Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Noninfectious influencers of early-onset sepsis biomarkers

Abstract

Diagnostic tests for sepsis aim to either detect the infectious agent (such as microbiological cultures) or detect host markers that commonly change in response to an infection (such as C-reactive protein). The latter category of tests has advantages compared to culture-based methods, including a quick turnaround time and in some cases lower requirements for blood samples. They also provide information on the immune response of the host, a critical determinant of clinical outcome. However, they do not always differentiate nonspecific host inflammation from true infection and can inadvertently lead to antibiotic overuse. Multiple noninfectious conditions unique to neonates in the first days after birth can lead to inflammatory marker profiles that mimic those seen among infected infants. Our goal was to review noninfectious conditions and patient characteristics that alter host inflammatory markers commonly used for the diagnosis of early-onset sepsis. Recognizing these conditions can focus the use of biomarkers on patients most likely to benefit while avoiding scenarios that promote false positives. We highlight approaches that may improve biomarker performance and emphasize the need to use patient outcomes, in addition to conventional diagnostic performance analysis, to establish clinical utility.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Singer, M. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 801–810 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  2. 2.

    Mukhopadhyay, S. et al. Impact of early-onset sepsis and antibiotic use on death or survival with neurodevelopmental impairment at 2 years of age among extremely preterm infants. J. Pediatr. 221, 39–46.e5 (2020).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Wynn, J., Cornell, T. T., Wong, H. R., Shanley, T. P. & Wheeler, D. S. The host response to sepsis and developmental impact. Pediatrics 125, 1031–1041 (2010).

    PubMed  Google Scholar 

  4. 4.

    Eschborn, S. & Weitkamp, J. H. Procalcitonin versus C-reactive protein: review of kinetics and performance for diagnosis of neonatal sepsis. J. Perinatol. 39, 893–903 (2019).

    PubMed  Google Scholar 

  5. 5.

    Stocker, M. et al. Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis: a multicentre, randomised controlled trial (NeoPIns). Lancet 390, 871–881 (2017).

    PubMed  CAS  Google Scholar 

  6. 6.

    Nabulsi, M., Hani, A. & Karam, M. Impact of C-reactive protein test results on evidence-based decision-making in cases of bacterial infection. BMC Pediatr. 12, 140–140 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  7. 7.

    Ayrapetyan, M., Carola, D., Lakshminrusimha, S., Bhandari, V. & Aghai, Z. H. Infants born to mothers with clinical chorioamnionitis: a cross-sectional survey on the use of early-onset sepsis risk calculator and prolonged use of antibiotics. Am. J. Perinatol. 36, 428 (2019).

    PubMed  Google Scholar 

  8. 8.

    Mukherjee, A., Davidson, L., Anguvaa, L., Duffy, D. A. & Kennea, N. NICE neonatal early onset sepsis guidance: greater consistency, but more investigations, and greater length of stay. Arch. Dis. Child Fetal Neonatal Ed. 100, 248 (2015).

    Google Scholar 

  9. 9.

    Kiser, C., Nawab, U., McKenna, K. & Aghai, Z. H. Role of guidelines on length of therapy in chorioamnionitis and neonatal sepsis. Pediatrics 133, 992–998 (2014).

    PubMed  Google Scholar 

  10. 10.

    Ting, J. Y. & Roberts, A. Association of early life antibiotics and health outcomes: evidence from clinical studies. Semin. Perinatol. 44, 151322 (2020).

    PubMed  Google Scholar 

  11. 11.

    Wang, T. et al. Early life antibiotic exposure and host health: Role of the microbiota-immune interaction. Semin. Perinatol. 44, 151323 (2020).

    PubMed  Google Scholar 

  12. 12.

    Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Healthcare Quality Promotion (DHQP). Biggest threats and data: 2019 AR threats report. https://www.cdc.gov/drugresistance/biggest-threats.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fdrugresistance%2Fbiggest_threats.html (2019).

  13. 13.

    Hofer, N., Müller, W. & Resch, B. Non-infectious conditions and gestational age influence C-reactive protein values in newborns during the first 3 days of life. Clin. Chem. Lab Med. 49, 297–302 (2011).

    PubMed  CAS  Google Scholar 

  14. 14.

