**4. Serial CRP determinations are of high sensitivity in diagnosis of neonatal sepsis**

CRP passes the placenta only in very low quantities, therefore, any elevation in the neonate always represents endogenous synthesis. [19] De novo hepatic synthesis starts very rapidly after a single stimulus with serum concentrations rising above 5 mg/l by about 6 hours and peaking around 48 hours. [20]

In diagnosis of early onset sepsis previous studies reported on widely differing sensitivities and specificities of CRP ranging from 29% to 100% and from 6% to 100%, respectively. [11,

21, 22] These extreme variations are a result of different reference-values, test methodologies, patient characteristics and inclusion criteria, number of samples taken, and sampling time. Furthermore, definitions of sepsis widely differ between studies making serious comparisons hardly possible.

The Role of C-Reactive Protein in the Diagnosis of Neonatal Sepsis 49

In neonates, non infection associated elevation of CRP was described in conditions of maternal and perinatal distress, neonatal hypoxia, and tissue damage. Several authors have described links of CRP to maternal fever, stressful delivery, prolonged rupture of membranes and/or prolonged labor, asphyxia, meconium aspiration syndrome, intraventricular hemorrhage, pneumothorax, and tissue injury. [19, 24, 34, 41-49] (see

**Table 1.** Non-infectious conditions associated with increased CRP values during the first days of life.

non-infectious conditions, though no statistical confirmation is given.

when adjusted for gestational age, gender, and sampling time. [44]

However, the issue on non-infectious CRP elevations in the neonate is not undisputed. Different studies gave to some extent inconsistent results and conditions that some authors described being associated with CRP elevation were not found in other analyses. The earliest descriptions on non infectious conditions influencing CRP derive from simple observations that elevated values in not infected infants might be connected to coincidental

Few investigations were performed on the association of CRP with non infectious conditions in healthy neonates. Chiesa et al. evaluated conditions influencing what constitutes normal CRP values in healthy neonates. In their analysis on 148 healthy term or near term neonates they identified low 5-minute Apgar score and premature rupture of membranes being significantly associated with CRP response at birth and pregnancy induced hypertension with CRP response at 24 hours of life. [45] In a similarly selected cohort of 421 healthy neonates including 200 premature infants they confirmed an association with the time of ruptured membranes and added duration of active labor, prenatal steroids, and intrapartum antimicrobial prophylaxis as variables that had a significant effect on CRP concentrations

The current literature suggests that CRP may be elevated in some non-infectious conditions, of which some may per se clinically mimic a bacterial infection as well. Thus, the up to date available information lacks in robust evidence to support a claim that withholding antibiotics may be justified in infants with raised CRP in the above

table 1)






mentioned conditions.

The sensitivity of CRP is known to be the lowest during the early stages of infection. [23-25] For a single CRP determination at the time of first sepsis evaluation the sensitivity and specificity range from 22% to 69% and from 90% to 96%, respectively. [23, 24, 26-29] Similar results were reported for cord blood CRP. Even with low cut-off values being used [1 to 5 mg/l) sensitivities and specificities ranged from 22 to 74% and from 78 to 97%, respectively. [30-33] Thus, a single normal value at the initial sepsis work-up is not sufficient to rule out an infection [11].

On the other hand a raised CRP is not necessarily diagnostic for sepsis, as elevations may as well occur due to the physiologic rise after birth or non infection associated conditions (see below). Therefore, concerns were raised about the reliability of CRP during the early stage of the disease being neither able to diagnose nor to rule out an infection with certainty. [23]

Benitz et al. [23] found that the sensitivity in the diagnosis of culture proven early onset sepsis increased from 35% at the initial sepsis work-up to 79% and 89% when CRP determination was performed on the two following days. In a large series of 689 neonates (187 with sepsis) Pourcyrous et al. [24] reported a higher sensitivity for CRP levels determined at least 12 hours after the initial evaluation compared to the first value (54% vs. 74%). In general the sensitivity substantially increases with serial determinations 24 to 48 hours after the onset of symptoms, and several studies reported on sensitivities and specificities ranging from 78% to 98% and from 81% to 97%, respectively. [11, 21, 23-27, 34]

Some authors have suggested that serial determinations may be useful for identification of infants who do not have a bacterial infection as well: Two consecutive CRP values <10 mg/l carry a 99% negative predictive value in accurately identifying infants not infected. [6, 21, 23, 35-37] At 48 h after onset of symptoms with at least two normal CRP values and negative blood cultures infection can be ruled out and antibiotics can be stopped. [38]

Similarly, serial CRP measurements can be helpful in monitoring the response to treatment in infected neonates, to determine the duration of antibiotic therapy, and to recognize possible complications. [24, 25, 39] In a cohort of 60 neonates with early onset sepsis Ehl et al. [40] demonstrated that after initiation of a successful antibiotic therapy CRP values further increased, peaking and consecutively decreasing after 16 hours. A CRP level that returned again to the normal range may indicate that the duration of antibiotic treatment has been sufficient allowing discontinuation of antibiotics. [35]
