http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2015; 28(2): 237–239 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.908842
SHORT REPORT
CRP levels in extremely low birth weight (ELBW) septic infants K. Dritsakou1, G. Liosis1, M. Gioni1, E. Glynou2, K. Avdeliodi2, and K. Papagaroufalis1 NICU and 2Microbiological Lab, Elena Venizelou Maternity Hospital, Athens, Greece
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/04/15 For personal use only.
1
Abstract
Keywords
Objective: Testing the validity of C-reactive protein (CRP) in extremely low birth weight (ELBW) infants. Methods: During a five-year period, 483 infants with probable (36%) and definite sepsis (64%) were enrolled in the study. Results: ELBW infants with definitive sepsis had CRP levels comparable with full-terms (p ¼ 0.992). However, the highest (hs) values were observed in infants 42500 g, 24 h after the septic work up whereas in those with birth weight (BW) 51000 g after 48 h. Highest CRP levels of infants with early sepsis were similar to those of the late onset ones (p ¼ 0.825). The causative microorganism had a strong influence on CRP values, as Gram negative germs produced significantly higher CRP levels in comparison to infants with Gram positive sepsis. Conclusions: Highest CRP values in 51000 g infants increase in levels comparable to full terms, but with a 24-h delay.
CRP, ELBW, full term, gram, infants, microorganism
Introduction C-reactive protein (CRP) is an acute-phase protein reactant that rises mainly in response to infectious processes in adults and neonates. It has been used for many years as a notable indicator of sepsis in Neonatal Intensive Care Units (NICUs). Recently it has become a point of debate. Some studies advocate that ELBW infants present with lower CRP levels compared to full-terms, following a septic attack. While others support the idea that ELBW infants are capable of mounting significant CRP responses during a septic event [1,2]. Objective To test the hypothesis that ELBW infants respond in a similar way with term infants by raising CRP levels following a sepsis.
Methods During a five-year period (1/1/2008 to 1/1/2013), infants with probable and definitive sepsis (CDC criteria) were enrolled in the study. A total of 483 infants with probable (36%) and definite sepsis (64%) were included in the analysis. Of those, 35.3% were full-terms (42500 g) and 12.7% were listed as ELBW infants (51000 g). Mean gestational age (GA) of all
Address for correspondence: Kalliopi Dritsakou, NICU, Elena Venizelou Maternity Hospital, Plateia Elenas Venizelou 2, 115 21, Athens, Greece. Tel: +306932523801, +306944715227. Fax: +302132051366, +302106467165. E-mail: [email protected], [email protected]
History Received 5 August 2013 Accepted 24 March 2014 Published online 16 April 2014
infants studied was 32.99 ± 4.7 w and mean birth weight (BW) 2.050 g ± 937 g.
Results From ‘‘definite sepsis’’ infants, 79.2% were diagnosed as Gram (+) sepsis, 11.2% as Gram () and 1% as candida infections, while in a proportion of 8.6% of septic infants, two or more microbes were simultaneously isolated in the same blood culture (poly-microbian). Thirty-three percent of septic infants had early and 67% late onset sepsis. Peak CRP levels in ELBW infants with definitive sepsis were comparable to those of the full-term ones: 37.49 ± 51.79 (17.6; 0–189) and 32.79 ± 45.6 (15.1; 0–195) mg/L, respectively (p ¼ 0.992) (Figure 1). Even the values of septic infants with BW 5750 g were not significantly different compared to full-terms: 33.3 ± 42.16 (14.4; 0–167) and 32.79 ± 45.6 (15.1; 0–195) mg/L, respectively (p ¼ 0.992). However, in the ELBW infant population these peak levels had a 24-h rising delay compared to full- term infants. The highest (hs) mean CRP values were observed 48 h after the septic workup in ELBW neonates in comparison with full-term infants where only 24 h were enough to reach the hs CRP levels (p ¼ 0.00). Similar results were observed in infants with probable sepsis (hs mean CRP in 51000 g; 20.14 ± 16.63 and in 42500 g; 18.78 ± 13.78 mg/L) (p ¼ 0.740). The age of infants had no significant effect to CRP levels with definitive and probable sepsis. The hs CRP levels of all infants with early onset sepsis were similar to those with late onset sepsis: 32.68 ± 50.3 (3.34; 0–189) versus 31.39 ± 44.60 (10; 0–195) mg/L, respectively (p ¼ 0.825). On the contrary, the causative microorganism had a strong significant influence to
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K. Dritsakou et al.