    Hillman, N. H., Kallapur, S. G. & Jobe, A. H. Physiology of transition from intrauterine to extrauterine life. Clin. Perinatol. 39, 769–783 (2012).

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Cantey, J. B., Wozniak, P. S. & Sánchez, P. J. Prospective surveillance of antibiotic use in the neonatal intensive care unit: results from the SCOUT study. Pediatr. Infect. Dis. J. 34, 267–272 (2015).

    PubMed  Google Scholar 

  16. 16.

    Benitz, W. E. Adjunct laboratory tests in the diagnosis of early-onset neonatal sepsis. Clin. Perinatol. 37, 421–438 (2010).

    PubMed  Google Scholar 

  17. 17.

    National Institute for Health and Care Excellence. Neonatal infection: antibiotics for prevention and treatment (NG195). https://www.nice.org.uk/guidance/ng195 (2021).

  18. 18.

    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 102, 25–36 (2012).

    PubMed  CAS  Google Scholar 

  19. 19.

    Macallister, K., Smith-Collins, A., Gillet, H., Hamilton, L. & Davis, J. Serial C-reactive protein measurements in newborn infants without evidence of early-onset infection. Neonatology 116, 85–91 (2019).

    PubMed  CAS  Google Scholar 

  20. 20.

    Sturgeon, J. P., Zanetti, B. & Lindo, D. C-reactive protein (CRP) levels in neonatal meningitis in England: an analysis of national variations in CRP cut-offs for lumbar puncture. BMC Pediatr. 18, 380–x (2018).

    Google Scholar 

  21. 21.

    Dumpa, V. & Kamity, R. Birth Trauma. [Updated 2021 Sep 6]. In StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK539831/ (Treasure Island (FL), StatPearls Publishing, 2021).

  22. 22.

    Emmerson, A. J. C-reactive protein and the newborn infant. Arch. Dis. Child Educ. Pract. Ed. 96, e1 (2011).

    PubMed  Google Scholar 

  23. 23.

    Berger, C., Uehlinger, J., Ghelfi, D., Blau, N. & Fanconi, S. Comparison of C-reactive protein and white blood cell count with differential in neonates at risk for septicaemia. Eur. J. Pediatr. 154, 138–144 (1995).

    PubMed  CAS  Google Scholar 

  24. 24.

    Pourcyrous, M., Bada, H. S., Korones, S. B., Baselski, V. & Wong, S. P. Significance of serial C-reactive protein responses in neonatal infection and other disorders. Pediatrics 92, 431–435 (1993).

    PubMed  CAS  Google Scholar 

  25. 25.

    Wagle, S., Grauaug, A., Kohan, R. & Evans, S. F. C-reactive protein as a diagnostic tool of sepsis in very immature babies. J. Paediatr. Child Health 30, 40–44 (1994).

    PubMed  CAS  Google Scholar 

  26. 26.

    Kääpä, P. & Koistinen, E. Maternal and neonatal C-reactive protein after interventions during delivery. Acta Obstet. Gynecol. Scand. 72, 543–546 (1993).

    PubMed  Google Scholar 

  27. 27.

    Mjelle, A. B., Guthe, H. J. T., Reigstad, H., Bjørke-Monsen, A. L. & Markestad, T. Serum concentrations of C-reactive protein in healthy term-born Norwegian infants 48-72h after birth. Acta Paediatr. 108, 849–854 (2019).

    PubMed  CAS  Google Scholar 

  28. 28.

    Perrone, S. et al. C reactive protein in healthy term newborns during the first 48h of life. Arch. Dis. Child Fetal Neonatal Ed. 103, F163–F166 (2018).

    PubMed  Google Scholar 

  29. 29.

    Chiesa, C. et al. C reactive protein and procalcitonin: reference intervals for preterm and term newborns during the early neonatal period. Clin. Chim. Acta 412, 1053–1059 (2011).

    PubMed  CAS  Google Scholar 

  30. 30.

    Ishibashi, M., Takemura, Y., Ishida, H., Watanabe, K. & Kawai, T. C-reactive protein kinetics in newborns: application of a high-sensitivity analytic method in its determination. Clin. Chem. 48, 1103–1106 (2002).

