequently ordered test for evaluating inflammation that has been in use in some manner since the 1920s. Initially designed to indirectly measure fibrinogen levels, it has become used as a measure of the rate at which red blood cells precipitate out of plasma in 1 hour. It is a nonspecific marker that rises in the setting of inflammation and has limited utility because it is elevated in multiple disease processes involving significant inflammatory response. It has been used to follow treatment response especially with rheumatologic disease. 35 In one study of burn patients, ESR was found to be elevated in this population but could not differentiate between those who were septic from those who were not. 36 Overall, ESR has largely fallen out of favor as a marker of sepsis in place of other biomarkers discussed above.
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In summary, the various biomarkers discussed above have distinct advantages and disadvantages for use in the ED (Table 2).
PHYSIOMARKERS Body Temperature One of the earliest clinical signs of infection is change in body temperature. In immunocompetent children, fever may be the initial marker of serious infection, whereas hypothermia may be the presenting sign in infants. Ultimately, although fever is part of the diagnostic criteria for SIRS and sepsis, it is too insensitive and nonspecific to be used alone in identifying patients with sepsis.
Heart Rate Heart rate is usually elevated in patients with sepsis and, like fever, it is an insensitive and nonspecific finding. However, loss of heart rate variability (HRV) or loss of the normal beat to beat oscillations present in healthy people has been associated with sepsis in both pediatric and adult patients. Development of autonomic dysfunction occurs early in sepsis and has been studied
extensively in critically ill adult patients. 37 -40 It is thought to be secondary to an “uncoupling” of the neurally mediated interorgan communication system, and one of the ways in which this is manifested is with loss of HRV. 37 Studies of adult patients with sepsis consistently show a loss of HRV before diagnosis of sepsis, and in one case, up to 24 hours before clinically evident sepsis. 41 The loss of HRV has also been shown to occur in neonates and pediatric patients with sepsis. 42,43 This loss of HRV is felt to reflect a loss of adaptive mechanisms and/or autonomic imbalance or dysfunction either as a consequence of critical illness or as a harbinger of clinical deterioration. In one study of adult ED patients, HRV analysis was able to predict development of sepsis. 44 However, the technology to evaluate these changes, although available, is difficult to implement in real time. As our monitoring methods improve, it is likely that we will be able to use this technique in the future.
Blood Pressure Hypotension is often a late finding in sepsis and septic shock, especially in the pediatric population. Using blood pressure at the time of presentation as a predictor of sepsis has been evaluated. In a small
TABLE 2. Biomarker usefulness for sepsis diagnosis. Biomarker CRP
Performance
Turnaround time
Somewhat sensitive somewhat specific Sensitive Specific Insensitive Not specific Insensitive Not specific Somewhat sensitive Moderately specific Somewhat sensitive
1-6 h
IL-6
Moderately specific Moderately sensitive Not specific
If not send out 1-3 hours if If not send out
IL-8
Variable sensitivity reported
Days
Moderately specific
Likely a send out lab
PCT Lactate WBC CD64 sTREM-1
0.5-3 h Immediate 0.5-1.5 h 1-2 h If not send out Approx. 5 hours
Lab indicates laboratory; approx, approximately.
Special considerations Does not differentiate viral from bacterial process; Elevated in noninfectious processes Useful in predicting serious bacterial infection early May be useful in immunosuppressed patients Widely available; higher levels associated with morbidity Elevated with certain inborn errors of metabolism Poor at predicting sepsis or septic shock Not widely available; useful for predicting bacterial infection Not widely available; moderate ability to discriminate sepsis from SIRS in adults Limited pediatric data Good at predicting sepsis and myocardial dysfunction May also be elevated in other conditions including trauma and stroke High levels associated with bacteremia in patients with febrile neutropenia Good marker of illness severity and predictor of survival
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study of adult patients with sepsis, there was no significant difference in mean arterial blood pressure on admission in survivors compared with nonsurvivors. However, aggressive treatment of hypotension did improve short-term survival. 45 Recent focus has shifted to evaluating pulse pressure or systolic pressure variability, but although it is commonly accepted that a widened pulse pressure is consistent with warm shock, it is not specific to septic shock.