J Matern Fetal Neonatal Med, 2015; 28(2): 237–239
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/04/15 For personal use only.
Figure 1. Highest CRP responses in ELBW and full-term infants.
CRP levels. Gram negative microorganisms were associated with higher CRP levels, even in the 5750 g BW category. CRP values in Gram (+) blood cultures were 24.18 ± 40.61 (3.34; 0–195) compared to 52.09 ± 50.54 (40; 0–184) mg/L in those with Gram () (p ¼ 0.03). It is also worth mentioning that only 48.7 and 44.4% of infants 51000 g and 41000 g, respectively, with Coagulase Negative Staphylococci (CONS) positive blood culture showed an increase of CRP410.0. On the other hand, 86.4% of Gram () sepsis elevated CRP410.0. Even though there were not enough candida infections, 80% of them increased a CRP410.0.
Discussion Neonatal sepsis is considered to be one of the major clinical problems faced in NICUs, as the symptoms are ambiguous and may be understated, while the evolution of a septic attack can rapidly lead to death within a few hours. Infection’s outcomes can be prevented if early and accurate diagnosis is achieved. So far, there is not a reliable laboratory method that can predict with high accuracy an invasive infection. CRP is widely used in NICUs, in almost all developed and developing countries, as it has the highest diagnostic validity, especially when serial measurements are performed. It is also cheap and easy to perform [3–6]. The increased survival of extremely prematures, has brought the diagnostic validity of the method to a point of great scientific controversy. Some clinicians suggest that CRP is an inappropriate method to be used in the extremely premature infants as they cannot respond sufficiently by increasing CRP levels following a septic event. One possible explanation is that extremely immature liver cannot respond to a following septic stimulus as it happens in more mature prematures and full-term infants [7–11]. Ishibashi et al. [12], found that infants with BW52500 g and GA538 w respond with lower CRP levels within 48 h after birth compared to term infants. Tuner and associates, in another study showed that, following a septic attack, the proportion of full-term infants who raise CRP
values 60 mg/dL was higher compared to preterms. On the other hand, many researchers support exactly the opposite view. Wagle et al. [1,2] in a study referring to 123 ELBW infants with mean GA 27 w and mean BW 1000 g, concluded that infants with Gram negative sepsis are capable of mounting significant CRP responses similar to those of full-term infants. According to Kordek et al. [13], even fetuses with 28 w GA, respond to infections by building high CRP values, although these levels rise irrespectively of the mother’s CRP values. The results of our study match to those of the above referred authors, suggesting the high accuracy of CRP in ELBW infants [11–15]. We concluded that not only ELBW infants are able to rise CRP levels in a similar way with the more mature prematures and full-term infants, but even the very immature ones with birth weight 5750 g can elevate significant CRP levels similar to the full terms. However, in this special population (5750 g) the CRP response reached the highest values with a 24-h delay to the full terms. According to our study, CRP can predict Gram () sepsis with high accuracy (86.4% of Gram () septic infants had elevated CRP410.0 mg/d). The same results were observed in candida infections, as 80% of candida septic infants had elevated CRP410.0 mg/d. On the contrary, CRP levels cannot serve to disclose CONS infections, as only 48.7 and 44.4% of infants 51000 g and 41000 g, respectively, showed an increase in CRP. This study confirmed the observations of Ronnestad et al. [16], who declined that the relatively lowvirulence CONS are less able to stimulate an acute-phase response, while Polakowska, Kawczynski and Chiesa found exactly the same results [17,18].