    PubMed  CAS  Google Scholar 

  31. 31.

    Bellieni, C. V. et al. C-reactive protein: a marker of neonatal stress? J. Matern. Fetal Neonatal Med. 27, 612–615 (2014).

    PubMed  CAS  Google Scholar 

  32. 32.

    Thompson, A. L., Houck, K. M. & Jahnke, J. R. Pathways linking caesarean delivery to early health in a dual burden context: immune development and the gut microbiome in infants and children from Galápagos, Ecuador. Am. J. Hum. Biol. e23219 (2019).

  33. 33.

    Schmutz, N., Henry, E., Jopling, J. & Christensen, R. D. Expected ranges for blood neutrophil concentrations of neonates: the Manroe and Mouzinho charts revisited. J. Perinatol. 28, 275–281 (2008).

    PubMed  CAS  Google Scholar 

  34. 34.

    Hasan, R., Inoue, S. & Banerjee, A. Higher white blood cell counts and band forms in newborns delivered vaginally compared with those delivered by cesarean section. Am. J. Clin. Pathol. 100, 116–118 (1993).

    PubMed  CAS  Google Scholar 

  35. 35.

    Chirico, G., Gasparoni, A., Ciardelli, L., Martinotti, L. & Rondini, G. Leukocyte counts in relation to the method of delivery during the first five days of life. Biol. Neonate 75, 294–299 (1999).

    PubMed  CAS  Google Scholar 

  36. 36.

    Chan, C. J., Summers, K. L., Chan, N. G., Hardy, D. B. & Richardson, B. S. Cytokines in umbilical cord blood and the impact of labor events in low-risk term pregnancies. Early Hum. Dev. 89, 1005–1010 (2013).

    PubMed  CAS  Google Scholar 

  37. 37.

    Barug, D. et al. Reference values for interleukin-6 and interleukin-8 in cord blood of healthy term neonates and their association with stress-related perinatal factors. PLoS ONE 9, e114109 (2014).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Jokic, M. et al. Fetal distress increases interleukin-6 and interleukin-8 and decreases tumour necrosis factor-alpha cord blood levels in noninfected full-term neonates. BJOG 107, 420–425 (2000).

    PubMed  CAS  Google Scholar 

  39. 39.

    Malamitsi-Puchner, A. et al. The influence of the mode of delivery on circulating cytokine concentrations in the perinatal period. Early Hum. Dev. 81, 387–392 (2005).

    PubMed  CAS  Google Scholar 

  40. 40.

    Mukhopadhyay, S., Eichenwald, E. C. & Puopolo, K. M. Neonatal early-onset sepsis evaluations among well-appearing infants: projected impact of changes in CDC GBS guidelines. J. Perinatol. 33, 198–205 (2012).

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Higgins, R. D. et al. Evaluation and management of women and newborns with a maternal diagnosis of chorioamnionitis: summary of a workshop. Obstet. Gynecol. 127, 426–436 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  42. 42.

    Mukhopadhyay, S. et al. Variation in sepsis evaluation across a national network of nurseries. Pediatrics 139, https://doi.org/10.1542/peds.2016-2845 (2017).

  43. 43.

    Turner, D. et al. Procalcitonin in preterm infants during the first few days of life: introducing an age related nomogram. Arch. Dis. Child Fetal Neonatal Ed. 91, 283 (2006).

    Google Scholar 

  44. 44.

    Assumma, M. et al. Serum procalcitonin concentrations in term delivering mothers and their healthy offspring: a longitudinal study. Clin. Chem. 46, 1583–1587 (2000).

    PubMed  CAS  Google Scholar 

  45. 45.

    Mathai, E. et al. Is C-reactive protein level useful in differentiating infected from uninfected neonates among those at risk of infection? Indian Pediatr. 41, 895–900 (2004).

    PubMed  Google Scholar 

  46. 46.

    Chiesa, C. et al. C-reactive protein, interleukin-6, and procalcitonin in the immediate postnatal period: influence of illness severity, risk status, antenatal and perinatal complications, and infection. Clin. Chem. 49, 60–68 (2003).

    PubMed  CAS  Google Scholar 

  47. 47.