Shock Index The Shock Index (SI) is defined as the ratio of heart rate to systolic blood pressure and was first described in 1967 as a way to assess for hypovolemia in various shock states. Over time, SI has been found to correlate with hypovolemia in both animal and human models as well as persistent left ventricular failure. 46,47 In one study of adult ED patients, an elevated SI that was greater than 0.7 was associated with a lactate level at least 4 mmol/L, a marker for disease severity, and SI performed just as well SIRS criteria. 48 In the pediatric population, there are few studies, but one group found that, among patients whose SI was above the 50th percentile at intensive care unit admission, improvement of SI was associated with lower intensive care unit mortality in children ages 1 to 3 and over 12 years. 49 Although blood pressure is not a good physiomarker for sepsis, SI may provide a useful tool to gauge effectiveness of resuscitation in the ED.
Capillary Refill Time Capillary refill time has long been considered an important component of the physical examination in patients with suspected sepsis for both assessment of disease severity as well as evaluation of adequate resuscitation. Normal capillary refill time is considered to be less than or equal to 2 seconds. Despite our reliance on this physiologic sign, there is wide variability in clinician assessment of capillary refill time, and overall, it alone is a poor indicator of sepsis. In addition, its ability to predict outcomes is limited. One study in the PICU showed that capillary refill time at least 2 seconds was a poor predictor of hemodynamic status and should thus be interpreted with caution. 50
Central Venous Oxygen Saturation Central venous oxygen saturation (ScvO2) is obtained by measuring the oxygen saturation in venous blood returning to the heart at the level of the superior vena cava/right atrium junction. It is
important to note that this serves as a substitute for true mixed venous oxygen saturation that is obtained from the pulmonary artery. Central venous oxygen saturation is an indirect index of global tissue oxygenation. It represents the balance between oxygen delivery and oxygen consumption. Although central venous access is often not obtained in many pediatric EDs, ScvO2 is a useful physiomarker to follow in the early phases of resuscitation in pediatric sepsis. Optimization of ScvO2 is considered one of the main resuscitation targets of the early goal-directed therapy along with normalization of central venous pressure, mean arterial pressure, and urine output as recommended by the Surviving Sepsis Campaign 2012 guidelines and American College of Critical Care Medicine/Pediatric Advanced Life Support guidelines. 3,51 A multicenter adult study found that, for patients in whom a normal ScvO2 goal was targeted during early goal-directed therapy, they were twice as likely to survive compared with patients who did not reach this end point. 52 Similar findings have been shown in children. 53 The limitation of using ScvO2 as a physiomarker in pediatric patients has proven to be the lack of central venous lines in septic pediatric patients in the ED. However, patients who already have a central venous line (such as patients requiring chemotherapy for oncologic disease or who require total parenteral nutrition) should have a central venous saturation checked.
SCORING SYSTEMS Mortality in Emergency Department Sepsis Score The Mortality in Emergency Department Sepsis (MEDS) score is a validated tool used to risk-stratify patients to predict 28-day mortality in adults with presumed sepsis. The MEDS score assigns patients to 1 of 5 mortality risk groups based on multiple clinical variables. The MEDS serves as a good predictor of mortality in septic adult patients. 54,55 Unfortunately, there is no equivalent score in the pediatric population, which makes this a potential area for future research.
The Pediatric Sepsis Biomarker Risk Model The pediatric sepsis biomarker risk model is a model that was created and validated as a riskstratification tool for outcomes prediction in pediatric septic shock. It includes 12 biomarkers derived from genome-wide expression profiling. The model was derived and tested using 355 subjects less than
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the age of 11years admitted with a diagnosis of septic shock. Testing of this model found a sensitivity of 93% and a specificity of 74% for 28day all-cause mortality. 56 A similar model was also recently tested and validated in adults, which found good sensitivity, although slightly less specificity for mortality in septic shock. 57 Once risk models like these are widely available with a rapid turnaround time, they could potentially become useful tools in the ED to assist clinicians in identifying who is at highest risk for dying of sepsis.
Summary The timely diagnosis of pediatric sepsis in the ED poses a significant challenge for clinicians for a variety of reasons. These include lack of rapid and accurate diagnostic tools, absence of simple and specific diagnostic criteria, and vague symptoms during the early phase of illness. The wide range of biomarkers currently available for testing offers an attractive option to assist with diagnosis, triage, and prognosis; however, none to date has been identified as the single best marker. Furthermore, many are not widely available in EDs nor is the testing turnaround time uniform from one institution to another. In addition, the physiomarkers described above also have limited utility in current practice, due to their lack of specificity for any one disease process. However, recent advances have been made in creating tools and algorithms that are able to combine the available biomarkers and physiomarkers. The best predictive tool in the future will likely be a combination of multiple biomarkers and physiomarkers that also account for patient-specific factors.
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