Conclusion The main results of our study are: (1) ELBW infants, even those with BW51000 g, can mount a significant response following sepsis; (2) their highest CRP levels were
DOI: 10.3109/14767058.2014.908842
comparable to those of full-terms, although the maximum rise in the ELBW infants occurred 24 h later than the full-term infants; (3) the causative organism had a strong effect to CRP levels. Infants with Gram negative sepsis can built much higher CRP levels compared to those with Gram positive sepsis and this rising was irrespectively of infant’s BW.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/04/15 For personal use only.
References 1. Wagle S, Grauaug A, Kohan R, Evans SF. C-reactive protein as a diagnostic tool of sepsis in very immature babies. J Paediatr Child Health 1994;30:40–4. 2. Turner MA, Power S, Emmerson AJB. Gestational age and the C reactive protein response. Arch Dis Child Fetal Neonatal Ed 2004; 89:272–3. 3. Maheshwari N. How useful is C-reactive protein in detecting occult bacterial infection in young children with fever without apparent focus? Arch Dis Child 2006;91:533–5. 4. Isaacman DJ, Burke BL. Utility of the serum C-reactive protein for detection of occult bacterial infection in children. Arch Pediatr Adolesc Med 2002;156:905–9. 5. Gendrel D, Raymond J, Coste J. Comparison of procalcitonin with C-reactive protein, interleukin-6 and interferon-alpha for differentiation of bacterial versus viral infections. Pediatr Infect Dis J 1999; 18:875–81. 6. Jaye DL, Waites KB. Clinical applications of C-reactive protein in pediatrics. Pediatr Infect Dis J 1997;16:735–46.
CRP levels in ELBW septic infants
239
7. Du Clos TW. Function of C-reactive protein. Ann Med 2000;32: 274–8. 8. Alpern ER, Alessandrini EA, Bell LM, et al. Occult bacteremia from a pediatric emergency department: current prevalence, time to detection and outcome. Paediatrics 2000;106:505–11. 9. Volanakis JE. Human C-reactive protein: expression, structure, and function. Mol Immunol 2001;38:189–97. 10. Du Clos TW. Function of C-reactive protein. Ann Med 2000;32: 274–8. 11. Benitz WE, Han MY, Madan A, Ramachandra P. Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics 1998;102:41–9. 12. Ishibashi M, Takemura Y, Ishida H. C-reactive protein kinetics in newborns: application of a high-sensitivity analytic method in its determination. Clin Chem 2002;48:7–9. 13. Kordek A, Hałasa M, Podraza W. Early detection of an early onset infection in the neonate based on measurements of procalcitonin and C-reactive protein concentrations in cord blood. Clin Chem Lab Med 2008;46:1143–8. 14. Escobar GJ. Effect of the systemic inflammatory response on biochemical markers of neonatal bacterial infection: a fresh look at old confounders. Clin Chem 2003;49:21–2. 15. Hofer N, Zacharias E, Muller W, Resch B. An update on the use of C-Reactive protein in early-onset neonatal sepsis: current insights and new tasks. Neonatology 2012;102:25–36. 16. Ronnestad A, Abrahamsen TG, Gaustad P, Finne PH. C-Reactive (CRP) response patterns in neonatal septicemia. Apmis 1999;107: 593–600. 17. Kawczyn´ski P, Polakowska E. Plasma levels of C-reactive protein, procalcitonin, interleukin-6 and interleukin-10 in preterm neonates evaluated for nosocomial sepsis. Med Sci Monit 2004;2:58–61. 18. Chiesa C, Pacifico L, Rossi N. Procalcitonin as a marker of nosocomial infections in the neonatal intensive care unit. Intensive Care Med 2000;26:175–7.