    Lee, J., Bang, Y. H., Lee, E. H., Choi, B. M. & Hong, Y. S. The influencing factors on procalcitonin values in newborns with noninfectious conditions during the first week of life. Korean J. Pediatr. 60, 10–16 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  48. 48.

    Goetzl, L., Evans, T., Rivers, J., Suresh, M. S. & Lieberman, E. Elevated maternal and fetal serum interleukin-6 levels are associated with epidural fever. Am. J. Obstet. Gynecol. 187, 834–838 (2002).

    PubMed  Google Scholar 

  49. 49.

    Chiesa, C. et al. Serial measurements of C-reactive protein and interleukin-6 in the immediate postnatal period: reference intervals and analysis of maternal and perinatal confounders. Clin. Chem. 47, 1016–1022 (2001).

    PubMed  CAS  Google Scholar 

  50. 50.

    Rallis, D. et al. C-reactive protein in infants with no evidence of early-onset sepsis. J. Matern. Fetal Neonatal Med. 1–8. https://doi.org/10.1080/14767058.2021.1888921 (2021). [Epub ahead of print].

  51. 51.

    Panero, A. et al. Interleukin 6 in neonates with early and late onset infection. Pediatr. Infect. Dis. J. 16, 370–375 (1997).

    PubMed  CAS  Google Scholar 

  52. 52.

    Henry, E. & Christensen, R. D. Reference intervals in neonatal hematology. Clin. Perinatol. 42, 483–497 (2015).

    PubMed  Google Scholar 

  53. 53.

    Newman, T. B., Puopolo, K. M., Wi, S., Draper, D. & Escobar, G. J. Interpreting complete blood counts soon after birth in newborns at risk for sepsis. Pediatrics 126, 903–909 (2010).

    PubMed  Google Scholar 

  54. 54.

    Jacobs, S. E. et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst. Rev. 2013, CD003311 (2013).

    PubMed Central  Google Scholar 

  55. 55.

    Hakobyan, M. et al. Outcome of infants with therapeutic hypothermia after perinatal asphyxia and early-onset sepsis. Neonatology 115, 127–133 (2019).

    PubMed  Google Scholar 

  56. 56.

    Rao, R. et al. Antimicrobial therapy utilization in neonates with hypoxic-ischemic encephalopathy (HIE): a report from the Children’s Hospital Neonatal Database (CHND). J. Perinatol. 40, 70–78 (2020).

    PubMed  CAS  Google Scholar 

  57. 57.

    Cantey, J. B. & Baird, S. D. Ending the culture of culture-negative sepsis in the neonatal ICU. Pediatrics 140, https://doi.org/10.1542/peds.2017-0044 (2017).

  58. 58.

    Okumuş, N. et al. Effect of therapeutic hypothermia on C-reactive protein levels in patients with perinatal asphyxia. Am. J. Perinatol. 32, 667–674 (2015).

    PubMed  Google Scholar 

  59. 59.

    Chakkarapani, E., Davis, J. & Thoresen, M. Therapeutic hypothermia delays the C-reactive protein response and suppresses white blood cell and platelet count in infants with neonatal encephalopathy. Arch. Dis. Child Fetal Neonatal Ed. 99, 458 (2014).

    Google Scholar 

  60. 60.

    Martín-Ancel, A. et al. Interleukin-6 in the cerebrospinal fluid after perinatal asphyxia is related to early and late neurological manifestations. Pediatrics 100, 789–794 (1997).

    PubMed  Google Scholar 

  61. 61.

    Jenkins, D. D. et al. Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J. Cereb. Blood Flow. Metab. 32, 1888–1896 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  62. 62.

    Polderman, K. H. Mechanisms of action, physiological effects, and complications of hypothermia. Crit. Care Med. 37, 186 (2009).

    Google Scholar 

  63. 63.

    Saito, J. et al. Temporal relationship between serum levels of interleukin-6 and c-reactive protein in therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy. Am. J. Perinatol. 33, 1401–1406 (2016).

    PubMed  Google Scholar 

  64. 64.

    Schuetz, P. 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. 40, 376–381 (2010).

    PubMed  CAS  Google Scholar 

  65. 65.

    Rath, S., Narasimhan, R. & Lumsden, C. C-reactive protein (CRP) responses in neonates with hypoxic ischaemic encephalopathy. Arch. Dis. Child Fetal Neonatal Ed. 99, F172 (2014).