SHORT REPORT
CRP levels in extremely low birth weight (ELBW) septic infants K. Dritsakou1, G. Liosis1, M. Gioni1, E. Glynou2, K. Avdeliodi2, and K. Papagaroufalis1 NICU and 2Microbiological Lab, Elena Venizelou Maternity Hospital, Athens, Greece
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/04/15 For personal use only.
1
Abstract
Keywords
Objective: Testing the validity of C-reactive protein (CRP) in extremely low birth weight (ELBW) infants. Methods: During a five-year period, 483 infants with probable (36%) and definite sepsis (64%) were enrolled in the study. Results: ELBW infants with definitive sepsis had CRP levels comparable with full-terms (p ¼ 0.992). However, the highest (hs) values were observed in infants 42500 g, 24 h after the septic work up whereas in those with birth weight (BW) 51000 g after 48 h. Highest CRP levels of infants with early sepsis were similar to those of the late onset ones (p ¼ 0.825). The causative microorganism had a strong influence on CRP values, as Gram negative germs produced significantly higher CRP levels in comparison to infants with Gram positive sepsis. Conclusions: Highest CRP values in 51000 g infants increase in levels comparable to full terms, but with a 24-h delay.
CRP, ELBW, full term, gram, infants, microorganism
Introduction C-reactive protein (CRP) is an acute-phase protein reactant that rises mainly in response to infectious processes in adults and neonates. It has been used for many years as a notable indicator of sepsis in Neonatal Intensive Care Units (NICUs). Recently it has become a point of debate. Some studies advocate that ELBW infants present with lower CRP levels compared to full-terms, following a septic attack. While others support the idea that ELBW infants are capable of mounting significant CRP responses during a septic event [1,2]. Objective To test the hypothesis that ELBW infants respond in a similar way with term infants by raising CRP levels following a sepsis.
Methods During a five-year period (1/1/2008 to 1/1/2013), infants with probable and definitive sepsis (CDC criteria) were enrolled in the study. A total of 483 infants with probable (36%) and definite sepsis (64%) were included in the analysis. Of those, 35.3% were full-terms (42500 g) and 12.7% were listed as ELBW infants (51000 g). Mean gestational age (GA) of all
Address for correspondence: Kalliopi Dritsakou, NICU, Elena Venizelou Maternity Hospital, Plateia Elenas Venizelou 2, 115 21, Athens, Greece. Tel: +306932523801, +306944715227. Fax: +302132051366, +302106467165. E-mail: [email protected], [email protected]
History Received 5 August 2013 Accepted 24 March 2014 Published online 16 April 2014
infants studied was 32.99 ± 4.7 w and mean birth weight (BW) 2.050 g ± 937 g.
Results From ‘‘definite sepsis’’ infants, 79.2% were diagnosed as Gram (+) sepsis, 11.2% as Gram () and 1% as candida infections, while in a proportion of 8.6% of septic infants, two or more microbes were simultaneously isolated in the same blood culture (poly-microbian). Thirty-three percent of septic infants had early and 67% late onset sepsis. Peak CRP levels in ELBW infants with definitive sepsis were comparable to those of the full-term ones: 37.49 ± 51.79 (17.6; 0–189) and 32.79 ± 45.6 (15.1; 0–195) mg/L, respectively (p ¼ 0.992) (Figure 1). Even the values of septic infants with BW 5750 g were not significantly different compared to full-terms: 33.3 ± 42.16 (14.4; 0–167) and 32.79 ± 45.6 (15.1; 0–195) mg/L, respectively (p ¼ 0.992). However, in the ELBW infant population these peak levels had a 24-h rising delay compared to full- term infants. The highest (hs) mean CRP values were observed 48 h after the septic workup in ELBW neonates in comparison with full-term infants where only 24 h were enough to reach the hs CRP levels (p ¼ 0.00). Similar results were observed in infants with probable sepsis (hs mean CRP in 51000 g; 20.14 ± 16.63 and in 42500 g; 18.78 ± 13.78 mg/L) (p ¼ 0.740). The age of infants had no significant effect to CRP levels with definitive and probable sepsis. The hs CRP levels of all infants with early onset sepsis were similar to those with late onset sepsis: 32.68 ± 50.3 (3.34; 0–189) versus 31.39 ± 44.60 (10; 0–195) mg/L, respectively (p ¼ 0.825). On the contrary, the causative microorganism had a strong significant influence to
238
K. Dritsakou et al.
J Matern Fetal Neonatal Med, 2015; 28(2): 237–239
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/04/15 For personal use only.
Figure 1. Highest CRP responses in ELBW and full-term infants.
CRP levels. Gram negative microorganisms were associated with higher CRP levels, even in the 5750 g BW category. CRP values in Gram (+) blood cultures were 24.18 ± 40.61 (3.34; 0–195) compared to 52.09 ± 50.54 (40; 0–184) mg/L in those with Gram () (p ¼ 0.03). It is also worth mentioning that only 48.7 and 44.4% of infants 51000 g and 41000 g, respectively, with Coagulase Negative Staphylococci (CONS) positive blood culture showed an increase of CRP410.0. On the other hand, 86.4% of Gram () sepsis elevated CRP410.0. Even though there were not enough candida infections, 80% of them increased a CRP410.0.
Discussion Neonatal sepsis is considered to be one of the major clinical problems faced in NICUs, as the symptoms are ambiguous and may be understated, while the evolution of a septic attack can rapidly lead to death within a few hours. Infection’s outcomes can be prevented if early and accurate diagnosis is achieved. So far, there is not a reliable laboratory method that can predict with high accuracy an invasive infection. CRP is widely used in NICUs, in almost all developed and developing countries, as it has the highest diagnostic validity, especially when serial measurements are performed. It is also cheap and easy to perform [3–6]. The increased survival of extremely prematures, has brought the diagnostic validity of the method to a point of great scientific controversy. Some clinicians suggest that CRP is an inappropriate method to be used in the extremely premature infants as they cannot respond sufficiently by increasing CRP levels following a septic event. One possible explanation is that extremely immature liver cannot respond to a following septic stimulus as it happens in more mature prematures and full-term infants [7–11]. Ishibashi et al. [12], found that infants with BW52500 g and GA538 w respond with lower CRP levels within 48 h after birth compared to term infants. Tuner and associates, in another study showed that, following a septic attack, the proportion of full-term infants who raise CRP
values 60 mg/dL was higher compared to preterms. On the other hand, many researchers support exactly the opposite view. Wagle et al. [1,2] in a study referring to 123 ELBW infants with mean GA 27 w and mean BW 1000 g, concluded that infants with Gram negative sepsis are capable of mounting significant CRP responses similar to those of full-term infants. According to Kordek et al. [13], even fetuses with 28 w GA, respond to infections by building high CRP values, although these levels rise irrespectively of the mother’s CRP values. The results of our study match to those of the above referred authors, suggesting the high accuracy of CRP in ELBW infants [11–15]. We concluded that not only ELBW infants are able to rise CRP levels in a similar way with the more mature prematures and full-term infants, but even the very immature ones with birth weight 5750 g can elevate significant CRP levels similar to the full terms. However, in this special population (5750 g) the CRP response reached the highest values with a 24-h delay to the full terms. According to our study, CRP can predict Gram () sepsis with high accuracy (86.4% of Gram () septic infants had elevated CRP410.0 mg/d). The same results were observed in candida infections, as 80% of candida septic infants had elevated CRP410.0 mg/d. On the contrary, CRP levels cannot serve to disclose CONS infections, as only 48.7 and 44.4% of infants 51000 g and 41000 g, respectively, showed an increase in CRP. This study confirmed the observations of Ronnestad et al. [16], who declined that the relatively lowvirulence CONS are less able to stimulate an acute-phase response, while Polakowska, Kawczynski and Chiesa found exactly the same results [17,18].