    PubMed  Google Scholar 

  66. 66.

    Cilla, A. et al. Effect of hypothermia and severity of hypoxic-ischemic encephalopathy in the levels of C-reactive protein during the first 120h of life. Am. J. Perinatol. 37, 722–730 (2020).

    PubMed  Google Scholar 

  67. 67.

    Muniraman, H. et al. Biomarkers of hepatic injury and function in neonatal hypoxic ischemic encephalopathy and with therapeutic hypothermia. Eur. J. Pediatr. 176, 1295–1303 (2017).

    PubMed  CAS  Google Scholar 

  68. 68.

    Munteanu, A. I., Manea, A. M., Jinca, C. M. & Boia, M. Basic biochemical and hematological parameters in perinatal asphyxia and their correlation with hypoxic ischemic encephalopathy. Exp. Ther. Med. 21, 259 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  69. 69.

    Sun, B. et al. A meta-analysis of interleukin-6 as a valid and accurate index in diagnosing early neonatal sepsis. Int. Wound J. 16, 527–533 (2019).

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Schelonka, R. L. et al. Volume of blood required to detect common neonatal pathogens. J. Pediatr. 129, 275–278 (1996).

    PubMed  CAS  Google Scholar 

  71. 71.

    Lancaster, D. P., Friedman, D. F., Chiotos, K. & Sullivan, K. V. Blood volume required for detection of low levels and ultralow levels of organisms responsible for neonatal bacteremia by use of bactec peds plus/F, plus aerobic/F medium, and the BD Bactec FX System: an in vitro study. J. Clin. Microbiol. 53, 3609–3613 (2015).

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Frymoyer, A., Meng, L., Bonifacio, S. L., Verotta, D. & Guglielmo, B. J. Gentamicin pharmacokinetics and dosing in neonates with hypoxic ischemic encephalopathy receiving hypothermia. Pharmacotherapy 33, 718–726 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  73. 73.

    Tran, S. H., Caughey, A. B. & Musci, T. J. Meconium-stained amniotic fluid is associated with puerperal infections. Am. J. Obstet. Gynecol. 189, 746–750 (2003).

    PubMed  Google Scholar 

  74. 74.

    Oyelese, Y. et al. Meconium-stained amniotic fluid across gestation and neonatal acid-base status. Obstet. Gynecol. 108, 345–349 (2006).

    PubMed  Google Scholar 

  75. 75.

    Ward, C. & Caughey, A. B. The risk of meconium aspiration syndrome (MAS) increases with gestational age at term. J. Matern. Fetal Neonatal Med. 1–6 https://doi.org/10.1080/14767058.2020.1713744 (2020). [Epub ahead of print].

  76. 76.

    Lee, J. et al. Meconium aspiration syndrome: a role for fetal systemic inflammation. Am. J. Obstet. Gynecol. 214, 366.e1–366.e9 (2016).

    Google Scholar 

  77. 77.

    Tyler, D. C., Murphy, J. & Cheney, F. W. Mechanical and chemical damage to lung tissue caused by meconium aspiration. Pediatrics 62, 454–459 (1978).

    PubMed  CAS  Google Scholar 

  78. 78.

    Jones, C. A. et al. Undetectable interleukin (IL)-10 and persistent IL-8 expression early in hyaline membrane disease: a possible developmental basis for the predisposition to chronic lung inflammation in preterm newborns. Pediatr. Res. 39, 966–975 (1996).

    PubMed  PubMed Central  CAS  Google Scholar 

  79. 79.

    Cayabyab, R. G., Kwong, K., Jones, C., Minoo, P. & Durand, M. Lung inflammation and pulmonary function in infants with meconium aspiration syndrome. Pediatr. Pulmonol. 42, 898–905 (2007).

    PubMed  Google Scholar 

  80. 80.

    Davey, A. M., Becker, J. D. & Davis, J. M. Meconium aspiration syndrome: physiological and inflammatory changes in a newborn piglet model. Pediatr. Pulmonol. 16, 101–108 (1993).