Conclusion The main results of our study are: (1) ELBW infants, even those with BW51000 g, can mount a significant response following sepsis; (2) their highest CRP levels were
DOI: 10.3109/14767058.2014.908842
comparable to those of full-terms, although the maximum rise in the ELBW infants occurred 24 h later than the full-term infants; (3) the causative organism had a strong effect to CRP levels. Infants with Gram negative sepsis can built much higher CRP levels compared to those with Gram positive sepsis and this rising was irrespectively of infant’s BW.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by UMEA University Library on 04/04/15 For personal use only.
References 1. Wagle S, Grauaug A, Kohan R, Evans SF. C-reactive protein as a diagnostic tool of sepsis in very immature babies. J Paediatr Child Health 1994;30:40–4. 2. Turner MA, Power S, Emmerson AJB. Gestational age and the C reactive protein response. Arch Dis Child Fetal Neonatal Ed 2004; 89:272–3. 3. Maheshwari N. How useful is C-reactive protein in detecting occult bacterial infection in young children with fever without apparent focus? Arch Dis Child 2006;91:533–5. 4. Isaacman DJ, Burke BL. Utility of the serum C-reactive protein for detection of occult bacterial infection in children. Arch Pediatr Adolesc Med 2002;156:905–9. 5. Gendrel D, Raymond J, Coste J. Comparison of procalcitonin with C-reactive protein, interleukin-6 and interferon-alpha for differentiation of bacterial versus viral infections. Pediatr Infect Dis J 1999; 18:875–81. 6. Jaye DL, Waites KB. Clinical applications of C-reactive protein in pediatrics. Pediatr Infect Dis J 1997;16:735–46.
CRP levels in ELBW septic infants
239
7. Du Clos TW. Function of C-reactive protein. Ann Med 2000;32: 274–8. 8. Alpern ER, Alessandrini EA, Bell LM, et al. Occult bacteremia from a pediatric emergency department: current prevalence, time to detection and outcome. Paediatrics 2000;106:505–11. 9. Volanakis JE. Human C-reactive protein: expression, structure, and function. Mol Immunol 2001;38:189–97. 10. Du Clos TW. Function of C-reactive protein. Ann Med 2000;32: 274–8. 11. Benitz WE, Han MY, Madan A, Ramachandra P. Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics 1998;102:41–9. 12. Ishibashi M, Takemura Y, Ishida H. C-reactive protein kinetics in newborns: application of a high-sensitivity analytic method in its determination. Clin Chem 2002;48:7–9. 13. Kordek A, Hałasa M, Podraza W. Early detection of an early onset infection in the neonate based on measurements of procalcitonin and C-reactive protein concentrations in cord blood. Clin Chem Lab Med 2008;46:1143–8. 14. Escobar GJ. Effect of the systemic inflammatory response on biochemical markers of neonatal bacterial infection: a fresh look at old confounders. Clin Chem 2003;49:21–2. 15. Hofer N, Zacharias E, Muller W, Resch B. An update on the use of C-Reactive protein in early-onset neonatal sepsis: current insights and new tasks. Neonatology 2012;102:25–36. 16. Ronnestad A, Abrahamsen TG, Gaustad P, Finne PH. C-Reactive (CRP) response patterns in neonatal septicemia. Apmis 1999;107: 593–600. 17. Kawczyn´ski P, Polakowska E. Plasma levels of C-reactive protein, procalcitonin, interleukin-6 and interleukin-10 in preterm neonates evaluated for nosocomial sepsis. Med Sci Monit 2004;2:58–61. 18. Chiesa C, Pacifico L, Rossi N. Procalcitonin as a marker of nosocomial infections in the neonatal intensive care unit. Intensive Care Med 2000;26:175–7.