    PubMed  CAS  Google Scholar 

  81. 81.

    de Beaufort, A. J. et al. Meconium is a source of pro-inflammatory substances and can induce cytokine production in cultured A549 epithelial cells. Pediatr. Res. 54, 491–495 (2003).

    PubMed  Google Scholar 

  82. 82.

    de Beaufort, A. J., Pelikan, D. M., Elferink, J. G. & Berger, H. M. Effect of interleukin 8 in meconium on in-vitro neutrophil chemotaxis. Lancet 352, 102–105 (1998).

    PubMed  Google Scholar 

  83. 83.

    Ochi, F. et al. Procalcitonin as a marker of respiratory disorder in neonates. Pediatr. Int. 57, 263–268 (2015).

    PubMed  CAS  Google Scholar 

  84. 84.

    Okazaki, K. et al. Serum cytokine and chemokine profiles in neonates with meconium aspiration syndrome. Pediatrics 121, 748 (2008).

    Google Scholar 

  85. 85.

    Hofer, N., Jank, K., Strenger, V., Pansy, J. & Resch, B. Inflammatory indices in meconium aspiration syndrome. Pediatr. Pulmonol. 51, 601–606 (2016).

    PubMed  Google Scholar 

  86. 86.

    Basu, S., Kumar, A. & Bhatia, B. D. Role of antibiotics in meconium aspiration syndrome. Ann. Trop. Paediatr. 27, 107–113 (2007).

    PubMed  Google Scholar 

  87. 87.

    Lin, H. C., Su, B. H., Tsai, C. H., Lin, T. W. & Yeh, T. F. Role of antibiotics in management of non-ventilated cases of meconium aspiration syndrome without risk factors for infection. Biol. Neonate 87, 51–55 (2005).

    PubMed  Google Scholar 

  88. 88.

    Shankar, V., Paul, V. K., Deorari, A. K. & Singh, M. Do neonates with meconium aspiration syndrome require antibiotics? Indian J. Pediatr. 62, 327–331 (1995).

    PubMed  CAS  Google Scholar 

  89. 89.

    Kelly, L. E., Shivananda, S., Murthy, P., Srinivasjois, R. & Shah, P. S. Antibiotics for neonates born through meconium-stained amniotic fluid. Cochrane Database Syst. Rev. 6, CD006183 (2017).

    PubMed  Google Scholar 

  90. 90.

    Natarajan, C. K., Sankar, M. J., Jain, K., Agarwal, R. & Paul, V. K. Surfactant therapy and antibiotics in neonates with meconium aspiration syndrome: a systematic review and meta-analysis. J. Perinatol. 36(Suppl. 1), 49 (2016).

    Google Scholar 

  91. 91.

    Wiswell, T. E. & Henley, M. A. Intratracheal suctioning, systemic infection, and the meconium aspiration syndrome. Pediatrics 89, 203–206 (1992).

    PubMed  CAS  Google Scholar 

  92. 92.

    Caglayan, F., Caglayan, O., Gunel, E. & Sahin, T. K. Monitoring the metabolic response to major surgery in neonates. Int J. Surg. Investig. 2, 309–312 (2000).

    PubMed  CAS  Google Scholar 

  93. 93.

    Günel, E., Cağlayan, O., Cağlayan, F. & Sahin, T. K. Acute-phase changes in children recovering from minor surgery. Pediatr. Surg. Int. 14, 199–201 (1998).

    PubMed  Google Scholar 

  94. 94.

    Buyukkocak, U. et al. Anaesthesia and the acute phase protein response in children undergoing circumcision. Mediat. Inflamm. 2005, 312–315 (2005).

    Google Scholar 

  95. 95.

    Ramadan, G., Rex, D., Okoye, B. & Kennea, N. L. Early high C-reactive protein in infants with open abdominal wall defects does not predict sepsis or adverse outcome. Acta Paediatr. 99, 126–130 (2010).

    PubMed  CAS  Google Scholar 

  96. 96.

    Bölke, E. et al. Different acute-phase response in newborns and infants undergoing surgery. Pediatr. Res. 51, 333–338 (2002).

    PubMed  Google Scholar 

  97. 97.

    Williams, S. L. et al. Evaluation of early onset sepsis, complete blood count, and antibiotic use in gastroschisis. Am. J. Perinatol. 35, 385–389 (2018).

    PubMed  Google Scholar 

  98. 98.

    Pavcnik-Arnol, M., Bonac, B., Groselj-Grenc, M. & Derganc, M. Changes in serum procalcitonin, interleukin 6, interleukin 8 and C-reactive protein in neonates after surgery. Eur. J. Pediatr. Surg. 20, 262–266 (2010).

    PubMed  CAS  Google Scholar 

  99. 99.

    Aryafar, A. et al. Procalcitonin concentration measured within the first days of cardiac surgery is predictive of postoperative infections in neonates: a case-control study. Pediatr. Cardiol. 40, 1289–1295 (2019).

    PubMed  CAS  Google Scholar 

  100. 100.

    Arkader, R. et al. Procalcitonin does discriminate between sepsis and systemic inflammatory response syndrome. Arch. Dis. Child. 91, 117–120 (2006).

    PubMed  CAS  Google Scholar 

  101. 101.

    Neunhoeffer, F. et al. Serum concentrations of interleukin-6, procalcitonin, and c-reactive protein: discrimination of septical complications and systemic inflammatory response syndrome after pediatric surgery. Eur. J. Pediatr. Surg. 26, 180–185 (2016).

    PubMed  Google Scholar 

  102. 102.

    Brown, J. V. E., Meader, N., Wright, K., Cleminson, J. & McGuire, W. Assessment of C-reactive protein diagnostic test accuracy for late-onset infection in newborn infants: a systematic review and meta-analysis. JAMA Pediatr. 174, 260–268 (2020).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Singh, N. & Gray, J. E. Antibiotic stewardship in NICU: De-implementing routine CRP to reduce antibiotic usage in neonates at risk for early-onset sepsis. J. Perinatol. 41, 2488–2494 (2021).

    PubMed  CAS  Google Scholar 

  104. 104.

    Garber, S. J. et al. Delivery-based criteria for empiric antibiotic administration among preterm infants. J. Perinatol. 41, 255–262 (2021).

    PubMed  CAS  Google Scholar 

  105. 105.

    Janes, H. & Pepe, M. S. Adjusting for covariates in studies of diagnostic, screening, or prognostic markers: an old concept in a new setting. Am. J. Epidemiol. 168, 89–97 (2008).

    PubMed  Google Scholar 

  106. 106.

    Liu, D. & Zhou, X. H. ROC analysis in biomarker combination with covariate adjustment. Acad. Radiol. 20, 874–882 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  107. 107.

    Reinhart, K., Meisner, M. & Brunkhorst, F. M. Markers for sepsis diagnosis: what is useful? Crit. Care Clin. 22, 503–x (2006).

    Google Scholar 

  108. 108.

    Keane, M., Fallon, R., Riordan, A. & Shaw, B. Markedly raised levels of C-reactive protein are associated with culture-proven sepsis or necrotising enterocolitis in extremely preterm neonates. Acta Paediatr. 104, 289 (2015).

    Google Scholar 

  109. 109.

    Emerging Risk Factors Collaboration. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N. Engl J. Med. 367, 1310–1320 (2012).

    Google Scholar 

  110. 110.

    Thompson, A. L. Caesarean delivery, immune function and inflammation in early life among Ecuadorian infants and young children. J. Dev. Orig. Health Dis. 10, 555–562 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  111. 111.

    Jiang, N. M. et al. Early life inflammation and neurodevelopmental outcome in bangladeshi infants growing up in adversity. Am. J. Trop. Med. Hyg. 97, 974–979 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

S.M. receives funding from Eunice Kennedy Shriver National Institute of Child Health and Human Development from the National Institutes of Health grant (K23HD088753).

Author information

Affiliations

Authors

Contributions

C.T. conducted a literature review, wrote the first draft of the manuscript, and reviewed, revised, and approved the final manuscript. S.M. conceptualized the review, conducted a literature review, edited, revised, and approved the final manuscript.

Corresponding author

Correspondence to Sagori Mukhopadhyay.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tiozzo, C., Mukhopadhyay, S. Noninfectious influencers of early-onset sepsis biomarkers. Pediatr Res (2021). https://doi.org/10.1038/s41390-021-01861-4

Download citation

Search

Quick links